Process development assistance system and process development assistance method

Abstract

Provided is a process development assistance system capable of creating a small-scale experimental condition based on a culture condition specific to a large-scale experiment even when experimental data on a large scale is insufficient. A process development assistance system (S) according to the present invention comprises: a calculation unit (41) that, on the basis of experimental data that includes information relating to the amount of change in a plurality of parameters obtained by subjecting a culture target to an culture experiment in a first-scale culture facility under a first culture condition, and second-scale facility information that includes information on at least the shape of a second-scale culture facility that is larger than the first-scale culture facility, simulates the case where the culture target is cultured in the second-scale culture facility under a second culture condition, and outputs condition range information indicating the relationship between the second culture condition and the plurality of parameters on the basis of a result of the simulation; and a planning unit (42) that, on the basis of these, outputs a culture condition for the culture experiment in the first-scale culture facility.

Description

Process development support system and process development support method

[0001] The present invention relates to a process development support system and a process development support method.

[0002] In the context of SDGs, climate change issues, and the realization of carbon neutrality, there is a need to balance sustainable economic growth with the resolution of social issues. In the field of manufacturing, the need for alternatives to petroleum products is growing, and with the advancement of biotechnology, attention is being paid to biomanufacturing (production of materials using microorganisms, etc.) that makes maximum use of biological functions such as smart cells.

[0003] The starting point for the industrialization of biomanufacturing is the development of microorganisms that maximize the biological functions of the organisms themselves, such as by creating smart cells. After that, it is necessary to develop a process to determine the culture conditions and scale-up technology to industrialize the cultivation in fermentors exceeding several thousand liters.

[0004] In particular, in process development, after selecting microorganisms capable of producing a substance, small-scale experiments at the level of a few mL to a few liters are conducted to determine the culture conditions for production. Here, it is necessary to identify the requirements for the culture medium, oxygen supply, and culture environment for production. For this reason, optimal culture conditions are derived by combining multiple conditions and ranges for controllable parameters.

[0005] However, because the number of combinations is enormous, in consideration of time and cost, culture conditions are generally searched for within a very limited range of combinations based on empirical data. Therefore, in some cases, a computer is used to efficiently search for optimal culture conditions for the large number of combinations. Related prior art includes the technology described in Patent Document 1.

[0006] Patent Document 1 discloses a "cell culture process exploration method including a process condition generating step of generating a plurality of process conditions for culturing cells, a culture result predicting step of acquiring a predicted result of cell culture for each of the plurality of process conditions generated in the process condition generating step, and an optimized process condition acquiring step of finding optimal process conditions from the predicted culture results acquired in the culture result predicting step."

[0007] Furthermore, the culture conditions obtained in small-scale experiments are then used to confirm productivity in large-scale fermentors with capacities of hundreds or even thousands of liters. In particular, scaling up typically involves maintaining similar geometric shapes and maintaining constant operating parameters, such as input power, through chemical engineering calculations. However, this approach alone can result in insufficient microbial performance and reduced productivity. Therefore, engineers rely on their past experience to perform intuitive tuning and adjustments, such as controlling oxygen supply and agitation speed. However, this process requires time and effort, and the cause often remains unclear. Furthermore, productivity declines without a clearly defined cause, requiring repeated small-scale experiments for verification, which not only increases the number of large-scale experiments but also significantly increases the time required.

[0008] Furthermore, even when similar conditions are used, the culture conditions obtained by combining a limited range of small-scale conditions can vary depending on the conditions in the culture tank and the scale. As a result, large-scale conditions may not be reflected, resulting in a loss of productivity. Therefore, technologies have been developed to improve the efficiency of the cycle of feedback between small-scale and large-scale results. Related prior art includes the technology described in Patent Document 2.

[0009] Patent Document 2 discloses a computer-implemented method for designing first-scale experiments for an organism to generate first-scale performance data for use in predicting the performance of the organism at a larger second scale, the method comprising: a. determining first-scale screening conditions based at least in part on the contribution of second-scale conditions to performance parameters of a first strain of the organism at the second scale, wherein the first-scale screening conditions include one or more surrogates for second-scale conditions that cannot be reproduced at the first scale; b. determining first-scale screening parameters based at least in part on computer modeling of the organism's metabolism at the second scale; and c. designing experiments for experimentally screening a second strain of the organism under the first-scale screening conditions based at least in part on the first-scale screening parameters.

[0010] International Publication No. 2021 / 166824 Special Publication No. 2022-531464

[0011] Data on culture conditions determined solely from small-scale experiments at the level of a few mL to a few liters can result in uncertain conditions and unexpected constraints that cannot be reproduced in the subsequent scale-up of large-scale fermentors to hundreds or thousands of liters or more. If these conditions are not taken into account, productivity cannot be achieved at the large scale, and a great deal of time and effort is required to reexamine the small-scale experiments. Therefore, to efficiently develop a scale-up process, it is desirable to conduct culture experiments while taking into account conditions specific to large scales that differ from small scales. However, conducting experiments to test various culture conditions at large scales requires significant time and expense for process development, and specialized equipment is required. Therefore, it has been difficult to obtain sufficient experimental data at large scales.

[0012] Therefore, in order to make scale-up studies more efficient, a system is desired that can create small-scale experimental conditions that take into account the specific culture conditions at a large scale, such as being able to compare the differences in behavior of the same parameters at a small scale and a large scale, even when there is a lack of large-scale experimental data.

[0013] The present invention has been made in view of the above circumstances, and an object of the present invention is to provide a process development support system and a process development support method that are capable of creating small-scale experimental conditions that take into account specific large-scale culture conditions, even when large-scale experimental data is insufficient.

[0014] The process development support system of the present invention, which solves the above-mentioned problems, comprises: a memory unit that stores experimental data including information on the amount of change in multiple parameters indicating the state within a first-scale culture facility when a culture experiment is conducted on a culture target under first culture conditions in the first-scale culture facility; and second-scale equipment information, which is information on equipment conditions including at least shape information on second-scale culture facility that is larger than the first-scale culture facility; a calculation unit that performs a simulation on the amount of change in parameters that are the same as the multiple parameters when the culture target is cultured under second culture conditions in the second-scale culture facility based on the experimental data and the second-scale equipment information, and outputs condition range information, which is information indicating the relationship between the second culture conditions and the multiple parameters, based on the results of the simulation; and a planning unit that outputs the culture conditions for the culture experiment in the first-scale culture facility based on the experimental data and the condition range information.

[0015] The present invention provides a process development support system and a process development support method that can create small-scale experimental conditions that take into account the specific culture conditions of large-scale experiments, even when large-scale experimental data is insufficient. Problems, configurations, and effects other than those described above will become clear from the description of the following embodiments.

[0016] FIG. 1 is a configuration diagram of a process development support system according to an embodiment of the present invention. FIG. 1 is an explanatory diagram illustrating an example of the principle of a small-scale experimental condition search program. FIG. 2 is an explanatory diagram illustrating another example of the principle of a small-scale experimental condition search program. FIG. 3 is an explanatory diagram illustrating another example of the principle of a small-scale experimental condition search program. FIG. 4 is an explanatory diagram illustrating another example of the principle of a small-scale experimental condition search program. FIG. 5 is an explanatory diagram illustrating recommending a more preferable first-scale experimental range. FIG. 6 is an explanatory diagram illustrating a solution concept in the process development support system according to an embodiment of the present invention. FIG. 7 is an explanatory diagram illustrating an example in which a calculation unit outputs information about equipment that meets first-scale experiment recommendation conditions. FIG. 8 is an explanatory diagram illustrating an example in which a calculation unit outputs information about equipment that meets second-scale experiment recommendation conditions. FIG. 9 is a flowchart illustrating an example of a culture equipment matching program. FIG. 10 is a flowchart illustrating the contents of a process development support method according to an embodiment of the present invention. FIG. 11 is a flowchart illustrating a specific example of the process development support method according to an embodiment of the present invention.

[0017] Hereinafter, an embodiment of the present invention will be described in detail with reference to the accompanying drawings. In the following description, the same components will be designated by the same terms and symbols, and duplicate descriptions will be omitted.

[0018] In the following embodiment, an example in which the process development support system S according to the present embodiment is applied to process development for scaling up a culture process currently being performed on a small scale (referred to as a first scale) to a large scale (referred to as a second scale) will be mainly described. However, the embodiment of the process development support system S according to the present embodiment is not limited to this example. For example, the process development support system S according to the present embodiment can be applied to the case where the culture target is not limited to a specific organism, but is also applicable to the case where microorganisms, cells, fungi, etc. are cultured. The first scale is at least smaller in capacity than the second scale to be scaled up. Although the capacity is not particularly limited, if the purpose is to obtain culture conditions through experiments, the first scale may be a laboratory-level scale. The first scale is preferably a scale of several mL to several tens of liters because it is easy to handle and to conduct multiple experiments. Furthermore, the equipment specifications of the first scale are preferably similar to those of the second scale, but do not necessarily have to be the same, and commonly used fermenter tanks and equipment may be used. On the other hand, the second scale may be a bench, pilot, or production scale. The second scale may be, for example, a scale of several tens of liters to several tens of thousands of liters. In this embodiment, the first scale and the second scale do not indicate a capacity of a certain fixed value, but indicate a capacity within a range having a predetermined width.

[0019] 1 is a configuration diagram of a process development support system S according to this embodiment. The process development support system S according to this embodiment is embodied as a management server 1, as an example. The management server 1 is a computer having a communication interface 2, a storage unit 3, a control unit 4, a memory 5, an input unit 6, and an output device 7. The communication interface 2 communicates with other servers other than the management server 1, user terminals, and culture equipment.

[0020] The memory unit 3 stores various information such as experimental data, equipment information, condition range information, experimental design information, past information, first equipment information, second equipment information, and a matching database (DB). The memory unit 3 also stores various programs such as a simulation program, a small-scale experimental condition search program, and a culture equipment matching program, which will be described later. The control unit 4 is, for example, a CPU (Central Processing Unit), and realizes various functions by reading and executing the programs stored in the memory unit 3. In this embodiment, the various functions include a calculation unit 41 and a planning unit 42, which will be described later. In this embodiment, the various functions also include an extraction unit 43 and a proposal output unit 44, which will be described later.

[0021] Note that the programs and various functions do not necessarily have a one-to-one correspondence. The process of reading and executing a single program may correspond to two or more different functions, or the process of reading and executing two or more programs may correspond to a single function. Therefore, in this embodiment, the calculation unit 41, planning unit 42, extraction unit 43, proposal output unit 44, etc. are shown as components corresponding to the functions realized by the control unit 4, but each function is realized by reading and executing one or more programs from among the simulation program, small-scale experimental condition search program, and culture equipment matching program. Furthermore, the classification of functions or programs in this embodiment is merely an example and is not limited to this example.

[0022] The memory 5 is a random access memory, a read-only memory, etc. The input unit 6 is a keyboard, a pointing device, etc. The output device 7 is a display, a printer, etc. The input unit 6 and the output device 7 are direct input / output interfaces with the management server 1.

[0023] The specific roles of the storage unit 3, the calculation unit 41, and the planning unit 42 in this embodiment are as follows.

[0024] The memory unit 3 stores experimental data and second-scale equipment information. The experimental data is experimental data obtained by culturing a culture target in a first-scale culture facility. The experimental data includes information regarding the amount of change in multiple parameters that indicate the state within the first-scale culture facility when a culture experiment is conducted on the culture target under first culture conditions in the first-scale culture facility. The first culture conditions refer to the culture conditions when culturing a culture target in the first-scale culture facility.

[0025] The experimental data may include information on the organism to be cultured, information on the culture environment including control information for the culture equipment, and information on the product produced by the organism to be cultured. Representative examples of items included in the information on the organism to be cultured include the type of organism, its characteristics, number of passages, seeding density, etc. These items can be used as culture conditions when culturing the organism to be cultured in the first-scale culture equipment.

[0026] Representative examples of items included in the information on the culture environment, including the control information of the culture equipment, include, for example, the amount of aeration, the number of stirring revolutions, pressure, bubble information, temperature, pH, dissolved oxygen (DO) concentration, and dissolved carbon dioxide (DCO ２ ) concentration, medium concentration and additive information, and liquid volume. The set values ​​for these items can be used as the culture conditions when culturing the culture target in the first-scale culture equipment. In addition, the information on the actual values ​​obtained in experiments for these items can be used as information on the amount of change in multiple parameters that indicate the state within the first-scale culture equipment.

[0027] Typical examples of items included in the information on the product produced by the organism to be cultured include the results of the cultured product and the amounts of various metabolic components. These items can also be used as information on the amount of change in multiple parameters that indicate the state within the first-scale culture facility. However, the parameter items used as experimental data are not limited to these.

[0028] The equipment information is information on equipment conditions including at least shape information on the culture equipment. The equipment information includes at least second-scale equipment information. The second-scale equipment information is information on equipment conditions including at least shape information on second-scale culture equipment that is larger than the first-scale culture equipment.

[0029] The culture equipment includes, in addition to the culture tank, equipment for supplying the culture medium, an aeration device for supplying air and oxygen, an agitator for stirring the inside of the tank, and various control devices for controlling the pH and oxygen concentration. Equipment conditions including at least shape information related to the culture equipment include, for example, the capacity of the culture tank and its aspect ratio, the tank diameter-to-impeller diameter ratio, the shape of the agitator impeller, and other incidental equipment information. The equipment information may also be information in the form of a drawing that comprehensively includes the above information.

[0030] The matching DB stores information on candidate culture tanks or culture devices corresponding to second-scale culture facilities. The matching DB stores information on the candidate culture tanks or culture devices, such as specifications, name, manufacturer, provider, base, location, cost of use, usage history, usage status, and peripheral equipment. The specification information also includes, for the culture tank or culture device, the chassis for cultivation, product, tank capacity, and equipment specifications.

[0031] The past information is information for identifying the type and range of parameters that affect the degree to which the culture result satisfies a predetermined standard. The past information is, for example, information on past performance data of the culture process at the first scale or the second scale. Based on the performance data, the type and range of parameters that affect the degree to which the culture result satisfies a predetermined standard can be extracted. This extraction can be performed by analyzing and evaluating the relationship between each parameter and an index of the culture result using techniques such as machine learning or statistical methods. Existing clustering analysis techniques may also be used. The past information may also be information from literature on the culture process, in addition to performance data of the culture process. The past information may also store information on important parameters that may be importantly involved in the purpose of the culture or the process development of the culture, or information indicating a specific range of such parameters, which are already known as knowledge. The past information may also be information obtained from an external server using the communication interface 2. Other information and programs will be described later.

[0032] The items stored in the storage unit 3 are not limited to the various information and data described above. The storage unit 3 can accumulate, for example, information on the first-scale culture facility and culture experiment data in the second-scale culture facility obtained after the process development support system S according to this embodiment is implemented. In this embodiment, the necessary data may be stored in the storage unit 3 of the management server 1, or may be stored in a distributed manner in multiple servers connected via a network.

[0033] The calculation unit 41 performs a simulation based on the first-scale experimental data and the second-scale equipment information regarding the amount of change in the same parameters as the above-mentioned multiple parameters when the culture target is cultured under second culture conditions in the second-scale culture equipment. The calculation unit 41 then outputs condition range information, which is information indicating the relationship between the second culture conditions and the multiple parameters, based on the results of the simulation. The second culture conditions refer to the culture conditions when the culture target is cultured in the second-scale culture equipment.

[0034] The condition range information is information created by the simulation program, i.e., the calculation unit 41. The condition range information is information indicating the relationship between the culture conditions (second culture conditions) and various parameters that may affect the culture in the second-scale culture equipment. The condition range information may be information indicating the behavior of various parameters that may affect the culture when the second culture conditions are changed in the second-scale culture equipment. The condition range information may be information indicating the range of values ​​that various parameters can take in the second-scale culture equipment. Here, the second culture conditions may be any experimental conditions that can be simulated in the simulation. Examples of the culture conditions include initial conditions such as viscosity and various concentrations, temperature setting values, pH setting values, rotation speed, and aeration conditions. Examples of the various parameters that may affect the culture include the flow rate distribution in the culture tank, shear stress distribution, temperature change amount, pH change amount, oxygen supply rate, DO concentration, and DCO ２ These include concentration, heat transfer, mass transfer, and gas dispersion.

[0035] Furthermore, the condition range information may include information on values ​​that various parameters can take for each culture condition. This information allows calculation of information on the degree of influence that the culture conditions have on changes in various parameters. The degree of influence that the culture conditions have on changes in various parameters may be specified as a plurality of evaluation levels. In this case, the greater the influence that a change in the culture conditions has on the various parameters, the greater the degree of influence is specified. As an example, the degree of influence that the culture conditions have on changes in various parameters is quantitatively calculated based on information on the rate at which the various parameters change when the culture conditions are changed by a predetermined rate. The degree of influence that the culture conditions have on changes in various parameters may be a value calculated for each type of parameter.

[0036] The planning unit 42 outputs the culture conditions (experimental planning information) for the culture experiment in the first-scale culture facility based on the experimental data and the condition range information. The culture conditions output here can be used as the first culture conditions for the next culture experiment in the first-scale culture facility.

[0037] The experimental design information is information created by the small-scale experimental condition search program, i.e., the planning unit 42. The experimental design information is information regarding an experimental plan for a first-scale culture facility that is necessary for process development for culturing a culture target in a second-scale culture facility. The experimental design information can assist in creating an experimental plan for the first-scale culture facility. The experimental design information may be in any format that suits the culture system, process system, and management form. The experimental design information may be, for example, information indicating the range of values ​​that should be set for parameters that can be set in the first-scale culture facility. The experimental design information may also include information regarding the culture conditions, experimental procedures, and experimental methods of a specific culture experiment.

[0038] The planning unit 42 can also output information for recommending culture equipment to be used at the first scale. In this case, information related to the experimental procedure and experimental method associated with the culture equipment to be used at the first scale may also be output. The planning unit 42 may also output information related to candidate culture equipment to be used as culture equipment at the second scale after scale-up.

[0039] The simulation program is a program for simulating the behavior of various parameters (called secondary parameters) when culturing is performed in the second-scale culturing equipment, based on predetermined culturing conditions and information on the second-scale culturing equipment (called primary parameters). The simulation program can be executed by the calculation unit 41. For example, a commonly used fluid dynamics (CFD) simulation can be used as the simulation program.

[0040] For the simulation that estimates the parameter changes of the second culture conditions from the first-scale experimental data and the second-scale equipment information, for example, chemical engineering calculations and fluid analysis can be used. Primary parameters include, for example, operating conditions such as the agitation speed, aeration rate, and volume, and equipment setting conditions such as the shape of the agitator blades and the aspect ratio of the tank. Secondary parameters calculated based on these include, for example, shear stress, DO concentration, and DCO ２ Gas-liquid volume such as concentration, velocity, energy, mixing time, product / substrate concentration distribution, flow rate distribution, Kolmogorov scale, foaming, carbon dioxide partial pressure (pCO ２ ), pH distribution, etc., and it is desirable for the simulation results to show the state of these distributions. The behavior of the aforementioned secondary parameters can be simulated using commonly used fluid analysis techniques based on the information on the aforementioned primary parameters. From these, the relationship between the parameters and the culture conditions can be shown, and condition range information for each parameter can be extracted, acquired, and output. A simulation using a simulation program can reveal, for example, that there are situations in which the DO concentration distribution in a second-scale culture facility is between 1 and 5 mg / L.

[0041] The small-scale experimental condition search program is a program for creating experimental planning information for a first-scale culture facility required for process development for culturing a culture target in a second-scale culture facility based on the results of a simulation by the simulation program. The small-scale experimental condition search program can be executed by the planning unit 42. An example of the principle of the small-scale experimental condition search program will be described later.

[0042] The small-scale experimental condition search program analyzes the difference between the behavior of a plurality of parameters that may affect the culture results in the first-scale culture equipment and the behavior of a second-scale culture equipment based on the condition range information. The small-scale experimental condition search program also extracts important parameters that should be noted when scaling up the target process based on the analysis results. The small-scale experimental condition search program may also use the information on the extracted important parameters to create recommendation information regarding experimental planning. Important parameters are parameters or specific ranges of such parameters that may be important in culturing the purpose of the culture or the process of culturing process development.

[0043] The small-scale experimental condition search program outputs parameters that can be directly set in the first-scale culture equipment. The small-scale experimental condition search program can also output culture conditions (new first culture conditions) through operations such as chemical engineering calculations to convert the parameters to be considered in the first scale. The small-scale experimental condition search program particularly outputs ranges for changing the setting values ​​of multiple operating condition items.

[0044] The small-scale experimental condition search program can output information on items not significantly reflected in the experimental data, items not considered, and important parameters to be considered in the second-scale culture equipment based on the condition range information, based on the first-scale experimental data and the acquired condition range information. Furthermore, the small-scale experimental condition search program can utilize clustering analysis, etc., when extracting important parameters, etc. Clustering analysis is preferably performed, for example, on new experimental data obtained by conducting a culture experiment under the newly output culture conditions (first culture conditions) of the culture experiment in the first-scale culture equipment. Clustering analysis is preferably performed repeatedly each time new experimental data is obtained. Performing clustering analysis in this manner can improve the accuracy of the experimental design information for the first-scale culture equipment.

[0045] Furthermore, the small-scale experimental condition search program not only outputs the culture conditions to be considered for culture experiments using first-scale culture equipment and sets the range of those conditions, but also proposes and recommends the conditions for the culture equipment required to obtain those conditions. For example, if there is a concentration distribution of the substrate, it is possible to propose equipment that can reproduce that concentration distribution. This also includes proposing the shape of the stirring blades.

[0046] The small-scale experimental condition search program can further propose and recommend conditions for the second-scale culture equipment required to minimize items with large distributions and highly influential parameters when taking into account the important parameters and condition range information.The small-scale experimental condition search program can propose and recommend, for example, the shape of the culture tank, the stirring blades used in the culture tank, the stirring conditions, and the aeration device conditions for the bubble diameter.The small-scale experimental condition search program can also propose information on the recommended culture equipment (first-scale culture equipment) based on culture equipment information stored in the memory unit 3, etc.In addition, when recommending equipment, it is preferable that the installation location, operating status, usage history, etc. be indicated in addition to equipment information and specifications.

[0047] Next, an example of the principle of a small-scale experimental condition search program will be described with reference to Figures 2A to 2D. Figures 2A to 2D are explanatory diagrams illustrating an example of the principle of a small-scale experimental condition search program. As described above, the small-scale experimental condition search program extracts important parameters. Important parameters are parameters that may be importantly involved in the purpose of the culture or the process of culture process development, or specific ranges of such parameters. There are several extraction methods for identifying important parameters, and some of the details of these methods will be described as an example of the principle of a small-scale experimental condition search program, but the methods are not limited to the following methods.

[0048] [1] Extraction by Scale Difference: As shown in FIG. 2A , if the analyzed parameter X, Y in the second-scale culture equipment analysis distribution range (second-scale analysis distribution range 2A1) is not included in the initial range of experimental conditions for the first-scale culture equipment (initial first-scale experimental range 2A2), the planning unit 42 can extract the parameter in that range or the parameters in that range as important parameters. Alternatively, if the proportion of the analysis distribution range in the second-scale culture equipment that is not included in the initial range of experimental conditions for the first-scale culture equipment is greater than a predetermined threshold, the parameter may be extracted as an important parameter. This allows parameters whose second-scale analysis distribution range 2A1 significantly deviates from the initial first-scale experimental range 2A2 to be recognized as important parameters in the culture process development. The predetermined threshold may be arbitrarily selected for each parameter. The initial first-scale experimental range 2A2 and the second-scale analysis distribution range 2A1 are also the recommended first-scale experimental ranges.

[0049] Furthermore, the influence of each parameter on the culture process development may be evaluated. Here, the influence on the culture process development may be calculated based on information about the proportion of the second scale analysis distribution range 2A1 that is not included in the initial first scale experimental range 2A2. As an example, the influence may be a relative value of the variation range of the second scale analysis distribution range 2A1 that is not included in the initial first scale experimental range 2A2, where the variation range of the initial first scale experimental range 2A2 is set to 1. In this case, the larger the relative value, the greater the influence on the culture process development is evaluated to be. This allows parameters whose second scale analysis distribution range 2A1 is significantly different from the initial first scale experimental range 2A2 to be recognized as having a large influence on the culture process development.

[0050] [2] Extraction from a Hardware Perspective As shown in FIG. 2B , when the planning unit 42 analyzes the second scale for the parameters X and Y of a parameter candidate and finds that the input experimental conditions (first-scale input experimental conditions 2B1) for the first-scale culture equipment cannot be realized in the second-scale culture equipment (a range 2B2 that is difficult to control in the second scale), the planning unit 42 can extract parameters that fall within the range 2B2 or parameters within the range 2B2 as important parameters. Alternatively, if the proportion of the range of the first-scale input experimental conditions 2B1 that cannot be realized in the second-scale culture equipment is greater than a predetermined threshold, the parameter may be extracted as an important parameter. This allows parameters that have a large overlap between the initial first-scale experimental range and the range that cannot be used in the second scale to be recognized as important parameters in the culture process development. In this case, the planning unit 42 can also specify a recommended first experimental range (second-scale analysis distribution range 2B3) by excluding the range 2B2 that is difficult to control in the second scale.

[0051] The planning unit 42 may also be configured to evaluate the influence of each parameter on the culture process development. Here, the influence on the culture process development may be calculated based on information regarding the proportion of the range of the first-scale Input experimental conditions 2B1 that cannot be realized with the second-scale culture equipment. In this case, the greater the proportion, the greater the influence on the culture process development is evaluated to be. This allows parameters that have a large overlap between the initial first-scale experimental range and the range that cannot be used in the second scale to be recognized as having a large influence on the culture process development.

[0052] In this embodiment, as additional configurations for improving accuracy, "extraction as past information" and "extraction from additional consideration" as described below may be added.

[0053] [3] Extraction as Past Information As shown in FIG. 2C , the planning unit 42 can extract, based on past information stored in the memory unit 3, parameters and parameter ranges previously considered important for the first-scale input experimental conditions 2C1 for the candidate parameters X and Y. These parameters can be extracted from information that may be specifically affected by the input culture object. That is, these parameters can be extracted as a range 2C2 that is affected by performance in a first-scale experiment or as a range that is considered affected by past information. Furthermore, it is also possible to check necessary information from commonly used literature, etc. for this past information. It is also possible to arbitrarily input information about important parameters that are previously known as past information into the memory unit 3. In particular, it is desirable to extract the affected parameters from past information, such as the information about the important parameters, when the conditions for the affected parameters are similar to the input experimental conditions for the first-scale culture equipment. It is desirable to allow the degree of similarity to be freely selectable. As mentioned above, extracting parameters and parameter ranges that have been considered important in the past and considering them as information on the order or priority when creating an experimental plan for the first scale can contribute to improving the efficiency of experiments at the first scale.

[0054] [4] Extraction from Additional Studies: As shown in FIG. 2D , the planning unit 42 can recommend additional experiments in advance, if necessary, based on the past information stored in the memory unit 3 if the number of parameters and related information in the input first-scale Input experimental conditions 2D1 are insufficient compared to previous studies. It is desirable to allow the planning unit 42 to select these conditions arbitrarily. Furthermore, experiments to measure the degree of influence or to identify influencing factors can be conducted as needed based on the above information, such as past information and scale differences, and these can also be recommended. These experiments can include experiments (experiments in the first-scale initial experimental range 2D2) with a wider range of experimental conditions (the second-scale analysis distribution range and the first recommended experimental range). This allows for the re-extraction of important parameters. Furthermore, if it is difficult to identify potentially influential parameters, it is possible to analyze culture components from experiments that have or may have an influence, derive differences using techniques such as machine learning or statistical methods, and extract them as important parameters. Furthermore, important parameters can be estimated or derived from information such as the metabolic pathways of the target culture. Important parameters can be extracted by adding this information to the memory unit 3 and the planning unit 42.

[0055] In this embodiment, the above [1] to [4] can be applied in appropriate combination. This makes it possible to more appropriately grasp which range should be tested in the first-scale culture equipment when considering the second-scale culture equipment. In other words, it is possible to recommend a more preferable first-scale experimental range. Here, FIG. 2E is an explanatory diagram for explaining how to recommend a more preferable first-scale experimental range. Note that FIG. 2E shows an example in which all of the above [1] to [4] are applied.

[0056] As shown in FIG. 2E , if the analyzed parameter candidate parameters X and Y in the second-scale culture equipment (second-scale analysis distribution range) include a range 2E2 that is not included in the initial experimental condition range of the first-scale culture equipment (initial first-scale experimental range 2E1), the planning unit 42 recognizes that the range 2E2 includes important parameters and extracts them. Furthermore, if the analysis of the analyzed parameter candidate parameters X and Y in the second scale reveals conditions (a range 2E4 that is difficult to control at the second scale) that cannot be realized in the second-scale culture equipment under the first-scale input experimental conditions 2E3 as a result of the analysis of the analyzed parameter candidate parameters X and Y in the second scale, the planning unit 42 extracts the range 2E4 as important parameters. Furthermore, for the parameter candidate parameters X and Y, the planning unit 42 can extract parameters previously considered important in the memory unit 3 for the first-scale input experimental conditions 2E3 (e.g., a range 2E5 that is significantly affected by performance in experiments at the first scale or a range 2E6 that is considered to be affected based on past information) as important parameters. Furthermore, the planning unit 42 can recommend an additional experiment in advance as necessary if the number of parameters and information thereof in the input first-scale Input experimental conditions 2E3 are insufficient compared to past studies. Such additional experiments can include increasing the number of samples in the first-scale Input experimental conditions 2E3, as well as experiments within the experimental condition range (experiments within the recommended culture condition range 2E7 that are not included in the ranges 2E1, 2E2, and 2E4 to 2E6).

[0057] 3 is an explanatory diagram illustrating the solution concept of the process development support system S according to this embodiment. As shown in Fig. 3, the process development support system S according to this embodiment can input first-scale experimental data when culturing a culture target at a first scale and equipment information for a scaled-up second scale, and output recommended first-scale experimental conditions required in process development for culturing a culture target in second-scale culture equipment.

[0058] Specifically, the calculation unit 41 performs chemical engineering calculations, simulations, and other analyses of the culture environment at the second scale based on the input information. Examples of input information related to the experimental data at the first scale include initial conditions such as the host, biological characteristics, viscosity, various concentrations, and equipment information, as well as operating conditions such as temperature, pH, DO concentration, stirring rotation, pressure, aeration, and additives. Examples of input information related to equipment information at the second scale include capacity, aspect ratio, blade tank ratio, ancillary equipment, drawings, and various control conditions.

[0059] Based on these, the planning unit 42 analyzes the difference between the behavior at the first scale and the behavior at the second scale for multiple parameters that may affect the culture results. This analysis outputs the state of the culture equipment at the second scale, such as temperature, pH, DO concentration, distribution of metabolites, flow force, shear force, etc. Examples of the state of the culture equipment at the second scale include temperature: 0 to 0, pH: 0 to 0, DO concentration: 0 to 0, target substance concentration: 0 to 0, shear force: 0 to 0, etc.

[0060] Based on the analysis results, the planning unit 42 then performs differential analysis on important parameters that should be considered when scaling up the target process, and extracts them, for example, as described above in [1] to [4]. Using the extracted important parameter information, the planning unit 42 creates recommended information regarding recommended conditions for a first-scale experiment (newly output first culture conditions) and outputs them as output information to the output device 7. Examples of recommended conditions for a first-scale experiment include temperature: 0 to 0, pH: 0 to 0, DO concentration: 0 to 0, concentrations of various components: 0 to 0, and impeller rotation speed: 0 to 0. In this case, the first culture conditions can be derived from the important parameter information by, for example, performing conversion based on a chemical engineering theoretical formula (theoretical model) that shows the relationship between various parameters and variables of the culture conditions. Alternatively, the first culture conditions can be derived from parameter information based on information regarding the correspondence between culture conditions and parameters included in the condition range information. As an example, in a method for deriving first culture conditions from the state of the second-scale culture equipment, shear force is determined from the specifications of the agitator, which are composed of the shape of the agitator blades and the rotation speed, from a chemical engineering perspective. If there is a range of shear force culture conditions in the second-scale culture equipment, for example, the rotation speed of the agitator in the first-scale culture equipment can be found from the shape of the agitator blades in the first-scale culture equipment based on the possible values ​​of the shear force. This rotation speed condition can be output as the recommended condition for the first-scale experiment.

[0061] When outputting recommendation information regarding the recommended conditions for a first-scale experiment, the planning unit 42 can output priority information for the first culture conditions or information about the importance of the first culture conditions based on information regarding the magnitude of the influence of various parameters when culturing a culture target in a second-scale culture facility output by the planning unit 42. As an example, an experiment using culture conditions corresponding to parameters evaluated to have a high influence may be determined to have a high priority, and information about the priority of the culture conditions may be output together with the information about the culture conditions. Also, as another example, a culture condition corresponding to a parameter evaluated to have a high influence may be determined to have a high influence, and information about the influence of the culture condition may be output together with the information about the culture conditions.

[0062] In this way, the process development support system S according to this embodiment can perform experiments in the first-scale culture facility taking into consideration the culture conditions specific to the second-scale culture facility. As a result, even without experimental data information from the second-scale culture facility, the process development support system S according to this embodiment can almost completely eliminate uncertain conditions that cannot be reproduced and unexpected constraints, thereby preventing a decrease in productivity at the second scale due to the culture facility.

[0063] (Preferred Aspects) Preferred aspects of the process development support system S according to the present embodiment described above will be described below.

[0064] (Aspect 1) The first culture conditions preferably include information on set values ​​for a plurality of operating conditions (culture conditions) for controlling the first-scale culture equipment. Furthermore, the planning unit 42 preferably outputs a range for changing the set values ​​in the culture experiment based on experimental data and condition range information. In other words, the input and output values ​​of the process development support system S are preferably set values ​​for the operating conditions (culture conditions). Here, the method for outputting the range for changing the set values ​​of the culture conditions in the culture experiment can be performed using the aforementioned method for extracting important parameters and the method for deriving the first culture conditions from information on the important parameters. In this way, the possible ranges of the primary parameters (explanatory variables) of the culture experiment in the first-scale culture equipment can be determined, allowing the calculation unit 41 and the planning unit 42 to more appropriately create an experimental plan for the first-scale culture equipment.

[0065] (Aspect 2) The planning unit 42 preferably outputs information regarding the magnitude of the influence when culturing the culture target in the second-scale culture equipment, based on information regarding the plurality of parameters included in the experimental data and information regarding the plurality of parameters included in the condition range information. The information regarding the magnitude of the influence when culturing the culture target in the second-scale culture equipment may be information regarding the influence of the various parameters described above. In this manner, secondary parameters (similar to primary parameters in this aspect) that are important when culturing in the second-scale culture equipment can be identified, which is expected to enable more optimal culturing when actually culturing in the second-scale culture equipment.

[0066] (Aspect 3) The memory unit 3 preferably stores first equipment information related to multiple candidates for first-scale culture equipment. The first equipment information may store, for example, information related to equipment conditions, including at least shape information related to the first-scale culture equipment, similar to the items included in the equipment information. Furthermore, the first equipment information may also store information related to the specifications of the first-scale culture equipment, such as the name, manufacturer, provider, base, location, cost of use, usage history, usage status, and peripheral equipment. The first equipment information may also be information related to equipment specifications in multiple standard formats. Furthermore, the planning unit 42 preferably outputs information related to the culture equipment to be used in the culture experiment, which is included in the first equipment information. The information related to the culture equipment to be used in the culture experiment, which is included in the first equipment information, may be information related to equipment conditions that meet the first-scale experiment recommendation conditions.

[0067] 4 is an explanatory diagram illustrating an example in which the planning unit 42 outputs information about equipment that meets first-scale experiment recommendation conditions. As shown in FIG. 4, when conditions (first-scale experiment recommendation conditions) are input from the input unit 6, the planning unit 42 performs analysis based on the first equipment information. The first-scale experiment recommendation conditions may be information output by the planning unit 42. Examples of first-scale experiment recommendation conditions include temperature, pH, DO concentration, metabolite concentration, and stirring / flow conditions.

[0068] Based on the analysis results, the planning unit 42 outputs information about equipment suitable for the first-scale experiment recommendation conditions as equipment conditions for the culture experiment in the first-scale culture facility. Examples of the output equipment conditions include concentration distribution experiment: equipment A, stirring condition experiment: agitator B, oxygen condition experiment: aeration device C, and toxicity test experiment: equipment D. In this way, the planning unit 42 can output information about multiple candidate equipment that meets the first-scale experiment recommendation conditions. When the memory unit 3 and the planning unit 42 perform these processes, it is possible to appropriately recommend culture facilities to be used for the first-scale culture experiment.

[0069] (Aspect 4) The memory unit 3 preferably stores second equipment information regarding multiple candidates for second-scale culture equipment. The second equipment information may store, for example, information regarding equipment conditions, including at least shape information, similar to the items included in the equipment information. Furthermore, the second equipment information may also store information such as the name, manufacturer, provider, base, location, usage costs, usage history, usage status, and peripheral equipment, in addition to the specifications of the second-scale culture equipment. The second equipment information may also be information regarding equipment specifications in multiple standard formats. Furthermore, the planning unit 42 preferably outputs information regarding candidates for second-scale culture equipment based on information regarding the ranges and behaviors of the same parameters as the multiple parameters, information regarding important parameters that require attention when scaling up the process to be cultured (i.e., important parameters in process development for scaling up from first-scale culture equipment to second-scale culture equipment), and the second equipment information. The information regarding candidates for second-scale culture equipment may be equipment conditions that meet the second-scale experiment recommendation conditions.

[0070] FIG. 5 is an explanatory diagram illustrating an example in which the planning unit 42 outputs information about equipment that meets second-scale experiment recommendation conditions. As shown in FIG. 5 , when conditions (second-scale experiment recommendation conditions) are input from the input unit 6, the planning unit 42 performs analysis based on the second equipment information. Examples of second-scale experiment recommendation conditions include temperature, pH, DO concentration, metabolite concentration, and agitation flow conditions. The planning unit 42 may output the second-scale experiment recommendation conditions required for input along with the first-scale experiment recommendation conditions. In this case, the second-scale experiment recommendation conditions may be information about the second-scale culture equipment conditions required to minimize items with high distributions and highly influential parameters based on important parameters and condition range information. In this case, the output information includes, for example, the shape of the culture tank, the agitator blades used in the culture tank, the agitation conditions, and the aeration device conditions for the bubble diameter.

[0071] Based on the analysis results and the second equipment information, the planning unit 42 outputs information about equipment suitable for the second-scale experiment recommendation conditions as equipment conditions for the second-scale culture equipment. Examples of the output equipment conditions include culture tank capacity: 0-0, aspect ratio: 0-0, agitator specifications: 0-0, impeller diameter / tank diameter ratio: 0-0, various equipment ancillary equipment conditions, and various control device conditions. The planning unit 42 may also output information about candidate second-scale culture equipment based on the specifications, name, manufacturer, provider, base, location, cost of use, usage history, usage status, or peripheral equipment information of the culture equipment included in the second equipment information, along with the equipment conditions suitable for the second-scale experiment recommendation conditions. In this way, the planning unit 42 can output information about multiple candidate equipment suitable for the second-scale experiment recommendation conditions. When the memory unit 3 and the planning unit 42 perform these processes, a culture equipment to be used for the second-scale culture experiment can be suitably recommended.

[0072] (Aspect 5) The first culture condition is preferably at least one of viscosity, concentration of various components, temperature, pH, DO concentration, agitation rotation speed, aeration volume, and pressure. When the first culture condition is selected from these, a culture experiment using the first-scale culture equipment can be suitably carried out.

[0073] (Aspect 6) The equipment conditions are preferably at least one of the aspect ratio of the culture tank, an aeration device, an agitator, a pH adjustment device, and a control device for controlling the dissolved oxygen concentration, and their specifications. When the equipment conditions are selected from these, cultivation using the second-scale culture equipment can be carried out favorably. This can also be provided as useful information for matching, which will be described later. Examples of pH adjustment equipment include a device for adding acidic or alkaline chemicals.

[0074] (Aspect 7) The calculation unit 41 preferably simulates the behavior of various parameters when culturing is performed in the second-scale culture equipment based on the second culture conditions and the second-scale equipment information. Furthermore, the various parameters are preferably at least one of shear force and DO concentration. When the calculation unit 41 performs the above processing and the various parameters are selected from the above, this can be suitably performed when culturing in the second-scale culture equipment.

[0075] (Aspect 8) In the production of useful substances by fermentation using microorganisms, only those who own the culture tank can carry out the cultivation. Furthermore, the holder often holds information about the culture tank. Furthermore, while the holder of the culture tank may provide the culture tank through a contract business, the contractor or user does not have detailed information about the culture tank, making it difficult to determine whether the culture tank is suitable for the desired cultivation conditions. Furthermore, there is a lack of information about available periods and appropriate culture tanks, leading to a haphazard search. Meanwhile, those who own culture tanks have varying utilization rates, and the tanks are sometimes idle during periods of inactivity, resulting in maintenance costs. Therefore, if a user who wants to use second-scale cultivation equipment could be matched with a provider of second-scale cultivation equipment (the aforementioned holder), it would be more efficient to cultivate using the second-scale cultivation equipment.

[0076] Therefore, the process development support system S according to this embodiment preferably includes a database storing information on candidate second-scale culture equipment and information on the specifications and use of each candidate. The information on candidate second-scale culture equipment may include information such as the name, provider, base, and location of each candidate culture tank or culture device corresponding to the second-scale culture equipment. The specification information on candidate second-scale culture equipment may include information on the product of the culture equipment, information on the equipment specifications such as the culture chassis and tank capacity, etc. The information on the use of candidate second-scale culture equipment may include information on costs, usage history, usage status, reservation status, or peripheral equipment. Furthermore, the equipment specification information may further include the aspect ratio of the culture tank, the tank diameter-to-impeller diameter ratio, the shape of the agitator blades, and other information on ancillary equipment. This embodiment utilizes this information to more accurately predict candidate culture equipment suitable for the user's desired conditions. Information in this database may be obtained from an external server via the communication interface 2. Furthermore, the aforementioned database may be stored in the storage unit 3 as a matching DB.

[0077] Furthermore, the process development support system S according to this embodiment preferably includes an input unit 6 into which the conditions of the second-scale culture equipment are input. For example, the user inputs information regarding the specifications of the culture tank or culture apparatus corresponding to the second-scale culture equipment that the user wishes to use. As another example, the user can input at least one of the specifications of the culture tank or culture apparatus corresponding to the second-scale culture equipment that the user wishes to use, information regarding the overview of the product, etc., and the functions of the culture tank or culture apparatus. The functions of the culture tank or culture apparatus may be information regarding a specific function in controlling culture in the culture tank or culture apparatus, or information regarding related ancillary equipment. In addition to the above, conditions regarding information regarding the use of the culture equipment may also be input.

[0078] Furthermore, the process development support system S according to this embodiment preferably includes an extraction unit 43 that extracts one or more candidates for second-scale culture equipment that are related to the conditions entered in the input unit 6 from among the candidates for second-scale culture equipment based on the information entered in the input unit 6 and the information stored in the database. As an example, one or more similar culture tanks or culture devices may be extracted from the information stored in the database based on the chassis, product, and tank capacity information entered in the input unit 6. This allows the present embodiment to accurately extract candidates for culture equipment that meet the user's desired conditions. To accurately execute the processing by the extraction unit 43, items in the information regarding the specifications and use of the candidate second-scale culture equipment stored in the database may be configured to correspond to items in the conditions for the second-scale culture equipment entered in the input unit 6. Here, the respective items do not necessarily have to correspond one-to-one; an item on one side may correspond to two or more items on the other side. Alternatively, a table defining this correspondence may be further stored in the database, and the extraction unit 43 may execute processing based on the information in the table.

[0079] The process development support system S according to this embodiment preferably includes a proposal output unit 44 that proposes the culture equipment candidates extracted by the extraction unit 43 and information on the use of each of the candidates. Multiple culture equipment candidates may be proposed. Furthermore, information on the available schedule of the culture tank or culture device, which is the culture equipment candidate, may be proposed as the information on use. Here, the available schedule information may be identified from information on the usage history, usage status, reservation status, etc. in the database. Information on the similarity between the conditions of the second-scale culture equipment input into the input unit 6 and the candidate may be output together with the culture equipment candidate. The similarity information may be represented by a predetermined index. For example, such an index may be calculated by comparing items in the conditions of the second-scale culture equipment input into the input unit 6 with corresponding items in the specifications and usage information of the second-scale culture equipment candidate stored in the database, and calculating the number of items that satisfy the conditions. Furthermore, information on the past usage status of the conditions of the second-scale culture equipment input into the input unit 6 may be output together with the culture equipment candidate. This configuration can assist the user in selecting second-scale culture equipment. The extraction unit 43 and the proposal output unit 44 can be realized by the control unit 4 executing a program (culture facility matching program) that performs these functions.

[0080] In this aspect, one or more available second-scale culture facilities can be extracted and proposed based on information such as the use of the culture tank contained in the database and the content entered by the user. In other words, this aspect can provide a matching system that matches users who want to use a culture tank with providers who provide culture tanks or culture devices to the users. This allows this aspect to improve the efficiency of culturing in second-scale culture facilities. In other words, this aspect can solve the problem of providing a matching system that matches users who want to use a culture tank with providers who provide culture tanks or culture devices to the users, as well as the problem of improving the efficiency of culturing in second-scale culture facilities. Furthermore, this aspect can propose an optimal culture tank while knowing the specifications and available time of the culture tank, allowing the user to use the optimal culture tank. Furthermore, this also reduces vacant space for culture tank owners, leading to development in the bioproduction field.

[0081] An example of using the present invention in a solution for matching culture vessels will be described. As an example, the database stores information on second-scale culture equipment candidates owned by one or more vendors (owners / providers) capable of providing second-scale culture equipment, as well as information on the specifications and usage of each of the candidates, acquired via the communication interface 2. Information on the second-scale culture equipment desired by a cell owner (user) who wishes to use a second-scale culture vessel is input to the input unit 6. After executing the processing of the extraction unit 43 described above, the proposal output unit 44 may be configured to output, to a screen for the cell owner's administrator, information on the culture equipment candidates extracted by the extraction unit 43, information on the owners of each of the candidates, and information on the usage of each of the candidates.

[0082] An example of such a process development support system S includes a database (storage unit 3) that stores information on second-scale culture equipment candidates owned by one or more vendors that can provide second-scale culture equipment, obtained via a communication interface 2, and information on the specifications and usage of each of the candidates; an input unit 6 into which conditions for second-scale culture equipment related to a cell owner who wishes to use the second-scale culture equipment are input; an extraction unit 43 that extracts one or more culture equipment candidates related to the conditions input into the input unit 6 from the second-scale culture equipment candidates based on the information input into the input unit 6 and the information stored in the database; and a proposal output unit 44 that outputs information on the culture equipment candidates extracted by the extraction unit 43, information on the owners of each of the candidates, and information on the usage of each of the candidates on a screen for the cell owner's administrator.

[0083] FIG. 6 is a flowchart illustrating an example of a culture equipment matching program. As shown in FIG. 6, equipment condition information is stored in the storage unit 3. Examples of the equipment condition information include specifications of the culture equipment, such as culture tank capacity: 0 to 0, aspect ratio: 0 to 0, agitator specifications: 0 to 0, impeller diameter / tank diameter ratio: 0 to 0, various equipment ancillary conditions, and various control device conditions. In addition to the above, the equipment condition information may also include the usage history and usage status of the culture equipment.

[0084] In addition, the user inputs proposed equipment conditions from the input unit 6. The proposed equipment conditions include, similar to the equipment condition information, specifications of the culture equipment such as culture tank capacity: 0 to 0, aspect ratio: 0 to 0, agitator specifications: 0 to 0, impeller diameter / tank diameter ratio: 0 to 0, various equipment ancillary equipment conditions, and various control device conditions. In addition to the above, the proposed equipment conditions may also include an overview and functions of the culture equipment.

[0085] The culture equipment matching program analyzes the equipment condition proposals and the equipment condition information and determines their similarity. The culture equipment matching program (extraction unit 43) then extracts similar culture equipment and lists them in descending order of similarity. The culture equipment matching program (proposal output unit 44) then proposes the extracted and listed equipment conditions (culture tanks or culture equipment) and their available periods. The listed equipment conditions can be presented, for example, as Recommendation 1: Equipment A, Recommendation 2: Equipment B, Recommendation 3: Equipment C, etc. Furthermore, the user can be presented with information such as the equipment number (e.g., HT00000001), the similarity (e.g., 80%), and the name of the region where the culture tank is located (e.g., XX City) as a "List of Optimal Culture Tank Proposals for Customers," as Proposal 1, Proposal 2, Proposal 3, etc. Furthermore, for example, selecting Proposal 1 provides access to information on past usage, such as "Comment: Frequently used for fermentation production using E. coli," and information such as "Culture Tank Type: Fermenter," as shown in FIG. 6. Such information can be obtained from the device condition information stored in the storage unit 3.

[0086] (Aspect 9) In Aspect 8, it is preferable that the information input to the input unit 6 includes information on the bacterial strain, cell line, or organism species to be cultured, and the planned culture volume. In this way, matching can be performed with higher accuracy.

[0087] (Aspect 10) In this aspect, a culture experiment is first conducted under the culture conditions (first culture conditions) of the previously output culture experiment in the first-scale culture equipment (i.e., this culture experiment is the second or subsequent culture experiment), and new experimental data is obtained, including information on the amount of change in multiple parameters that indicate the state within the first-scale culture equipment. The calculation unit 41 then preferably conducts the simulation described above based on the new experimental data and the second-scale equipment information, and outputs condition range information, which is information indicating the relationship between the second culture conditions and the multiple parameters, based on the results of the simulation. Furthermore, the planning unit 42 preferably analyzes the new experimental data and the condition range information, and outputs new culture conditions (first culture conditions) for the culture experiment in the first-scale culture equipment.

[0088] In this embodiment, a culture experiment is performed under the previously output first culture conditions, and a simulation is performed using the experimental data to output condition range information, thereby improving the accuracy of the newly output first culture conditions. In this embodiment, these processes can be repeated any number of times. Furthermore, in this embodiment, these processes can be repeated until the newly output first culture conditions are sufficiently accurate, for example, until the newly output first culture conditions are substantially the same multiple times. In this way, sufficient simulation is performed at the first scale, further improving the accuracy of the first culture conditions.

[0089] Improving the accuracy of the first culture conditions can improve the probability of success when culturing in a second-scale culture facility, for example, the probability of maintaining a certain level of productivity. This leads to avoiding failure after moving to the second scale (i.e., inability to maintain a certain level of productivity) and the need to start over from the first scale. As a result, this can reduce the time and cost of investigation.

[0090] (Aspect 11) In Aspect 10, it is preferable that the calculation unit 41 performs a clustering analysis on new experimental data before performing the simulation. Furthermore, it is preferable that the planning unit 42 outputs, based on the results of the clustering analysis, at least one of the optimal culture conditions under the second culture conditions and important parameters that should be noted when scaling up the process to be cultured. It is also preferable that the planning unit 42 performs the simulation using at least one of the optimal culture conditions and the important parameters. In this aspect, by performing a clustering analysis before performing the simulation, the calculation unit 41 can more accurately extract and output the optimal culture conditions under the second culture conditions and important parameters that should be noted when scaling up the process to be cultured. Therefore, the simulation results obtained using these can be more accurate.

[0091] Next, a process development support method according to this embodiment will be described. Fig. 7 is a flowchart illustrating the process development support method according to this embodiment. As shown in Fig. 7, the process development support method according to this embodiment includes an acquisition step S1, a calculation step S2, and a planning step S3.

[0092] (Acquisition Step S1) In acquisition step S1, experimental data and second-scale equipment information are acquired. The experimental data and second-scale equipment information have already been described, so their description will be omitted. These can be acquired from the storage unit 3, but they may also be acquired by being transmitted via the communication interface 2 or the input unit 6.

[0093] (Calculation Step S2) In calculation step S2, a simulation is performed based on the experimental data and the second-scale equipment information regarding the amount of change in the same parameters as the above-mentioned multiple parameters when the culture target is cultured under the second culture conditions in the second-scale culture equipment. Then, in calculation step S2, condition range information, which is information indicating the relationship between the second culture conditions and the multiple parameters, is output based on the results of the simulation. Calculation step S2 can be performed by the calculation unit 41.

[0094] (Planning Step S3) In the planning step S3, the culture conditions for the culture experiment in the first-scale culture facility are output based on the experimental data and the condition range information. The planning step S3 can be performed by the planning unit 42.

[0095] (Specific Example of Process Development Support Method) FIG. 8 is a flowchart illustrating a specific example of the process development support method according to this embodiment. As shown in FIG. 8 , a user inputs at least one piece of information from the specifications, outline, and functions of a culture vessel or culture device corresponding to the second-scale culture equipment that the user wants to use into the input unit 6 (step S11), and the information is stored in the storage unit 3 of the process development support system S. The user also inputs experimental data into the input unit 6, the experimental data including information on the amount of change in multiple parameters that indicate the state of the first-scale culture equipment when a culture experiment is conducted on a culture target under first culture conditions in the first-scale culture equipment (step S11), and the information is stored in the storage unit 3 of the process development support system S. Next, the calculation unit 41 acquires the first-scale experimental data and the second-scale equipment information from the storage unit 3 (step S12).

[0096] Next, the calculation unit 41 performs a simulation regarding the amount of change in multiple parameters when culturing the culture target in the second-scale culture equipment based on the first-scale experimental data and the second-scale equipment information (step S13).

[0097] Next, the calculation unit 41 outputs condition range information, which is information indicating the relationship between the culture conditions (second culture conditions) when culturing the culture target in the second-scale culture equipment and the multiple parameters, based on the simulation results (step S14). Next, the planning unit 42 extracts candidates for important parameters based on the first-scale experimental data, the condition range information, etc. (step S15).

[0098] Next, the planning unit 42 outputs culture conditions (new first culture conditions) for a new culture experiment at the first scale based on the first experimental data and the condition range information (step S16). Here, the planning unit 42 may be configured to calculate key parameters for the process development of scaling up from the first-scale culture equipment to the second-scale culture equipment based on the condition range information and the experimental data, and output the culture conditions for the new culture experiment based on the information on the key parameters. In this way, since the culture conditions for the new culture experiment are output based on the information on the key parameters, a culture experiment conducted in the first-scale culture equipment based on these output conditions will obtain more favorable results, taking into account the unique culture conditions at the second scale. The planning unit 42 then displays the output information on the display unit (output device 7) (step S17).

[0099] (Explanation of Effects and Alternative Configurations) The planning unit 42, which outputs the culture conditions for the culture experiment to be considered at the first scale, can not only set the range of conditions, but also propose and recommend the conditions of the culture equipment to obtain those conditions. For example, if there is a concentration distribution of the substrate, it is possible to propose equipment that can reproduce the concentration distribution. Furthermore, this also applies to proposals such as the shape of the stirring blades.

[0100] Furthermore, the process development support system S and the process development support method can propose and recommend conditions for second-scale culture equipment necessary to minimize items with high distributions and highly influential parameters when taking into account the important parameters and condition range information. For example, the process development support system S and the process development support method can propose and recommend the shape of the culture tank, the stirring blades and stirring conditions used in the culture tank, and the aeration device conditions for the bubble diameter. Furthermore, the process development support system S and the process development support method can propose information on recommended culture equipment based on equipment information stored in the memory unit 3, etc. In addition, when recommending culture equipment, it is preferable to display the installation location, operating status, usage history, etc. in addition to equipment information and specifications.

[0101] This method can assist in the creation of an experimental plan for the first scale by understanding the specific culture conditions at the second scale and taking them into consideration. This allows for the reduction of uncertain conditions that cannot be reproduced or unexpected constraints, even when sufficient experimental data information is not available at the second scale, thereby preventing equipment-related productivity declines at the second scale. Ultimately, it is preferable to perform a state simulation at the second scale using data from the first-scale experiment to confirm whether the results are within expectations, i.e., to conduct a culture experiment using second-scale culture equipment to confirm productivity, etc. Furthermore, while an example has been shown in which data is acquired using first-scale culture equipment to consider the proposed culture conditions, it is not necessarily required to conduct the experiment at the first scale. In other words, the proposed culture conditions may also be considered using culture equipment at a scale other than the first scale. In this case, when the planning unit 42 outputs the recommended experimental conditions, information on the available scales can also be output.

[0102] (Example of Microorganism A) Here, an example will be described in which the process development support system S and the process development support method described in this embodiment are applied to a process in which microorganism A is batch-cultured using sugars as raw materials to produce organic compounds.

[0103] In this example, the following experimental data were prepared. First, as the first scale, culture conditions and experimental data for a 10 L culture tank were used. The experimental data included information about microorganism A, as well as temperature, pH, DO concentration, and medium concentration as addition conditions, liquid volume, viscosity, and the like. In addition, conditions for aeration volume, stirring speed, and pressure were prepared as control indices for adjusting the environment. Next, as the second scale assuming culture, equipment information for a 1000 L culture facility was prepared. As equipment conditions, the aspect ratio of the culture tank, the aeration device, the agitator, the pH adjustment equipment, and the control device for controlling the DO concentration, as well as their specifications, were prepared.

[0104] Based on these, fluid analysis software was used to analyze the amount of change in the culture conditions parameters in a 1000 L fermentor. Changes in temperature, pH, DO concentration, medium concentration, additive concentration, etc. were analyzed to clarify the distribution of various concentrations. In this example, we will describe the details focusing on DO concentration. Taking into account the degree of oxygen dissolution from the agitator rotation conditions, aeration conditions, viscosity conditions, temperature, etc., the distribution of DO concentration in a steady state was found.

[0105] It was confirmed that the DO concentration varies depending on the agitator rotation conditions and aeration conditions based on the initial conditions. Here, it was confirmed that the DO concentration in the culture tank ranges from 0.5 to 8 mg / L. It was also found that when the agitator rotation conditions are increased, the shear stress increases. On the other hand, when the DO concentration is low, the DO concentration increases. ２ We also found that the concentration increased, demonstrating a relationship between the culture conditions and multiple parameters.

[0106] From the first-scale experimental data, it was confirmed that the DO concentration in the culture condition test using a 10 L fermenter tank was 5 mg / L or more as a representative value of one sensor point, but since there was no condition for the range of DO concentration, it was set as an important parameter. ２ Concentration and shear stress were also found to have a certain range, and were therefore considered important parameters.

[0107] The planning unit 42 specified and output the culture conditions including the DO concentration range of 0.5 to 8 mg / L as the experimental conditions.２ The range of culture conditions that satisfied the conditions of concentration and shear stress was output. In addition, the planning unit 42 proposed a culture facility that can change the DO concentration using nitrogen gas and oxygen gas, and output the proposal to the display unit.

[0108] Based on this, the experimenter conducted an organic compound productivity test in a 500 mL culture tank at a DO concentration of 0.5 to 8 mg / L. As a result, it was confirmed that productivity significantly decreased when DO was less than 1 mg / L, more specifically, at 0.5 mg / L.

[0109] Under the conditions of the second-scale cultivation facility, the DO concentration is 1 mg / L or more. ２ Tests were conducted to confirm whether there was any effect on concentration and shear stress, and the results showed that there was no significant effect on organic compound production.

[0110] Based on these conditions, a simulation was performed again and it was confirmed that a sufficient state was achieved in a 1000 L fermenter. As a result of considering the above, optimal culture conditions for a 1000 L fermenter were found.

[0111] The process development support system S and the process development support method according to the present invention have been described in detail above through embodiments and examples. However, the present invention is not limited to the above-described embodiments and examples, and various modifications are included. For example, the above-described embodiments have been described in detail to clearly explain the present invention, and the present invention is not necessarily limited to those including all of the described configurations. Furthermore, it is possible to replace part of the configuration of one embodiment with the configuration of another embodiment, or to add the configuration of another embodiment to the configuration of one embodiment. Furthermore, it is possible to add, delete, or replace part of the configuration of each embodiment with other configurations.

[0112] S Process development support system 1 Management server 2 Communication interface 3 Storage unit 4 Control unit 41 Calculation unit 42 Planning unit 43 Extraction unit 44 Proposal output unit 5 Memory 6 Input unit 7 Output device 2A1 Second scale analysis distribution range 2A2 Initial first scale experimental range 2B1 First scale input experimental conditions 2B2 Range 2B3 Second scale analysis distribution range 2C1 First scale input experimental conditions 2C2 Range 2D1 First scale input experimental conditions 2D2 First scale initial experimental range 2E1 Initial first scale experimental range 2E2 Range 2E3 First scale input experimental conditions 2E4 Range 2E5 Range 2E6 Range 2E7 Culture condition range

Claims

1. A process development support system comprising: a memory unit that stores experimental data including information on amounts of change in a plurality of parameters indicating a state within a first-scale culture equipment when a culture experiment is conducted on a culture target under first culture conditions in the first-scale culture equipment; and second-scale equipment information that is information on equipment conditions including at least shape information on second-scale culture equipment that is larger than the first-scale culture equipment; a calculation unit that performs a simulation on amounts of change in parameters that are the same as the plurality of parameters when the culture target is cultured under second culture conditions in the second-scale culture equipment based on the experimental data and the second-scale equipment information, and outputs condition range information that is information indicating a relationship between the second culture conditions and the plurality of parameters based on the results of the simulation; and a planning unit that outputs culture conditions for a culture experiment in the first-scale culture equipment based on the experimental data and the condition range information.

2. The process development support system described in claim 1, characterized in that the planning unit identifies important parameters in the process development of scaling up from a first-scale culture equipment to a second-scale culture equipment based on the condition range information and the experimental data, and outputs culture conditions for the culture experiment at the first scale based on information on the important parameters.

3. The process development support system described in claim 1, characterized in that the first culture conditions include information on setting values ​​of a plurality of operating condition items for controlling the first-scale culture equipment, and the planning unit outputs a range for changing the setting values ​​in the culture experiment based on the experimental data and the condition range information.

4. The process development support system described in claim 1, characterized in that the planning unit outputs information regarding the magnitude of the influence when culturing the culture target in the second scale culture equipment based on the information of the multiple parameters contained in the experimental data and the information of the multiple parameters contained in the condition range information.

5. The process development support system described in claim 1, characterized in that the memory unit stores first equipment information regarding multiple candidates for the first-scale culture equipment, and the planning unit outputs information regarding the culture equipment to be used for the culture experiment from the first equipment information.

6. The process development support system described in claim 2, characterized in that the memory unit stores second equipment information regarding multiple candidates for the second-scale culture equipment, and the planning unit outputs information regarding candidates for culture equipment to be used as the second-scale culture equipment from information on the range and behavior of parameters identical to the multiple parameters, information on the important parameters, and the second equipment information.

7. The process development support system according to claim 1, characterized in that the first culture condition is at least one of viscosity, concentration of various components, temperature, pH, dissolved oxygen concentration, agitation rotation speed, aeration amount, and pressure.

8. The process development support system according to claim 1, characterized in that the equipment conditions are at least one of the aspect ratio of the culture tank, an aeration device, an agitator, a pH adjustment device, and a control device for controlling the dissolved oxygen concentration, and their specifications.

9. The process development support system described in claim 1, characterized in that the calculation unit simulates the behavior of various parameters when culturing is performed in a second-scale culture equipment based on the second culture conditions and the second-scale equipment information, and the various parameters are at least one of shear force and dissolved oxygen concentration.

10. The process development support system according to claim 1, further comprising: a database storing information on the second-scale culture equipment candidates and information regarding the specifications and usage of each of the candidates; an input unit into which conditions for the second-scale culture equipment are input; an extraction unit that extracts, from the second-scale culture equipment candidates based on the information input to the input unit and the information stored in the database, one or more culture equipment candidates that relate to the conditions input to the input unit; and a proposal output unit that proposes the culture equipment candidates extracted by the extraction unit and information regarding the usage of each of the candidates.

11. The process development support system according to claim 10, wherein the information input to the input section includes information on the bacterial strain, cell line or organism to be cultured, and the planned culture volume.

12. The process development support system described in claim 1, characterized in that a culture experiment is conducted under culture conditions for a culture experiment in the first-scale culture equipment, and new experimental data including information regarding the amount of change in multiple parameters indicating the state within the first-scale culture equipment is obtained; the calculation unit conducts the simulation based on the new experimental data and the second-scale equipment information, and outputs condition range information, which is information indicating the relationship between the second culture conditions and the multiple parameters, based on the results of the simulation; and the planning unit analyzes based on the new experimental data and the condition range information, and outputs new culture conditions for the culture experiment in the first-scale culture equipment.

13. The process development support system described in claim 12, characterized in that the calculation unit performs a clustering analysis on the new experimental data before performing the simulation, and the planning unit outputs, based on the results of the clustering analysis, at least one of optimal culture conditions for the second culture conditions and important parameters that should be noted when scaling up the process to be cultured, and performs the simulation using the optimal culture conditions and at least one of the important parameters.

14. A process development support method comprising: an acquisition step of acquiring experimental data including information regarding amounts of change in multiple parameters indicating a state within a first-scale culture equipment when a culture experiment is conducted on a culture target under first culture conditions in the first-scale culture equipment, and second-scale equipment information which is information regarding equipment conditions including at least shape information regarding second-scale culture equipment which is larger than the first-scale culture equipment; a calculation step of performing a simulation regarding amounts of change in parameters identical to the multiple parameters when the culture target is cultured under second culture conditions in the second-scale culture equipment based on the experimental data and the second-scale equipment information, and outputting condition range information which is information indicating a relationship between the second culture conditions and the multiple parameters based on the results of the simulation; and a planning step of outputting culture conditions for a culture experiment in the first-scale culture equipment based on the experimental data and the condition range information.

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