A cell factory automation device and control method thereof

Abstract

The present invention proposes a cell factory automation device and a control method thereof, which relate to the field of automation technology of cell factories. The cell factory automation device includes an operating device, a tube sealing machine, a sterile pipe taking-up machine and a control and monitoring module; the tube sealing machine and the sterile pipe taking-up machine are used for sterile connection of pipelines; the operating device is used to clean and digest the cells and resuspend them in culture medium after the sterile connection is completed, and then package them into 10-layer cell factories, 40-layer cell factories and disposable liquid storage bags; the sterile pipe taking-up machine includes a main unit, 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. By automatically controlling and monitoring the cell factory, sterile automated processing and abnormality identification are realized, processing efficiency is improved, and abnormal losses are reduced.

Description

Technical Field

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

[0002] The use and operation of cell factories are currently carried out manually. The traditional Vero cell passaging operation process uses manual cleaning and digestion of the cell factory, and completes operations such as cell factory passaging and cell suspension collection. The cell factory needs to be opened when adding or changing liquid, which has extremely high requirements on the environmental level and needs to be carried out in a sterile environment, generally under Class A laminar flow protection. The cell factory has a heavy weight, especially after adding cell culture medium, it is more difficult to carry and prone to collision. After the collision, the factory will not be able to be used for production, which will result in product production reduction. In the cell factory digestion oscillation operation, there is an uneven shaking effect, and the cell number and cell viability decrease, resulting in certain batch differences. Traditional methods can easily lead to contamination or uneven quality of biological products. Traditional cell engineering automation equipment is difficult to perform separate control abnormality analysis for each control stage and adjacent continuous abnormality analysis for multiple control stages, which makes it difficult to accurately identify control abnormalities, resulting in low yield 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:

[0004] The present invention proposes a cell factory automation device and a control method thereof, wherein the cell factory automation device includes an operating device, a tube sealing machine, a sterile tube receiving machine, and a control and monitoring module;

[0005] The tube sealing machine and the sterile pipe connecting machine are used for aseptic connection of the pipes;

[0006] The operating device is used to wash, digest and resuspend the cells in culture medium after the sterile connection is completed, and then distribute them into 10-layer cell factories, 40-layer cell factories and disposable liquid storage bags;

[0007] The control monitoring module is used to perform control analysis on multiple control stages of the preset operation process, obtain judgment information of the control stage, and then perform stage judgment warning and marking;

[0008] The aseptic pipe connecting machine includes a main unit, a pipe support and a power supply;

[0009] The operating device includes a mechanical arm, a cell culture rack, an operating platform and a system operating panel.

[0010] Furthermore, the control method includes:

[0011] Connect the connecting pipe of the cell factory to the cell factory through a sterile pipe connection machine to obtain a connected pipeline;

[0012] The robot arm is controlled by the operating device to grab the cell factory and cell culture rack with connected pipelines to the designated workstation and perform preset operations to complete the cell passage operation;

[0013] Obtaining a preset operation process, dividing it into multiple control stages, obtaining control acquisition data for each control stage, and performing control status analysis and scoring for each control stage based on the control acquisition data to obtain control scoring data;

[0014] Obtaining control score data of adjacent control stages and sub-adjacent control stages, performing comparative analysis on the control score data, and thereby obtaining stage determination information of the adjacent control stages and sub-adjacent control stages;

[0015] Perform stage judgment warning and marking based on the stage judgment information.

[0016] Beneficial effects of the present invention: The present invention provides an automated process method for use in a biological product production workshop, which uses a pipe-connecting machine and a pipe-sealing machine for docking and sealing, and can perform aseptic operations in a sterile environment at a lower environmental level. The cell factory automated operating system transports and the cell factory prepares Vero cells, which are upgraded from traditional manual operations to robotic operations. The advantages of the robot's high consistency, good stability, high precision, and high efficiency are utilized to reduce labor intensity, achieve an efficient and safe biological product preparation plan, save materials, improve product quality, significantly reduce manpower input, and improve operational efficiency. The present invention provides a simple and easy-to-use operating scheme to implement the operation of a cell factory, thereby saving materials, reducing costs, and ensuring consistency of operation.

[0017] This method uses a cell factory automated operating system to complete the transportation and shaking of the cell factory, which can effectively reduce labor costs, improve culture efficiency, enhance product quality, and reduce space occupation.

[0018] The process is completely enclosed, with no open areas. During cell passaging, the tubing is aseptically connected using a tube sealer and a pipette connection machine. A peristaltic pump is used to pump the culture medium from the flask. The cells are then cleaned and digested using the cell factory's automated operating system. The digested cells are then resuspended in culture medium and dispensed into 10-layer cell factories, 40-layer cell factories, and disposable liquid storage bags. This process involves no openings, lowering the requirements for the operating environment and minimizing contamination risks.

[0019] The fully automatic operating system of the cell factory transfers the cell factory placed in the constant temperature chamber to the operating table for operation, avoiding movement, reducing the risk of damage, and improving the quality of cell production.

[0020] The present invention also realizes independent abnormality monitoring and continuous abnormality monitoring of multiple control stages, thereby improving the product yield and reducing the losses caused by the difficulty in discovering abnormal control. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic diagram of a cell factory automation control method. DETAILED DESCRIPTION

[0022] The preferred embodiments of the present invention are 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.

[0023] One embodiment of the present invention provides a cell factory automation device, comprising an operating device, a tube sealing machine, a sterile tube receiving machine, and a control and monitoring module;

[0024] The tube sealing machine and the sterile pipe connecting machine are used for aseptic connection of the pipes;

[0025] The operating device is used to wash, digest and resuspend the cells in culture medium after the sterile connection is completed, and then distribute them into 10-layer cell factories, 40-layer cell factories and disposable liquid storage bags;

[0026] The control monitoring module is used to perform control analysis on multiple control stages of the preset operation process, obtain judgment information of the control stage, and then perform stage judgment warning and marking;

[0027] The aseptic pipe connecting machine includes a main unit, a pipe support and a power supply;

[0028] The operating device includes a mechanical arm, a cell culture rack, an operating platform and a system operating panel.

[0029] The working principle of the above technical solution is as follows: the present invention uses a sterile tube-sealing machine for docking and sealing, performing aseptic operations in a relatively low-level sterile environment. The cell factory automated operating system handles and shakes, and the cell factory prepares Vero cells using robotic operations, which are completed using the cell factory automated operating system. During cell passaging, the pipes are aseptically connected using the tube-sealing machine and the tube-sealing machine, and the culture medium in the culture flask is pumped out using a peristaltic pump. The cells are then washed and digested using the cell factory automated operating system. The digested cells are resuspended in culture medium and distributed into a 10-layer cell factory, a 40-layer cell factory, and disposable liquid storage bags.

[0030] The technical effects of the above technical solution are as follows: the device uses a pipe-sealing machine for docking and sealing, and can perform aseptic operation in a sterile environment at a lower environmental level. The cell factory automated operating system handles and oscillates, and the operation mode of preparing Vero cells in the cell factory is upgraded from traditional manual operation to robot operation. The advantages of the robot's high consistency, good stability, high precision, and high efficiency are utilized to reduce labor intensity, realize an efficient and safe biological product preparation solution, save materials, improve product quality, greatly reduce manpower input, and improve operating efficiency. The present invention provides a simple and easy-to-use operating scheme to realize the operation of the cell factory, thereby saving materials, reducing costs, and ensuring consistency of operation.

[0031] Using a cell factory automated operating system to complete cell factory transportation and shaking can effectively reduce labor costs, improve culture efficiency, enhance product quality, and reduce space occupation.

[0032] The process is completely enclosed, with no open areas. During cell passaging, the tubing is aseptically connected using a tube sealer and a pipette connection machine. A peristaltic pump is used to pump the culture medium from the flask. The cells are then cleaned and digested using the cell factory's automated operating system. The digested cells are then resuspended in culture medium and dispensed into 10-layer cell factories, 40-layer cell factories, and disposable liquid storage bags. No openings are present throughout the process, minimizing the risk of contamination.

[0033] The fully automatic operating system of the cell factory transfers the cell factory placed in the constant temperature chamber to the operating table for operation, avoiding movement, reducing the risk of damage, and improving the quality of cell production.

[0034] In one embodiment of the present invention, the control method includes:

[0035] S1. Connect the connecting pipe of the cell factory to the cell factory through a sterile pipe connection machine to obtain a connected pipeline;

[0036] S2. The operating device controls the robotic arm to grab the cell factory and cell culture rack with connected pipelines to the designated workstation and perform preset operations to complete the cell passage operation;

[0037] S3. Obtain a preset operation process, divide it into multiple control stages, obtain control acquisition data for each control stage, and perform control status analysis and scoring for each control stage based on the control acquisition data to obtain control scoring data;

[0038] The image data of each control stage is collected by the sensor, and the analysis and judgment data of the control stage are obtained by analyzing the image data;

[0039] S4. Obtain 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; the re-adjacent control stages are two adjacent control stages, for example, 1 and 2 are one adjacent control stage, 3 and 4 are one control stage, and 1, 2 and 3, 4 are re-adjacent control stages.

[0040] S5. Perform stage determination warning and marking based on the stage determination information.

[0041] The working principle of this technical solution is as follows: The sterile pipe connection machine uses automated cutting and welding methods to aseptically connect the cell factory's connecting pipes to the main cell factory. The host computer controls the cutting tool to create a smooth incision at the contact point of the pipes. The welding module then uses heat fusion to seamlessly connect the pipes to the cell factory, forming a complete piping system.

[0042] The operating device uses a robotic arm to grab the cell factory and cell culture rack with connected pipelines and move them to the designated workstation for cell processing;

[0043] In the preset operation process, the system collects parameters (images, etc.) of each control stage in real time, conducts status evaluation of each control stage based on the control collection data, and generates control score data.

[0044] Obtain control score data for adjacent control stages (e.g., stage 1 and stage 2) and sub-adjacent control stages (e.g., stages 1-2 and stages 3-4).

[0045] Compare the score differences between adjacent stages to analyze operational stability or cell state change trends.

[0046] Determine whether there are abnormalities in adjacent stages and adjacent stages (such as operational deviations and cell contamination risks).

[0047] Based on the comparison results, the stage judgment information (such as "normal", "abnormal", "needs attention") is generated, and the specific abnormality type or risk level is marked.

[0048] The technical effects of the above technical solution are: the automated operation of the sterile pipe connection machine eliminates the risk of artificial contamination, ensures the sterile connection between the pipeline and the cell factory, and reduces the failure rate of cell culture.

[0049] The robotic arm performs cell culture operations according to preset procedures, reducing human errors and improving operational consistency and cell survival rate.

[0050] The control acquisition data reflects the operation status in real time and supports dynamic adjustment of parameters (such as flow rate and temperature) to ensure stable cell culture conditions.

[0051] By comparing the scores of adjacent and adjacent control stages, operational deviations or abnormal cell status can be identified in advance, reducing the risk of contamination or culture failure.

[0052] Through automated connection, standardized operation, real-time data collection and intelligent analysis, precise control and risk warning of the cell factory culture process can be achieved, significantly improving cell culture efficiency and reliability.

[0053] In one embodiment of the present invention, the step of connecting the connecting pipe of the cell factory to the cell factory by a sterile pipe connection machine to obtain a connected pipeline includes:

[0054] Connect the power supply and turn on the switch button to start the sterile pipe machine and perform self-test;

[0055] After the self-test is completed, insert the pipe holder into the pipe holder base inside the machine through the sterile pipe top cover, and install the blade on the blade socket;

[0056] Install the two connecting pipes to be installed in the grooves inside the pipe bracket;

[0057] The blade is heated and then cooled to the welding temperature to cut and weld the connecting pipes;

[0058] After welding is completed, the blade is cooled down;

[0059] Get the connected pipeline and close the sterile pipe connection machine.

[0060] The working principle of the above technical solution is as follows: The main structure of the BioWelderTC sterile pipe welding machine consists of a main unit, a pipe holder and a power supply. It mainly cuts and welds the pipe by heating the blade.

[0061] The steps include:

[0062] 60. Turn on the power and turn on the switch button.

[0063] 61. The device enters the login interface and the top cover automatically pops open. Press "▼" on the touch screen and select "Example" in the box under User name. The box under Password will be blank.

[0064] 62. Press “√” on the touch screen to enter the waiting state for self-test. Close the top cover of the machine and the machine will start routine self-test.

[0065] 63. Installation

[0066] After the self-test is completed, the top cover of the machine will pop open automatically, and "Insert blade, tubes (C-Flex374) and close cover" will be displayed in the middle box of the screen.

[0067] Insert the pipe support into the pipe support base inside the machine, making sure the side with the pipe diameter mark on the pipe is facing outwards, so that the pipe support fits the base.

[0068] Install the blade firmly onto the blade socket, making sure the side with the identification point faces downward and the identification point faces the right.

[0069] 64. Sterile pipe

[0070] Install the two pipes that need to be connected in the grooves inside the pipe support, and make sure the pipes are installed firmly and locked.

[0071] Close the top cover of the machine and press “►” on the screen to start aseptic takeover.

[0072] The blade is heated to 410 degrees to remove all heat sources, then cooled to welding temperature for cutting and welding.

[0073] After welding is completed, the blade will be cooled down inside the machine, and the top cover will pop open automatically after the automatic operation ends.

[0074] Take out the connected pipes, remove the blades with the blade clip, remove the pipe support, cover the machine top cover, and the operation is completed.

[0075] The technical effect of the above technical solution is: through a series of designs such as takeover startup, installation, and sterile takeover, the entire process from starting the sterile takeover machine to obtaining the connection to complete the pipeline and shutting down the machine is automated, reducing manual intervention, improving the accuracy and consistency of operations, and reducing the risk of operational errors caused by human factors.

[0076] The entire connection process is completed in a sterile pipe connection machine. The machine's closed structure and specific design effectively prevent the entry of external contaminants, ensuring the sterile conditions of the cell factory pipe connection process, maintaining the purity of the cell culture environment, and improving the quality and success rate of cell culture.

[0077] The sterile pipe module heats the blade and then cools it to the welding temperature before cutting and welding the connecting pipe. This precise temperature control enables accurate cutting and high-quality welding, ensuring the sealing and connection strength of the connecting pipe, and reducing problems such as cell culture fluid leakage caused by loose connections or poor seals.

[0078] After the power is connected and the switch button is turned on, the sterile pipe connection machine starts and performs self-inspection, which can timely detect potential faults or problems of the equipment, ensure that the equipment can perform pipeline connection operations under normal operating conditions, and improve the reliability and stability of the equipment operation.

[0079] In one embodiment of the present invention, the operation of controlling a robotic arm to grab a cell factory with connected pipelines and a cell culture rack to a designated station and perform a preset operation to complete the cell passage operation includes:

[0080] Install the robotic arm on the operating platform and place the cell culture rack on the operating platform;

[0081] Turn on the power of the robotic arm and control it through the system operation panel to grab the cell culture rack and the cell factory with connected pipelines at the corresponding station according to the preset operation process for operation;

[0082] After the operation is completed, turn off the power of the robotic arm to complete the cell passaging operation.

[0083] The operation includes: sequentially performing cell confirmation, pipeline connection, cell washing, cell digestion, cell resuspension, cell inoculation and cell culture.

[0084] The working principle of the above technical solution is as follows: The equipment consists of a robotic arm, a cell culture rack, an operating platform, and a system operation panel. The system operation panel issues operating instructions to the robotic arm, which then operates according to the operating instructions and the process steps to complete cell passage.

[0085] The specific steps include

[0086] 70. The system starts up and enters the login interface. The operator enters the user name and password and enters the main interface;

[0087] 71. Create a new recipe

[0088] Click "Formula Management" to create the batch number for the subculture;

[0089] After selecting the newly created batch in the batch list, click "Confirm Batch" to confirm the subculture batch for this operation.

[0090] Click to return to the main page, click the "Power" button to turn on the power of the robotic arm.

[0091] According to the batch of cells to be passaged, click "CF10 / CF40 process selection" in the lower left corner of the selection interface, click the "Start" button to perform cell passage, and according to the operation process, grab the cell culture rack on the corresponding station to operate.

[0092] 72. After the operation is completed, turn off the power switch of the main interface and the cell passaging operation is completed.

[0093] Specific implementation example: The preparation process of freeze-dried human rabies vaccine (Vero cells) cell suspension, the passaging process of 10-layer cell factory and 40-layer cell factory and the collection process of cell suspension all use the cell factory automated operating system. The specific process is as follows:

[0094] 1. Cell passaging (10-layer cell factory passaging)

[0095] 1.1 Pipeline connection

[0096] (1) Start the cell factory automation operating system, enter the user name and password, log in to the program, connect the cell factory connecting pipe to the 10-layer cell factory through the sterile takeover machine, use the cell factory automation operating system to grab the 10-layer cell factory with the completed pipe connection to the designated workstation, use the sterile takeover machine to connect the 10-layer cell factory to the cell factory connecting pipe, and grab it to the designated workstation.

[0097] (2) Use a sterile pipe connection machine to connect the digestion liquid separation pipeline to the cell factory connecting pipeline, the washing liquid supply pipeline, the cell growth liquid supply pipeline, the hot melt pipe on the three-way valve of the digestion liquid supply pipeline, and the disposable liquid storage bag, and place the 113L disposable liquid storage bag on the weighing and shaking car.

[0098] 1.2 Cell washing and digestion

[0099] (1) Cell washing

[0100] a. Enter the cell factory automated operating system's passaging program. Click "Drain" on the screen. Open the valve connecting the disposable reservoir bag to the cell factory. Use a peristaltic pump to drain the culture medium from the cell factory. Once all the liquid is drained, close the valve on the disposable reservoir bag.

[0101] b. Open the valve on the wash solution supply pipeline. Click the "Next" button on the cell factory automation operating system screen. Use a peristaltic pump to add wash solution to each cell factory. Close the valve on the wash solution supply pipeline.

[0102] c. Wash the cells. After washing, open the pipe valve of the disposable liquid storage bag. Click the "Next" button on the cell factory automated operating system screen. Use a peristaltic pump to drain the washing solution in the cell factory. After all the liquid is drained, close the pipe valve of the disposable liquid storage bag. Click the "Next" button on the cell factory automated operating system screen to enter the digestion program.

[0103] (2) Cell digestion

[0104] a. Open the digestion solution supply pipe valve, click the "Next" button on the cell factory automated operating system screen, add digestion solution via the peristaltic pump, close the digestion solution supply pipe valve, and digest the cells. After the cells have been digested, open the pipe valve of the disposable liquid storage bag, click the "Next" button on the cell factory automated operating system screen, and use the peristaltic pump to drain the digestion solution from the cell factory. After all the liquid has been drained, close the pipe valve of the disposable liquid storage bag.

[0105] b. Stop digestion when obvious intercellular spaces appear in the cells.

[0106] 1.3 Cell resuspension

[0107] (1) Open the valve of the cell growth fluid supply pipeline, add cell growth fluid to the disposable liquid storage bag through the peristaltic pump, and close the valve of the cell growth fluid supply pipeline.

[0108] (2) Click the "Next" button on the cell factory automation operating system screen, use a peristaltic pump to add the cell growth medium to the 10-layer cell factory after digestion, and click the "Next" button on the cell factory automation operating system screen to perform cell shaking.

[0109] (3) After the shaking is completed, the cell suspension in the 10-layer cell factory is added to the disposable liquid storage bag through a peristaltic pump, and the connection between the cell factory pipeline and the digestion liquid separation pipeline is disconnected by a sterile tube sealing machine, and the 10-layer cell factory with completed cell resuspension is moved out of the cell culture room.

[0110] (4) Start the weighing oscillation vehicle.

[0111] 1.4 Cell seeding

[0112] (1) Use the cell factory automation operating system to grab a set of 10-layer cell factories with completed pipeline connections to the designated workstation.

[0113] (2) Connect the cell factory connecting pipe to the digestion liquid separation pipe through a sterile pipe connection machine.

[0114] (3) Click the “Next” button on the cell factory automation operating system screen, and use the peristaltic pump to inoculate the cell suspension into the 10-layer cell factory, and perform subculture according to the corresponding ratio.

[0115] (4) After the subculture is completed, disconnect the cell factory connection pipe from the digestion and separation pipe using a sterile tube sealing machine, click the operation button on the cell factory automation operating system screen, and place the 10-layer cell factory after subculture at the designated workstation.

[0116] (5) Perform 10-layer cell factory passaging.

[0117] 1.5 Cell culture

[0118] The 10-layer cell factory was cultured statically in a cell culture room at 37°C.

[0119] 2. Cell suspension preparation

[0120] 2.1 Pipeline connection

[0121] 2.1.1 Start the cell factory automation operating system, enter the user name 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 workstation. Connect the cell suspension pipeline to the hot melt pipes on the three-way valves of the wash solution supply pipeline, cell growth solution supply pipeline, and digestion solution supply pipeline respectively.

[0122] 2.1.2 Connect the cell suspension tubes to the disposable liquid storage bag and place the 50L disposable liquid storage bag on the weighing and shaking cart.

[0123] 2.1.3 Connect the cell suspension tubing to the cell factory connecting tubing.

[0124] 2.2 Cell washing and digestion

[0125] 2.2.1 Cell washing

[0126] (1) Click to enter the cell suspension preparation program of the cell factory automated operating system, click "Drain" on the screen, open the pipe valve connecting the disposable liquid storage bag and the cell factory, use a peristaltic pump to drain the culture medium in the cell factory, and close the pipe valve of the disposable liquid storage bag after all the liquid is drained.

[0127] (2) Open the valve of the wash solution supply pipeline, click the "Next" button on the cell factory automation operating system screen, use a peristaltic pump to add wash solution to each cell factory, and close the valve of the wash solution supply pipeline.

[0128] (3) Wash the cells. After washing, open the pipe valve of the disposable liquid storage bag, click the "Next" button on the cell factory automation operating system screen, and use a peristaltic pump to drain the washing liquid in the cell factory. After all the liquid is drained, close the pipe valve of the disposable liquid storage bag and click the cell factory automation operating system screen to enter the digestion program.

[0129] 2.2.2 Cell digestion

[0130] (1) Open the valve of the digestion solution supply pipeline, click the "Next" button on the cell factory automation operating system screen, add digestion solution through the peristaltic pump, and close the valve of the digestion solution supply pipeline.

[0131] (2) Digest the cells. After the cells have been digested, open the pipe valve of the 208L disposable liquid storage bag, click the "Next" button on the cell factory automation operating system screen, and use a peristaltic pump to drain the digestion fluid in the cell factory. After all the liquid has been drained, close the pipe valve of the disposable liquid storage bag.

[0132] 2.2.3 Cell resuspension

[0133] (1) Open the valve of the cell growth solution supply pipeline, click the "Next" button on the cell factory automation operating system screen, add cell growth solution to each 40-layer cell factory through the peristaltic pump, and close the valve of the cell growth solution supply pipeline.

[0134] (2) Click the “Next” button on the cell factory automated operating system screen to perform cell shaking.

[0135] 2.3 Cell suspension collection

[0136] 2.3.1 Cell suspension collection

[0137] (1) Open the valve of the disposable liquid storage bag pipeline.

[0138] (2) Click the "Next" button on the cell factory automation operating system screen to collect the cell suspension in the cell factory into a disposable liquid storage bag through the peristaltic pump, and start the weighing oscillation car at the same time.

[0139] 2.3.2 Use a sterile tube sealer to disconnect the cell suspension tubing from the cell factory connection tubing. Use a sterile tube sealer to reconnect another set of cell factory connection tubing. Repeat this procedure to collect 40 layers of cell factories.

[0140]

[0141] The technical effect of the above technical solution is: through the preset 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 cell passaging process (cell confirmation, pipeline connection, cleaning, digestion, resuspension, inoculation, and culture), reducing human errors and improving operational consistency and repeatability.

[0142] The preset operation process ensures that each subculture operation follows the same parameters (such as time, temperature, flow rate, etc.), improving the stability of cell culture quality.

[0143] After the robotic arm is installed on the operating platform, it can be quickly powered on and start the preset process, shortening the operation preparation time.

[0144] The entire process from cell confirmation to cell culture is automated, reducing manual intervention and shortening single-batch processing time by 30%-50%.

[0145] Adjust the digestion 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 consistent cell density.

[0146] The robotic arm completes pipe connection and cell manipulation under sterile conditions, reducing the risk of external contamination and lowering the failure rate of cell culture.

[0147] Automated processes reduce direct contact between operators and cell samples, further reducing the possibility of contamination.

[0148] The system operation panel records the entire process control and generates electronic batch records.

[0149] In one embodiment of the present invention, obtaining a preset operation process, dividing the process into multiple control stages, obtaining control acquisition data for each control stage, and performing control status analysis and scoring for each control stage based on the control acquisition data to obtain control scoring data include:

[0150] The operation process is divided into control stages according to the preset operation process to obtain multiple control stages of the operation process;

[0151] 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 inoculation stage and a cell culture stage;

[0152] The cell confirmation process involves using an automated device to transfer the cell factory to a designated location and using other equipment to confirm the cell status;

[0153] The sensor group is set to collect control data in each control stage to obtain control collection data; the control collection data includes images and the like.

[0154] Preprocessing the control acquisition data to obtain control processing data;

[0155] The image features of each control stage are compared and analyzed on the control processing data to obtain the control state judgment information of each control stage.

[0156] Each control stage includes multiple feature analysis types, comparing the image feature data of each feature analysis type with the target feature data to obtain control state determination information of the image feature data of each feature analysis type;

[0157] When the image feature data meets the target feature data, the control state score of the feature analysis type is set to 1;

[0158] 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;

[0159] 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;

[0160] 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.

[0161] 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 and missing value filling on the control data;

[0162] Extract key features from image data (e.g., cell density, tubing integrity, cell morphology uniformity). Compare real-time image features with pre-set standard templates to identify anomalies (e.g., cell clumps, tubing deviation).

[0163] Based on the feature comparison results, control status judgment information (such as "normal", "pipeline leakage", "abnormal cell density") is generated.

[0164] Each control stage is scored (1 or 2) based on the control acquisition data (feature data of the image) and the status judgment information.

[0165] The technical benefits of this solution include: Through multi-stage data collection, control, analysis, and monitoring of multiple stages of the entire cell passage process can be achieved. This allows for rapid identification of problematic stages (e.g., a low score during the cell digestion stage) and reduces troubleshooting time.

[0166] Generate control score data in real time, quantify operational quality, and provide early warning of potential risks.

[0167] By comparing image features, it automatically identifies abnormal cell states (such as excessive cell clumps), avoiding subjective judgment errors. By comparing stage scores, it ensures that each operation meets qualification requirements. Using status information, it quickly locates stage faults, reducing downtime. It supports parameter adjustment for different cell types (such as adherent and suspension cells) and is compatible with 10-layer and 40-layer cell factories and disposable culture bags.

[0168] In one embodiment of the present invention, performing comparative analysis of image features of the control processing data at each control stage to obtain control state determination information at each control stage includes:

[0169] Sequentially acquiring image data of the control processing data of each control stage, performing feature extraction on the image data of the control stage to obtain image feature data;

[0170] 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;

[0171] The control state analysis of the control stage is performed according to the characteristic deviation type and the characteristic deviation data to obtain the control state analysis data; when the control state analysis data shows that the control state is normal, the control state score is determined to be 1; when the control state analysis data shows that the control state is abnormal, the control state score is determined to be 2.

[0172] The control status is scored based on the control status analysis data to obtain the control score data of the control stage.

[0173] The working principle of the above technical solution is: for each control stage (such as cell confirmation, pipeline connection, etc.), the corresponding image data is extracted from the control processing data.

[0174] Extract key image features through image processing algorithms (such as edge detection, texture analysis, and morphological operations), such as:

[0175] Cell morphology, density, and distribution uniformity during the cell confirmation phase. Pipeline interface integrity and liquid flow conditions during the pipeline connection phase. Cell clump size and dispersion during the cell digestion phase.

[0176] Target feature data for each control stage (such as ideal cell morphology, image templates with leak-free pipeline connections) are preset.

[0177] Perform multi-dimensional comparisons between real-time image feature data and target feature data to identify deviation types (such as morphological deviation, density deviation) and deviation values ​​(such as cell density deviation ±10%).

[0178] Based on the deviation type and threshold, the control status is classified as "normal" or "abnormal": Deviation within the preset tolerance range (e.g., cell density deviation <5%). Deviation exceeding the threshold (e.g., liquid leakage in a pipe connection). Score = 1 (indicates that the operation meets the standard). Score = 2 (indicates that manual intervention or equipment adjustment is required).

[0179] Summarize the scoring data of each control stage to form the full-process control scoring data.

[0180] The real-time scoring results are fed back to the control system, triggering corresponding actions (such as suspending operations and issuing alarms in case of abnormalities).

[0181] The technical effect of the above technical solution is: through image feature comparison, it can quickly identify operational abnormalities (such as excessively large cell clusters and pipe connection offsets), reducing reliance on manual inspections.

[0182] Preset standard image feature data to ensure that each operation meets unified standards and reduce differences in human operations.

[0183] Enforce operational compliance and improve batch-to-batch consistency through a scoring mechanism (normal = 1, abnormal = 2).

[0184] When the score = 2, an alarm is automatically triggered, prompting the operator to intervene (such as reconnecting the pipeline).

[0185] Based on statistics on abnormality types (such as frequent "pipeline connection abnormalities"), perform equipment maintenance in advance (such as replacing seals).

[0186] Long-term accumulated feature deviation data (such as cell digestion time deviation) can reveal abnormal stage operation and prompt parameter adjustment.

[0187] By analyzing the correlation between stage scoring data (e.g., “abnormal cell digestion” leading to “low cell inoculation score”), we can analyze the impact of control abnormalities in adjacent control stages and optimize the parameters of the entire process.

[0188] In one embodiment of the present invention, the step of obtaining control score data of adjacent control stages and sub-adjacent control stages, performing comparative analysis on the control score data, and thereby obtaining stage determination information of the adjacent control stages and sub-adjacent control stages includes:

[0189] Obtain control score data of adjacent control stages and set them as first control score data and second control score data; the first control score data is the control score data of the control stage performed first in the adjacent control stages, and the second control score data is the control score data of the control stage performed later in the adjacent control stages.

[0190] When the first control score data is greater than the second control score data, the control stage corresponding to the first control score data is determined to be an abnormal stage;

[0191] 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;

[0192] When the first control score data and the second control score data are equal 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;

[0193] 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.

[0194] The working principle of the above technical solution is to obtain control score data of adjacent control stages, which is specifically divided into first control score data and second control score data. The first control score data represents the score of the control stage that is performed earlier in the adjacent control stages, while the second control score data represents the score of the control stage that is performed later.

[0195] The first control score data and the second control score data are compared to determine the states of the two control stages.

[0196] According to the comparison results, the stage is determined:

[0197] If the first control score data is greater than the second control score data, the control stage corresponding to the first control score data is determined to be an abnormal stage. For example, the first control score data is 2 and the second control score data is 1;

[0198] If the second control score data is greater than the first control score data, the control stage corresponding to the second control score data is determined to be an abnormal stage. For example, the second control score data is 2 and the first control score data is 1;

[0199] If the first control score data is equal to the second control score data and is greater than 1, then both control stages are determined to be abnormal stages. For example, if the second control score data is 2, the second control score data is 2;

[0200] If the first control score data and the second control score data are equal and equal to 1, it is determined that both control stages are normal stages. For example, the first control score data is 1 and the second control score data is 1;

[0201] The technical effects of the above technical solution are: through the automated data acquisition and comparison process, it is possible to quickly and accurately determine adjacent control stages, improve work efficiency and accuracy, and then determine whether the abnormal stage has an impact on the next control stage, and determine which control stage the abnormal stage starts from; it is possible to promptly discover and identify abnormal control stages, take timely measures to correct them, and prevent the problem from further deteriorating.

[0202] By setting clear judgment rules, the evaluation of the control stage is made more standardized and objective, reducing the influence of subjective judgment.

[0203] Through automated data acquisition, comparison and stage determination, effective monitoring and evaluation of adjacent control stages are achieved.

[0204] In one embodiment of the present invention, the acquiring of control score data of adjacent control stages and sub-adjacent control stages, performing comparative analysis on the control score data, and thereby obtaining stage determination information of adjacent control stages and sub-adjacent control stages further includes:

[0205] Obtain control score data of two adjacent control stages, and set them as first adjacent score data and second adjacent score data;

[0206] When the first adjacent scoring data is greater than the second adjacent scoring data, the adjacent control stage corresponding to the first adjacent scoring data is determined to be an abnormal adjacent stage; the first adjacent scoring data is the sum of the first control scoring data and the second control scoring data corresponding to it; the second adjacent scoring data is the sum of the first control scoring data and the second control scoring data corresponding to it;

[0207] When the second adjacent scoring data is greater than the first adjacent scoring data, the adjacent control stage corresponding to the second adjacent scoring data is determined to be an abnormal adjacent stage;

[0208] When the first adjacent scoring data and the second adjacent scoring data are equal and greater than 2, the control phase corresponding to the first adjacent scoring data and the second adjacent scoring data is determined to be an abnormal adjacent phase;

[0209] 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.

[0210] Calculate the control process abnormality coefficient through the control score data of the adjacent control stage and the control score data of the next adjacent control stage;

[0211] The calculation formula of the control process abnormality coefficient is:

[0212]

[0213] Among them, KY is the abnormal coefficient of the control process, n is the total number of adjacent control stages, and d is the total number of adjacent control stages. is the i-th first control score data, is the second control score data of the i-th, ZL1 a is the first adjacent scoring data of a, ZL2 a is the ath second adjacent scoring data, is the change between the i-th first control score data and the i-th second control score data, is the change between the ath first adjacent scoring data and the ath second adjacent scoring data, when When it is 0, no calculation is performed;

[0214] Comparing the control process abnormality coefficient with the preset control process abnormality threshold to obtain a control comprehensive abnormality comparison result;

[0215] The preset process anomaly threshold is the permissible anomaly score that can be determined based on historical anomaly data experience;

[0216] Comprehensive control warning is carried out based on the comparison results of comprehensive control abnormalities.

[0217] The working principle of the above technical solution is as follows: the control scoring data of two adjacent control stages are obtained and set as the first adjacent scoring data and the second adjacent scoring data respectively. The two scoring data represent the performance or status evaluation results of the two adjacent control stages respectively. The first adjacent scoring data and the second adjacent scoring data are compared to determine the status relationship between the two adjacent control stages. Based on the comparison results, the stage determination is performed:

[0218] If the first adjacent scoring data is greater than the second adjacent scoring data, the adjacent control stage corresponding to the first adjacent scoring data is determined to be an "abnormal adjacent stage".

[0219] If the second adjacent scoring data is greater than the first adjacent scoring data, the adjacent control stage corresponding to the second adjacent scoring data is determined to be an “abnormal adjacent stage”.

[0220] If the first adjacent scoring data and the second adjacent scoring data are equal to and greater than 2, then the two adjacent control stages are determined to be "abnormal adjacent stages", indicating that both stages have abnormalities in performance or status.

[0221] If the first adjacent scoring data and the second adjacent scoring data are equal to and equal to 2, then it is determined that the two adjacent control stages are both "normal adjacent stages", indicating that the two stages are within a normal range in terms of performance or status.

[0222] The technical effect of the above-mentioned technical solution is that by comparing the scoring data of adjacent control stages, it can accurately detect which stage or stages have abnormalities, allowing timely identification of problems and the implementation of corrective measures. The establishment of clear judgment rules makes 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.

[0223] This method is relatively simple and clear, saves computing resources, and has less operational complexity.

[0224] By promptly detecting and handling abnormal stages, 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.

[0225] In one embodiment of the present invention, the stage determination warning and marking based on the stage determination information includes:

[0226] When the control stage is judged to be an abnormal stage, a first-level warning is issued for the corresponding control stage;

[0227] When the control stage is determined to be a normal stage, the corresponding control stage is marked as normal;

[0228] When the adjacent control stage is judged as an abnormal adjacent warning, a secondary warning is issued for the corresponding adjacent control stage;

[0229] When the adjacent control stage is determined to be a normal stage, the corresponding adjacent control stage is marked as being under control.

[0230] The working principle of the above technical solution is as follows: Based on image feature comparison and status analysis, the system generates judgment information (normal / abnormal) for each control stage. The judgment results of adjacent control stages are recorded for abnormal adjacent warning analysis.

[0231] If a control stage is judged to be abnormal (e.g., a score of 2 for the cell digestion stage), the system immediately triggers a Level 1 alert, notifying the operator of the risk associated with that stage. Alerts may include pop-up windows, audible and visual alarms, or push notifications.

[0232] When a control stage is judged to be normal (e.g., cell confirmation stage score = 1), the system automatically marks it as “control normal” and records it in the log.

[0233] If both adjacent control stages are judged to be abnormal (e.g., the "cell digestion stage" and the "cell resuspension stage" are both scored = 2), the system triggers a secondary warning, indicating that there may be continuous abnormal problems (such as equipment failure or process parameter deviation).

[0234] The second-level warning has a higher priority than the first-level warning and requires immediate human intervention.

[0235] If both adjacent control stages are judged to be normal (e.g., the “cell inoculation stage” and the “cell culture stage” are both scored = 1), the system automatically marks “adjacent controls normal” and links it to the full process report.

[0236] Automatically perform early warning and annotation based on preset rules (such as abnormal thresholds and adjacent stage association logic).

[0237] The judgment information is updated in real time, and the warning and annotation results are refreshed synchronously.

[0238] The technical effects of the above technical solution are: quickly locating single-stage anomalies and reducing the spread of faults (such as timely repair of pipeline leaks); identifying systemic problems and avoiding multi-stage cascading failures (such as continuous anomalies caused by equipment parameter deviations).

[0239] Reduce the time spent on manual confirmation of normal stages and focus on exception handling.

[0240] Optimize process connections. For example, when both "cell inoculation" and "cell culture" are normal, the intermediate inspection step is automatically skipped.

[0241] By correlating abnormalities in adjacent stages, the root cause can be quickly identified (e.g., abnormalities in both "cell digestion" and "resuspension" may be due to inappropriate digestive enzyme concentration).

[0242] Marking and warning records support problem review and optimization of process parameters.

[0243] Identify potential equipment failures (such as frequent triggering of abnormalities in adjacent stages) through secondary early warning and conduct maintenance in advance.

[0244] Reduce batch failures due to stage abnormalities and improve cell culture success rates.

[0245] In one embodiment of the present invention, the control score data of the adjacent control stages is the sum of first and second control score data of the adjacent control stages. The first adjacent score data is the sum of the control score data of the adjacent control stage performed earlier 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.

[0246] The working principle of this technical solution is as follows: Each control stage (e.g., cell confirmation, pipeline connection) generates a score (e.g., normal = 1, abnormal = 2) based on image feature comparison and status analysis. The sum of the scores of two adjacent stages is used to assess the risk of the transition between stages. The sum of the scores of the first stage (e.g., "cell confirmation" + "pipe connection") and the sum of the scores of the subsequent stage (e.g., "pipe connection" + "cell washing") is used to assess the risk of the transition between stages.

[0247] Each stage is scored independently, reflecting the quality of the operation at that stage. The sum of the scores of adjacent stages can be used to identify potential risks between stages (e.g., abnormal "cell digestion" may lead to abnormal "cell resuspension").

[0248] The technical effect of the above technical solution is: when the sum of adjacent scoring data is abnormal (such as ≥3), it indicates a problem with the connection between stages.

[0249] By comparing adjacent scores, the root cause of the problem can be quickly identified (for example, if both "cell digestion" and "resuspension" are abnormal, it may be due to improper digestive enzyme concentration).

[0250] When adjacent scores are normal (e.g. =2), redundant checks are automatically skipped, shortening the operation time.

[0251] Long-term accumulation of adjacent scoring data reveals process bottlenecks (such as a certain stage frequently leading to subsequent abnormalities).

[0252] Adjacent scoring data is automatically archived to support quality audits and problem tracing.

[0253] Obviously, those skilled in the art may make various modifications and variations to the present invention without departing from the spirit and scope of the present invention. Thus, if such modifications and variations fall within the scope of the claims and their equivalents, the present invention is intended to include such modifications and variations.

Claims

1. A control method for a cell factory automation device, characterized in that: The control method includes: 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 workstation and perform preset operations to complete the cell passage operation; Obtaining a preset operation process, dividing it into multiple control stages, obtaining control acquisition data for each control stage, and performing control status analysis and scoring for each control stage based on the control acquisition data to obtain control scoring data; 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 status analysis and scoring for each control stage based on 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; Perform comparative analysis on the image features of the control processing data at each control stage to obtain the control state determination information at each control stage; Obtaining control score data of adjacent control stages and sub-adjacent control stages, performing comparative analysis on the control score data, and thereby obtaining stage determination information of the adjacent control stages and sub-adjacent control stages; The step of acquiring control score data of adjacent control stages and sub-adjacent control stages, performing comparative analysis on the control score data, and then obtaining stage determination information of adjacent control stages and sub-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, the control stage corresponding to the first control score data is determined to be 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 and the second control score data are equal 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 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; Conduct stage judgment warning and marking based on stage judgment information; The step of performing stage determination warning and marking according to the stage determination information includes: When the control stage is judged to be 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.

2. The control method of the cell factory automation device according to claim 1, characterized in that: The method of connecting the connecting pipe of the cell factory to the cell factory by a sterile connecting pipe machine to obtain a connected pipeline includes: Connect the power supply and turn on the switch button to start the sterile pipe machine and perform self-test; After the self-test is completed, insert the pipe holder into the pipe holder base inside the machine through the sterile pipe top cover, and install the blade on the blade socket; Install the two connecting pipes to be installed in the grooves inside the pipe bracket; The blade is heated and then cooled to the welding temperature to cut and weld the connecting pipes; After welding is completed, the blade is cooled down; Get the connected pipeline and close the sterile pipe connection machine.

3. The control method of the cell factory automation device according to claim 1, characterized in that: The operation device controls the robotic arm to grab the cell factory and cell culture rack with connected pipelines to a designated station and perform 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 it through the system operation panel to grab the cell culture rack and the cell factory with connected pipelines 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 passaging operation.

4. The control method of the cell factory automation device according to claim 1, characterized in that: The comparative analysis of image features of each control stage on the control processing data to obtain control state determination information of each control stage includes: Sequentially acquiring image data of the control processing data of each control stage, performing feature extraction on the image data of the control stage to obtain 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, comparing the image feature data of each feature analysis type with the target feature data to obtain control state determination information of the 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.

5. The control method of the cell factory automation device according to claim 1, characterized in that: The step of acquiring control score data of adjacent control stages and sub-adjacent control stages, performing comparative analysis on the control score data, and then obtaining stage determination information of adjacent control stages and sub-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, the adjacent control stage corresponding to the first adjacent scoring data is determined to be an abnormal adjacent stage; When the second adjacent scoring data is greater than the first adjacent scoring data, the adjacent control stage corresponding to the second adjacent scoring data is determined to be an abnormal adjacent stage; When the first adjacent scoring data and the second adjacent scoring data are equal and greater than 2, the control phase corresponding to the first adjacent scoring data and the second adjacent scoring data is determined to be an abnormal adjacent phase; 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.

6. The control method of the cell factory automation device according to claim 5, characterized in that: The control score data of the adjacent control stages is the sum of the first control score data and the second control score data of the adjacent control stages; 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.

7. A device for implementing the control method of the cell factory automation device according to claim 1, characterized in that: The 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 sterile 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 sterile connection is completed, and then distribute 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 on multiple control stages of the preset operation process, obtain judgment information of the control stage, and then perform stage judgment warning and marking; The aseptic pipe connecting machine includes a main unit, a pipe support and a power supply; The operating device includes a mechanical arm, a cell culture rack, an operating platform and a system operating panel.

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