Solution preparation device, method for operating solution preparation device, and program for operating solution preparation device

Abstract

This solution preparation device continuously supplies a solvent and a powder to a mixing container to continuously prepares a solution having a set concentration in the mixing container, and continuously supplies the solution having the set concentration from the mixing container to a processing container. The solution preparation device comprises a processor, wherein, if the continuous supply of the powder to the mixing container is stopped, the processor subjects the solution remained in the mixing container to a concentration preparation processing for maintaining the set concentration, and supplies the solution having the set concentration, which has been subjected to the concentration preparation processing, to the processing container, to satisfy the required amount of the solution having the set concentration.

Description

Solution preparation device, operation method of solution preparation device, and operation program of solution preparation device

[0001] The technology of the present disclosure relates to a solution preparation device, an operation method for a solution preparation device, and an operation program for a solution preparation device.

[0002] For example, bioprocesses such as culturing Chinese hamster ovary cells incorporating antibody genes to obtain antibody pharmaceuticals require various solutions. International Publication No. 2021 / 123248 describes a solution preparation device that continuously prepares a solution of a set concentration by continuously supplying a solvent and a powder to a mixing vessel and stirring and mixing the solvent and powder in the mixing vessel. The mixing vessel is connected to a processing vessel, and the solution is continuously supplied from the mixing vessel to the processing vessel. The solvent is, for example, purified water such as pure water, the powder is, for example, a powder culture medium, and the solution is, for example, a culture medium (culture solution). The processing vessel is, for example, a culture tank.

[0003] In a solution preparation apparatus, when processing in a processing vessel is completed and the required amount of solution has been supplied from the mixing vessel to the processing vessel, the continuous supply of solvent and powder to the mixing vessel is stopped. The preparation of a solution with a set concentration in the mixing vessel may continue until the required amount of solution has been supplied from the mixing vessel to the processing vessel. In this case, when the continuous supply of solvent and powder to the mixing vessel is stopped, some solution remains in the mixing vessel. The remaining solution in the mixing vessel is then discarded without being supplied to the processing vessel. This wastes a lot of resources, especially powder.

[0004] One possible measure to reduce wasted powder is to supply at least a portion of the solution remaining in the mixing container after the supply of the solvent and powder is stopped to the processing container to add to the required amount. However, the solution remaining in the mixing container after the supply of the solvent and powder is stopped will have a concentration higher than the set concentration over time because the undissolved powder gradually dissolves. For this reason, the solution remaining in the mixing container after the supply of the solvent and powder is stopped cannot be supplied to the processing container as is.

[0005] One embodiment of the technology disclosed herein provides a solution preparation device, an operating method for the solution preparation device, and an operating program for the solution preparation device, which can reduce costs by reducing wasted powder.

[0006] The solution preparation apparatus of the present disclosure is a solution preparation apparatus that continuously prepares a solution of a set concentration in a mixing container by continuously supplying a solvent and powder to the mixing container, and continuously supplies the solution of the set concentration from the mixing container to a processing container, and is equipped with a processor.When the continuous supply of powder to the mixing container is stopped, the processor performs a concentration adjustment process on the solution remaining in the mixing container to maintain the set concentration, and supplies the solution of the set concentration that has been subjected to the concentration adjustment process to the processing container, thereby satisfying the required amount of solution of the set concentration.

[0007] As the concentration adjustment process, the processor preferably performs a process of diluting the solution by supplying a solvent to the mixing container.

[0008] The processor preferably performs the concentration adjustment process by gradually reducing the amount of powder supplied.

[0009] The processor preferably performs a concentration adjustment process in accordance with the measurement result of the concentration of the solution.

[0010] The measurement results are preferably based on spectroscopic data of the solution.

[0011] The mixing vessel is preferably equipped with a measuring instrument for measuring spectroscopic data.

[0012] Preferably, the solvent is purified water, the powder is a powder medium, and the solution is a medium.

[0013] The method of operating the solution preparation apparatus disclosed herein is a method of operating a solution preparation apparatus that continuously prepares a solution of a set concentration in a mixing container by continuously supplying a solvent and a powder to the mixing container, and continuously supplies the solution of the set concentration from the mixing container to a processing container, and includes, when the continuous supply of powder to the mixing container is stopped, performing a concentration adjustment process on the solution remaining in the mixing container to maintain the set concentration, and supplying the solution of the set concentration that has been subjected to the concentration adjustment process to the processing container, thereby satisfying the required amount of solution of the set concentration.

[0014] The operating program of the solution preparation device disclosed herein is an operating program of a solution preparation device that continuously prepares a solution of a set concentration in a mixing container by continuously supplying a solvent and powder to the mixing container, and continuously supplies the solution of the set concentration from the mixing container to a processing container.When the continuous supply of powder to the mixing container is stopped, the operating program causes a computer to execute processes including performing a concentration adjustment process on the solution remaining in the mixing container to maintain the set concentration, and supplying the solution of the set concentration that has been subjected to the concentration adjustment process to the processing container to meet the required amount of solution of the set concentration.

[0015] According to the technology disclosed herein, it is possible to provide a solution preparation device, an operating method for a solution preparation device, and an operating program for a solution preparation device that can reduce costs by reducing wasted powder.

[0016] FIG. 1 is a diagram showing a culture medium preparation device and a culture tank. FIG. 2 is a block diagram showing the configuration of a control unit. FIG. 3 is a block diagram showing a processing unit of a CPU. FIG. 4 is a diagram showing processing of a concentration prediction unit. FIG. 5 is an explanatory diagram of conventional processing. FIG. 6 is an explanatory diagram of processing of a first embodiment. FIG. 7 is an explanatory diagram of processing of a second embodiment.

[0017] [First embodiment] As shown in FIG. 1 as an example, a culture medium preparation apparatus 10 prepares a culture medium CM. The culture medium preparation apparatus 10 is connected to a culture tank 11 and continuously supplies the prepared culture medium CM to the culture tank 11. The culture medium preparation apparatus 10 is an example of a "solution preparation apparatus" according to the technology of the present disclosure. The culture tank 11 is an example of a "processing container" according to the technology of the present disclosure. The culture medium CM is an example of a "solution" according to the technology of the present disclosure. Note that FIG. 1 illustrates an example in which the culture medium preparation apparatus 10 is directly connected to the culture tank 11, but this is not limiting. A tank for temporarily storing the culture medium CM may be provided between the culture medium preparation apparatus 10 and the culture tank 11.

[0018] Culture tank 11 is seeded with, for example, Chinese hamster ovary cells into which an antibody gene has been incorporated. In culture tank 11, the Chinese hamster ovary cells are cultured in culture medium CM for a predetermined culture period, such as one month. As described above, culture medium CM is continuously supplied to culture tank 11 from culture medium preparation device 10, and therefore the culture of Chinese hamster ovary cells performed in culture tank 11 is perfusion culture. Culture tank 11 is connected to a purification device (not shown). The purification device purifies the antibody produced by the Chinese hamster ovary cells during the culture process and uses it as a drug substance for an antibody pharmaceutical.

[0019] The culture medium preparation device 10 includes a pure water storage tank 15, a mixing container 16, a powder culture medium supplier 17, a waste liquid recovery tank 18, a control unit 19, an operation unit 20, and the like.

[0020] The pure water storage tank 15 stores pure water PW. The pure water PW is an example of the "solvent" and "purified water" according to the technology of the present disclosure. One end of a pure water supply line 21 is connected to the pure water storage tank 15. The other end of the pure water supply line 21 is connected to the mixing container 16. A pure water supply pump 22 and a pure water flow meter 23 are provided in the pure water supply line 21. The pure water supply pump 22 is driven and controlled by the control unit 19. When the pure water supply pump 22 is driven, the pure water PW in the pure water storage tank 15 is supplied to the mixing container 16 through the pure water supply line 21. The pure water flow meter 23 is disposed downstream of the pure water supply pump 22 and measures the inflow rate of the pure water PW that passes through the pure water supply line 21 and flows into the mixing container 16. The pure water flow meter 23 outputs the measured inflow rate to the control unit 19. The control unit 19 controls the operation of the pure water supply pump 22 so that the inflow rate of the pure water flow meter 23 becomes the set inflow rate.

[0021] The mixing vessel 16 is a vessel for mixing the pure water PW and the powdered medium PM to produce a set concentration of medium CM, and has, for example, a wide cylindrical shape. The mixing vessel 16 has a capacity equal to the amount of medium CM required in the culture tank 11 over the entire culture period, i.e., approximately 0.001 to 0.1 times the required amount of medium CM. Using a mixing vessel 16 that is smaller than the required amount of medium CM allows for a reduced installation area. However, because the volume of the mixing vessel 16 is smaller than the required amount of medium CM, preparation of medium CM in the mixing vessel 16 continues until the required amount of medium CM has been supplied from the mixing vessel 16 to the culture tank 11.

[0022] The top of the mixing container 16 is sealed with a lid 25. A through-hole 26 is formed in the center of the lid 25. An outlet 27 of the powdered culture medium PM of the powdered culture medium supplier 17 is aseptically connected to the upper end of the through-hole 26. This aseptically connects the mixing container 16 and the powdered culture medium supplier 17. The powdered culture medium PM discharged from the outlet 27 is supplied to the mixing container 16 through the through-hole 26. The powdered culture medium PM is an example of the "powder" according to the technology of the present disclosure.

[0023] The powdered medium supplying machine 17 is composed of a hopper 30 that stores the powdered medium PM, and a feeder 31 that continuously discharges the powdered medium PM from the hopper 30 through a discharge port 27. The hopper 30 is funnel-shaped, and a sterile bag (not shown) containing the powdered medium PM is set in its upper opening. The powdered medium PM is introduced from the sterile bag into the hopper 30 without coming into contact with the outside air. This maintains the sterility of the powdered medium PM.

[0024] The feeder 31 is attached to the narrowed lower portion of the hopper 30. The feeder 31 is driven and controlled by the control unit 19 to continuously discharge a set amount of powdered medium PM from the outlet 27. The feeder 31 is, for example, a screw feeder (also called an auger feeder) that continuously discharges a set amount of powdered medium PM from the outlet 27 by rotating a spiral screw with a motor under the control of the control unit 19. Although not shown, an agitator is installed inside the hopper 30 to break up ratholes that occur during prolonged use. The inner wall of the hopper 30 may be treated with a sliding surface to improve the discharge of the powdered medium PM. The feeder 31 is not limited to a screw feeder; it may also be a table feeder (also called a circle feeder), rotary feeder, belt feeder, vibratory feeder, etc.

[0025] The mixing container 16 is placed on the agitator 32. A stirrer 33 is placed in the mixing container 16. The stirrer 33 has a long, cocoon-like shape with both ends curled and a slightly bulging center. A magnet is built into the stirrer 33. The agitator 32 is driven and controlled by the control unit 19. The agitator 32 generates a magnetic force to rotate the stirrer 33. The agitator 32 rotates the stirrer 33 at a set stirring rotation speed, mixing the pure water PW and the powdered medium PM to produce the medium CM. Note that the pure water PW and the powdered medium PM may be mixed by rotating an agitating blade (also called a stirring impeller) instead of the agitator 33.

[0026] A weigh scale 34 is built into the agitator 32. The weigh scale 34 measures the weight of the mixing container 16 placed on the agitator 32. The weigh scale 34 outputs the measured weight to the control unit 19. The control unit 19 controls the operation of the powdered medium supply machine 17 so that the weight becomes a set amount. The supply amount of powdered medium PM related to the weight of the mixing container 16 is set based on the set concentration of the medium CM to be prepared, the outflow amount of medium CM into the culture tank 11, etc.

[0027] One end of a medium supply path 35 is connected to the mixing vessel 16. The other end of the medium supply path 35 is connected to the culture tank 11. A medium supply pump 36 and a medium flow meter 37 are provided in the medium supply path 35. The medium supply pump 36 is driven and controlled by the control unit 19. When the medium supply pump 36 is driven, the medium CM in the mixing vessel 16 is supplied to the culture tank 11 through the medium supply path 35. The medium flow meter 37 is disposed downstream of the medium supply pump 36 and measures the outflow rate of the medium CM that passes through the medium supply path 35 and flows out into the culture tank 11. The medium flow meter 37 outputs the measured outflow rate to the control unit 19. The control unit 19 controls the drive of the medium supply pump 36 so that the outflow rate of the medium flow meter 37 becomes the set outflow rate.

[0028] The inflow rate of pure water PW into the mixing container 16 and the outflow rate of medium CM from the mixing container 16 are set to values ​​that prevent the amount of liquid (medium CM containing undissolved powdered medium PM) in the mixing container 16 from changing from start to finish. More specifically, the outflow rate of medium CM is set according to the combined amount of the inflow rate of pure water PW and the supply rate of powdered medium PM. In practice, the weight of the mixing container 16 is measured with a weighing scale 34, and the inflow rate of pure water PW and the outflow rate of medium CM are set so that the measured weight is the set amount.

[0029] The required amount of medium CM can be easily calculated by multiplying the amount of medium CM required for culture per unit time by the culture period. The control unit 19 integrates the outflow amount of medium CM measured by the medium flow meter 37. When the integrated value of the outflow amount reaches the required amount, the supply of medium CM from the mixing container 16 to the culture tank 11 is stopped.

[0030] A filter 38 is disposed upstream of the culture medium supply pump 36 in the culture medium supply path 35. The filter 38 removes unwanted materials from the culture medium CM. The unwanted materials include, for example, undissolved powdered culture medium PM. Note that if the amount of unwanted materials, such as undissolved powdered culture medium PM, can be kept below the allowable amount, the filter 38 need not be provided.

[0031] The mixing vessel 16 is provided with a connector 40. A sensor 42 of a Raman spectrometer 41 is connected to the connector 40. The Raman spectrometer 41 is an instrument that evaluates substances using the characteristics of Raman scattered light and is an example of a "measuring instrument" according to the technology of the present disclosure. When excitation light is irradiated onto a substance, the excitation light interacts with the substance, generating Raman scattered light having a wavelength different from that of the excitation light. The wavelength difference between the excitation light and the Raman scattered light corresponds to the energy of the molecular vibrations of the substance. Therefore, Raman scattered light with different wavenumbers can be obtained between substances with different molecular structures. Of the Stokes line and the anti-Stokes line, it is preferable to use the Stokes line for the Raman scattered light.

[0032] The Raman spectrometer 41 is composed of the aforementioned sensor unit 42 and analyzer 43. The sensor unit 42 is connected to the connector unit 40, and its tip is immersed in the culture medium CM in the mixing container 16. The sensor unit 42 emits excitation light from its tip. The excitation light is irradiated onto the culture medium CM. Raman scattered light is generated by the interaction between this excitation light and components such as the powder culture medium PM dissolved in the culture medium CM. The sensor unit 42 receives the Raman scattered light and guides it to the analyzer 43.

[0033] The analyzer 43 resolves the Raman scattered light into wavenumbers and derives the intensity values ​​of the Raman scattered light for each wavenumber, thereby generating Raman spectrum data 80 (see FIG. 4 ) representing the spectrum of the Raman scattered light, i.e., the Raman spectrum. The Raman spectrum data 80 is data in which the intensity values ​​of the Raman scattered light for each wavenumber are registered. The Raman spectrum data 80 is used to predict the concentration of the culture medium CM, as described below. The Raman spectrum data 80 is an example of "spectroscopic spectrum data" according to the technology of the present disclosure.

[0034] A hydrogen ion exponent meter 45 is disposed downstream of the culture medium flow meter 37 in the culture medium supply path 35. A waste liquid path 47 is connected to the culture medium supply path 35 downstream of the hydrogen ion exponent meter 45 via a three-way valve 46. The three-way valve 46 is driven and controlled by the control unit 19. A waste liquid recovery tank 18 is connected to the waste liquid path 47. The waste liquid recovery tank 18 recovers waste liquid WL, such as culture medium CM that does not have the set concentration or culture medium CM with an abnormal value for the hydrogen ion exponent.

[0035] The control unit 19 determines whether the medium CM is at the set concentration based on the medium CM concentration prediction result 75 (see FIG. 3 ) calculated based on the Raman spectrum data 80. If it is determined that the medium CM is not at the set concentration, the control unit 19 directs the flow path of the three-way valve 46 to the waste liquid path 47 and discharges the waste liquid WL, which is medium CM not at the set concentration, into the waste liquid recovery tank 18. On the other hand, if it is determined that the medium CM is at the set concentration, the control unit 19 directs the flow path of the three-way valve 46 to the culture tank 11 and introduces medium CM at the set concentration into the culture tank 11. In this way, only medium CM at the set concentration is supplied to the culture tank 11. This prevents problems such as failure to culture Chinese hamster ovary cells due to medium CM not at the set concentration being supplied to the culture tank 11.

[0036] The hydrogen ion exponent meter 45 measures the hydrogen ion exponent of the culture medium CM passing through the culture medium supply path 35. The hydrogen ion exponent meter 45 outputs the measured hydrogen ion exponent to the control unit 19. If the hydrogen ion exponent value from the hydrogen ion exponent meter 45 is an abnormal value, the control unit 19 switches the flow path of the three-way valve 46 to the waste liquid path 47 side, and discharges the waste liquid WL, which is the culture medium CM with an abnormal hydrogen ion exponent, into the waste liquid recovery tank 18.

[0037] The operation unit 20 is, for example, a touch panel, and receives various operation instructions from an operator of the culture medium preparation apparatus 10. The various operation instructions include an instruction to start preparation of the culture medium CM, an instruction to forcibly stop supply of the culture medium CM from the mixing container 16 to the culture tank 11, etc.

[0038] The pure water storage tank 15, mixing container 16, hopper 30 and feeder 31 of the powdered culture medium supplier 17, and waste liquid collection tank 18 are all single-use, meaning they are disposed of after one use. The pure water supply line 21, culture medium supply line 35, filter 38, three-way valve 46, and waste liquid line 47 are also single-use.

[0039] The flow paths from the pure water storage tank 15 through the pure water supply path 21, the mixing container 16, and the culture medium supply path 35 to the culture tank 11 are all connected in a sterile manner. The culture medium supply path 35, the three-way valve 46, and the waste liquid path 47 are also connected in a sterile manner.

[0040] 2, the control unit 19 includes a storage 50, a CPU (Central Processing Unit) 51, and a memory 52. ​​The storage 50, the CPU 51, and the memory 52 are interconnected via a bus line 53. The control unit 19 is an example of a "computer" according to the technology of the present disclosure.

[0041] The storage 50 is a hard disk drive or a solid state drive, and stores control programs such as an operating system, various application programs, and various data associated with these programs.

[0042] The memory 52 is a work memory for the CPU 51 to execute processing. The CPU 51 loads programs stored in the storage 50 into the memory 52 and executes processing in accordance with the programs. In this way, the CPU 51 comprehensively controls each part of the computer. The CPU 51 is an example of a "processor" according to the technology of the present disclosure. The memory 52 may be built into the CPU 51.

[0043] 3, an operation program 60 is stored in the storage 50. The operation program 60 is an example of an "operation program for a solution preparation apparatus" according to the technology of the present disclosure. In addition to the operation program 60, the storage 50 also stores a concentration prediction model 61 and the like.

[0044] When the operating program 60 is started, the CPU 51 functions as a pure water supply pump drive control unit 65, a powder culture medium supply machine drive control unit 66, an agitator drive control unit 67, a culture medium supply pump drive control unit 68, a concentration prediction unit 69, and a three-way valve drive control unit 70.

[0045] The pure water supply pump drive control unit 65 controls the drive of the pure water supply pump 22 based on the inflow rate of the pure water PW into the mixing container 16 measured by the pure water flow meter 23. The pure water supply pump drive control unit 65 also controls the drive of the pure water supply pump 22 based on a concentration prediction result 75 by the concentration prediction unit 69. The drive control of the pure water supply pump 22 based on the concentration prediction result 75 will be described later.

[0046] The powdered culture medium supplying device drive control unit 66 controls the drive of the powdered culture medium supplying device 17 based on the weight of the mixing container 16 measured by the weighing scale 34. The agitator drive control unit 67 controls the drive of the agitator 32 so that the agitation rotation speed of the agitator 33 becomes the set rotation speed.

[0047] The culture medium supply pump drive control unit 68 controls the drive of the culture medium supply pump 36 based on the outflow rate of the culture medium CM from the mixing container 16 measured by the culture medium flow meter 37. The concentration prediction unit 69 predicts the concentration of the culture medium CM from the Raman spectrum data 80 using the concentration prediction model 61, and outputs the resulting concentration prediction result 75 to the pure water supply pump drive control unit 65 and the three-way valve drive control unit 70. The concentration prediction result 75 is an example of a "measurement result" according to the technology of the present disclosure.

[0048] The three-way valve drive control unit 70 controls the drive of the three-way valve 46 based on the concentration prediction result 75 by the concentration prediction unit 69 and the hydrogen ion exponent of the culture medium CM measured by the hydrogen ion exponent meter 45 .

[0049] 4 , the concentration prediction unit 69 inputs Raman spectrum data 80 from the Raman spectrometer 41 into the concentration prediction model 61. The concentration prediction model 61 then outputs a concentration prediction result 75. The concentration prediction model 61 is a machine learning model such as a neural network or a support vector machine, and is trained in advance to output the concentration prediction result 75 in response to the input of the Raman spectrum data 80.

[0050] In this example, the Raman spectrum data 80 is obtained at a wavenumber of 700 cm －１ ~1800cm －１ The intensity values ​​of Raman scattered light in the range from 1 cm －１ The data is derived in increments of 100. In this example, the concentration prediction result 75 is expressed in mg / ml. The graph shown to the right of the Raman spectrum data 80 is a graph in which the intensity values ​​of the Raman spectrum data 80 are plotted for each wavenumber and connected by a line.

[0051] The conventional process is shown in Figure 5. At time TA, when an operator issues an instruction to start preparation of culture medium CM via the operation unit 20, the pure water supply pump 22 and the powdered culture medium supplier 17 are driven under the control of the pure water supply pump drive control unit 65 and the powdered culture medium supplier drive control unit 66, and the supply of pure water PW and powdered culture medium PM to the mixing container 16 is initiated.

[0052] At time TB, when the amount of liquid in the mixing container 16 reaches the set amount, the agitator 32 is driven under the control of the agitator drive control unit 67, although not shown in the figure. Also, the culture medium supply pump 36 is driven under the control of the culture medium supply pump drive control unit 68. At this time, the concentration of the culture medium CM in the mixing container 16 has not yet reached the set concentration, so the three-way valve drive control unit 70 switches the flow path of the three-way valve 46 to the waste liquid path 47 side, and the waste liquid WL, which is culture medium CM that does not have the set concentration, is discharged into the waste liquid recovery tank 18.

[0053] When the concentration of medium CM in the mixing vessel 16 reaches the set concentration at time TC, the three-way valve drive control unit 70 switches the flow path of the three-way valve 46 to the culture tank 11 side, and the introduction of medium CM at the set concentration into the culture tank 11 begins. The supply of pure water PW and powdered medium PM to the mixing vessel 16 and the supply of medium CM from the mixing vessel 16 to the culture tank 11 continue until the culture in the culture tank 11 is completed and the required amount of medium CM has been supplied from the mixing vessel 16 to the culture tank 11. Note that the medium supply pump 36 may be started at time TC when the concentration of medium CM in the mixing vessel 16 reaches the set concentration, rather than at time TB when the amount of liquid in the mixing vessel 16 reaches the set amount.

[0054] At time TD, when the required amount of medium CM has been supplied from the mixing vessel 16 to the culture vessel 11, the supply of pure water PW and powdered medium PM to the mixing vessel 16 and the supply of medium CM from the mixing vessel 16 to the culture vessel 11 are stopped. At this time TD, medium CM and undissolved powdered medium PM remain in the mixing vessel 16. Conventionally, the medium CM and the like remaining in the mixing vessel 16 are all discarded without being supplied to the culture vessel 11. As a result, the powdered medium PM is wasted.

[0055] In contrast, in the technology disclosed herein, the medium CM remaining in the mixing vessel 16 is supplied to the culture vessel 11 to supplement the required amount, thereby reducing the amount of wasted powdered medium PM. However, the medium CM remaining in the mixing vessel 16 becomes more concentrated than the set concentration over time because the undissolved powdered medium PM gradually dissolves, and therefore cannot be supplied as is to the culture vessel 11. Therefore, in the technology disclosed herein, the concentration of the medium CM remaining in the mixing vessel 16 is maintained at the set concentration by performing a concentration adjustment process shown in FIG. 6 as an example.

[0056] As shown in FIG. 6 , when the cumulative amount of medium CM flowing into the mixing container 16 reaches the required amount −Δ at time TE, the supply of powdered medium PM to the mixing container 16 is stopped. However, only the supply of powdered medium PM is stopped; the supply of pure water PW to the mixing container 16 continues. That is, in this first embodiment, the concentration adjustment process involves diluting the medium CM by supplying pure water PW to the mixing container 16. In addition to the supply of pure water PW to the mixing container 16, the supply of a set amount of medium CM from the mixing container 16 to the culture tank 11 also continues. Note that the sufficiency amount Δ is a preset value that is smaller than the set amount of liquid in the mixing container 16 and is, for example, a value equal to or greater than ¼ of the set amount of liquid in the mixing container 16. In this case, the period from time TE, when the continuous supply of powdered medium PM to the mixing container 16 is stopped, is an example of a case in which the continuous supply of powder to the mixing container is stopped according to the technology of the present disclosure.

[0057] The pure water supply pump drive control unit 65 adjusts the amount of pure water PW supplied to the mixing vessel 16 by the pure water supply pump 22 so that the concentration prediction result 75 from the concentration prediction unit 69 matches the set concentration. That is, the pure water supply pump drive control unit 65 performs a concentration adjustment process according to the concentration prediction result 75. This suppresses an increase in the concentration of the medium CM remaining in the mixing vessel 16 due to undissolved powder medium PM, and maintains the concentration of the medium CM remaining in the mixing vessel 16 at the set concentration. Under the control of the medium supply pump drive control unit 68, the medium CM remaining in the mixing vessel 16, maintained at this set concentration, is supplied from the mixing vessel 16 to the culture vessel 11 by the medium supply pump 36 as an additional supply of the required amount by the sufficiency amount Δ. Then, at time TF, when the required amount of medium CM has been supplied from the mixing vessel 16 to the culture vessel 11, the supply of medium CM from the mixing vessel 16 to the culture vessel 11 is stopped.

[0058] As described above, the culture medium preparation apparatus 10 includes a CPU 51. As shown in FIG. 6 , the pure water supply pump drive control unit 65 of the CPU 51 performs a concentration adjustment process on the culture medium CM remaining in the mixing container 16 after the time TE when the continuous supply of the powdered culture medium PM to the mixing container 16 is stopped, in order to maintain the set concentration. The culture medium supply pump drive control unit 68 supplies the culture medium CM having the set concentration that has been subjected to the concentration adjustment process to the culture tank 11, thereby satisfying the required amount of culture medium CM having the set concentration. Therefore, compared to the conventional method in which the culture medium CM remaining in the mixing container 16 was completely discarded without being supplied to the culture tank 11, it is possible to reduce the amount of wasted powdered culture medium PM. This, in turn, enables cost reduction compared to the conventional method.

[0059] 6, the pure water supply pump drive control unit 65 performs a concentration adjustment process by diluting the medium CM by supplying pure water PW to the mixing container 16. This allows effective use of the powder medium PM that has not dissolved in the medium CM at time TE, further reducing the amount of powder medium PM that is wasted.

[0060] 6, the pure water supply pump drive control unit 65 performs concentration adjustment processing in accordance with the concentration prediction result 75. Therefore, the concentration of the medium CM remaining in the mixing container 16 can be more reliably maintained at the set concentration.

[0061] As shown in Figure 4, the concentration prediction result 75 is based on Raman spectrum data 80 of the culture medium CM. The Raman spectrum data 80 tends to reflect the physical properties of the culture medium CM. Therefore, by using the Raman spectrum data 80, a highly reliable concentration prediction result 75 can be obtained. Note that the spectroscopic spectrum data is not limited to the exemplified Raman spectrum data 80. It may also be infrared absorption spectrum data, near-infrared absorption spectrum data, nuclear magnetic resonance spectrum data, ultraviolet-visible absorption spectroscopy (UV-Vis) spectrum data, or fluorescence spectrum data.

[0062] 1, the mixing vessel 16 is equipped with a sensor unit 42 of a Raman spectrometer 41, which is a measuring instrument for Raman spectral data 80. This allows for more accurate prediction of the concentration of the medium CM in the mixing vessel 16. Alternatively, a flow cell may be connected to an appropriate location on the medium supply path 35, such as upstream of the filter 38, and the sensor unit 42 may be attached to the flow cell to measure the Raman spectral data 80 of the medium CM flowing through the flow cell.

[0063] As shown in Figure 1, the solvent is pure water PW, the powder is powder medium PM, and the solution is medium CM. Therefore, medium CM of a set concentration, which is essential for cultivation, can be prepared at a lower cost than conventional methods.

[0064] Second Embodiment In the first embodiment, the concentration adjustment process is exemplified as a process of diluting the culture medium CM by supplying pure water PW to the mixing container 16, but the present invention is not limited to this.

[0065] 7, in the second embodiment, at time TG before time TH at which the cumulative amount of medium CM flowing into mixing container 16 reaches the required amount -Δ, a concentration adjustment process is initiated under the control of powdered medium supply device drive control unit 66 to gradually reduce the amount of powdered medium PM supplied to mixing container 16 by powdered medium supply device 17. This concentration adjustment process, which gradually reduces the amount of powdered medium PM supplied, is completed by time TH at which the cumulative amount of medium CM flowing into mixing container 16 reaches the required amount -Δ. In this case, the period immediately before time TH at which the continuous supply of powdered medium PM to mixing container 16 is stopped (between time TG and TH) is an example of "when the continuous supply of powder to the mixing container is stopped" according to the technology of the present disclosure.

[0066] Even during the concentration adjustment process in which the supply amount of powdered medium PM is gradually reduced, the supply of a set amount of pure water PW to the mixing vessel 16 continues. In addition to the supply of a set amount of pure water PW to the mixing vessel 16, the supply of a set amount of medium CM from the mixing vessel 16 to the culture tank 11 also continues. Note that the times TG and TH can be calculated backward from the time TI when the supply of the required amount of medium CM from the mixing vessel 16 to the culture tank 11 is completed.

[0067] In the second embodiment, the concentration prediction unit 69 outputs a concentration prediction result 75 to the powdered medium supplying machine drive control unit 66. The powdered medium supplying machine drive control unit 66 adjusts the amount of powdered medium PM supplied to the mixing container 16 by the powdered medium supplying machine 17 so that the concentration prediction result 75 from the concentration prediction unit 69 matches the set concentration. That is, the powdered medium supplying machine drive control unit 66 performs a concentration adjustment process according to the concentration prediction result 75. As in the first embodiment, this prevents the concentration of the medium CM remaining in the mixing container 16 from increasing due to undissolved powdered medium PM, and maintains the concentration of the medium CM remaining in the mixing container 16 at the set concentration. The medium CM remaining in the mixing container 16, maintained at this set concentration, is supplied from the mixing container 16 to the culture tank 11 by the medium supplying pump 36 under the control of the medium supplying pump drive control unit 68, as an additional supply of the required amount by the sufficiency amount Δ. Then, at time TI, when the required amount of medium CM has been supplied from the mixing vessel 16 to the culture vessel 11, the supply of medium CM from the mixing vessel 16 to the culture vessel 11 is stopped.

[0068] In this way, in the second embodiment, the powdered medium supplying device drive control unit 66 performs a concentration adjustment process by gradually reducing the supply amount of powdered medium PM. This concentration adjustment process also suppresses an increase in the concentration of medium CM due to undissolved powdered medium PM, so as in the first embodiment, it is possible to reduce the amount of powdered medium PM that is wasted, thereby enabling cost savings.

[0069] The time when the culture in the culture tank 11 is to be completed is preset, and the time TE in the first embodiment or the time TG and TH in the second embodiment is calculated backward from the preset time. Then, the concentration adjustment process may be started at the calculated time TE or TG.

[0070] The concentration adjustment process may be performed using a preset supply amount of pure water PW or powdered medium PM without referring to the concentration prediction result 75. In this case, the supply amount of pure water PW or powdered medium PM is set based on various parameters such as the dissolution rate of the powdered medium PM and the amount of undissolved powdered medium PM at the start of the concentration adjustment process. In this case, the supply amount of pure water PW or powdered medium PM may be changed linearly or in a stepwise manner.

[0071] The method for measuring the concentration of the culture medium CM is not limited to the method using spectroscopic data such as the exemplified Raman spectrum data 80. A conductivity meter may be connected to the mixing container 16 or the culture medium supply path 35, and the conductivity measured by the conductivity meter may be converted into concentration. An example of the connection location of the conductivity meter is a location in the culture medium supply path 35 between the culture medium flow meter 37 and the hydrogen ion exponent meter 45. Alternatively, the hydrogen ion exponent measured by the hydrogen ion exponent meter 45 may be converted into concentration.

[0072] The method for timing the cessation of waste liquid of medium CM and the start of supply to the culture tank 11 is not limited to a method based on the concentration measurement results. The time until the concentration of medium CM reaches a set concentration is measured and stored in advance. Then, the elapsed time from the start of continuous supply of pure water PW and powdered medium PM to the mixing vessel 16 is measured, and when the elapsed time reaches the stored time, the cessation of waste liquid of medium CM and the start of supply to the culture tank 11 may be stopped.

[0073] In the above embodiments, pure water PW is used as an example of the solvent and purified water, but this is not limited to this. Distilled water, etc., may also be used. Furthermore, in the above embodiments, the medium CM is used as an example of the solution, but this is not limited to this. The solution may also be a buffer solution. Therefore, the powder is not limited to the exemplified powder medium PM, but may also be a powder that constitutes the solid component of the buffer solution.

[0074] In each of the above embodiments, the hardware structure of the processing unit that executes various processes, such as the pure water supply pump drive control unit 65, the powder culture medium supply machine drive control unit 66, the agitator drive control unit 67, the culture medium supply pump drive control unit 68, the concentration prediction unit 69, and the three-way valve drive control unit 70, can be any of the various processors shown below. As described above, the various processors include the CPU 51, which is a general-purpose processor that executes software (operating program 60) and functions as various processing units, as well as programmable logic devices (PLDs) that are processors whose circuit configuration can be changed after manufacture, such as FPGAs (Field Programmable Gate Arrays), and dedicated electrical circuits that are processors having a circuit configuration designed specifically for executing specific processing, such as ASICs (Application Specific Integrated Circuits).

[0075] A single processing unit may be configured with one of these various processors, or may be configured with a combination of two or more processors of the same or different types (e.g., a combination of multiple FPGAs and / or a combination of a CPU and an FPGA).Furthermore, multiple processing units may be configured with a single processor.

[0076] Examples of configuring multiple processing units with a single processor include, first, a form in which one processor is configured with a combination of one or more CPUs and software, as typified by computers such as client and server, and this processor functions as multiple processing units. Second, a form in which a processor is used to realize the functions of the entire system including multiple processing units with a single IC (Integrated Circuit) chip, as typified by systems on chips (SoCs). In this way, various processing units are configured using one or more of the above-mentioned various processors as a hardware structure.

[0077] Furthermore, more specifically, the hardware structure of these various processors can be an electric circuit (circuitry) that combines circuit elements such as semiconductor elements.

[0078] From the above description, the technology described in the following supplementary paragraphs can be understood.

[0079] [Supplementary Item 1] A solution preparation apparatus that continuously prepares a solution of a set concentration in a mixing container by continuously supplying a solvent and a powder to the mixing container, and continuously supplies the solution of the set concentration from the mixing container to a processing container, the solution preparation apparatus comprising: a processor that, when the continuous supply of the powder to the mixing container is stopped, performs a concentration adjustment process on the solution remaining in the mixing container to maintain the set concentration, and supplies the solution of the set concentration that has been subjected to the concentration adjustment process to the processing container, thereby satisfying the required amount of solution of the set concentration. [Supplementary Item 2] The solution preparation apparatus according to Supplementary Item 1, in which the processor performs a process of diluting the solution by supplying the solvent to the mixing container as the concentration adjustment process. [Supplementary Item 3] The solution preparation apparatus according to Supplementary Item 1, in which the processor performs a process of gradually reducing the amount of powder supplied as the concentration adjustment process. [Supplementary Item 4] The solution preparation device according to any one of Supplementary Items 1 to 3, wherein the processor performs the concentration adjustment process according to a measurement result of the concentration of the solution. [Supplementary Item 5] The solution preparation device according to Supplementary Item 4, wherein the measurement result is based on spectroscopic spectrum data of the solution. [Supplementary Item 6] The solution preparation device according to Supplementary Item 5, wherein a measuring device for the spectroscopic spectrum data is installed in the mixing container. [Supplementary Item 7] The solution preparation device according to any one of Supplementary Items 1 to 6, wherein the solvent is purified water, the powder is a powder culture medium, and the solution is a culture medium.

[0080] The technology of the present disclosure can be appropriately combined with the various embodiments and / or various modified examples described above. Furthermore, it is not limited to the above-described embodiments, and various configurations can be adopted without departing from the spirit of the present disclosure. Furthermore, the technology of the present disclosure extends not only to programs, but also to storage media that non-temporarily store programs, and computer program products that include programs.

[0081] The above-described description and illustrations are a detailed explanation of the parts related to the technology of the present disclosure and are merely an example of the technology of the present disclosure. For example, the above description of the configuration, functions, actions, and effects is an explanation of an example of the configuration, functions, actions, and effects of the parts related to the technology of the present disclosure. Therefore, it goes without saying that unnecessary parts may be deleted, new elements may be added, or replacements may be made to the above-described description and illustrations within the scope of the gist of the technology of the present disclosure. Furthermore, to avoid confusion and facilitate understanding of the parts related to the technology of the present disclosure, the above-described description and illustrations omit explanations of common technical knowledge that do not require particular explanation to enable the implementation of the technology of the present disclosure.

[0082] In this specification, "A and / or B" is synonymous with "at least one of A and B." In other words, "A and / or B" means that it may be only A, only B, or a combination of A and B. Furthermore, in this specification, the same concept as "A and / or B" is also applied when three or more things are expressed by connecting them with "and / or."

[0083] All publications, patent applications, and technical standards mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent application, or technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. A solution preparation apparatus that continuously prepares a solution of a set concentration in a mixing container by continuously supplying a solvent and a powder to the mixing container, and continuously supplies the solution of the set concentration from the mixing container to a processing container, the solution preparation apparatus comprising: a processor, wherein when the continuous supply of the powder to the mixing container is stopped, the processor performs a concentration adjustment process on the solution remaining in the mixing container to maintain the set concentration, and supplies the solution of the set concentration that has been subjected to the concentration adjustment process to the processing container, thereby satisfying the required amount of solution of the set concentration.

2. The solution preparation device according to claim 1, wherein the processor performs a process of diluting the solution by supplying the solvent to the mixing container as the concentration adjustment process.

3. The solution preparation device according to claim 1, wherein the processor performs the concentration adjustment process by gradually decreasing the amount of powder supplied.

4. The solution preparation device according to claim 1, wherein the processor performs the concentration adjustment process in accordance with a measurement result of the concentration of the solution.

5. The solution preparation apparatus according to claim 4, wherein the measurement results are based on spectroscopic spectrum data of the solution.

6. The solution preparation apparatus according to claim 5, wherein a measuring device for measuring the spectroscopic data is installed in the mixing vessel.

7. The solution preparation device according to claim 1, wherein the solvent is purified water, the powder is a powder culture medium, and the solution is a culture medium.

8. A method for operating a solution preparation device that continuously prepares a solution of a set concentration in a mixing container by continuously supplying a solvent and a powder to the mixing container, and continuously supplies the solution of the set concentration from the mixing container to a processing container, the method comprising: when the continuous supply of the powder to the mixing container is stopped, performing a concentration adjustment process on the solution remaining in the mixing container to maintain the set concentration; and supplying the solution of the set concentration that has been subjected to the concentration adjustment process to the processing container, thereby satisfying the required amount of the solution of the set concentration.

9. An operating program for a solution preparation device that continuously prepares a solution of a set concentration in a mixing container by continuously supplying a solvent and a powder to the mixing container, and continuously supplies the solution of the set concentration from the mixing container to a processing container, the operating program for the solution preparation device causing a computer to execute processes including: when the continuous supply of the powder to the mixing container is stopped, performing a concentration adjustment process on the solution remaining in the mixing container to maintain the set concentration; and supplying the solution of the set concentration that has been subjected to the concentration adjustment process to the processing container, thereby satisfying the required amount of solution of the set concentration.

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