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

Abstract

This solution preparation device comprises: a first pump that continuously causes a solvent to flow into a mixing container; a powder feeder that continuously supplies powder to the mixing container; a stirrer that stirs the solvent and the powder in the mixing container; and a second pump that causes a solution of a set concentration prepared by mixing the solvent and the powder to continuously flow out from the mixing container. The solution preparation device includes a processor that controls driving of the first pump, the powder feeder, the stirrer, and the second pump. The processor periodically changes at least one among the inflow amount of the solvent caused to flow into the mixing container by the first pump, the outflow amount of the solution caused to flow out from the mixing container by the second pump, and the stirring rotation speed of the stirrer.

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 bioprocess vessel, and the solution is continuously supplied from the mixing vessel to the bioprocess 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 bioprocess vessel is, for example, a culture tank.

[0003] There is a considerable amount of undissolved powder in the mixing vessel. If this undissolved powder accumulates on the surface of the solution and / or the bottom of the mixing vessel, the amount of the undissolved powder increases unnecessarily, and the continuous powder dissolution process does not reach a steady state, causing the solution concentration to become unstable. However, WO 2021 / 123248 does not address the problem of instability of the solution concentration due to the unnecessary accumulation of undissolved powder.

[0004] One embodiment of the technology of the present disclosure provides a solution preparation device, an operating method for the solution preparation device, and an operating program for the solution preparation device that can contribute to stabilizing the solution concentration due to undissolved powder.

[0005] The solution preparation apparatus of the present disclosure includes a first pump that continuously flows a solvent into a mixing container, a powder supplying machine that continuously supplies a powder to the mixing container, an agitator that agitates the solvent and powder in the mixing container, and a second pump that continuously flows out a solution of a set concentration prepared by mixing the solvent and powder from the mixing container, and the solution preparation apparatus includes a processor that controls the operation of the first pump, the powder supplying machine, the agitator, and the second pump, and the processor periodically varies at least one of the amount of solvent flowing into the mixing container by the first pump, the amount of solution flowing out of the mixing container by the second pump, and the agitation rotation speed by the agitator.

[0006] It is preferable that the fluctuation amplitude and fluctuation period of at least one of the inflow volume, outflow volume, and stirring rotation speed are set to values ​​that bring the concentration fluctuation of the solution caused by periodic fluctuation of at least one of the inflow volume, outflow volume, and stirring rotation speed within an acceptable range.

[0007] It is preferable that the concentration fluctuation index CFI shown in the following formula is equal to or less than the amount L of liquid in the mixing vessel: CFI = {(V x T) / 60} x A, where V is the set amount of inflow or outflow, A is the fluctuation amplitude of at least one of the inflow and outflow amounts, and T is the fluctuation period of at least one of the inflow and outflow amounts.

[0008] When the processor periodically varies the stirring rotation speed, it is preferable that the processor also periodically varies the stirring rotation direction of the stirrer.

[0009] Preferably, the solvent is purified water, the powder is a powder medium, and the solution is a medium.

[0010] The method of operating a solution preparation apparatus disclosed herein includes a first pump that continuously flows a solvent into a mixing container, a powder supplying machine that continuously supplies a powder to the mixing container, an agitator that agitates the solvent and powder in the mixing container, and a second pump that continuously flows out a solution of a set concentration prepared by mixing the solvent and powder from the mixing container, and includes controlling the operation of the first pump, the powder supplying machine, the agitator, and the second pump, and periodically varying at least one of the amount of solvent flowing into the mixing container by the first pump, the amount of solution flowing out of the mixing container by the second pump, and the agitation rotation speed by the agitator.

[0011] The operating program for the solution preparation apparatus of the present disclosure is an operating program for a solution preparation apparatus including a first pump that continuously flows a solvent into a mixing container, a powder supplying machine that continuously supplies a powder to the mixing container, an agitator that agitates the solvent and powder in the mixing container, and a second pump that continuously flows out of the mixing container a solution of a set concentration prepared by mixing the solvent and powder, and causes a computer to execute processes including controlling the operation of the first pump, the powder supplying machine, the agitator, and the second pump, and periodically varying at least one of the amount of solvent flowing into the mixing container by the first pump, the amount of solution flowing out of the mixing container by the second pump, and the agitation rotation speed by the agitator.

[0012] According to the technology of the present disclosure, 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 contribute to stabilizing the solution concentration due to undissolved powder.

[0013] 1 is a diagram illustrating a culture medium preparation device and a culture tank. FIG. 2 is a block diagram illustrating the configuration of a control unit. FIG. 3 is a block diagram illustrating the processing unit of a CPU. FIG. 4 is a graph illustrating the time change in the inflow amount of pure water into a mixing container. FIG. 5 is a graph illustrating the time change in the concentration of the culture medium. FIG. 6 is a graph illustrating a method for setting the fluctuation amplitude and fluctuation period of the inflow amount of pure water into a mixing container. FIG. 7 is a diagram illustrating a concentration fluctuation index, and conditions for the concentration fluctuation index and the amount of liquid in the mixing container under which the concentration fluctuation of the culture medium in the mixing container falls within an allowable range. FIG. 8 is a block diagram illustrating the processing unit of a CPU of a second embodiment. FIG. 9 is a graph illustrating the time change in the outflow amount of culture medium from the mixing container. FIG. 10 is a block diagram illustrating the processing unit of a CPU of a third embodiment. FIG. 11 is a graph illustrating the time change in the stirring rotation speed. FIG. 12 is a graph illustrating an aspect in which the stirring rotation direction is also periodically changed in addition to the periodic fluctuation of the stirring rotation speed. FIG. 13 is a table illustrating examples and comparative examples.

[0014] [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 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.

[0015] 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.

[0016] 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.

[0017] 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. The pure water supply pump 22 is an example of the "first pump" according to the technology of the present disclosure. 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. The set inflow rate is an example of the "set amount of inflow rate or outflow rate" according to the technology of the present disclosure.

[0018] The mixing container 16 is a container for mixing pure water PW and powdered medium PM to produce medium CM at a set concentration, and has, for example, a wide cylindrical shape. 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 for the powdered medium PM of the powdered medium supply device 17 is aseptically connected to the upper end of the through-hole 26. This aseptically connects the mixing container 16 and the powdered medium supply device 17. The powdered medium PM discharged from the outlet 27 is supplied to the mixing container 16 through the through-hole 26. The powdered medium PM is an example of a "powder" according to the technology of the present disclosure.

[0019] The powdered medium supplying machine 17 is an example of a "powder supplying machine" according to the technology of the present disclosure. 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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. The medium supply pump 36 is an example of a "second pump" according to the technology of the present disclosure. 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 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 is equal to the set outflow rate. The set outflow rate is an example of a "set amount of inflow or outflow rate" according to the technology of the present disclosure.

[0024] The amount of pure water PW flowing into the mixing container 16 and the amount of medium CM flowing out from the mixing container 16 are set to values ​​that will keep the amount of liquid in the mixing container 16 constant from start to finish. More specifically, the amount of medium CM flowing out is set according to the combined amount of pure water PW flowing in and powder medium PM supplied. In practice, the weight of the mixing container 16 is measured with a weighing scale 34, and the amount of pure water PW flowing in and the amount of medium CM flowing out are set so that the measured weight is the set amount.

[0025] 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.

[0026] A conductivity meter 39 and a hydrogen ion exponent meter 40 are disposed downstream of the medium flow meter 37 in the medium supply path 35. A waste liquid path 42 is connected to the medium supply path 35 downstream of the hydrogen ion exponent meter 40 via a three-way valve 41. The three-way valve 41 is driven and controlled by the control unit 19. A waste liquid recovery tank 18 is connected to the waste liquid path 42. The waste liquid recovery tank 18 recovers waste liquid WL, such as medium CM that does not have the set concentration or medium CM with an abnormal hydrogen ion exponent.

[0027] The conductivity meter 39 measures the conductivity (unit: mS / cm) of the medium CM passing through the medium supply path 35 as a proxy for the concentration of the medium CM. The conductivity meter 39 outputs the measured conductivity to the control unit 19. The control unit 19 determines whether the medium CM is at the set concentration based on the conductivity from the conductivity meter 39. If the control unit 19 determines that the medium CM is not at the set concentration, the control unit 19 switches the flow path of the three-way valve 41 to the waste flow path 42 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 the control unit 19 determines that the medium CM is at the set concentration, the control unit 19 switches the flow path of the three-way valve 41 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.

[0028] The hydrogen ion exponent meter 40 measures the hydrogen ion exponent of the culture medium CM passing through the culture medium supply path 35. The hydrogen ion exponent meter 40 outputs the measured hydrogen ion exponent to the control unit 19. If the hydrogen ion exponent value from the hydrogen ion exponent meter 40 is an abnormal value, the control unit 19 switches the flow path of the three-way valve 41 to the waste liquid path 42 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.

[0029] 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 end 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.

[0030] 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 41, and waste liquid line 42 are also single-use.

[0031] 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 41, and the waste liquid path 42 are also connected in a sterile manner.

[0032] 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.

[0033] 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.

[0034] 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.

[0035] 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 fluctuation amplitude / fluctuation period information 61 and the like.

[0036] 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, and a three-way valve drive control unit 69.

[0037] 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 the fluctuation amplitude / fluctuation period information 61. The drive control of the pure water supply pump 22 based on the fluctuation amplitude / fluctuation period information 61 will be described later.

[0038] 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.

[0039] 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 three-way valve drive control unit 69 controls the drive of the three-way valve 41 based on the conductivity of the culture medium CM measured by the conductivity meter 39 and the hydrogen ion exponent of the culture medium CM measured by the hydrogen ion exponent meter 40.

[0040] 4, the fluctuation amplitude / fluctuation period information 61 registers the fluctuation amplitude AI and fluctuation period TI of the inflow rate of pure water PW into the mixing container 16 by the pure water supply pump 22. The pure water supply pump drive control unit 65 periodically fluctuates the inflow rate of pure water PW into the mixing container 16 around a set inflow rate, using the fluctuation amplitude AI and fluctuation period TI registered in the fluctuation amplitude / fluctuation period information 61. By periodically fluctuating the inflow rate of pure water PW into the mixing container 16 in this manner, the liquid level of the liquid in the mixing container 16 also periodically fluctuates. Furthermore, since the inflow rate of pure water PW into the mixing container 16 is periodically fluctuated around the set inflow rate, on average, the inflow rate of pure water PW into the mixing container 16 becomes the set inflow rate.

[0041] Periodically varying the inflow rate of pure water PW into the mixing vessel 16 provides a moderate stimulus to the liquid in the mixing vessel 16. This makes it less likely that undissolved powdered medium PM will accumulate on the surface of the medium CM in the mixing vessel 16 and / or on the bottom of the mixing vessel 16, compared to when no stimulus is applied to the liquid in the mixing vessel 16. To further reduce the likelihood of undissolved powdered medium PM accumulating, the fluctuation amplitude AI can be increased or the fluctuation period TI can be lengthened. However, increasing the fluctuation amplitude AI or lengthening the fluctuation period TI can result in concentration fluctuations in the medium CM in the mixing vessel 16 that are outside the acceptable range, as shown by the dashed-dot line in the graph of FIG. 5 . Conversely, decreasing the fluctuation amplitude AI and shortening the fluctuation period TI can reduce the concentration fluctuations in the medium CM in the mixing vessel 16 to within the acceptable range, as shown by the solid line in the graph of FIG. 5 , but the effect of reducing the likelihood of undissolved powdered medium PM accumulating is diminished. That is, there are optimum values ​​for the fluctuation amplitude AI and fluctuation period TI of the inflow rate of the pure water PW into the mixing vessel 16 .

[0042] Here, the concentration fluctuation is, in other words, the rate of change in concentration, and is calculated, for example, by the following formula (1): Concentration fluctuation = [(maximum value - minimum value) / {(maximum value + minimum value) / 2}] × 100 (1) The maximum and minimum values ​​are the maximum and minimum values ​​of the conductivity of the medium CM measured by the conductivity meter 39 until the concentration of the medium CM in the mixing container 16 reaches a steady state. The steady state is, for example, a state in which the concentration of the medium CM in the mixing container 16 remains at a set concentration ±α for a set period of time.

[0043] If the concentration fluctuation is large, it takes a long time for the concentration of the medium CM in the mixing container 16 to converge to a steady state, and therefore the amount of medium CM not at the set concentration that is discharged as waste liquid WL increases. The allowable range of concentration fluctuation is set based on the limit amount of medium CM not at the set concentration that is discharged as waste liquid WL. The allowable range of concentration fluctuation is, for example, 3% or less.

[0044] Prior to operating the culture medium preparation apparatus 10, the operator performs the setting experiment described below to set the fluctuation amplitude AI and fluctuation period TI of the inflow rate of pure water PW into the mixing container 16. Specifically, as shown in FIG. 6 as an example, the fluctuation amplitude AI and fluctuation period TI are set to various values, and a culture medium CM of a set concentration is actually prepared in the mixing container 16. The concentration fluctuations of each are calculated. The operator then sets the fluctuation amplitude AI and fluctuation period TI to a value below the dashed line that is sufficiently effective in preventing the accumulation of undissolved powder culture medium PM and that keeps the concentration fluctuation within an acceptable range. The operator stores the set fluctuation amplitude AI and fluctuation period TI in the storage 50 as fluctuation amplitude / fluctuation period information 61. In FIG. 6, the size of the circle represents the magnitude of the concentration fluctuation, and the numbers inside or beside the circle represent the concentration fluctuation.

[0045] In the experiment setup, the operator also sets the amount of liquid in the mixing container 16. Specifically, the amount of liquid is gradually increased from a small value, and the medium CM is actually prepared in the mixing container 16 while periodically varying the inflow rate of the pure water PW into the mixing container 16 with the previously set fluctuation amplitude AI and fluctuation period TI. Then, the minimum value that can be visually determined to be effective in preventing the accumulation of undissolved powder medium PM is set as the amount of liquid in the mixing container 16.

[0046] To make it difficult for undissolved powdered medium PM to accumulate, it is better to have a large amount of liquid in the mixing container 16. However, as the amount of liquid in the mixing container 16 increases, the capacity of the mixing container 16 increases accordingly, and the installation area of ​​the mixing container 16 also increases. For this reason, the amount of liquid in the mixing container 16 is set to the minimum value that can be expected to have a sufficient effect of making it difficult for undissolved powdered medium PM to accumulate.

[0047] 7, the operator sets the set inflow volume VI of the pure water PW and the fluctuation amplitude AI and fluctuation period TI of the inflow volume of the pure water PW into the mixing vessel 16 so that the concentration fluctuation index CFI is equal to or less than the amount L of liquid in the mixing vessel 16 (CFI≦L). If the concentration fluctuation index CFI is equal to or less than the amount L of liquid in the mixing vessel 16, the concentration fluctuation of the culture medium CM in the mixing vessel 16 caused by periodic fluctuations in the inflow volume of the pure water PW into the mixing vessel 16 falls within the allowable range. The concentration fluctuation index CFI is expressed by the following formula (2A): CFI={(VI×TI) / 60}×AI (2A)

[0048] Next, the operation of the above configuration will be described. First, before operating the culture medium preparation apparatus 10, the operator performs the setting experiment shown in FIG. 6 to set the fluctuation amplitude AI and fluctuation period TI of the inflow rate of pure water PW into the mixing container 16. The set fluctuation amplitude AI and fluctuation period TI are stored in the storage 50 by the operator as fluctuation amplitude / fluctuation period information 61. The amount of liquid in the mixing container 16 is also set by the operator. The set inflow rate VI of pure water PW and the fluctuation amplitude AI and fluctuation period TI of the inflow rate of pure water PW into the mixing container 16 are set to values ​​such that the concentration fluctuation index CFI is equal to or less than the amount L of liquid in the mixing container 16.

[0049] An operator issues an instruction to start preparation of culture medium CM via the operation unit 20. As a result, under the control of the pure water supply pump drive control unit 65, the pure water supply pump 22 is driven to supply pure water PW to the mixing container 16. At the same time, under the control of the powdered culture medium supply machine drive control unit 66, the powdered culture medium supply machine 17 is driven to supply powdered culture medium PM to the mixing container 16. In other words, continuous supply of pure water PW and powdered culture medium PM to the mixing container 16 begins.

[0050] 4, the pure water supply pump drive control unit 65 periodically varies the inflow rate of pure water PW into the mixing vessel 16 at the fluctuation amplitude AI and fluctuation period TI of the fluctuation amplitude / fluctuation period information 61. Also, under the control of the agitator drive control unit 67, the agitator 32 is driven to rotate the agitator 33 at a set agitation rotation speed.

[0051] Shortly after the start of supplying the pure water PW and the powdered medium PM to the mixing container 16, the medium supply pump 36 is driven under the control of the medium supply pump drive control unit 68. The amount of pure water PW flowing into the mixing container 16 and the amount of medium CM flowing out of the mixing container 16 are adjusted according to the weight measured by the weighing scale 34 so that the amount of liquid in the mixing container 16 becomes the value set in the experiment.

[0052] The three-way valve drive control unit 69 determines whether the medium CM is at the set concentration based on the conductivity measured by the conductivity meter 39. If it is determined that the medium CM is not at the set concentration, under the control of the three-way valve drive control unit 69, the flow path of the three-way valve 41 is switched to the waste liquid path 42 side, and the waste liquid WL, which is the medium CM not at the set concentration, is discharged to the waste liquid recovery tank 18. On the other hand, if it is determined that the medium CM is at the set concentration, under the control of the three-way valve drive control unit 69, the flow path of the three-way valve 41 is switched to the culture tank 11 side, and the medium CM at the set concentration is introduced into the culture tank 11.

[0053] The continuous supply of the pure water PW and the powdered medium PM to the mixing vessel 16 and the continuous supply of the medium CM to the culture tank 11 are continued until the end of the culture in the culture tank 11. When the culture in the culture tank 11 is completed, the operation of the pure water supply pump 22, the powdered medium supplier 17, the medium supply pump 36, etc. is stopped, and the supply of the pure water PW and the powdered medium PM to the mixing vessel 16 and the supply of the medium CM to the culture tank 11 are stopped.

[0054] As described above, the culture medium preparation apparatus 10 includes the pure water supply pump 22 that continuously introduces pure water PW into the mixing container 16, the powdered culture medium supplier 17 that continuously supplies powdered culture medium PM to the mixing container 16, the agitator 32 that agitates the pure water PW and the powdered culture medium PM in the mixing container 16, and the culture medium supply pump 36 that continuously discharges the culture medium CM of a set concentration prepared by mixing the pure water PW and the powdered culture medium PM from the mixing container 16. The culture medium preparation apparatus 10 includes a CPU 51 that controls the operation of the pure water supply pump 22, the powdered culture medium supplier 17, the agitator 32, and the culture medium supply pump 36. The pure water supply pump drive control unit 65 of the CPU 51 periodically varies the amount of pure water PW that flows into the mixing container 16 by the pure water supply pump 22. This makes it difficult for undissolved powder medium PM to accumulate on the liquid surface of the medium CM in the mixing container 16 and / or on the bottom surface of the mixing container 16, which can contribute to stabilizing the concentration of the medium CM.

[0055] 5 and 6, the fluctuation amplitude AI and fluctuation period TI of the inflow rate of pure water PW into the mixing vessel 16 are set to values ​​that keep the concentration fluctuation of the culture medium CM caused by periodic fluctuations in the inflow rate within an allowable range, thereby reducing the amount of culture medium CM not having the set concentration that is discharged as waste liquid WL.

[0056] 7, the set inflow volume VI of pure water PW and the fluctuation amplitude AI and fluctuation period TI of the inflow volume of pure water PW into the mixing container 16 are set so that the concentration fluctuation index CFI is equal to or less than the amount L of liquid in the mixing container 16. Therefore, the concentration fluctuation of the medium CM in the mixing container 16 caused by periodic fluctuations in the inflow volume of pure water PW into the mixing container 16 can be kept within an allowable range. As a result, the amount of medium CM not having the set concentration discharged as waste liquid WL can be reduced.

[0057] 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 the set concentration essential for culture can be prepared in a short time.

[0058] Second Embodiment In the first embodiment, the amount of pure water PW flowing into the mixing vessel 16 is periodically varied, but the present invention is not limited to this.

[0059] As shown in FIG. 8 as an example, in the second embodiment, fluctuation amplitude / fluctuation period information 75 is provided to the culture medium supply pump drive control unit 68. As shown in FIG. 9 as an example, the fluctuation amplitude / fluctuation period information 75 includes the fluctuation amplitude AO and fluctuation period TO of the outflow rate of culture medium CM from the mixing container 16 by the culture medium supply pump 36. As in the first embodiment, the fluctuation amplitude AO and fluctuation period TO are set to appropriate values ​​that are expected to sufficiently prevent the accumulation of undissolved powder culture medium PM and that keep concentration fluctuations within an acceptable range, as determined through experimental setup. The culture medium supply pump drive control unit 68 periodically fluctuates the inflow rate of culture medium CM from the mixing container 16 around the set outflow rate using the fluctuation amplitude AO and fluctuation period TO registered in the fluctuation amplitude / fluctuation period information 75. As in the first embodiment, periodically fluctuating the inflow rate of culture medium CM from the mixing container 16 in this manner provides an appropriate stimulation to the liquid in the mixing container 16. Furthermore, since the outflow rate of the medium CM from the mixing container 16 is periodically varied around the set outflow rate, on average the outflow rate of the medium CM from the mixing container 16 becomes the set outflow rate.

[0060] Thus, in the second embodiment, the culture medium supply pump drive control unit 68 of the CPU 51 periodically varies the amount of culture medium CM flowing out from the mixing container 16 by the culture medium supply pump 36. This method also makes it difficult for undissolved powder culture medium PM to accumulate on the liquid surface of the culture medium CM in the mixing container 16 and / or on the bottom surface of the mixing container 16, which can contribute to stabilizing the concentration of the culture medium CM.

[0061] The concentration fluctuation index CFI in the second embodiment is expressed by the following formula (2B): CFI={(VO×TO) / 60}×AO (2B) where VO is the set outflow amount of pure water PW.

[0062] The first and second embodiments may be combined. That is, the inflow rate of pure water PW into the mixing container 16 may be periodically varied, and the outflow rate of medium CM from the mixing container 16 may be periodically varied. In this case, the fluctuation period TI of the inflow rate of pure water PW into the mixing container 16 and the fluctuation period TO of the outflow rate of medium CM from the mixing container 16 are made the same. Furthermore, the waveforms of the inflow rate of pure water PW into the mixing container 16 and the waveforms of the outflow rate of medium CM from the mixing container 16 are made in phase so as to reinforce each other.

[0063] [Third Embodiment] In the third embodiment, as shown in FIG. 10 , fluctuation amplitude / fluctuation period information 80 is provided to the agitator drive control unit 67. As shown in FIG. 11 , the fluctuation amplitude / fluctuation period information 80 includes the fluctuation amplitude AR and fluctuation period TR of the agitation rotation speed of the agitator 33 by the agitator 32. As in the first and second embodiments, the fluctuation amplitude AR and fluctuation period TR are set to appropriate values ​​that are expected to sufficiently prevent the accumulation of undissolved powder medium PM and that keep concentration fluctuations within an acceptable range, as determined through experimental setup. The agitator drive control unit 67 periodically fluctuates the agitation rotation speed of the agitator 32's agitator 33 around the set rotation speed, using the fluctuation amplitude AR and fluctuation period TR registered in the fluctuation amplitude / fluctuation period information 80. As in the first and second embodiments, periodically fluctuating the agitation rotation speed in this manner provides an appropriate stimulation to the liquid in the mixing container 16. Furthermore, since the stirring rotation speed is periodically varied around the set rotation speed, on average the stirring rotation speed becomes the set rotation speed.

[0064] Thus, in the third embodiment, the agitator drive control unit 67 of the CPU 51 periodically varies the agitation rotation speed of the agitator 32's agitator bar 33. This method also makes it difficult for undissolved powdered medium PM to accumulate on the liquid surface of the medium CM in the mixing container 16 and / or on the bottom surface of the mixing container 16, which can contribute to stabilizing the concentration of the medium CM.

[0065] As an example, as shown in Fig. 12, not only the rotation speed of the stirrer 33 but also the rotation direction of the stirrer 33 may be periodically changed. Fig. 12 illustrates a case where the rotation direction of the stirrer 33 is switched between clockwise (CW) and counterclockwise (CCW) every cycle. By periodically changing the rotation direction of the stirrer 33 in this manner, undissolved powder medium PM is less likely to accumulate on the liquid surface in the mixing container 16 and / or on the bottom surface of the mixing container 16, and the concentration of the medium CM can be further stabilized.

[0066] The first embodiment and the third embodiment, the second embodiment and the third embodiment, or the first and second embodiments and the third embodiment may be combined and implemented.

[0067] In all of the above first to third embodiments, existing components of the culture medium preparation apparatus 10, such as the pure water supply pump 22, the agitator 32, and the culture medium supply pump 36, are used to provide an appropriate stimulus to the liquid in the mixing container 16. Therefore, compared to an embodiment in which new components are added to provide an appropriate stimulus to the liquid in the mixing container 16, it is possible to prevent the culture medium preparation apparatus 10 from becoming too costly and large in scale.

[0068] [Examples] Figure 13 shows Table 85 summarizing the examples and comparative examples. First, the equipment used in the examples and comparative examples will be listed. A beaker manufactured by HARIO Corporation was used as the mixing container 16. A powder metering feeder (model number PSF-100SA) manufactured by AS ONE Corporation was used as the powder medium feeder 17. A Tornado (mixer) with timer (model number SMT-104) manufactured by AS ONE Corporation was used as the agitator for breaking up the ratholes in the hopper 30.

[0069] For each of the channels such as the pure water supply channel 21, the culture medium supply channel 35, and the waste channel 42, a lab silicone tube (product number 9-869-07, inner diameter x outer diameter = φ4 mm x φ6 mm) manufactured by AS ONE Corporation was used, cut appropriately.

[0070] A Masterflex pump (model number 07528-30) manufactured by Yamato Scientific Co., Ltd. was used as the drive unit for the pure water supply pump 22 and the culture medium supply pump 36. A Masterflex pump head (model number 77201-60) manufactured by Yamato Scientific Co., Ltd. was used as the pump head for the pure water supply pump 22 and the culture medium supply pump 36. The drive unit for the pure water supply pump 22 and the culture medium supply pump 36 was the same Masterflex pump described above, and two of the Masterflex pump heads described above were attached to one Masterflex pump.

[0071] The pure water flow meter 23 and the culture medium flow meter 37 were clamp-on flow sensors (model number FD-XA1) manufactured by Keyence Corporation.

[0072] An Ultra Stirrer (Model No. MSD-1) manufactured by AS ONE Corporation was used as the stirrer 32. A regular stirrer (Model No. C 8×30, diameter×length=φ8 mm×30 mm) manufactured by AS ONE Corporation was used as the stirrer 33.

[0073] The main body of the conductivity meter 39 and the hydrogen ion index meter 40 was a benchtop pH (Potential Hydrogen) / electrical conductivity meter (model number F-74) manufactured by Horiba, Ltd. The electrodes of the conductivity meter 39 were a general-purpose electrical conductivity cell (model number 3562-10D) manufactured by Horiba, Ltd. The electrodes of the hydrogen ion index meter 40 were a refill-free pH electrode (model number 9652-20D) manufactured by Horiba, Ltd. Both of these electrodes are capable of measuring conductivity and hydrogen ion index in-line. The flow cell installed together with these electrodes was a flow cell manufactured by Horiba, Ltd. (product number 3200844642).

[0074] Next, the materials used in the examples and comparative examples are listed below. As the powder medium PM, Gibco Minimum Essential Medium (MEM) (product number 41500083) was used.

[0075] Finally, the experimental conditions for the examples and comparative examples are listed below. The set inflow rate of pure water PW and the set outflow rate of culture medium CM are 100 ml / min unless otherwise specified. The supply rate of powdered culture medium PM to the mixing container 16 per unit time is 0.76 g / min. The screw rotation speed of the feeder 31 of the powdered culture medium supply device 17 is 1 rpm (rotations per minute). The set rotation speed of the stirrer 33 of the agitator 32 is 200 rpm unless otherwise specified. The measurement intervals of the conductivity meter 39 and the hydrogen ion exponent meter 40 are 10 seconds.

[0076] The flow rate of pure water PW was calculated from the amount of powder medium PM supplied, using a value that matched the "amount of water to be added per certain amount of powder" stated in the instruction manual for powder medium PM. The amount of powder medium PM supplied was determined by rotating the screw of feeder 31 at a set rotation speed to actually supply powder medium PM, and measuring the weight of powder medium PM supplied per unit time using an electronic balance. A compact balance (model number EW-150i) manufactured by A&D Co., Ltd. was used as the electronic balance.

[0077] As mentioned above, the amount of liquid in the mixing container 16 does not change from start to finish and is the value set in the experiment because the amount of pure water PW flowing into the mixing container 16 and the amount of culture medium CM flowing out of the mixing container 16 are appropriately controlled.

[0078] Examples 1 to 5 are examples employing the first embodiment, in which the inflow rate of pure water PW into the mixing container 16 was periodically varied. In Example 1, the inflow rate of pure water PW into the mixing container 16 was periodically varied with a fluctuation amplitude AI of 20% and a fluctuation period TI of 2000 seconds. In this case, the amount of liquid in the mixing container 16 was only 800 ml. Furthermore, the concentration fluctuation index CFI was 666.7, which was less than the amount of liquid in the mixing container 16. Furthermore, there was no accumulation of undissolved powdered medium PM, the installation area of ​​the mixing container 16 was small, and the concentration fluctuation of the medium CM due to the periodic fluctuation of the inflow rate of pure water PW into the mixing container 16 was within the acceptable range. Therefore, Example 1 is the best.

[0079] In Example 2, the fluctuation period TI was set longer, from 2000 seconds in Example 1 to 3000 seconds. The amount of liquid in the mixing container 16 in this case was also 800 ml, the same as in Example 1. However, the concentration fluctuation index CFI in this case was 1000, which was larger than the amount of liquid in the mixing container 16. There was no accumulation of undissolved powdered medium PM, and the installation area of ​​the mixing container 16 was small, the same as in Example 1. However, the concentration fluctuation of the medium CM due to periodic fluctuations in the inflow amount of pure water PW into the mixing container 16 was "outside the acceptable range." The concentration fluctuation was "outside the acceptable range" because the fluctuation period was set longer.

[0080] In Example 3, the fluctuation amplitude AI was set to 25%, higher than in Example 1, from 20%. The amount of liquid in the mixing container 16 in this case was 800 ml, the same as in Examples 1 and 2. However, the concentration fluctuation index CFI in this case was 833.3, which was larger than the amount of liquid in the mixing container 16. There was no accumulation of undissolved powdered medium PM, and the installation area of ​​the mixing container 16 was small, the same as in Examples 1 and 2. However, the concentration fluctuation of the medium CM due to periodic fluctuations in the inflow rate of pure water PW into the mixing container 16 was "outside the acceptable range," as in Example 2. The concentration fluctuation was "outside the acceptable range" because the fluctuation amplitude was set too high.

[0081] In Example 4, the set inflow rate of the pure water PW and the set outflow rate of the culture medium CM were 150 ml / min. The fluctuation amplitude AI and fluctuation period TI were the same as in Example 1. The amount of liquid in the mixing vessel 16 in this case was 2000 ml. The concentration fluctuation index CFI in this case was 1500, which was less than the amount of liquid in the mixing vessel 16. There was no accumulation of undissolved powder culture medium PM, and the concentration fluctuation of the culture medium CM due to periodic fluctuations in the inflow rate of the pure water PW into the mixing vessel 16 was within the acceptable range, but the installation area of ​​the mixing vessel 16 was large.

[0082] In Example 5, the fluctuation amplitude AI was set lower, from 20% in Example 1 to 10%, and the fluctuation period TI was set longer, from 2000 seconds in Example 1 to 4000 seconds. In this case, the amount of liquid in the mixing container 16 was 800 ml, the same as in Example 1. The concentration fluctuation index CFI was also 666.7, the same as in Example 1, which was less than the amount of liquid in the mixing container 16. Furthermore, there was no accumulation of undissolved powdered medium PM, the installation area of ​​the mixing container 16 was small, and the concentration fluctuation of the medium CM due to periodic fluctuations in the inflow rate of pure water PW into the mixing container 16 was within the acceptable range. Therefore, Example 5, like Example 1, is the best.

[0083] Examples 6 to 10 employ the third embodiment, but periodically vary the rotation speed of the stirrer 33 driven by the stirrer 32. In Example 6, the rotation speed of the stirrer 33 driven by the stirrer 32 is varied between 100 rpm and 300 rpm with a variation period TR of 60 seconds. The amount of liquid in the mixing vessel 16 in this case was 800 ml, the same as in Example 1. Furthermore, there was no accumulation of undissolved powdered medium PM, the installation area of ​​the mixing vessel 16 was small, and the concentration fluctuation of the medium CM due to the periodic variation in the rotation speed of the stirrer 33 driven by the stirrer 32 was within the acceptable range. Therefore, Example 6, like Example 1, is also the best.

[0084] In Example 7, the rotation speed of the stirrer 33 of the stirrer 32 was varied between 300 rpm and 600 rpm with a variation period TR of 60 seconds. The amount of liquid in the mixing vessel 16 in this case was 800 ml, the same as in Example 1. Furthermore, there was no accumulation of undissolved powdered medium PM, the installation area of ​​the mixing vessel 16 was small, and the concentration fluctuation of the medium CM due to the periodic fluctuation of the rotation speed of the stirrer 33 of the stirrer 32 was within the acceptable range. Therefore, Example 7, like Example 1, is also the best.

[0085] In Example 8, the stirring rotation speed of the stirrer 33 by the stirrer 32 was varied between 100 rpm and 300 rpm, the same as in Example 6, with a fluctuation period TR of 2000 seconds. The amount of liquid in the mixing vessel 16 in this case was also 800 ml, the same as in Example 1. Furthermore, there was no accumulation of undissolved powdered medium PM, and the installation area of ​​the mixing vessel 16 was small. However, the concentration fluctuation of the medium CM caused by the periodic fluctuation of the stirring rotation speed of the stirrer 33 by the stirrer 32 was outside the acceptable range. The concentration fluctuation was outside the acceptable range because the fluctuation period was set too long.

[0086] In Example 9, the stirring rotation speed of the stirrer 33 by the stirrer 32 was varied between 100 rpm and 300 rpm, the same as in Example 6, with a fluctuation period TR of 3,000 seconds. The amount of liquid in the mixing vessel 16 in this case was also 800 ml, the same as in Example 1. Furthermore, although there was no accumulation of undissolved powdered medium PM and the installation area of ​​the mixing vessel 16 was small, the concentration fluctuation of the medium CM caused by the periodic fluctuation of the stirring rotation speed of the stirrer 33 by the stirrer 32 was outside the acceptable range. The concentration fluctuation was outside the acceptable range because the fluctuation period was set too long.

[0087] In Example 10, the rotation speed of the stirrer 33 of the stirrer 32 was varied between 100 rpm and 600 rpm with a fluctuation period TR of 2000 seconds. The amount of liquid in the mixing vessel 16 in this case was 800 ml, the same as in Example 1. Although there was no accumulation of undissolved powdered medium PM and the installation area of ​​the mixing vessel 16 was small, the concentration fluctuation of the medium CM due to the periodic fluctuation of the rotation speed of the stirrer 33 of the stirrer 32 was outside the acceptable range. The concentration fluctuation was outside the acceptable range because the fluctuation amplitude was set high and the fluctuation period was set long.

[0088] In addition, examples employing the second embodiment, i.e., examples in which the outflow rate of culture medium CM from the mixing container 16 was periodically varied, are essentially the same as examples 1 to 5 employing the first embodiment, and therefore are not described here.

[0089] Comparative Examples 1 to 3 are examples in which the amount of liquid in the mixing container 16 was simply changed without periodically varying the amount of pure water PW flowing into the mixing container 16, periodically varying the amount of medium CM flowing out of the mixing container 16, or periodically varying the stirring rotation speed of the stirrer 33 by the agitator 32. Comparative Example 1 is a case in which the amount of liquid in the mixing container 16 was 500 ml. In this case, deposition of undissolved powdered medium PM was "present," and the installation area of ​​the mixing container 16 was "small." The deposition of undissolved powdered medium PM was "present" because the amount of liquid in the mixing container 16 was reduced.

[0090] Comparative Example 2 is a case where the amount of liquid in the mixing container 16 was 1000 ml. In this case, there was no accumulation of undissolved powdered medium PM, but the installation area of ​​the mixing container 16 was medium. Comparative Example 3 is a case where the amount of liquid in the mixing container 16 was 5000 ml. In this case, there was no accumulation of undissolved powdered medium PM, but the installation area of ​​the mixing container 16 was large.

[0091] Comparative Examples 2 and 3 also showed no accumulation of undissolved powdered medium PM. However, the amount of liquid in the mixing container 16 in Comparative Example 2 was 1,000 ml, and the amount of liquid in the mixing container 16 in Comparative Example 3 was 5,000 ml, which is greater than the 800 ml in Examples 1 to 3 and 5 to 10. Therefore, Comparative Examples 2 and 3 are inferior to Examples 1 to 3 and 5 to 10 in terms of installation area requirements. In other words, by periodically varying the inflow rate of pure water PW into the mixing container 16, periodically varying the outflow rate of medium CM from the mixing container 16, or periodically varying the stirring rotation speed of the stirrer 33 of the agitator 32, the amount of liquid in the mixing container 16 can be reduced, contributing to a smaller installation area. Note that if there are no installation area constraints, the configuration of Comparative Example 2 or 3 may be adopted.

[0092] From the above, it was confirmed that Examples 1 to 10 relating to the technology disclosed herein make it difficult for undissolved powdered medium PM to accumulate, contributing to stabilizing the concentration of medium CM. It was also found that Examples 1 to 3 and 5 to 10 relating to the technology disclosed herein contribute to reducing the installation area of ​​the mixing container 16. Furthermore, it was found that Examples 1 and 4 to 7 kept the concentration fluctuation of medium CM within an acceptable range. In particular, it was found that Examples 1, 4, and 5, in which the concentration fluctuation index CFI was set to be equal to or less than the amount of liquid L in the mixing container 16, kept the concentration fluctuation of medium CM caused by periodic fluctuations in the inflow rate of pure water PW into the mixing container 16 within an acceptable range.

[0093] There are many types of powder medium PM. The optimum values ​​for the fluctuation amplitude, fluctuation period, and amount of liquid in the mixing vessel 16 vary depending on the type of powder medium PM. For this reason, the operator must conduct setting experiments each time the type of powder medium PM is changed to set the optimum values ​​for the fluctuation amplitude, fluctuation period, and amount of liquid in the mixing vessel 16.

[0094] The properties of the culture medium CM supplied to the culture tank 11 that are measured in-line are not limited to the exemplified conductivity and hydrogen ion exponent. In addition to or instead of these, Raman spectrum, infrared absorption spectrum, near-infrared absorption spectrum, ultraviolet absorption spectrum, fluorescence spectrum, etc. may also be measured.

[0095] The method for timing the cessation of wastewater of medium CM and the start of supply to the culture tank 11 is not limited to the method based on conductivity in the above embodiments. 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 wastewater of medium CM may be stopped and the supply to the culture tank 11 may be started. In this case, the conductivity meter 39 is not required.

[0096] 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.

[0097] In each of the above embodiments, the following various processors can be used as the hardware structure of the processing units that perform various processes, such as the pure water supply pump drive control unit 65, the powdered culture medium supply machine drive control unit 66, the agitator drive control unit 67, the culture medium supply pump drive control unit 68, and the three-way valve drive control unit 69. 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 dedicated electrical circuits that are processors having a circuit configuration designed specifically for performing specific processes, such as a programmable logic device (PLD) that is a processor whose circuit configuration can be changed after manufacture, such as an FPGA (Field Programmable Gate Array), and an ASIC (Application Specific Integrated Circuit).

[0098] 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.

[0099] 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.

[0100] Furthermore, more specifically, the hardware structure of these various processors can be an electric circuit (circuitry) that combines circuit elements such as semiconductor elements.

[0101] From the above description, the technology described in the following supplementary paragraphs can be understood.

[0102] [Supplementary Item 1] A solution preparation apparatus comprising a first pump that continuously flows a solvent into a mixing container, a powder feeder that continuously supplies a powder to the mixing container, an agitator that agitates the solvent and the powder in the mixing container, and a second pump that continuously flows out of the mixing container a solution of a set concentration prepared by mixing the solvent and the powder, the solution preparation apparatus further comprising a processor that controls operation of the first pump, the powder feeder, the agitator, and the second pump, the processor periodically varying at least one of an amount of the solvent inflow into the mixing container by the first pump, an amount of the solution outflow from the mixing container by the second pump, and a stirring rotation speed by the agitator. [Supplementary Item 2] The solution preparation apparatus according to Supplementary Item 1, wherein the fluctuation amplitude and fluctuation period of at least one of the inflow amount, the outflow amount, and the stirring rotation speed are set to values ​​that keep fluctuations in concentration of the solution due to periodic fluctuations of at least one of the inflow amount, the outflow amount, and the stirring rotation speed within an acceptable range. [Supplementary Item 3] The solution preparation apparatus according to Supplementary Item 2, wherein a concentration fluctuation index CFI shown in the following formula is equal to or less than the amount L of liquid in the mixing container. Formula: CFI = {(V x T) / 60} x A, where V is a set amount of the inflow rate or the outflow rate, A is a fluctuation amplitude of at least one of the inflow rate and the outflow rate, and T is a fluctuation period of at least one of the inflow rate and the outflow rate. [Supplementary Item 4] The solution preparation apparatus according to any one of Supplementary Items 1 to 3, wherein the processor, when periodically varying the stirring rotation speed, also periodically changes the stirring rotation direction of the stirrer. [Supplementary Item 5] The solution preparation apparatus according to any one of Supplementary Items 1 to 4, wherein the solvent is purified water, the powder is a powder culture medium, and the solution is a culture medium.

[0103] 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.

[0104] 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.

[0105] 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."

[0106] 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 comprising a first pump that continuously flows a solvent into a mixing container, a powder supplying machine that continuously supplies a powder to the mixing container, an agitator that agitates the solvent and the powder in the mixing container, and a second pump that continuously flows out of the mixing container a solution of a set concentration prepared by mixing the solvent and the powder, the solution preparation apparatus further comprising a processor that controls the operation of the first pump, the powder supplying machine, the agitator, and the second pump, the processor periodically varying at least one of the amount of the solvent flowing into the mixing container by the first pump, the amount of the solution flowing out of the mixing container by the second pump, and the agitation rotation speed by the agitator.

2. A solution preparation apparatus as described in claim 1, wherein the fluctuation amplitude and fluctuation period of at least one of the inflow volume, the outflow volume, and the stirring rotation speed are set to values ​​such that the concentration fluctuation of the solution caused by periodic fluctuation of at least one of the inflow volume, the outflow volume, and the stirring rotation speed is within an acceptable range.

3. The solution preparation apparatus according to claim 2, wherein a concentration fluctuation index CFI shown in the following formula is equal to or less than the amount L of liquid in the mixing vessel: CFI={(V×T) / 60}×A, where V is a set amount of the inflow or outflow, A is a fluctuation amplitude of at least one of the inflow and outflow, and T is a fluctuation period of at least one of the inflow and outflow.

4. The solution preparation apparatus according to claim 1, wherein the processor periodically changes the stirring rotation direction of the agitator when periodically varying the stirring rotation speed.

5. 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.

6. A method for operating a solution preparation apparatus including a first pump that continuously flows a solvent into a mixing container, a powder feeder that continuously supplies a powder to the mixing container, an agitator that agitates the solvent and the powder in the mixing container, and a second pump that continuously flows out of the mixing container a solution of a set concentration prepared by mixing the solvent and the powder, the method comprising: controlling the operation of the first pump, the powder feeder, the agitator, and the second pump; and periodically varying at least one of the amount of the solvent flowing into the mixing container by the first pump, the amount of the solution flowing out of the mixing container by the second pump, and the agitation rotation speed by the agitator.

7. An operating program for a solution preparation apparatus comprising a first pump that continuously flows a solvent into a mixing container, a powder supplying machine that continuously supplies a powder to the mixing container, an agitator that agitates the solvent and the powder in the mixing container, and a second pump that continuously flows out of the mixing container a solution of a set concentration prepared by mixing the solvent and the powder, the operating program for the solution preparation apparatus causing a computer to execute processes including controlling the operation of the first pump, the powder supplying machine, the agitator, and the second pump, and periodically varying at least any of the amount of the solvent flowing into the mixing container by the first pump, the amount of the solution flowing out of the mixing container by the second pump, and the agitation rotation speed by the agitator.

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