Cell culture control system, cell culture control method, and cell culture control program

Abstract

To ensure appropriate cell culture with bioreactors, by automatically controlling the bioreactors in accordance with culture control information generated based on culture data derived from the bioreactors and analyzers.SOLUTION: A cell culture control system 100 comprises: a bioreactor 3 that cultures cells; an analyzer 4 that analyzes the culture state of the cells; a bioreactor control device 1; and an advice generation server 2. The advice generation server 2 is provided with an advice generation unit 23 that generates culture control information on the basis of culture data acquired from the bioreactor 3 and the analyzer 4. The bioreactor control device 1 is provided with: a control unit 14 that controls the bioreactor 3; and an advice processing unit 151 that acquires the culture control information from the advice generation server 2 and instructs the control unit 14 to perform, for the bioreactor 3, control for causing the cells to proliferate or extending the life span of the cells in accordance with the culture control information.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a cell culture control system, a cell culture control method, and a cell culture control program.

Background Art

[0002] A bioreactor is a device that uses biological catalysts such as microorganisms and enzymes to perform synthesis and decomposition of substances, and is also called a biological reaction device. Bioreactors are being researched and developed as core technologies together with recombinant DNA technology and cell fusion technology in various industrial fields such as food, clothing, diagnostic services, livestock and fisheries industries, aquaculture, chemical products, resource energy, bioelectronics, and environmental purification.

[0003] Also in the operation of such bioreactors, as in other fields, in recent years, from the viewpoints of reducing individual differences in manual operations, reducing human errors, and expanding the working range, the need for operation support has been rapidly increasing. As the usage procedures of operation support tools for bioreactors, the following have been proposed. For example, based on a pre-determined procedure manual, adjustment of the operation support tool is performed. Then, an operator who actually operates the bioreactor operates the bioreactor while referring to the operation information provided by the operation support tool.

[0004] In addition, as an operation support technology for bioreactors, a technology for detecting changes in the total amount of proteins contained in a culture medium while cells are growing in the bioreactor has been proposed (Patent Document 1).

Prior Art Documents

Patent Documents

[0005]

Patent Document 1

Non-Patent Documents

[0006]

Non-Patent Document 1

[0007] However, when performing cell culture operations, since the subject being controlled is a living organism, it is sometimes desirable to change the operation depending on the culture conditions. In this respect, with conventional technology, the operation support tools are adjusted according to predetermined procedures, making it difficult to change the operation according to the culture conditions, and thus difficult to properly perform cell culture using a bioreactor.

[0008] One aspect of the present invention is to enable proper cell culture using a bioreactor by automatically controlling the bioreactor according to culture control information generated based on culture data obtained from the bioreactor and analyzer. [Means for solving the problem]

[0009] The cell culture control system relating to one aspect comprises a bioreactor for culturing cells, an analyzer for analyzing the culture state of the cells, a cell culture control device, and a culture control information generation device. The culture control information generation device includes a culture control information generation unit that generates culture control information including execution time based on culture data obtained from the bioreactor and the analyzer, and adds a creation time. The cell culture control device includes a control unit that controls the bioreactor, and acquires the culture control information from the culture control information generation device, and based on the creation time... Check whether new culture control information exists, and if new culture control information exists, check whether new Whether or not to accept culture control information Accepting the instructions ,accept If the instructions are received, the new The system includes a culture control information processing unit that stores culture control information, periodically checks the stored culture control information, and instructs the control unit to perform control to extend the cell proliferation or the lifespan of the cells according to the culture control information that has the closest execution time to the current time among the stored culture control information after the current time. [Effects of the Invention]

[0010] According to the present invention, cell culture using a bioreactor can be performed appropriately. [Brief explanation of the drawing]

[0011] [Figure 1] This is a block diagram of the cell culture control system according to the embodiment. [Figure 2] This figure shows glucose and cellular transitions in the control of nutrient depletion prevention. [Figure 3] This figure shows the transitions in the input amounts of glucose and feed agent in controlling the nutrient input ratio. [Figure 4] This figure shows an example of advice data. [Figure 5] This is a flowchart of the operation support process by the bioreactor control device according to the embodiment. [Figure 6] This is a flowchart for the advice acceptance process. [Figure 7] This is a flowchart of the bioreactor control process, following the advice given. [Figure 8] This is a block diagram of a cell culture control system using edge computing. [Figure 9] This is a diagram showing an example of the hardware configuration of a bioreactor control system. [Figure 10] This is a diagram illustrating another example of the hardware configuration of a bioreactor control system. [Modes for carrying out the invention]

[0012] Embodiments of the cell culture control system, cell culture control method, and cell culture control program will be described below with reference to the drawings. The same elements are denoted by the same reference numerals, and redundant explanations are omitted as appropriate. Furthermore, each embodiment can be combined as appropriate within the bounds of consistency.

[0013] (Overall structure) FIG. 1 is a block diagram of a cell culture control system according to an embodiment. The cell culture control system 100 includes a bioreactor control device 1, an advice generation server 2, a bioreactor 3, and an analyzer 4. The cell culture control system 100 is a system that generates advice on appropriate operations from the state of cell culture in the bioreactor 3 and presents it to an operator, and controls the operation of the bioreactor 3 according to the advice, which is culture control information generated upon receiving the operator's permission.

[0014] The bioreactor 3 is a device for performing cell culture. The purposes of cell culture by the bioreactor 3 are as follows. One is to increase the cells to be managed and obtain the cells themselves. The other is to obtain products such as antibodies from the cells. In order to obtain more products, it is important to increase and prolong the life of the cells.

[0015] Although not shown in the figure, the bioreactor 3 is attached with various sensors such as a temperature sensor, a pH sensor, and a lactic acid value measurement sensor. The bioreactor 3 acquires sensor information using various sensors. In addition, the bioreactor 3 is attached with a mechanism for measuring culture solution information such as the weight and volume of the culture solution. Furthermore, the bioreactor 3 can calculate respective predicted values such as cell density, glucose concentration, and lactic acid value using NIR or Raman spectroscopy. The sensor information and the culture solution information include predicted viable cell density value, predicted glucose concentration value, predicted lactic acid value, dissolved oxygen amount, pH, culture tank temperature, culture solution weight, and culture solution volume. The sensor information and the culture solution information obtained from the bioreactor 3 are sometimes referred to as in-line data. The bioreactor 3 notifies the bioreactor control device 1 of the sensor information and the culture solution information obtained by various sensors. The bioreactor 3 may be one or plural.

[0016] The analyzer 4 acquires the culture medium from the bioreactor 3 and analyzes the acquired culture medium to measure various culture state information indicating the state of the culture medium, such as glucose concentration and cell density. Culture state information includes, for example, cell density, live cell density, dead cell density, cell viability, cell diameter, cell roundness, glucose concentration, glutamine, glutamic acid, lactate level, ammonium, IgG, LDH, sodium, potassium, calcium, pH, PO2, PCO2, Osm, etc. The analyzer 4 may be an offline analyzer in which an operator manually acquires the culture medium from the bioreactor 3 and puts it into the analyzer 4, or it may be an at-line analyzer that automatically acquires the culture medium from the bioreactor 3. If it is an at-line analyzer, the analyzer 4 may transmit the measured culture state information to the bioreactor 3. Also, there may be one analyzer 4 or multiple analyzers. The culture state information obtained by an offline analyzer or an at-line analyzer may be called offline data or at-line data, respectively.

[0017] While the bioreactor 3 provides a predicted value for the culture state, the analyzer 4 measures the culture state information by analyzing the actual culture medium. Therefore, the cell culture control system 100 can obtain more accurate culture state information by using the measurement values ​​from the analyzer 4. The analyzer 4 outputs the measured culture state information to the bioreactor control device 1.

[0018] The bioreactor control device 1 is connected to the advice generation server 2 via a network. The bioreactor control device 1 is also connected to the bioreactor 3. The bioreactor control device 1 acquires sensor information and culture medium information notified by the bioreactor 3. The bioreactor control device 1 also acquires culture state information obtained from the analyzer 4 through measurement by the analyzer 4. The bioreactor control device 1 also acquires advice data generated by the advice generation server 2 based on culture data that combines the sensor information, culture medium information, and culture state information. The bioreactor control device 1 then confirms with the operator whether or not to accept the advice contained in the acquired advice data, and if the operator accepts the advice, it controls the operation of the bioreactor 3 according to the advice. The bioreactor control device 1 is an example of a "cell culture control device".

[0019] The advice generation server 2 is connected to the bioreactor control device 1 via a network. The advice generation server 2 acquires culture data from the bioreactor control device 1 and generates advice data, including advice on the operation of the bioreactor 3, based on the acquired culture data. The advice generation server 2 then transmits the generated advice data to the bioreactor control device 1. The advice generation server 2 may be a device in an in-house system managed as on-premises, or it may be a device located in the cloud. The advice generation server 2 is an example of a "culture control information generation device".

[0020] (Control device) Next, with reference to Figure 1, the details of the bioreactor control device 1 will be described. As shown in Figure 1, the bioreactor control device 1 includes a transmitting / receiving unit 11, an input / output control unit 12, a data conversion unit 13, a control unit 14, and an operation support unit 15.

[0021] The transmitting / receiving unit 11 controls the transmission and reception of data with the advice generation server 2. The transmitting / receiving unit 11 receives input of culture data from the bioreactor 3 and the analyzer 4, including sensor information, culture medium information, and culture state information. The transmitting / receiving unit 11 then transmits the acquired culture data from the bioreactor 3 to the advice generation server 2. The transmitting / receiving unit 11 also receives advice data generated from the advice generation server 2 based on the transmitted culture data. The transmitting / receiving unit 11 then outputs the acquired advice data to the data conversion unit 13.

[0022] Thus, the transmitting / receiving unit 11 relays communication between, for example, the data conversion unit 13 and the control unit 14 and the advice generation server 2. However, in the following explanation, for the sake of clarity, the transmitting / receiving unit 11 may be omitted, and the data conversion unit 13 and the control unit 14 may be described as communicating directly with the advice generation server 2.

[0023] The input / output control unit 12 includes a display device such as a monitor and an input device such as a mouse or keyboard. The input / output control unit 12 controls the transfer of data between the operator and the system via the display device and input device. For example, the input / output control unit 12 displays an advice acceptance selection screen on the display device, allowing the operator to choose whether or not to accept the advice included in the advice data provided by the driving support unit 15. The input / output control unit 12 then uses the advice acceptance selection screen displayed on the display device to obtain information from the input device regarding whether or not the advice selected by the operator is accepted. Subsequently, the input / output control unit 12 outputs the information regarding whether or not the advice is accepted to the driving support unit 15.

[0024] The data conversion unit 13 receives input advice data transmitted from the advice generation server 2 via the transmission / reception unit 11. The data conversion unit 13 then converts the advice data transmitted from the advice generation server 2 into a format that the driving support unit 15 can process. For example, the data conversion unit 13 receives advice data in JSON format from the advice generation server 2 and converts it into Excel format data. After that, the data conversion unit 13 outputs the advice data converted into a format that the driving support unit 15 can process to the driving support unit 15.

[0025] The control unit 14 performs the collection of culture data from the bioreactor 3 and controls the operation of the bioreactor 3. For example, the control unit 14 collects sensor information and culture medium information measured in the bioreactor 3. The control unit 14 also collects culture state information measured by the analyzer 4. Culture data includes, for example, inline data and offline / atline data.

[0026] In this embodiment, the control unit 14 acquires culture status information from the data input unit 153 of the operation support unit 15. However, if the analyzer 4 is an atline analyzer, the control unit 14 may directly acquire culture status information from the analyzer 4. The control unit 14 then collects the sensor information, culture medium information, and culture status information and transmits it to the advice generation server 2 via the transmission / reception unit 11 as culture data representing the state of the bioreactor 3. In other words, the control unit 14 collects culture data from the bioreactor 3 and the analyzer 4 and transmits it to the culture control information generation device.

[0027] Furthermore, the control unit 14 receives instructions from the operation support unit 15 to control the bioreactor 3 in accordance with the advice included in the advice data. When using culture state information for control, the control unit 14 obtains the culture state information from the operation support unit 15 along with the instructions to control the bioreactor 3. The control unit 14 then controls the operation of the bioreactor 3 according to the instructions. The control information that the control unit 14 sends to the bioreactor 3 includes control values ​​for the stirrer, heater or sparger (air, oxygen, carbon dioxide, nitrogen, etc.), glucose input amount, feed agent input amount, and alkaline solution input amount.

[0028] For example, the control unit 14 receives an instruction from the operation support unit 15 to add a predetermined amount of glucose, along with information on the time of addition. In this case, when the specified time is reached, the control unit 14 adds the specified amount of glucose to the bioreactor 3. This promotes cell growth in the bioreactor 3, extends cell lifespan, and increases cell population. Also, if the culture medium is acidic and unfavorable to the target cells, the control unit 14 receives an instruction from the operation support unit 15 to add a predetermined amount of alkaline solution, along with information on the time of addition. In this case, when the specified time is reached, the control unit 14 adds the specified amount of alkaline solution to the bioreactor 3. This improves the culture environment in the bioreactor 3, extends cell lifespan, and increases cell population.

[0029] The operation support unit 15 assists the operator in operating the bioreactor 3 based on the advice data generated by the advice generation server 2. The operation support unit 15 includes an advice processing unit 151, an advice input unit 152, and a data input unit 153.

[0030] The advice input unit 152 receives advice data converted into a format that can be processed by the device from the data conversion unit 13. The advice input unit 152 then outputs the acquired advice data to the advice processing unit 151.

[0031] The advice processing unit 151 receives advice data generated by the advice generation server 2 from the advice input unit 152. Next, the advice processing unit 151 extracts and stores the creation time of the advice attached to the advice data. After that, the advice processing unit 151 performs the advice acceptance process described below for each piece of advice data.

[0032] The advice processing unit 151 determines whether a new piece of advice exists among the advice data it holds, using the time the advice was created. Here, the advice processing unit 151 may determine whether a piece of advice is new each time advice data is input from the advice input unit 152, or it may periodically determine whether a new piece of advice exists among the advice data that has been stored.

[0033] If new advice exists, the advice processing unit 151 instructs the input / output control unit 12 to display an advice selection screen that allows the user to choose whether or not to accept the new advice, and displays the advice selection screen on the display device. This allows the advice processing unit 151 to confirm with the user whether or not to accept the advice using the advice selection screen.

[0034] If the worker notifies the system that they accept the advice, the advice processing unit 151 stores the advice data, including the new advice that has been approved, as accepted advice data. If the worker notifies the system that they do not accept the advice, the advice processing unit 151 terminates the acceptance process for that advice.

[0035] Furthermore, the advice processing unit 151 periodically determines, asynchronously with the advice acceptance process, whether or not accepted advice data exists among the advice data it holds. If accepted advice data exists, the advice processing unit 151 obtains the nearest future execution time among the execution times of the unprocessed accepted advice data. Then, the advice processing unit 151 determines whether or not the current time exceeds the obtained execution time. If the current time does not exceed the obtained execution time, the advice processing unit 151 waits until the obtained execution time.

[0036] In response to this, if the current time exceeds the acquired execution time, the advice processing unit 151 instructs the control unit 14 to control the bioreactor 3 in accordance with the advice contained in the advice data. In this case, if the culture state information from the analyzer 4 is to be used in the control in accordance with the advice, the advice processing unit 151 instructs the data input unit 153 to input the culture state information to be used to the control unit 14.

[0037] The advice processing unit 151 instructs the control unit 14 to implement control of the bioreactor 3 in accordance with the advice contained in all unprocessed accepted advice data. If there is no more unprocessed accepted advice data, the advice processing unit 151 waits until new accepted advice data is generated.

[0038] Here, we will explain the control that follows the advice. The bioreactor control device 1 controls the bioreactor 3 to increase the number of cells and extend their lifespan. In other words, the control that follows the advice instructed by the advice processing unit 151 to the control unit 14 also results in control that increases the number of cells and extends their lifespan. Examples of this control include nutrient depletion prevention control, which prevents nutrient depletion during the cell proliferation phase, and nutrient input ratio control, which appropriately controls the input ratio of various nutrients during the proliferation phase, stationary phase, and death phase.

[0039] The advice processing unit 151, for example, as a nutrient depletion prevention control, instructs the control unit 14 to perform control according to advice on the amount of glucose to be input based on monitoring results such as the density of living cells and glucose concentration.

[0040] Figure 2 shows the glucose and cell transitions in nutrient depletion prevention control. Graph 201 represents the change in glucose concentration, graph 202 represents the change in viable cell density, and graph 203 represents the glucose input. In Figure 2, the vertical axis represents glucose concentration, viable cell density, or glucose input, corresponding to graphs 201-203, and the horizontal axis represents the phase. In Figure 2, a phase of 0 represents the delayed phase, a phase of 1 represents the proliferation phase, a phase of 2 represents the stationary phase, and a phase of 3 represents the death phase. For example, if the viable cell density increases rapidly and the glucose concentration decreases rapidly, the advice processing unit 151 instructs the control unit 14 to increase the glucose input in order to raise the glucose concentration and prolong cell life. In other words, the advice processing unit 151 instructs the control unit 14 to control the bioreactor 3 so that the frequency of culture data collection is increased during the cell proliferation phase compared to the stationary phase and death phase.

[0041] Here, since glucose concentration and cell density may change rapidly during the cell proliferation phase compared to other phases, the data collection frequency by the control unit 14 may be increased. For example, the control unit 14 may utilize inline data that can be collected at a high frequency to increase the data collection frequency. Also, if the data collection frequency is increased, the advice generation unit 23 of the advice generation server 2, described later, may reduce the analysis load and speed up the process by narrowing the types of data to be analyzed.

[0042] Furthermore, the advice processing unit 151, for example, as a control of nutrient input ratio, instructs control according to advice to increase the feed rate as the cell approaches the death phase, based on the growth phase, stationary phase, and death phase determined using culture data such as live cell density.

[0043] Figure 3 shows the transitions in the input amounts of glucose and feed agent in nutrient input ratio control. Graph 211 shows the change in glucose input amount, and graph 212 shows the change in feed agent input amount. In Figure 2, the vertical axis represents the input amount and the horizontal axis represents Ph. For example, when the slope of the viable cell density decreases, the advice processing unit 151 instructs the control unit 14 to increase the ratio of feed agent input amount based on the determination that the cell has transitioned from the proliferation phase to the stationary phase. The advice processing unit 151 also instructs the control unit 14 to increase the ratio of feed agent input amount based on the determination that the cell has transitioned from the stationary phase to the death phase, depending on the slope of the cell density and time.

[0044] The data input unit 153 acquires culture status information obtained from the measurement of the analyzer 4. The data input unit 153 may acquire the culture status information automatically from the analyzer 4, or it may acquire the culture status information by manual input by an operator. The data input unit 153 then outputs the acquired culture status information to the control unit 14.

[0045] Furthermore, the data input unit 153 receives instructions from the advice processing unit 151 to input the culture state information to be used to the control unit 14. The data input unit 153 then acquires the culture state information to be used, as specified by the data input unit 153, from the analyzer 4. Subsequently, the data input unit 153 outputs the culture state information acquired from the analyzer 4 to the control unit 14.

[0046] (server) Next, with reference to Figure 1, the details of the advice generation server 2 will be described. As shown in Figure 1, the advice generation server 2 has a transmitting / receiving unit 21, a storage unit 22, and an advice generation unit 23.

[0047] The transmitting / receiving unit 21 controls the transmission and reception of data between it and the bioreactor control device 1. The transmitting / receiving unit 21 receives culture data from the bioreactor 3, including sensor information, culture medium information, and culture state information, from the transmitting / receiving unit 11 of the bioreactor control device 1. The transmitting / receiving unit 21 then stores the acquired culture data from the bioreactor 3 in the storage 22.

[0048] Furthermore, the transmitting / receiving unit 21 acquires advice data, including the advice stored in the storage 22 and the creation time of each piece of advice. The transmitting / receiving unit 21 then transmits the advice data to the transmitting / receiving unit 11 of the bioreactor control device 1.

[0049] The storage unit 22 stores the culture data of the bioreactor 3 received by the transmitting / receiving unit 21 from the bioreactor control device 1. The storage unit 22 also stores advice data, including the advice generated by the advice generation unit 23 and the time the advice was created.

[0050] The advice generation unit 23 acquires the culture data of the bioreactor 3 stored in the storage unit 22. Then, the advice generation unit 23 generates advice data regarding the operation of the bioreactor 3 based on the culture data. More specifically, the advice generation unit 23 creates advice data written in JSON format or similar, which indicates advice regarding operation.

[0051] For example, the advice generation unit 23 may determine advice corresponding to the input culture data using simple conditional judgment and generate advice data. Alternatively, the advice generation unit 23 may determine advice corresponding to the input culture data using AI (Artificial Intelligence) and generate advice data.

[0052] The advice generation unit 23 generates advice data, for example, regarding processes to extend the proliferation and lifespan of cells in the bioreactor 3. More specifically, the advice generation unit 23 generates advice data such as which solution to add and in what amount in milliliters at what time and minute. In this case, the advice generation unit 23 may add the reasons for the operations to be performed to the advice data. Also, if the data collection frequency is increased during the cell proliferation phase, the advice generation unit 23 may reduce the analysis load and speed up the analysis process by narrowing down the types of data to be analyzed.

[0053] For example, the advice generation unit 23 obtains the cell density and glucose concentration from the culture data and, if it determines that the glucose level is too low for the cells being cultured and that cell growth will be inhibited, it generates advice data specifying the time and amount of glucose to be added. Furthermore, the advice generation unit 23 obtains the lactic acid value contained in the sensor information and, if it determines that the culture medium is acidic and that cells will not grow easily, it generates advice data specifying the time and amount of alkaline solution to be added.

[0054] In addition, the advice generation unit 23 determines the proliferation phase, stationary phase, and death phase based on culture data such as live cell density, and generates advice data to increase the feed rate as the cell approaches the death phase. For example, the advice generation unit 23 detects a decrease in the increasing trend of live cell density and determines the transition from the proliferation phase to the stationary phase of cells. The advice generation unit 23 also determines the transition from the stationary phase to the death phase based on live cell density and elapsed time.

[0055] Here, the advice data is an example of "culture control information," and the advice generation unit 23 is an example of a "culture control information generation unit." In other words, the advice generation unit 23 determines the cell proliferation phase, stationary phase, and death phase based on the culture data, and generates culture control information to increase the feed agent input ratio in the order of proliferation phase, stationary phase, and death phase.

[0056] The advice generation unit 23 then adds the creation time of each piece of advice to the generated advice data and stores it in the storage unit 22.

[0057] Figure 4 shows an example of advice data. The advice generation unit 23 generates advice data 220 written in JSON format, for example, as shown in Figure 4. In the advice data 220, last_update is the time the advice was created or sent, status is the priority and urgency of the advice, contents is the operation information of reactor 3, and execute_timing is the time the advice is executed. Furthermore, feeds is control information for various pumps, such as pump ID, input amount, and quantitative flow time, and temperature is control information for the heater. The advice data may also include other information such as sparger control information for various gases, stirring control, and sampling instructions for the culture medium. The advice generation unit 23 can use the advice data 220 to specify the execution time and the processing to be executed.

[0058] (Driving assistance process flow) Figure 5 is a flowchart of the operation support process by the bioreactor control device according to this embodiment. Next, referring to Figure 5, the flow of operation support processes performed by the operator on the bioreactor 3 by the bioreactor control device 1 according to this embodiment will be explained.

[0059] The control unit 14 collects sensor information and culture medium information measured in the bioreactor 3. The control unit 14 also collects culture state information measured by the analyzer 4. Then, the control unit 14 transmits culture data, which is a compilation of the collected sensor information, culture medium information, and culture state information, to the advice generation server 2 (step S1).

[0060] The transmitting / receiving unit 21 of the advice generation server 2 receives culture data transmitted from the control unit 14 of the bioreactor control device 1 and stores it in the storage 22. The advice generation unit 23 retrieves the culture data stored in the storage 22, generates advice data regarding the operation of the bioreactor 3 according to the culture data, and stores it in the storage 22. The transmitting / receiving unit 21 transmits the advice data, including the advice stored in the storage 22 and the time the advice was created, to the bioreactor control device 1 (step S2).

[0061] The transmitting / receiving unit 11 receives advice data from the transmitting / receiving unit 21 of the advice generation server 2 and outputs it to the data conversion unit 13. The data conversion unit 13 converts the advice data transmitted from the advice generation server 2 into a format that the driving support unit 15 can process (step S3).

[0062] The driver support unit 15 acquires the advice data, which has been converted into a format that can be processed by the data conversion unit 13. Then, the driver support unit 15 performs an advice acceptance process to confirm with the operator whether or not to accept the advice (step S4).

[0063] Furthermore, the driving support unit 15 instructs the control unit 14 to execute control of the operation of the bioreactor 3 in accordance with the advice contained in the advice data. The control unit 14 operates the bioreactor 3 by executing control of the operation of the bioreactor 3 in accordance with the advice instructed by the driving support unit 15 (step S5).

[0064] The control unit 14 and the operation support unit 15 determine whether or not the cell culture in the bioreactor 3 is complete (step S6). If the cell culture is not complete (step S6: negative), the operation support process returns to step S1. On the other hand, if the cell culture is complete (step S6: positive), the control unit 14 and the operation support unit 15 terminate the operation support process.

[0065] Here, for illustrative purposes, the advice acceptance process is designated as step S4, and the control of the bioreactor 3 according to the advice is designated as step S5. However, in reality, the bioreactor control device 1 performs the advice acceptance process and the control according to the advice in parallel. Furthermore, the bioreactor control device 1 may perform the processes of steps S1 to S3 in parallel with these processes.

[0066] (Advice acceptance process) Figure 6 is a flowchart of the advice acceptance process. Each process in the flow shown in Figure 6 is an example of the process performed in step S4 in Figure 5.

[0067] The advice processing unit 151 receives advice data generated by the advice generation server 2 from the advice input unit 152. Next, the advice processing unit 151 extracts and stores the creation time of the advice. Then, the advice processing unit 151 determines whether or not there is new advice among the advice data it stores (step S101). If there is no new advice (step S101: negative), the advice acceptance process proceeds to step S105.

[0068] In response to this, if new advice exists (step S101: affirmative), the advice processing unit 151 outputs an advice selection screen to the input / output control unit 12, which displays whether or not the new advice can be accepted, and displays it on the display device. This allows the advice processing unit 151 to confirm with the operator whether or not to accept the new advice using the advice selection screen (step S102).

[0069] Based on the operator's selection result using the advice selection screen displayed on the display device, the advice processing unit 151 determines whether or not to accept the new advice (step S103). If the new advice is not accepted (step S103: negation), the advice acceptance process proceeds to step S105.

[0070] In response to this, if the new advice is accepted (step S103: affirmative), the advice processing unit 151 sets the advice data containing the new advice as accepted advice data (step S104).

[0071] Subsequently, the advice processing unit 151 determines whether or not the cell culture is complete (step S105). If the cell culture is not complete (step S105: negative), the advice acceptance process returns to step S101.

[0072] In contrast, if cell culture is completed (step S105: affirmative), the advice processing unit 151 terminates the advice acceptance process.

[0073] (Bioreactor control processing) Figure 7 is a flowchart of the bioreactor control process according to the advice. Each process in the flow shown in Figure 7 is an example of the process performed in step S5 in Figure 5.

[0074] The advice processing unit 151 determines whether or not there is any unprocessed accepted advice data among the advice data it holds (step S201). If there is no unprocessed accepted advice data (step S201: negative), the bioreactor control process proceeds to step S206.

[0075] In contrast, if there is unprocessed accepted advice data (step S201: affirmative), the advice processing unit 151 obtains the nearest future execution time among the execution times of the unprocessed accepted advice data (step S202).

[0076] Next, the advice processing unit 151 determines whether the current time has exceeded the acquired execution time (step S203). If the current time has exceeded the advice execution time (step S203: affirmative), the bioreactor control process proceeds to step S205.

[0077] In contrast, if the current time has not exceeded the advice execution time (step S203: negative), the advice processing unit 151 waits until the advice execution time (step S204).

[0078] Subsequently, the advice processing unit 151 instructs the control unit 14 to control the bioreactor 3 in accordance with the advice contained in the advice data. In this case, if the measurement results from the analyzer are to be used in the control according to the advice, the advice processing unit 151 instructs the data input unit 153 to input the information of the measurement results to be used to the control unit 14. The control unit 14 receives the instructions from the advice processing unit 151 and controls the operation of the bioreactor 3 in accordance with the advice (step S205).

[0079] Subsequently, the advice processing unit 151 determines whether or not the cell culture is complete (step S206). If the cell culture is not complete (step S206: negative), the bioreactor control process returns to step S201.

[0080] In contrast, if cell culture is completed (step S206: affirmative), the advice processing unit 151 and the control unit 14 terminate the bioreactor control process.

[0081] [effect] As described above, the cell culture control system 100 according to the embodiment generates advice on operating the bioreactor 3 to extend cell proliferation and lifespan, based on culture data representing the most recent culture status of the bioreactor 3. Next, the cell culture control system 100 confirms with the operator whether or not to accept the generated advice, and if the operator decides to accept the advice, it controls the operation of the bioreactor 3 according to that advice.

[0082] In this way, the cell culture control system 100 monitors culture data related to cell culture from the bioreactor 3 and analyzer 4, and proposes a control method for the bioreactor 3 based on that culture data. This allows the operation of the bioreactor 3 to be changed according to the culture status, making it possible to perform optimal culture regardless of the operator's skill level. Furthermore, it becomes possible to perform the appropriate operation at the appropriate time, making it easy to extend and increase the lifespan of cells cultured in the bioreactor 3, and enabling proper cell culture using the bioreactor 3.

[0083] (modified version) The control unit 14 can be implemented using a DCS (Distributed Control System), SCADA (Supervisory Control And Data Acquisition), PLC (Programmable Logic Controller), recorder, or controller. When the control unit 14 is implemented using SCADA, the transmitting / receiving unit 11, input / output control unit 12, data conversion unit 13, control unit 14, and driving support unit 15 can be implemented together within a single computer. Alternatively, when the control unit 14 is implemented using dedicated hardware such as a DCS, PLC, recorder, or controller, the control unit 14 and the driving support unit 15 can be configured as separate devices.

[0084] The transmitting / receiving unit 11, control unit 14, data input unit 153, and transmitting / receiving unit 21 can utilize communication interfaces such as MQTT (Message Queueing Telemetry Transport), Web server / client communication (REST (Representational State Transfer), API (Application Programming Interface)), OPC (Open Platform Communications), HART IP, DNP (Distributed Network Protocol), PROFINET, and Modbus. Furthermore, the transmitting / receiving unit 11, control unit 14, data input unit 153, and transmitting / receiving unit 21 can use, for example, txt data, csv data, Excel data, etc., as the data to be exchanged.

[0085] The bioreactor control device 1 can also be configured to include an advice generation unit 23. Figure 8 is a block diagram of a cell culture control system using edge computing. For example, by adopting an edge computing configuration, the cell culture control system 100 can be configured as shown in Figure 8.

[0086] The bioreactor control device 1 has an advice generation unit 16 in addition to the parts described in Example 1. The advice generation unit 16 has the same function as the advice generation unit 23 in the advice generation server 2 according to Example 1. In this case, the bioreactor control device 1 does not need to transmit culture data to the advice generation server 2 or receive advice from the advice generation server 2.

[0087] For example, the advice generation unit 16 can generate advice using AI. In this case, the bioreactor control device 1 may receive training data for AI training from the advice generation server 2 and train the AI ​​used by the advice generation unit 16. In this case, the training unit 24 of the advice generation server 2 may increase the amount of machine learning data. By increasing the amount of machine learning data, it is possible to improve the accuracy of the AI.

[0088] Alternatively, the advice generation server 2 may hold an AI that is a digital twin of the AI ​​held by the advice generation unit 16. In that case, the advice generation server 2 may perform AI training and notify the advice generation unit 16 of the bioreactor control device 1 of the hyperparameters determined by the training.

[0089] Furthermore, in this embodiment, the operator was asked whether or not to accept the advice in order to reflect the operator's judgment. However, the bioreactor control device 1 can also completely automate the control of the operation of the bioreactor 3 by omitting this confirmation process.

[0090] (system) Unless otherwise specified, the processing procedures, control procedures, specific names, and various data and parameters shown in the above documents and drawings may be changed at will.

[0091] Furthermore, the components of each illustrated device are functionally conceptual and do not necessarily need to be physically configured as shown. In other words, the specific forms of distribution and integration of each device are not limited to those shown. That is, all or part of them can be functionally or physically distributed and integrated in any unit according to various loads and usage conditions.

[0092] Furthermore, each processing function performed by each device may be implemented, in whole or in part, by a CPU (Central Processing Unit) and a program executed by that CPU, or by wired logic hardware.

[0093] [Hardware] Next, an example of the hardware configuration of the bioreactor control device 1 will be described. Figure 9 is a diagram of an example of the hardware configuration of the bioreactor control device. As shown in Figure 9, the bioreactor control device 1 has a processor 91, memory 92, storage 93, and communication device 94. The processor 91 is connected to the memory 92, storage 93, and communication device 94 via a bus.

[0094] The communication device 94 is a network interface card or the like, and is used for communication with other information processing devices. For example, the communication device 94 relays communication between the processor 91 and the advice generation server 2. The communication device 94 also implements some of the functions of the transmitting and receiving unit 11.

[0095] Storage 93 is an auxiliary storage device. Storage 93 stores various programs, including programs for realizing the functions of the transmitting / receiving unit 11, input / output control unit 12, data conversion unit 13, control unit 14, and driving support unit 15, as illustrated in Figure 1.

[0096] The processor 91 reads various programs stored in the storage 93, loads them into the memory 92, and executes them. In this way, the processor 91 realizes the functions of the transmission / reception unit 11, the input / output control unit 12, the data conversion unit 13, the control unit 14, and the driving support unit 15.

[0097] However, although the description here assumes that the control unit 14 and the operation support unit 15 are implemented in a single computer, the control unit 14 may be a different device from the computer on which the operation support unit 15 operates, such as a PLC, recorder, or controller. For example, the bioreactor control device 1 can also be implemented with the hardware configuration shown in Figure 10. Figure 10 is a diagram of another example of the hardware configuration of the bioreactor control device. As shown in Figure 10, the bioreactor control device 1 may have a computer 95 and a controller 96. The controller 96 is connected to the computer 95 via a communication device 94.

[0098] In this case, the controller 96 implements the functions of the control unit 14. Since the control unit 14 requires long-term stability, it may be difficult to use a computer, and by using the controller 96 instead, long-term stability can be ensured. In this case, the processor 91 implements the functions of the transmitting / receiving unit 11, the input / output control unit 12, the data conversion unit 13, and the driving support unit 15.

[0099] Thus, the bioreactor control device 1 operates as an information processing device that performs various processing methods by reading and executing a program. Furthermore, the bioreactor control device 1 can also achieve the same functionality as the embodiment described above by reading the program from a recording medium using a media reader and executing the read program. It should be noted that the program referred to here is not limited to being executed by the bioreactor control device 1. For example, the present invention can be similarly applied when another computer or server executes the program, or when they collaborate to execute the program.

[0100] This program can be distributed via networks such as the Internet. Furthermore, this program can be recorded on computer-readable storage media such as hard disks, flexible disks (FDs), CD-ROMs, MO (Magneto-Optical disks), and DVDs (Digital Versatile Discs), and executed by reading the program from these media using a computer.

[0101] Some examples of the combinations of technical features that will be disclosed are listed below.

[0102] (1) A cell culture control system comprising a bioreactor for culturing cells, an analyzer for analyzing the culture state of the cells, a cell culture control device, and a cell culture control information generation device, The culture control information generation device is The system includes a culture control information generation unit that generates culture control information based on culture data obtained from the bioreactor and the analyzer, The aforementioned cell culture control device is A control unit for controlling the bioreactor, The system includes a culture control information processing unit that acquires the culture control information from the culture control information generating device and instructs the control unit to perform control on the bioreactor to proliferate the cells or extend the lifespan of the cells in accordance with the culture control information. A cell culture control system characterized by the following features. (2) The cell culture control system according to (1), characterized in that the culture control information processing unit checks whether or not to accept the culture control information, and if the culture control information is accepted, instructs the control unit to control the bioreactor according to the culture control information. (3) The cell culture control system according to (1) or (2), characterized in that the control unit collects the culture data from the bioreactor and the analyzer and transmits it to the culture control information generation device. (4) The cell culture control system according to (3), characterized in that the culture control information processing unit causes the control unit to control the bioreactor so as to increase the frequency of collecting culture data during the cell proliferation phase compared to the stationary phase and death phase. (5) The cell culture control system according to (4), characterized in that the culture control information processing unit causes the control unit to control the bioreactor to increase the frequency of collection of the culture data obtained from the bioreactor, which has an adjustable collection frequency. (6) The cell culture control system according to (4) or (5), characterized in that the culture control information generation unit limits the types of culture data used to generate culture control information. (7) The cell culture control system according to any one of (1) to (6), characterized in that the culture control information generation unit determines the proliferation phase, stationary phase, and death phase of the cells based on the culture data, and generates the culture control information so as to increase the feed rate in the order of proliferation phase, stationary phase, and death phase. (8) The cell culture control system according to (7), characterized in that the culture control information generation unit detects a decrease in the increasing trend of the viable cell density for the cells and determines the transition from the proliferation phase to the stationary phase. (9) The cell culture control system according to (7) or (8), characterized in that the culture control information generation unit determines the transition from the stationary phase to the death phase based on the viable cell density and elapsed time for the cells. (10) The cell culture control system according to (1) to (9), characterized in that the cell culture control device includes the culture control information generation device and operates in an edge computing manner. (11) In the culture control information generation device, Culture data obtained from a bioreactor for culturing cells and an analyzer for analyzing the culture state of the cells is acquired. Based on the culture data, culture control information is generated. In the cell culture control device, The culture control information is obtained from the culture control information generation device. The bioreactor is instructed to perform controls to proliferate the cells or extend the lifespan of the cells in accordance with the culture control information. A method for controlling cell culture characterized by the following features. (12) Culture data obtained from a bioreactor for culturing cells and an analyzer for analyzing the culture state of the cells is acquired. Based on the aforementioned culture data, culture control information is generated. The first computer will perform the process, The culture control information is obtained from the first computer, The bioreactor is controlled to proliferate the cells or extend the lifespan of the cells according to the culture control information. The process is then executed by a second computer. A cell culture control program characterized by the following features. [Explanation of symbols]

[0103] 1. Bioreactor control device 2. Advice generation server 3. Bioreactor 4 Analyzer 11 Transmitter / Receiver 12 Input / Output Control Unit 13. Data Conversion Unit 14 Control Unit 15. Driver Support Department 21 Transmitter / Receiver 22 storage 23 Advice Generation Unit 24 Learning Department 100 Cell Culture Control Systems 151 Advice Processing Unit 152 Advice Input Section 153 Data Input Section

Claims

1. A cell culture control system comprising a bioreactor for culturing cells, an analyzer for analyzing the culture state of the cells, a cell culture control device, and a cell culture control information generation device, The culture control information generation device is The system includes a culture control information generation unit that generates culture control information including the execution time based on the culture data obtained from the bioreactor and the analyzer, and adds the creation time. The cell culture control device is A control unit for controlling the bioreactor, The system includes a culture control information processing unit which acquires the culture control information from the culture control information generation device, checks whether new culture control information exists based on the creation time, receives an instruction to accept or reject the new culture control information if it exists, retains the new culture control information if an acceptance instruction is received, periodically checks the retained culture control information, and instructs the control unit to perform control on the bioreactor to proliferate the cells or extend the lifespan of the cells according to the culture control information that has the closest execution time to the current time among the retained culture control information after the current time. A cell culture control system characterized by the following features.

2. The cell culture control system according to claim 1, characterized in that the control unit collects the culture data from the bioreactor and the analyzer and transmits it to the culture control information generation device.

3. The cell culture control system according to claim 2, characterized in that the culture control information processing unit causes the control unit to control the bioreactor so as to increase the frequency of collecting culture data during the cell proliferation phase compared to the stationary phase and death phase.

4. The cell culture control system according to claim 3, characterized in that the culture control information processing unit causes the control unit to control the bioreactor to increase the frequency of collection of the culture data obtained from the bioreactor, which has an adjustable collection frequency.

5. The cell culture control system according to claim 3, characterized in that the culture control information generation unit limits the types of culture data used to generate culture control information.

6. The cell culture control system according to claim 1, characterized in that the culture control information generation unit determines the proliferation phase, stationary phase, and death phase of the cells based on the culture data, and generates culture control information such that the ratio of feed agent input is increased in the order of proliferation phase, stationary phase, and death phase.

7. The cell culture control system according to claim 6, characterized in that the culture control information generation unit detects a decrease in the increasing trend of the viable cell density for the cells and determines the transition from the proliferation phase to the stationary phase.

8. The cell culture control system according to claim 6, characterized in that the culture control information generation unit determines the transition from the stationary phase to the death phase based on the viable cell density and elapsed time for the cells.

9. The cell culture control system according to claim 1, characterized in that the cell culture control device includes the culture control information generation device and operates in an edge computing manner.

10. In the culture control information generation device, Culture data obtained from a bioreactor for culturing cells and an analyzer for analyzing the culture state of the cells is acquired. Based on the culture data, culture control information including the execution time is generated and the creation time is added. In the cell culture control device, The culture control information is obtained from the culture control information generation device. Based on the creation time, check whether new culture control information exists, and if new culture control information exists, receive an instruction to accept or reject the new culture control information. When an acceptance instruction is received, the new culture control information is retained. The system periodically checks the stored culture control information and instructs the bioreactor to proliferate the cells or extend the lifespan of the cells according to the culture control information that has the closest creation time to the current time among the stored culture control information after the current time. A method for controlling cell culture characterized by the following features.

11. Culture data obtained from a bioreactor for culturing cells and an analyzer for analyzing the culture state of the cells is acquired. Based on the culture data, culture control information including the execution time is generated and the creation time is added. The process is to be executed by the first computer. The culture control information is obtained from the first computer, Based on the creation time, check whether new culture control information exists, and if new culture control information exists, receive an instruction to accept or reject the new culture control information. When an acceptance instruction is received, the new culture control information is retained. The culture control information stored periodically is checked, and the bioreactor is instructed to proliferate the cells or extend the lifespan of the cells according to the culture control information that has the closest execution time to the current time among the stored culture control information after the current time. The process is to be executed by a second computer. A cell culture control program characterized by the following features.

Images