Patent Publication Number: US-2021163874-A1

Title: Program for operating cell culture support apparatus, cell culture support apparatus, and method for operating cell culture support apparatus

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation application of International Application No. PCT/JP2019/021822 filed May 31, 2019, the disclosure of which is incorporated herein by reference in its entirety. Further, this application claims priority from Japanese Patent Application No. 2018-155748 filed on Aug. 22, 2018, the disclosure of which is incorporated herein by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     1. Technical Field 
     The present disclosure relates to a program for operating a cell culture support apparatus, the cell culture support apparatus, and a method for operating the cell culture support apparatus. 
     2. Description of the Related Art 
     Cell culture for culturing cells collected from a living body has been actively performed. JP2009-044974A discloses a technique for performing a fuzzy neural network analysis on the basis of a set of indicators related to cell morphology such as a cell area and a circumference length and measured data related to cell quality such as a cell proliferation rate and the degree of differentiation, and predicting cell quality from the indicators related to the cell morphology. 
     SUMMARY 
     Cell culture requires a relatively long period of about 40 weeks. This is because, as conceptually shown in  FIG. 19 , an intermediate culture process, which requires many experiments, should be performed from a relatively small initial culture process using a petri dish or a flask having a capacity of several to several tens of milliliters to a relatively large production culture process using a tank with a capacity of several hundred to several thousand liters. For example, in the intermediate culture process, it is necessary to repeat an experiment for optimizing various parameters such as the amount of components to be added daily to a medium, a stirring rate, and an environment temperature/humidity by using cells into which an antibody gene has been introduced and a medium, selected in the initial culture process.  FIG. 19  shows a state where setting of culture conditions, culture, and evaluation are repeated until an evaluation result is OK in an initial culture process and three intermediate culture processes (intermediate culture processes 1 to 3). 
     The technique described in JP2009-044974A is configured to predict the cell quality from the indicators related to the cell morphology in one culture process such as an initial culture process. Therefore, the technique contributes to shortening one culture process, but its effect is limiting. 
     An object of the present disclosure is to provide a program for operating a cell culture support apparatus, the cell culture support apparatus, and a method for operating the cell culture support apparatus capable of significantly shortening a period from an initial culture process to a production culture process, in cell culture. 
     In order to achieve the above object, according to an aspect of the present disclosure, there is provided a program for operating a cell culture support apparatus for supporting cell culture from an initial culture process to a production culture process performed in a facility larger than the initial culture process, the program causing a computer to function as: a first acquisition unit that acquires a learned model indicating a relationship between the initial culture process and the production culture process, derived by performing machine learning on the basis of initial record data for learning including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the initial culture process, and production record data for learning, corresponding to the initial record data for learning and including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the production culture process; a second acquisition unit that acquires initial record data for analysis including a set of the culture condition data indicating the record of the culture conditions and the culture result data indicating the record of the culture results in the initial culture process, and temporary culture condition data indicating temporary culture conditions in the production culture process; and a first derivation unit that derives predicted culture result data obtained by predicting the culture result data in the production culture process, from the learned model acquired in the first acquisition unit, and the initial record data for analysis and the temporary culture condition data acquired in the second acquisition unit. 
     It is preferable that the program causes the computer to function as a first output control unit that performs a control for outputting the predicted culture result data. 
     It is preferable that in a case where a plurality of pieces of the temporary culture condition data are acquired by the second acquisition unit, the first derivation unit derives the predicted culture result data for each of the plurality of pieces of the temporary culture condition data, and selects the best temporary culture condition data having the best predicted culture result data among the plurality of pieces of the temporary culture condition data. 
     It is preferable that the program causes the computer to function as a second output control unit that performs a control for outputting the best temporary culture condition data. 
     It is preferable that the program causes the computer to function as a third acquisition unit that acquires the initial record data for learning and the production record data for learning, and a second derivation unit that derives the learned model by performing the machine learning on the basis of the initial record data for learning and the production record data for learning acquired in the third acquisition unit. 
     It is preferable that the initial culture process is a process of selecting cells into which an antibody gene has been introduced and a medium, and the production culture process is a process of producing an antibody-based medicine. 
     According to another aspect of the present disclosure, there is provided a cell culture support apparatus for supporting cell culture from an initial culture process to a production culture process performed in a facility larger than the initial culture process, the apparatus comprising: a first acquisition unit that acquires a learned model indicating a relationship between the initial culture process and the production culture process, derived by performing machine learning on the basis of initial record data for learning including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the initial culture process, and production record data for learning, corresponding to the initial record data for learning and including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the production culture process; a second acquisition unit that acquires initial record data for analysis including a set of the culture condition data indicating the record of the culture conditions and the culture result data indicating the record of the culture results in the initial culture process, and temporary culture condition data indicating temporary culture conditions in the production culture process; and a first derivation unit that derives predicted culture result data obtained by predicting the culture result data in the production culture process, from the learned model acquired in the first acquisition unit, and the initial record data for analysis and the temporary culture condition data acquired in the second acquisition unit. 
     According to still another aspect of the present disclosure, there is provided a method for operating a cell culture support apparatus for supporting cell culture from an initial culture process to a production culture process performed in a facility larger than the initial culture process, the method comprising: a first acquisition step of acquiring a learned model indicating a relationship between the initial culture process and the production culture process, derived by performing machine learning on the basis of initial record data for learning including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the initial culture process, and production record data for learning, corresponding to the initial record data for learning and including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the production culture process; a second acquisition step of acquiring initial record data for analysis including a set of the culture condition data indicating the record of the culture conditions and the culture result data indicating the record of the culture results in the initial culture process, and temporary culture condition data indicating temporary culture conditions in the production culture process; and a first derivation step of deriving predicted culture result data obtained by predicting the culture result data in the production culture process, from the learned model acquired in the first acquisition step, and the initial record data for analysis and the temporary culture condition data acquired in the second acquisition step. 
     Further, according to still another aspect of the present disclosure, there is provided a cell culture support apparatus for supporting cell culture from an initial culture process to a production culture process performed in a facility larger than the initial culture process, the apparatus comprising: a first acquisition processor that acquires a learned model indicating a relationship between the initial culture process and the production culture process, derived by performing machine learning on the basis of initial record data for learning including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the initial culture process, and production record data for learning, corresponding to the initial record data for learning and including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the production culture process; a second acquisition processor that acquires initial record data for analysis including a set of the culture condition data indicating the record of the culture conditions and the culture result data indicating the record of the culture results in the initial culture process, and temporary culture condition data indicating temporary culture conditions in the production culture process; and a first derivation processor that derives predicted culture result data obtained by predicting the culture result data in the production culture process, from the learned model acquired in the first acquisition processor, and the initial record data for analysis and the temporary culture condition data acquired in the second acquisition processor. 
     According to the present disclosure, it is possible to provide a program for operating a cell culture support apparatus, the cell culture support apparatus, and a method for operating the cell culture support apparatus capable of significantly shortening a period from the initial culture process to the production culture process, in cell culture. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Exemplary embodiments according to the technique of the present disclosure will be described in detail based on the following figures, wherein: 
         FIG. 1  is a diagram showing a cell culture system; 
         FIG. 2  is a diagram showing a request transmitted from an operator terminal to a cell culture support server and information transmitted from the cell culture support server to the operator terminal; 
         FIG. 3  is a diagram showing a request transmitted from the operator terminal to the cell culture support server; 
         FIG. 4  is a diagram showing initial record data; 
         FIG. 5  is a diagram showing production record data; 
         FIG. 6  is a block diagram showing a computer that configures the operator terminal and the cell culture support server; 
         FIG. 7  is a block diagram showing a processing unit of a CPU of the operator terminal; 
         FIG. 8  is a block diagram showing a processing unit of a CPU of the cell culture support server; 
         FIG. 9  is a diagram showing content of a learned model; 
         FIG. 10  is a diagram showing content of training data; 
         FIG. 11  is a diagram showing an input screen of a culture purpose, culture condition data and culture result data of an initial culture process, and temporary culture condition data of a production culture process; 
         FIG. 12  is a diagram showing a deriving process of predicted culture result data in a first derivation unit; 
         FIG. 13  is a diagram showing a deriving process of the best temporary culture condition data in the first derivation unit; 
         FIG. 14  is a diagram showing a guideline information display screen; 
         FIG. 15  is a diagram showing a guideline information display screen; 
         FIG. 16  is a diagram showing a state where a learned model is derived in a second derivation unit; 
         FIG. 17  is a flowchart showing a processing procedure of the cell culture support server; 
         FIG. 18  is a flowchart showing a processing procedure of the cell culture support server; and 
         FIG. 19  is a diagram showing a cell culture procedure. 
     
    
    
     DETAILED DESCRIPTION 
     In  FIG. 1 , a cell culture system  2  comprises an operator terminal  10  and a cell culture support server  11 , and is installed in one cell culture laboratory, for example. The operator terminal  10  is a terminal operated by an operator of cell culture, and is configured by a desktop personal computer, for example. The cell culture support server  11  corresponds to a cell culture support apparatus, and is configured by a server computer. The operator terminal  10  and the cell culture support server  11  are connected to each other through a network  12  such as a local area network (LAN) to communicate with each other. 
     The operator terminal  10  and the cell culture support server  11  are based on a computer such as a personal computer, a server computer, or a workstation. The operator terminal  10  and the cell culture support server  11  are configured by installing a control program such as an operating system and various application programs on such a computer. 
     In  FIG. 2 , the operator terminal  10  transmits an output request for predicted culture result data or an output request of the best temporary culture condition data to the cell culture support server  11 . The predicted culture result data is data obtained by predicting a culture result of cell culture in a production culture process of producing an antibody-based medicine in a relatively large-scale facility such as a tank having a capacity of several hundred to several thousand liters. The best temporary culture condition data is such data that the predicted culture result data is the best among a plurality of pieces of temporary culture condition data. The temporary culture condition data is data showing temporary culture conditions of cell culture in the production culture process. 
     The cell culture support server  11  receives the output request for the predicted culture result data, derives the predicted culture result data, and outputs the derived predicted culture result data to the operator terminal  10  that is an output request source. Further, the cell culture support server  11  receives the output request for the best temporary culture condition data, selects the best temporary culture condition data from the plurality of pieces of temporary culture condition data, and outputs the selected best temporary culture condition data to the operator terminal  10  that is the output request source. In the following description, unless it is necessary to distinguish between the predicted culture result data and the best temporary culture condition data, the predicted culture result data and the best temporary culture condition data are collectively referred to as guideline information. 
     The cell culture support server  11  generates a guideline information display screen  80  (see  FIGS. 14 and 15 ) that is viewable on a web browser of the operator terminal  10  as one form of an output of the guideline information, and outputs the generated guideline information display screen  80  to the operator terminal  10 . More specifically, the cell culture support server  11  outputs the guideline information display screen  80  in the form of screen data for web distribution created in a markup language such as Extensible Markup Language (XML). Instead of XML, another data description language such as JavaScript (registered trademark) Object Notation (JSON) may be used. In addition to the guideline information display screen  80 , the cell culture support server  11  outputs various screens to the operator terminal  10  in the form of screen data for web distribution. 
     In  FIG. 3 , the operator terminal  10  further transmits a registration request for initial record data (see  FIG. 4 ) and a registration request for production record data (see  FIG. 5 ) to the cell culture support server  11 . The cell culture support server  11  receives the registration request for the initial record data, and registers the initial record data. Further, the cell culture support server  11  receives the registration request for the production record data, and registers the production record data. 
     The output request for the guideline information includes the initial record data and the temporary culture condition data. Further, the registration request for the initial record data includes the initial record data, and the registration request of the production record data includes the production record data, respectively. 
     As shown in  FIG. 4 , the initial record data is a set of culture condition data X1 showing a record of culture conditions in the initial culture process and culture result data X2 showing a record of culture results obtained by performing cell culture with the culture condition data X1. Here, the initial culture process is performed prior to the production culture process, which is a process of selecting antibody gene introduced cells and a medium in a relatively small-scale facility such as a petri dish or a flask having a capacity of several to several tens of milliliters. The culture condition data X1 of the initial record data is a set of respective conditions of a plurality of processes performed in the initial culture process. Specifically, the culture condition data X1 of the initial record data includes a seed density, a temperature, a stirring rate, a medium addition amount, an air flow rate, an oxygen flow rate, a carbon dioxide flow rate, and the like. In addition, the culture result data X2 of the initial record data specifically includes a cell viability, the number of cells, the number of viable cells, a cell diameter, a hydrogen ion index (pH), an oxygen concentration, a carbon dioxide concentration, a glutamate concentration, and a lactose concentration, an ammonium concentration, a sodium ion concentration, a potassium ion concentration, an osmotic pressure, an antibody concentration, and the like. 
     As shown in  FIG. 5 , the production record data is a set of culture condition data X3 showing a record of culture conditions in the production culture process and culture result data Y showing a record of culture results obtained by performing cell culture with the culture condition data X3. The culture condition data X3 of the production record data is a set of respective conditions of a plurality of processes performed in the production culture process, similarly to the culture condition data X1 of the initial record data. The culture condition data X3 of the production record data includes a seed density, a temperature, a stirring rate, a medium addition amount, an air flow rate, an oxygen flow rate, a carbon dioxide flow rate, and the like, similar to the culture condition data X1 of the initial record data. In addition, the culture result data Y of the production record data includes a cell viability, the number of cells, the number of viable cells, a cell diameter, a hydrogen ion index (pH), an oxygen concentration, a carbon dioxide concentration, a glutamate concentration, a lactose concentration, an ammonium concentration, a sodium ion concentration, a potassium ion concentration, an osmotic pressure, an antibody concentration, and the like, similar to the culture result data X2 of the initial record data. 
     In  FIG. 6 , the computers that constitute the operator terminal  10  and the cell culture support server  11  have the same basic configuration, and each computer comprises a storage device  30 , a memory  31 , a central processing unit (CPU)  32 , a communication unit  33 , a display  34 , and an input device  35 , respectively. These components are connected to each other through a data bus  36 . 
     The storage device  30  is a hard disk drive that is built in the computer that constitutes the operator terminal  10  or the like or is connected to the computer through a cable or a network. Alternatively, the storage device  30  is a disk array in which a plurality of hard disk drives are connected in series. The storage device  30  stores a control program such as an operating system, various application programs, various types of data associated with these programs, and the like. 
     The memory  31  is a work memory used when the CPU  32  executes processing. The CPU  32  loads the program stored in the storage device  30  into the memory  31 , and executes processing according to the program, thereby comprehensively controlling the respective units of the computer. 
     The communication unit  33  is a network interface that performs a transmission control of various types of information through the network  12 . The display  34  displays various screens. Various screens are provided with an operation function by Graphical User Interface (GUI). The computer that constitutes the operator terminal  10  or the like receives an input of an operation command through the input device  35  on the various screens. The input device  35  is a keyboard, a mouse, a touch panel, or the like. 
     In the following description, a suffix “A” is assigned to each unit of the computer that configures the operator terminal  10 , and a suffix “B” is assigned to each unit of the computer that configures the cell culture support server  11 , respectively. 
     In  FIG. 7 , in a case where a web browser is activated, the CPU  32 A of the operator terminal  10  functions as a browser control unit  40  in cooperation with the memory  31 , and the like. The browser control unit  40  controls an operation of the web browser. The browser control unit  40  receives screen data of various screens from the cell culture support server  11 . The browser control unit  40  reproduces the various screens displayed on the web browser on the basis of the screen data, and displays the various screens on a display  34 A. 
     The browser control unit  40  also receives various operation commands input through the input device  35 A on the various screens. The browser control unit  40  issues various requests corresponding to the various operation commands to the cell culture support server  11 . The operation commands include a guideline information output command. In a case where the guideline information output command is received, the browser control unit  40  issues an output request for guideline information to the cell culture support server  11 . 
     In  FIG. 8 , a storage device  30 B of the cell culture support server  11  stores an operating program  45  that is an application program. The operating program  45  is an application program for causing the computer that constitutes the cell culture support server  11  to function as a cell culture support apparatus. That is, the operating program  45  is an example of a “program for operating the cell culture support apparatus” according to the technique of the present disclosure. The storage device  30 B stores a learned model  46  and training data  47  in addition to the operating program  45 . 
     In a case where the operating program  45  is activated, the CPU  32 B of the cell culture support server  11  functions as a first acquisition unit  50 , a second acquisition unit  51 , a first derivation unit  52 , an output control unit  53 , a third acquisition unit  54 , and a second derivation unit  55  in cooperation with the memory  31 , and the like. 
     In an operating phase of machine learning, the first acquisition unit  50  reads out the learned model  46  from the storage device  30 B to acquire the learned model  46 . The first acquisition unit  50  outputs the acquired learned model  46  to the first derivation unit  52 . 
     In the operating phase, the second acquisition unit  51  receives the output request for the guideline information from the operator terminal  10 . As described above, the output request for the guideline information includes the initial record data and the temporary culture condition data. For this reason, the second acquisition unit  51  acquires the initial record data and the temporary culture condition data by receiving the output request for the guideline information. The second acquisition unit  51  outputs the acquired initial record data and temporary culture condition data to the first derivation unit  52 . The initial record data acquired by the second acquisition unit  51  and output to the first derivation unit  52  is the initial record data for analysis to be analyzed by the first derivation unit  52  using the learned model  46 . 
     Further, in a learning phase of machine learning, the second acquisition unit  51  also receives the registration request for the initial record data from the operator terminal  10 . That is, the second acquisition unit  51  acquires the initial record data by receiving the registration request for the initial record data. The second acquisition unit  51  registers the acquired initial record data in the storage device  30 B as the training data  47 . The initial record data acquired by the second acquisition unit  51  and registered in the storage device  30 B is initial record data for learning. 
     Further, in the learning phase, the second acquisition unit  51  also receives the registration request for the production record data from the operator terminal  10 . That is, the second acquisition unit  51  acquires the production record data by receiving the registration request for the production record data. The second acquisition unit  51  registers the acquired production record data in the storage device  30 B as the training data  47 . The production record data acquired by the second acquisition unit  51  and registered in the storage device  30 B is the production record data for learning. 
     In the operating phase, the first derivation unit  52  derives guideline information from the learned model  46  acquired in the first acquisition unit  50 , the initial record data for analysis acquired in the second acquisition unit  51 , and the temporary culture condition data. The first derivation unit  52  outputs the derived guideline information to the output control unit  53 . 
     In the operating phase, the output control unit  53  corresponds to a first output control unit and a second output control unit, and performs a control for outputting the guideline information from the first derivation unit  52 . More specifically, the output control unit  53  generates screen data of the guideline information display screen  80  for web distribution. Then, the generated screen data of the guideline information display screen  80  is output to the operator terminal  10  that is an output request source. The output control unit  53  generates screen data of various screens other than the guideline information display screen  80 , and outputs the result to the operator terminal  10 . 
     In the learning phase, the third acquisition unit  54  reads out the training data  47  from the storage device  30 B to acquire the training data  47 . The training data  47  includes initial record data for learning and production record data for learning (see  FIG. 10 ). That is, the third acquisition unit  54  acquires the training data  47  to acquire the initial record data for learning and the production record data for learning. The third acquisition unit  54  outputs the acquired training data  47  to the second derivation unit  55 . 
     In the learning phase, the second derivation unit  55  performs machine learning on the basis of the training data  47  from the third acquisition unit  54  to derive the learned model  46 . The second derivation unit  55  registers the derived learned model  46  in the storage device  30 B. 
     The acquisition of the training data  47  in the third acquisition unit  54  and the derivation of the learned model  46  in the second derivation unit  55  are performed at preset timings such as every month. Of course, the acquisition of the training data  47  in the third acquisition unit  54  and the derivation of the learned model  46  in the second derivation unit  55  may be performed at timings commanded by the operator. 
     Further, the acquisition of the training data  47  in the third acquisition unit  54  and the derivation of the learned model  46  in the second derivation unit  55  are not performed while the number of samples of the training data  47  is smaller than a set value. In other words, the learned model  46  is derived by the second derivation unit  55  only in a case where the number of samples of the training data  47  is equal to or larger than the set value. The number of samples of the training data  47  is the number of records shown in  FIG. 10 . 
     In  FIG. 9 , the learned model  46  is derived for each culture purpose such as for medicine α or medicine β. 
     The learned model  46  sets the culture result data Y of the production culture process as an objective variable, and sets the culture condition data X1 of the initial culture process, the culture result data X2 of the initial culture process, and the culture condition data X3 of the production culture process as explanatory variables. The first derivation unit  52  inputs the initial record data for analysis from the second acquisition unit  51 , that is, the culture condition data and the culture result data in the initial culture process, and the temporary culture condition data into the learned model  46  for calculation to derive predicted culture result data. In  FIG. 9 , the learned model  46  for the medicine a is shown. Accordingly, each variable is assigned a suffix α as in “Yα”. 
     In  FIG. 10 , the training data  47  is registered for each culture purpose, similar to the learned model  46 . In the training data  47 , an area separated by a culture ID that is assigned to each cell culture from the initial culture process to the production culture process forms one record. The culture condition data X1 and the culture result data X2 in the initial culture process, that is, the initial record data for learning, and the culture condition data X3 and the culture result data Y in the production culture process, that is, the production record data for learning are registered in one record. That is, the training data  47  includes the initial record data for learning and the production record data for learning. Note that  FIG. 10  shows the training data  47  for the medicine α in a similar way to  FIG. 9 . A numeral after an underscore in each piece of data indicates a culture ID. For example, culture condition data of initial record data of a culture ID “001” is represented as “X1α_001”. 
     The initial record data for learning and the production record data for learning are input by an operator, for example, through an input screen (not shown) displayed on the display  34 A of the operator terminal  10 . The culture purpose and the culture ID are also input at this time. The input screen is generated in the output control unit  53  of the cell culture support server  11 , and is output to the operator terminal  10 . Then, the input screen is displayed on the display  34 A by the browser control unit  40  of the operator terminal  10 . 
     The input screen is provided with a send button for performing a command for transmitting the input initial record data for learning or the production record data for learning to the cell culture support server  11 . In a case where this send button is selected, the browser control unit  40  issues a registration request for the initial record data for learning or a registration request for the production record data for learning to the cell culture support server  11 . 
     The initial record data for learning is input at the end of the initial culture process, for example, and the production record data for learning is input at the end of the production culture process, for example. The culture condition data and the culture result data in an intermediate culture process between the initial culture process and the production culture process are not input, and therefore, the culture condition data and the culture result data in the intermediate culture process are not registered in the training data  47 . 
       FIG. 11  shows an example of an input screen  60  for performing an output request for guideline information, which is displayed on the display  34 A of the operator terminal  10 . The input screen  60  is generated in the output control unit  53  of the cell culture support server  11 , and is output to the operator terminal  10 . Then, the input screen  60  is displayed on the display  34 A by the browser control unit  40  of the operator terminal  10 . 
     A first area  61 , a second area  62 , a third area  63 , a fourth area  64 , and an OK button  65  are provided on the input screen  60 . An input box  66  for the culture purpose is input to the first area  61 , an input box  67  for the culture condition data X1 in the initial culture process is input to the second area  62 , an input box  68  for the culture result data X2 in the initial culture process is input to the third area  63 , and an input box  69  for the temporary culture condition data in the production culture process is input to the fourth area  64 . As shown in  FIGS. 4 and 5 , the reason why the plurality of input boxes  67  to  69  are respectively prepared is that there are a plurality of types of data in the culture condition data X1 in the initial culture process, the culture result data X2 in the initial culture process, and the culture result data Y in the production culture process, respectively. 
     A reference button  70  is provided next to the second area  62 . The reference button  70  is selected in a case where it is necessary to input the culture condition data X1 in the initial culture process, which has been requested to be registered in advance and has already been registered in the training data  47 , in the input box  67 . In a case where the reference button  70  is selected, the culture condition data X1 in the initial culture process registered in the training data  47  is displayed in a list on the input screen  60  together with the culture ID, and the like. The operator selects the culture condition data X1 in the initial culture process to be input from the list. Then, the selected culture condition data X1 in the initial culture process is read out from the training data  47 , and is input to the input box  67 . 
     A reference button  71  is also provided next to the third area  63 . The reference button  71  is also selected in a case where it is necessary to input the culture result data X2 in the initial culture process that has already been registered in the training data  47  to the input box  68 , similarly to the reference button  70 . 
     A data set button  72  is provided next to the fourth area  64 . The data set button  72  is selected in a case where a plurality of pieces of preset temporary culture condition data are input as the temporary culture condition data. The plurality of pieces of temporary culture condition data are, for example, five pieces of data in which the temperature among the culture condition data in the production culture process is changed in steps of 2.5° C. and the remaining data except for the temperature is the same. Alternatively, the plurality of pieces of temporary culture condition data are 10 pieces of data in which values of certain 3 types of data among the culture condition data in the production culture process are randomly changed and values of data other than the certain 3 types of data are the same. The plurality of pieces of temporary culture condition data may be fixed, or may be configured so that the operator can change their settings. In addition, the plurality of pieces of temporary culture condition data may be set on the basis of design of experiments. 
     The culture purpose is input to the input box  66 , the culture condition data X1 in the initial culture process is input to the input box  67 , the culture result data X2 in the initial culture process is input to the input box  68 , and the temporary culture condition data in the production culture process is input to the input box  69 , and then, the OK button  65  is selected. In this case, the browser control unit  40  issues an output request for predicted culture result data to the cell culture support server  11 . 
     The culture purpose is input to the input box  66 , the culture condition data X1 in the initial culture process is input to the input box  67 , the culture result data X2 in the initial culture process is input to the input box  68 , and then, the data set button  72  is selected and the OK button  65  is selected. In this case, the browser control unit  40  issues an output request for the best temporary culture condition data to the cell culture support server  11 . 
       FIGS. 12 and 13  are diagrams showing a guideline information deriving process in the first derivation unit  52 .  FIG. 12  shows a deriving process of the predicted culture result data, and  FIG. 13  shows a deriving process of the best temporary culture condition data. 
       FIG. 12  shows a case where the medicine α is input to the input box  66  for the culture purpose, culture condition data X1α_010 in the initial culture process is input to the input box  67 , culture result data X2α_010 in the initial culture process is input to the input box  68 , and temporary culture condition data PX3α in the production culture process is input to the input box  69 . In this case, the first derivation unit  52  inputs the culture condition data X1α_010 in the initial culture process, the culture result data X2α_010 in the initial culture process, and the temporary culture condition data PX3α to Yα=F (X1α, X2α, X3α), which is the learned model  46  for the medicine a, for calculation. As a result, predicted culture result data RYα is obtained. The first derivation unit  52  outputs the predicted culture result data RYα to the output control unit  53  as guideline information. 
       FIG. 13  shows a case where the medicine α is input to the input box  66  for the culture purpose, the culture condition data X1α_010 in the initial culture process is input to the input box  67 , and the culture result data X2α_010 in the initial culture process is input to the input box  68 , similarly to  FIG. 12 . However,  FIG. 13  shows a case where the data set button  72  is selected and a total of five pieces of temporary culture condition data of preset 1_PX3α, 2_PX3α, . . . , and 5_PX3α are input. In this case, the first derivation unit  52  derives predicted culture result data for each of the temporary culture condition data 1_PX3α to 5_PX3α. More specifically, the first derivation unit  52  inputs the culture condition data X1α_010 in the initial culture process, the culture result data X2α_010 in the initial culture process, and the temporary culture condition data 1_PX3α to Yα=F (X1α, X2α, X3α), which is the learned model  46  for the medicine α, for calculation. As a result, predicted culture result data 1_RYα is obtained. Similarly, the first derivation unit  52  inputs the temporary culture condition data 2_PX3α for calculation to obtain predicted culture result data 2_RYα, . . . , and inputs the temporary culture condition data 5_PX3α for calculation to obtain predicted culture result data 5_RYα. Here, the notation of “ . . . ” including that in the figures means omission. 
     Subsequently, the first derivation unit  52  selects the best temporary culture condition data PX3αBEST having the best predicted culture result data from the temporary culture condition data 1_PX3α to 5_PX3α.  FIG. 13  shows a case where the predicted culture result data 2_RYα is the best among the obtained predicted culture result data 1_RYα to 5_RYα and the temporary culture condition data 2_PX3α is selected as the best temporary culture condition data PX3αBEST. To give a more specific example, the first derivation unit  52  obtains the antibody concentration as the predicted culture result data RY, and selects the temporary culture condition data PX3 having the highest antibody concentration as the best temporary culture condition data PX3BEST. The first derivation unit  52  outputs the best temporary culture condition data 2_PX3α to the output control unit  53  as guideline information. 
       FIGS. 14 and 15  show examples of the guideline information display screen  80  displayed on the display  34 A of the operator terminal  10 . The guideline information display screen  80  is generated in the output control unit  53  of the cell culture support server  11 , and is output to the operator terminal  10 . Then, the guideline information display screen  80  is displayed on the display  34 A by the browser control unit  40  of the operator terminal  10 . The display of the guideline information display screen  80  disappears in a case where the OK button  81  is selected. 
     The guideline information display screen  80  shown in  FIG. 14  is an example in which the predicted culture result data RYα (here, the antibody concentration) is displayed as the guideline information. More specifically, a sentence “In a case where the culture conditions in the production culture process are input conditions, the antibody concentration in the production culture process is predicted to be 150 mg/ml” is displayed as guideline information. In the sentence, “150 mg/ml” is the predicted culture result data RYα. 
     The guideline information display screen  80  shown in  FIG. 15  is an example in which the best temporary culture condition data PX3αBEST is displayed as guideline information. More specifically, a sentence “The best culture result in the production culture process among the temporary culture conditions 1 to 5 is a temporary culture condition 2.” is displayed as guideline information. In the sentence, the “temporary culture condition 2” is the best temporary culture condition data PX3αBEST. On the guideline information display screen  80  shown in  FIG. 15 , in addition to the best temporary culture condition data PX3BEST, the predicted culture result data RY in the case of the best temporary culture condition data PX3BEST may be displayed. In addition, for example, by displaying a plurality of pieces of temporary culture condition data PX3 and its predicted culture result data RY in a list, and displaying the best temporary culture condition data PX3BEST in a shaded manner, the display may be performed to be distinguished from display of other temporary culture condition data PX3. 
     A detail button  82  for displaying details of guideline information is provided on the guideline information display screen  80 . In a case where the detail button  82  is selected on the guideline information display screen  80  shown in  FIG. 14 , detailed content and the like of the temporary culture condition data PX3α input through the input screen  60  are displayed. In a case where the detail button  82  is selected on the guideline information display screen  80  shown in  FIG. 15 , detailed content and the like of the best temporary culture condition data PX3αBEST are displayed. 
     As shown in  FIG. 16 , the second derivation unit  55  uses a neural network  90  as a machine learning method for deriving the learned model  46 , for example. The neural network  90  includes an input layer, a plurality of intermediate layers (hidden layers), and an output layer, as shown as an example. The neural network  90  is an estimation model for simulating the culture result data Y in the production culture process from the culture condition data X1 in the initial culture process, the culture result data X2 in the initial culture process, and the culture condition data X3 in the production culture process. A set of the culture condition data X1 in the initial culture process, the culture result data X2 in the initial culture process, and the culture condition data X3 in the production culture process is input to the input layer of the neural network  90 . The culture result data Y in the production culture process corresponding to the above data set input to the input layer is output to the output layer of the neural network  90 . 
     The second derivation unit  55  causes the neural network  90  to perform learning using the training data  47  according to a backpropagation method as an example of machine learning. Specifically, the second derivation unit  55  inputs the set of the culture condition data X1 in the initial culture process, the culture result data X2 in the initial culture process, and the culture condition data X3 in the production culture process included in one record of the training data  47  to the neural network  90 , and outputs the culture result data Y in the production culture process from the neural network  90 . Then, the second derivation unit  55  causes the neural network  90  to perform learning so that a difference between the culture result data Y in the production culture process output to the neural network  90  and the culture result data Y in the actual production culture process registered in the training data  47  is minimized. 
     An output value of the neural network  90  is, for example, a sum of output values output by respective nodes of respective layers according to an input value. Each node in the input layer, the intermediate layers, and the output layer is assigned a weight with respect to an input value. For example, each node is set to have a threshold value to be compared with the input value. In this case, in each node, the input value to each node is compared with the threshold value, and an output value of “0” or “1” is output according to the comparison result. In addition, a sigmoid function may be set for each node. In this case, the output value changes between “0” and “1” according to the input value. A coefficient of the threshold value or the sigmoid function for each node may be given as the weight for the input value input to each node. 
     The second derivation unit  55  changes the weight of the node so that the difference between the culture result data Y in the production culture process output to the neural network  90  and the culture result data Y in the actual production culture process registered in the training data  47  is minimized. The second derivation unit  55  registers the neural network  90  adjusted so that the above difference is minimized by changing the weights of the nodes in this way in the storage device  30 B as the learned model  46 . 
     Hereinafter, an operation based on the above configuration will be described with reference to flowcharts of  FIGS. 17 and 18 .  FIG. 17  shows an operating phase of machine learning, and  FIG. 18  shows a learning phase of the machine learning. 
     First, as shown in  FIG. 17 , in the cell culture support server  11 , the learned model  46  is read out from the storage device  30 B to the first acquisition unit  50 , so that the learned model  46  is acquired by the first acquisition unit  50  (step ST 100 , a first acquisition step). The learned model  46  is output from the first acquisition unit  50  to the first derivation unit  52 . 
     In the operator terminal  10 , the input screen  60  shown in  FIG. 11  is displayed on the display  34 A by the browser control unit  40 . Then, the culture purpose, the culture condition data X1 in the initial culture process, the culture result data X2 in the initial culture process, and the temporary culture condition data PX3 in the production culture process are input through the input screen  60 . Each input data is transmitted to the cell culture support server  11  as an output request for guideline information. Thus, the second acquisition unit  51  acquires the culture condition data X1 in the initial culture process, the culture result data X2 in the initial culture process, that is, initial record data for analysis, and the temporary culture condition data PX3 in the production culture process (step ST 110 , a second acquisition step). Each data is output from the second acquisition unit  51  to the first derivation unit  52 . 
     In the first derivation unit  52 , as shown in  FIGS. 12 and 13 , the predicted culture result data RY is derived (step ST 120 , a first derivation step). More specifically, the predicted culture result data RY is derived by inputting each data into the learned model  46  for calculation. The predicted culture result data RY is output from the first derivation unit  52  to the output control unit  53 . 
     In a case where there are a plurality of pieces of temporary culture condition data PX3 acquired in step ST 110  (YES in Step ST 130 ), the first derivation unit  52  selects the best temporary culture condition data PX3BEST as shown in  FIG. 13  (step ST 140 ). More specifically, in step ST 120 , the predicted culture result data RY is derived for each of the plurality of pieces of temporary culture condition data PX3, and the best temporary culture condition data PX3BEST is selected from the plurality of pieces of temporary culture condition data PX3. The best temporary culture condition data PX3BEST is output from the first derivation unit  52  to the output control unit  53 . 
     In the output control unit  53 , screen data of the guideline information display screen  80  shown in  FIGS. 14 and 15  is generated. The screen data of the guideline information display screen  80  is output to the operator terminal  10  that is an output request source by the output control unit  53  (Step ST 150 ). 
     In the operator terminal  10 , the guideline information display screen  80  from the cell culture support server  11  is displayed on the display  34 A by the browser control unit  40 . The operator browses the guideline information displayed on the guideline information display screen  80 , and performs the culture work according to the guideline information. For example, in a case where the guideline information display screen  80  shown in  FIG. 15  is displayed, the operator starts the production culture process under the temporary culture condition 2. 
     The predicted culture result data RY in the production culture process is derived by the first derivation unit  52  using the learned model  46  showing a relationship between the initial culture process and the production culture process, and using the culture condition data X1 in the initial culture process, the culture result data X2 in the initial culture process, and the temporary culture condition data PX3. Accordingly, it is possible to predict a culture result in the production culture process without data in an intermediate culture process. Accordingly, it is possible to save an effort for carrying out the intermediate culture process, and thus, to significantly reduce a period from the initial culture process to the production culture process in the cell culture. 
     Since the predicted culture result data RY is output by the output control unit  53  to be provided to an operator for viewing, it is possible for the operator to easily know what the predicted culture result data RY will be in the temporary culture condition data PX3 input by the operator. 
     In a case where a plurality of pieces of temporary culture condition data PX3 are acquired by the second acquisition unit  51 , the first derivation unit  52  derives the predicted culture result data RY for each of the plurality of pieces of temporary culture condition data PX3, and selects the best temporary culture condition data PX3BEST from the plurality of pieces of temporary culture condition data PX3. Accordingly, it is possible for the operator to easily know the best temporary culture condition data PX3BEST. Further, in a case where the culture conditions in the production culture process are set according to the best temporary culture condition data PX3BEST, relatively good culture result data Y is promised, and thus, medicine production efficiency is also improved. 
     As shown in  FIG. 18 , in the cell culture support server  11 , the training data  47  is read out from the storage device  30 B to the third acquisition unit  54  at a preset timing, so that the training data  47  is acquired by the third acquisition unit  54  (step ST 200 ). The training data  47  is output from the third acquisition unit  54  to the second derivation unit  55 . 
     In the second derivation unit  55 , as shown in  FIG. 16 , the neural network  90  performs learning by the training data  47 , and thus, the learned model  46  is derived (step ST 210 ). The learned model  46  is registered in the storage device  30 B by the second derivation unit  55  (step ST 220 ). 
     In this way, since the third acquisition unit  54  acquires the training data  47  and the second derivation unit  55  derives the learned model  46  on the basis of the training data  47 , it is possible to update the learned model  46  according to the training data  47  that is constantly updated. Further, it is possible to save an effort for providing the learned model  46  from another computer. 
     In the above embodiment, an example in which the learned model  46  and the training data  47  are registered in the storage device  30 B of the cell culture support server  11  is shown, but the present disclosure is not limited thereto. A configuration in which the learned model  46  and the training data  47  are registered in a database server different from the cell culture support server  11  and the learned model  46  and the training data  47  are transmitted from the database server to the cell culture support server  11  may be used. 
     In the above embodiment, an example in which various screens such as the guideline information display screen  80  are output from the output control unit  53  to the operator terminal  10  in the form of screen data for web distribution is shown, but the present disclosure is not limited thereto. A configuration in which an application program for displaying various screens is installed in the operator terminal  10  and a command for instructing the application program to display various screens is output from the output control unit  53  may be used. 
     The output form of the guideline information is not limited to the guideline information display screen  80  of the above embodiment. The guideline information may be printed by a printer connected to the operator terminal  10 , or a file indicating the guideline information may be transmitted to the operator terminal  10  by e-mail. 
     The machine learning method is not limited to the neural network  90 . Other methods such as a regression tree or a classification tree may be used. 
     In the above embodiment, an example in which the initial culture process is a process of selecting cells into which an antibody gene has been introduced and a medium and the production culture process is a process of producing an antibody-based medicine is shown, but the present disclosure limited thereto. As long as the production culture process is at least a process performed in a facility larger than the initial culture process, the present disclosure may be applied. 
     Various modifications may be made to the hardware configuration of the computer that configures the cell culture support server  11 . For example, the cell culture support server  11  may be configured of a plurality of server computers separated as hardware for the purpose of improving processing capacity and reliability. Specifically, the functions of the first acquisition unit  50 , the second acquisition unit  51 , the first derivation unit  52 , and the output control unit  53 , the functions of the third acquisition unit  54  and the second derivation unit  55  may be assigned to two server computers in a distributed manner. In this case, the cell culture support server  11  is configured by two server computers. 
     In the above embodiment, the output control of the predicted culture result data RY and the output control of the best temporary culture condition data PX3BEST are assigned to one output control unit  53 , but the present disclosure is not limited to thereto. A configuration in which a first output control unit that performs a control for outputting the predicted culture result data RY and a second output control unit that performs a control for outputting the best temporary culture condition data PX3BEST are dividedly provided may be used. 
     Further, a configuration in which the operating program  45  is installed in the operator terminal  10 , each processing unit built in the cell culture support server  11  in the above embodiment is built in the operator terminal  10 , and the operator terminal  10  is operated as the cell culture support apparatus may be used. 
     In this way, the hardware configuration of the computer may be appropriately modified according to necessary performance such as processing capacity, security, and reliability. Further, as well as the hardware, the application program such as the operating program  45  may be duplicated or stored in a plurality of storage devices in a distributed manner for the purpose of ensuring security and reliability. 
     In the above embodiment, a configuration in which the cell culture support server  11  is installed and used in one cell culture laboratory is shown, but a configuration in which the cell culture support server  11  is used in a plurality of cell culture laboratories may be used. In order to make the cell culture support server  11  available in a plurality of cell culture laboratories, the cell culture support server  11  is connected to a plurality of operator terminals  10  installed in the plurality of cell culture laboratories through a wide area network (WAN) such as the Internet or a public communication network in a communicable manner. Then, the cell culture support server  11  receives an output request from each operator terminal  10  through the WAN, and outputs guideline information to each operator terminal  10 . In this case, an installation location and an operating party of the cell culture support server  11  may be, for example, a data center operated by a company other than the cell culture laboratories, or one of the plurality of cell culture laboratories. 
     In the above embodiment, for example, as a hardware structure of processing units that execute various processes, such as the first acquisition unit  50 , the second acquisition unit  51 , the first derivation unit  52 , the output control unit  53 , the third acquisition unit  54 , and the second derivation unit  55 , the following various processors may be used. As described above, in addition to the CPU  32 B that is a general-purpose processor that executes software (operating program  45 ) to function as various processing units, various processors include a programmable logic device (PLD) that is a processor of which a circuit configuration is changeable after manufacturing, such as a field programmable gate array (FPGA), a dedicated electrical circuit that is a processor having a circuit configuration specifically designed to execute a specific process, such as an application specific integrated circuit (ASIC), or the like. 
     One processing unit may be configured by one of these various processors, or may be configured by a combination of two or more processors of the same type or different types (for example, a combination of a plurality of FPGAs and/or a combination of a CPU and an FPGA). Further, a plurality of processing units may be configured by one processor. 
     As an example in which the plurality of processing units is configured by one processor, first, as represented by a computer such as a client and a server, there is a configuration in which one processor is configured by a combination of one or more CPUs and software and the processor functions as a plurality of processing units. Secondly, as represented by a system on chip (SoC) or the like, there is a configuration in which a processor that realizes the functions of the entire system including a plurality of processing units by one integrated circuit (IC) chip is used. As described above, the various processing units are configured using one or more of the above various processors as a hardware structure. 
     Further, as a hardware structure of these various processors, more specifically, electric circuitry in which circuit elements such as semiconductor elements are combined may be used. 
     From the above description, the disclosure described in Supplementary note 1 below can be understood. 
     [Supplementary Note 1] 
     A cell culture support apparatus for supporting cell culture from an initial culture process to a production culture process performed in a facility larger than the initial culture process, the apparatus comprising: a first acquisition processor that acquires a learned model indicating a relationship between the initial culture process and the production culture process, derived by performing machine learning on the basis of initial record data for learning including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the initial culture process, and production record data for learning, corresponding to the initial record data for learning and including a set of culture condition data indicating a record of culture conditions and culture result data indicating a record of culture results in the production culture process; a second acquisition processor that acquires initial record data for analysis including a set of the culture condition data indicating the record of the culture conditions and the culture result data indicating the record of the culture results in the initial culture process, and temporary culture condition data indicating temporary culture conditions in the production culture process; and a first derivation processor that derives predicted culture result data obtained by predicting the culture result data in the production culture process, from the learned model acquired in the first acquisition processor, and the initial record data for analysis and the temporary culture condition data acquired in the second acquisition processor. 
     The technique of the present disclosure may be appropriately combined with the above-described various embodiments and various modifications. Further, it is needless to say that the above embodiments are not limiting and various configurations may be adopted within a scope without departing from the concept of the present disclosure. Furthermore, the technique of the present disclosure extends to a storage medium that stores the program in a non-temporary manner, in addition to the program. 
     The above-described content and the above-illustrated content are detailed descriptions of portions related to the technique of the present disclosure, which are merely an example of the technique of the present disclosure. For example, the description of the above configurations, functions, operations, and effects is an example of description of configurations, functions, operations, and effects of portions related to the technique of the present disclosure. Therefore, within the scope without departing from the concept of the technique of the present disclosure, unnecessary portions may be removed, new elements may be added or replaced for the above-described content and the above-illustrated content. In addition, in order to avoid complication and facilitate understanding of the portions related to the technique of the present disclosure, in the above-described content and the above-illustrated content, description of common knowledge or the like that does not need special explanation in implementing the technique of the present disclosure is omitted. 
     In the present specification, “A and/or B” is synonymous with “at least one of A or B”. That is, “A and/or B” may refer to only A, only B, or a combination of A and B. In addition, in the present specification, the same concept as “A and/or B” is also applied to a case where three or more matters are linked by “and/or”. 
     All documents, patent applications and technical standards disclosed in this specification are incorporated in this specification by reference in such a manner that the incorporation by reference of individual document, patent application and technical standard are handled to the same extent as in specific and individual description thereof