Sensor unit for spectroscopic analysis device, measurement system, and measurement method

Abstract

A sensor unit for a spectroscopic analysis device is provided with a tip section that is attached to a container of a fluid containing a substance to be measured, said tip section having a built-in optical system for irradiating the substance to be measured having physical property data with measurement light and capturing return light from the substance to be measured, the front end part is provided with an opposite wall surface which is opposite to the emission surface of the measurement light of the optical system; and a holding part that protrudes from the emission surface side to the opposing wall surface side, holds the opposing wall surface in a state in which a space through which the fluid flows is provided between the holding part and the emission surface, and includes an inlet and an outlet for the fluid, and side wall surfaces disposed on both sides in the flow direction of the fluid.

Description

Technical Field

[0001] The technology of the present invention relates to a sensor unit, a measurement system, and a measurement method of a spectroscopic analysis device. Background Art

[0002] The spectroscopic analysis device has a sensor unit. An optical system for irradiating a measuring light to a measuring object of physical property data and capturing return light from the measuring object is built into the front end of the sensor unit. As described in Japanese Patent Publication No. 2020-511635, the front end is sometimes mounted on a circulation cell. The circulation cell has a flow path for a fluid containing a measuring object to flow. The circulation cell is a type of container for a fluid containing a measuring object. Circulation cells with various flow path diameters are described in Japanese Patent Publication No. 2020-511635.

[0003] Japanese Patent Application Laid-Open No. 2021-048872 describes a sensor unit having an L-shaped cross-section provided at the front end of an optical system (transparent element). The leg has an end facing the emission surface of the measurement light of the optical system at a certain distance. Summary of the invention

[0004] Technical issues to be solved by the invention

[0005] As described in Japanese Patent Publication No. 2020-511635, the flow path diameter of the circulation cell is varied. Therefore, the interval between the focusing position of the measurement light of the optical system and the wall surface of the flow path opposite to the exit surface of the measurement light of the optical system widens or narrows according to the flow path diameter. In this way, even if the same measurement object substance is measured, the physical property data will be different according to the flow path diameter of the circulation cell. Specifically, compared to the flow path diameter of the circulation cell is relatively small, the interval between the focusing position and the wall surface of the flow path opposite to the exit surface is relatively narrow, and the flow path diameter of the circulation cell is relatively large, and the interval between the focusing position and the wall surface of the flow path opposite to the exit surface is relatively wide, and the intensity value of the physical property data is reduced as a whole.

[0006] In Japanese Patent Publication No. 2021-048872, a foot portion having an end portion opposed to the emission surface of the measurement light of the optical system at a certain interval is provided. The cross section of the foot portion in Japanese Patent Publication No. 2021-048872 is L-shaped, and is open except for the portion connected to the end portion. Therefore, for example, when the flow cell contains resin, the measurement light leaking from the open portion of the foot portion irradiates the resin of the flow cell, and the return light thereof is captured from the open portion, resulting in a new problem of adversely affecting the physical property data.

[0007] One embodiment of the technology according to the present invention provides a sensor unit, a measurement system, and a measurement method of a spectroscopic analysis device that can reduce the possibility of adversely affecting physical property data.

[0008] Means for solving technical problems

[0009] The sensor portion of the spectral analysis device of the present invention comprises a front end portion, in which an optical system is built-in for irradiating a measurement light to a measurement object of physical property data and capturing return light from the measurement object, and the front end portion is installed in a container for a fluid containing the measurement object, wherein the front end portion has: an opposing wall surface opposing an exit surface of the measurement light of the optical system; and a holding portion, which protrudes from the exit surface side to the opposing wall surface side and holds the opposing wall surface in a state in which a space for fluid flow is provided between the exit surface and the holding portion, and the holding portion includes an inlet and an outlet for the fluid, and side wall surfaces arranged on both sides of the flow direction of the fluid.

[0010] Preferably, the container is a flow cell having a flow path for fluid flow.

[0011] Preferably, the tip portion is mounted on a flow cell containing the resin.

[0012] The tip portion is preferably mounted on a plurality of flow cells having different flow path diameters.

[0013] It is preferable that metal is disposed on at least a portion of the surface of the opposing wall surface.

[0014] It is preferable that the area of ​​the metal on the opposing wall surface is larger than the irradiation area of ​​the measuring light on the opposing wall surface.

[0015] The surface roughness of the opposing wall surface is preferably 1.6 μm or less.

[0016] Preferably, the opposing wall surfaces are flat surfaces.

[0017] When the emission surface side is set to the upper side and the opposing wall surface side is set to the lower side, it is preferable that the opposing wall surface is a curved surface convex toward the lower side.

[0018] It is preferable to include a main body portion made of resin.

[0019] The inlet and outlet are preferably circular or rectangular.

[0020] It is preferable that the focusing position of the measurement light by the optical system is located between the emission surface and the opposing wall surface.

[0021] Preferably the optical system comprises a lens having positive refractive power.

[0022] Preferably, the optical system further includes an optical element whose emission surface of the measurement light is a flat surface.

[0023] The thickness of the optical element in the optical axis direction is preferably not less than half of the distance between the point intersecting the optical axis on the emission surface of the lens and the focusing position of the measurement light and not more than the distance.

[0024] It is preferable that metal is disposed on at least a portion of the surface of the side wall surface.

[0025] Preferably, the distance between the emission surface and the opposing wall surface is fixed.

[0026] Preferably, the physical property data is Raman spectroscopy data.

[0027] The turbidity of the fluid is preferably 250 NTU or more and 1000 NTU or less.

[0028] Preferably the fluid is a cell culture medium.

[0029] A measurement system of the present invention includes: a sensor unit of any one of the above-described spectroscopic analysis devices and a container to which a front end unit is attached.

[0030] When the container is a flow cell and the tip portion is attached to the flow cell, preferably, a flow path through which the fluid flows exists inside and outside the tip portion.

[0031] When the container is a flow cell and the tip portion is attached to the flow cell, it is preferred that a line connecting the centers of the inlet and the outlet be parallel to the flow direction.

[0032] In the measurement method of the present invention, physical property data is measured using the sensor unit of any one of the above-mentioned spectroscopic analysis devices.

[0033] Effects of the Invention

[0034] According to the technology of the present invention, it is possible to provide a sensor unit of a spectroscopic analysis device, a measurement system, and a measurement method that can reduce the possibility of adversely affecting physical property data. BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 This is a diagram showing a state where Raman spectrum data of a measurement target substance in a cell culture fluid obtained from a culture tank during culturing is measured by a measurement system.

[0036] Figure 2 It is a diagram showing excitation light and Raman scattered light.

[0037] Figure 3 This is an exploded perspective view of the flow cell.

[0038] Figure 4 This is an exploded perspective view of the sensor unit.

[0039] Figure 5 This is a cross-sectional view of the flow cell and sensor section.

[0040] Figure 6 It is a diagram showing the positional relationship between the flow channel of the flow cell and the inlet and outlet at the front end.

[0041] Figure 7 This is a diagram showing an example in which a tip portion is attached to a flow cell having a relatively small flow channel diameter.

[0042] Figure 8 This is a diagram showing an example in which the tip portion is attached to a flow cell having a medium flow channel diameter.

[0043] Fig. 9 This is a diagram showing an example in which a tip portion is attached to a flow cell having a relatively large flow channel diameter.

[0044] Fig.10 It is an explanatory diagram regarding the focusing position of the excitation light and the thickness of the optical element in the optical axis direction.

[0045] Fig.11 This is a diagram showing the relationship between the area of ​​metal on the opposing wall surface and the irradiation area of ​​the excitation light on the opposing wall surface.

[0046] Fig.12 This is a diagram showing opposing wall surfaces that are curved surfaces convex toward the downward side.

[0047] Fig.13 It is a figure which shows a circular inlet and an outlet.

[0048] Fig.14 It is a diagram showing an information processing device.

[0049] Fig.15 It is a block diagram of a computer constituting an information processing device.

[0050] Fig.16 This is a block diagram showing a processing unit of a CPU of an information processing device.

[0051] Fig.17 It is a diagram showing the structure of a dataset group.

[0052] Fig.18 It is a diagram showing the processing in the learning phase of the concentration prediction model.

[0053] Fig.19 This is a diagram showing a state where Raman spectrum data measured using a flow cell having a medium flow channel diameter is applied to a concentration prediction model, and a concentration prediction result is output from the concentration prediction model.

[0054] Fig. 20 This is a diagram showing a situation where Raman spectrum data measured using a flow cell having a relatively large flow channel diameter is applied to a concentration prediction model, and a concentration prediction result is output from the concentration prediction model.

[0055] Fig.21 This is a diagram showing a Raman spectroscopy analysis screen.

[0056] Fig. 22 The figure shows a Raman spectrum analysis screen showing the concentration prediction result.

[0057] Fig.23 This is a flowchart showing the processing steps in the learning phase of the concentration prediction model.

[0058] Fig.24 This is a flowchart showing the processing steps of the information processing device. DETAILED DESCRIPTION

[0059] [First embodiment]

[0060] As an example, Figure 1 As shown, the measuring system 2 includes a circulation cell 10 and a Raman spectrometer 11. The measuring system 2 is, for example, assembled in a cell culture section 12 in a manufacturing system of a raw material of a biopharmaceutical. The cell culture section 12 includes a culture tank 13 and a cell removal filter 14. A cell culture fluid 15 is stored in the culture tank 13. The circulation cell 10 is an example of a "container" involved in the technology of the present invention. Furthermore, the Raman spectrometer 11 is an example of a "spectral analysis device" involved in the technology of the present invention. In addition, the cell removal filter 14 may also be an alternating tangential flow filtration (ATF: Alternating Tangential Flow Filtration) filter.

[0061] Antibody-producing cells 16 are sown in a culture tank 13 and cultured in a cell culture medium 15. Antibody-producing cells 16 are, for example, cells established by integrating antibody genes into host cells such as Chinese hamster ovary cells (CHO cells (Chinese Hamster Ovary cells)). Antibody-producing cells 16 produce immunoglobulins, i.e., antibodies 17, during the culture process. Therefore, not only antibody-producing cells 16 but also antibodies 17 are present in the cell culture medium 15. Antibodies 17 are, for example, monoclonal antibodies, which become active ingredients of biopharmaceuticals. In addition, antibodies 17 are an example of "substances to be measured" involved in the technology of the present invention.

[0062] The first conveying path 18 is connected to the culture tank 13. The cell-removing filter 14 is arranged in the first conveying path 18. The cell-removing filter 14 captures the antibody-producing cells 16 in the cell culture fluid 15 with a filter membrane not shown in the figure, for example, by tangential flow filtration (TFF) method, and removes the antibody-producing cells 16 from the cell culture fluid 15. In addition, the cell-removing filter 14 allows the antibody 17 to pass through. Therefore, at the downstream of the cell-removing filter 14 in the first conveying path 18, the cell culture fluid 15 mainly containing the antibody 17 flows. In this way, the cell culture fluid 15 obtained by removing the antibody-producing cells 16 through the cell-removing filter 14 is called the culture supernatant. Hereinafter, the cell culture fluid 15 obtained by removing the antibody-producing cells 16 through the cell-removing filter 14 is expressed as the culture supernatant 15A. The culture supernatant 15A is an example of the "fluid" involved in the technology of the present invention.

[0063] The turbidity of the culture supernatant 15A is greater than 250 NTU (Nephelometric Turbidity Unit) and less than 1000 NTU. NTU is a liquid turbidity unit based on a formazin standard solution. In addition, the culture supernatant 15A contains, in addition to the antibody 17, proteins derived from cells, DNA (Deoxyribonucleic Acid) derived from cells, aggregates of the antibody 17, or viruses, etc. These proteins derived from cells, DNA derived from cells, aggregates of the antibody 17, and viruses, etc. are also examples of the "substance to be measured" involved in the technology of the present invention.

[0064] The flow cell 10 is connected to the first delivery path 18 on the downstream side of the cell removal filter 14. As shown by the arrow FD, the culture supernatant 15A from the first delivery path 18 flows at a preset flow rate in the flow cell 10. A delivery pump (not shown) is provided downstream of the cell removal filter 14 in the first delivery path 18 (between the cell removal filter 14 and the flow cell 10). The delivery pump delivers the culture supernatant 15A to the flow cell 10 at a flow rate of 200cc / min or more, for example, 300cc / min.

[0065] The second transport path 19 is also connected to the flow cell 10. The culture supernatant 15A that flows into the flow cell 10 from the first transport path 18 flows out to the second transport path 19. The second transport path 19 is connected to a purification section that purifies the antibody 17 from the culture supernatant 15A using a chromatography device, for example, and transports the culture supernatant 15A from the flow cell 10 to the purification section.

[0066] As an example, Figure 2As shown, the Raman spectrometer 11 is a device that uses the characteristics of Raman scattered light RSL to evaluate the substance M. If the excitation light EL is irradiated to the substance M, the Raman scattered light RSL having a wavelength different from that of the excitation light EL is generated through the interaction between the excitation light EL and the substance M. The wavelength difference between the excitation light EL and the Raman scattered light RSL is equivalent to the energy part of the molecular vibration of the substance M. Therefore, between substances M with different molecular structures, Raman scattered light RSL with different wave numbers can be obtained. The excitation light EL is an example of the "measurement light" involved in the technology of the present invention. The Raman scattered light RSL is an example of the "return light" involved in the technology of the present invention. In addition, the Raman scattered light RSL preferably uses the Stokes line among the Stokes line and the anti-Stokes line.

[0067] return Figure 1 The Raman spectrometer 11 is composed of a sensor unit 25 and an analyzer 26. The sensor unit 25 is connected to the flow cell 10. The sensor unit 25 emits an excitation light EL from the front end. The excitation light EL is irradiated to the culture supernatant 15A flowing in the flow cell 10. Raman scattered light RSL is generated by the interaction between the excitation light EL and the antibody 17 and the like in the culture supernatant 15A. The sensor unit 25 receives the Raman scattered light RSL and outputs the received Raman scattered light RSL to the analyzer 26.

[0068] The analyzer 26 decomposes the Raman scattered light RSL for each wave number, derives the intensity value of the Raman scattered light RSL for each wave number, and thereby generates Raman spectrum data 27. The Raman spectrum data 27 is data in which the intensity value of the Raman scattered light RSL for each wave number is registered. Figure 1 In the figure, the Raman spectrum data 27 is at 1 cm -1 Scale derived wave number 700cm -1 ~1800cm -1 The graph shown below the Raman spectrum data 27 is a graph in which the intensity values ​​of the Raman spectrum data 27 are plotted for each wave number and connected by lines. The Raman spectrum data 27 is an example of the "physical property data" involved in the technology of the present invention.

[0069] In this way, the measurement system 2 allows the culture supernatant 15A obtained from the culture tank 13 in which the antibody-producing cells 16 are cultured to flow into the flow cell 10. Then, the culture supernatant 15A flowing into the flow cell 10 is irradiated with the excitation light EL by the sensor unit 25, thereby measuring the Raman spectrum data 27 of the antibody 17 and the like in the culture supernatant 15A.

[0070] As an example, Figure 3As shown, the flow cell 10 is a cylindrical component having a straight flow path 30 with a circular cross section at the center. The flow cell 10 contains resin. The content of the resin in the flow cell 10 is 95% or more, for example, 99%. Alternatively, the content of the resin is 100%, and the flow cell 10 is entirely formed of resin. In other words, the flow cell 10 is made of resin. The resin is, for example, a polyolefin resin. In this case, the flow cell 10 can be disposable. In addition, the flow cell 10 can also be made of metal.

[0071] A cylindrical boss-shaped first connection portion 31 and a second connection portion 32 are provided at the center of both end surfaces of the flow cell 10. The first connection portion 31 has an inlet 33 of the flow path 30, and the second connection portion 32 has an outlet 34 of the flow path 30. The direction parallel to the flow path 30 from the inlet 33 toward the outlet 34 is the flow direction FD of the culture supernatant 15A. The direction FD is an example of the "flow direction" involved in the technology of the present invention.

[0072] The first connection part 31 and the second connection part 32 are parallel threads or tapered threads. A sterile connector 35 provided at one end of the first conveying path 18 is installed in a liquid-tight manner on the first connection part 31. In addition, a sterile connector 36 provided at one end of the second conveying path 19 is installed in a liquid-tight manner on the second connection part 32. In addition, a cannula can also be used in the connection between the first connection part 31 and the second connection part 32 and the sterile connectors 35 and 36.

[0073] A mounting portion 37 is provided at the center of the peripheral plate of the flow cell 10. The mounting portion 37 is a cylindrical hole for detachably mounting the sensor unit 25 on the flow cell 10, and a thread 38 is cut on the inner wall surface. The mounting portion 37 is provided to the front of the flow path 30. A part of the sensor unit 25 is accommodated in the mounting portion 37.

[0074] The sensor portion 25 includes a main body 39 and a front end portion 40. The main body 39 is a cylindrical member having a straight optical path 41 with a circular cross section at the center thereof. The excitation light EL and the Raman scattered light RSL pass through the optical path 41. The excitation light EL passes through the optical path 41 from the main body 39 toward the front end portion 40. Conversely, the Raman scattered light RSL passes through the optical path 41 from the front end portion 40 toward the main body 39 and toward the analyzer 26. The main body 39 contains a resin, similarly to the flow cell 10. The content of the resin in the main body 39 is 95% or more, for example, 99%. Alternatively, the content of the resin is 100%, and the main body 39 is entirely formed of the resin. In other words, the main body 39 is made of resin. The resin is similar to the flow cell 10, for example, a polyolefin resin.

[0075] As an example, Figure 4As shown, the main body 39 has a large diameter portion 45, a middle diameter portion 46 and a small diameter portion 47 in order from the base end side. The large diameter portion 45 is the portion with the largest diameter in the main body 39. The middle diameter portion 46 is a portion with a smaller diameter than the large diameter portion 45 and a larger diameter than the small diameter portion 47. A thread 48 is cut on the middle diameter portion 46. The thread 48 is screwed with the thread 38 of the mounting portion 37. That is, the main body 39 and the sensor portion 25 are detachably mounted on the mounting portion 37 through the middle diameter portion 46. Therefore, the middle diameter portion 46 and the frontmost portion of the sensor portion 25 from the middle diameter portion 46, that is, the front end portion 40 and the small diameter portion 47 are accommodated in the circulation pool 10. The small diameter portion 47 is the portion with the smallest diameter in the main body 39. A thread 49 is cut on the small diameter portion 47.

[0076] The front end portion 40 has an optical system 55, an inner shell portion 56, and an outer shell portion 57. The optical system 55 is held between the small diameter portion 47 of the main body 39 and the inner shell portion 56 and inside the outer shell portion 57. The optical system 55 includes a hemispherical lens 58 and a transparent plate 59. The hemispherical lens 58 is a hemispherical lens as the name indicates, and is made of, for example, quartz glass. The hemispherical lens 58 has an exit surface 60 for the excitation light EL. The exit surface 60 is a plane. The hemispherical lens 58 is an example of a "lens with positive refractive power" involved in the technology of the present invention.

[0077] The transparent plate 59 is a circular plate having an exit surface 61 and an incident surface 62 of the excitation light EL which are parallel to each other, and is made of, for example, quartz glass. The exit surface 60 of the hemispherical lens 58 and the incident surface 62 of the transparent plate 59 have the same curvature (0 in this case). The exit surface 60 and the incident surface 62 may be fixedly joined by an adhesive or the like, or may be maintained in a state where the surfaces are joined to each other without an adhesive or the like. The transparent plate 59 is an example of an "optical element" involved in the technology of the present invention. Furthermore, the exit surface 61 of the transparent plate 59 is an example of an "exit surface of the measurement light of the optical system" involved in the technology of the present invention.

[0078] When the main body 39 side (the emission surface 61 side of the transparent plate 59) is set as the upper side and the front end 40 side (the inner wall surface 63A side of the bottom plate 63 of the inner case 56) is set as the lower side (see also Figure 5 ), the inner shell 56 and the outer shell 57 are both in the shape of cylindrical containers with an open upper side and a lower side closed by planar bottom plates 63 and 64. The inner shell 56 has a peripheral plate 65, and the outer shell 57 has a peripheral plate 66. The peripheral plate 65 is erected upward from the bottom plate 63, and forms a cylindrical space 67 with the bottom plate 63. Similarly, the peripheral plate 66 is erected upward from the bottom plate 64, and forms a cylindrical space 68 with the bottom plate 64.

[0079] The height of the peripheral plate 65 is lower than that of the peripheral plate 66. That is, the height of the inner shell 56 is lower than that of the outer shell 57. The inner shell 56 is smaller than the outer shell 57 as a whole and is accommodated in the space 68 of the outer shell 57 without any gap (see also Figure 5 ).

[0080] The inner shell 56 is made of metal, for example, Hastelloy. On the other hand, the outer shell 57 contains resin, similarly to the flow cell 10. The content of the resin in the outer shell 57 is 95% or more, for example, 99%. Alternatively, the content of the resin is 100%, and the outer shell 57 is entirely formed of resin. In other words, the outer shell 57 is made of resin. The resin is similar to the flow cell 10, for example, a polyolefin resin.

[0081] A thread 69 is cut on the upper side of the inner wall surface 66A of the peripheral plate 66 of the outer shell 57. The thread 69 is screwed with the thread 49 of the small diameter portion 47. Thus, the outer shell 57 and the front end portion 40 are integrated with the main body 39.

[0082] Rectangular cutouts 70A and 71A are formed at 180° symmetrical positions on the upper side of the peripheral plate 65. Also, rectangular holes 70B and 71B are formed at 180° symmetrical positions in the center of the peripheral plate 66. More precisely, the holes 70B and 71B are square. The cutouts 70A and 71A have the same size as the holes 70B and 71B. The cutout 70A corresponds to the hole 70B, and the cutout 71A corresponds to the hole 71B. The cutout 70A and the hole 70B function as the inlet 70 for the culture supernatant 17. Also, the cutout 71A and the hole 71B function as the outlet 71 for the culture supernatant 17.

[0083] The inner wall surface 63A of the bottom plate 63 of the inner shell portion 56 is flat. The inner wall surface 63A is located on the side toward which the excitation light EL is directed (the downstream side in the irradiation direction of the excitation light EL), and the excitation light EL irradiates the inner wall surface 63A (reference Fig.10 and Fig.11 ). The inner wall surface 63A is opposite to the emission surface 61 of the transparent plate 59. That is, the inner wall surface 63A is an example of the "opposing wall surface" involved in the technology of the present invention. When the optical system 55 and the inner shell 56 are accommodated in the space 68 of the outer shell 57, and the thread 69 of the outer shell 57 is screwed into the thread 49 of the small diameter portion 47 to integrate the front end portion 40 with the main body 39, the interval between the emission surface 61 and the inner wall surface 63A is fixed.

[0084] The surface roughness (arithmetic mean roughness) Ra of the inner wall surface 63A is greater than 0 and is less than 6.4 μm (0<Ra≤6.4 μm), preferably less than 1.6 μm (0<Ra≤1.6 μm). Although not shown in the figure, the surface roughness Ra of the inner wall surface 65A is also greater than 0 and is less than 6.4 μm, preferably less than 1.6 μm. In order to set the surface roughness Ra to the target value, the inner wall surfaces 63A and 65A are subjected to smoothing treatment such as grinding. In addition, the surface roughness Ra is a value measured in accordance with JIS B0601-2001 specified in Japanese Industrial Standards.

[0085] When viewed from the upper side, the inner wall surface 65A of the peripheral plate 65 of the inner shell 56 protrudes from the side of the exit surface 61 of the transparent plate 59 to the inner wall surface 63A side. In addition, the inner wall surface 65A maintains the inner wall surface 63A in a state where a space 67 for the culture supernatant 17 to flow is provided between the inner wall surface 65A and the exit surface 61. In addition, the inner wall surface 65A is arranged on both sides of the direction FD and closes both sides of the direction FD. That is, the inner wall surface 65A is an example of the "side wall surface" involved in the technology of the present invention, and the inner shell 56 is an example of the "holding portion" involved in the technology of the present invention. It can be seen from the inner shell 56 that the functions of the "opposing wall surface" and the "holding portion" involved in the technology of the present invention can be assumed by one component. In addition, the symbol 64A represents the inner wall surface of the bottom plate 64 of the outer shell 57.

[0086] As an example, Figure 5 As shown, the optical system 55 is held so as to be sandwiched between the front end of the small diameter portion 47 of the main body 39 and the edge of the peripheral plate 65 of the inner shell 56. The height of the exit surface 61 of the transparent plate 59 is consistent with the edge of the upper end of the inlet 70 and the outlet 71. A circular groove 80 is formed in the portion of the mounting portion 37 that is connected to the middle diameter portion 46 of the main body 39. An O-ring 81 is embedded in the groove 80. The O-ring 81 is a rubber having elasticity, and is compressed between the middle diameter portion 46 and the bottom plate of the groove 80 by fastening the main body 39 to the mounting portion 37 with the threads 38 and 48. The O-ring 81 is compressed between the middle diameter portion 46 and the bottom plate of the groove 80, thereby preventing the culture supernatant 15A flowing in the flow path 30 from leaking out of the mounting portion 37. Although not shown in the figure, O-rings are also arranged between the small diameter portion 47 and the hemispherical lens 58 and between the inner shell portion 56 and the transparent plate 59 to prevent leakage of the culture supernatant 15A.

[0087] like Figure 5As shown, when the front end portion 40 is mounted on the flow cell 10, the line LIO connecting the center CI of the inlet 70 and the center CO of the outlet 71 is parallel to the direction FD. In other words, the line LIO is parallel to the center line of the flow path 30. Here, "parallel" refers to parallelism in the sense of including errors that are generally allowed in the technical field to which the technology of the present invention belongs and that do not violate the technical spirit of the present invention, in addition to completely parallel.

[0088] And, as an example, Figure 6 As shown, when the front end 40 is installed in the circulation pool 10, the center CI of the inlet 70, the center CO of the outlet 71 and the center CP of the flow path 30 are consistent. Here, "consistent" means not only completely consistent, but also consistent in the sense of errors that are generally allowed in the technical field to which the technology of the present invention belongs and do not violate the technical purpose of the present invention. The error mentioned here is preferably ±10%, and more preferably ±5%.

[0089] from Figure 6 It can also be seen that, when the front end portion 40 is attached to the flow cell 10, the flow path for the culture supernatant 15A to flow exists inside and outside the front end portion 40. In other words, the culture supernatant 15A flows inside and outside the front end portion 40. The flow path inside the front end portion 40 is defined by the inlet 70 and the outlet 71, the exit surface 61 of the transparent plate 59, the inner wall surface 63A of the bottom plate 63 of the inner shell portion 56, and the inner wall surface 65A of the peripheral plate 65 of the inner shell portion 56. The flow path outside the front end portion 40 is defined by the flow path 30 of the flow cell 10, the outer wall surface 64B of the bottom plate 64 of the outer shell portion 57, and the outer wall surface 66B of the peripheral plate 66 of the outer shell portion 57. In addition, the area of ​​the inlet 70 and the outlet 71 is preferably less than 1 / 2 of the area of ​​the peripheral plate 65 of the inner shell portion 56, more preferably less than 1 / 4, and further preferably less than 1 / 8.

[0090] As an example, Figure 7 to Figure 9 As shown, the front end portion 40 is installed in a plurality of flow cells 10 with different flow path diameters. Specifically, first, as Figure 7 As shown in FIG. 1 , the front end portion 40 is mounted on a flow cell 10S having a flow path 30S having a flow path diameter φS. Figure 8 As shown, the front end portion 40 is mounted on a flow cell 10M having a flow path 30M having a flow path diameter φM. Fig. 9As shown, the front end portion 40 is mounted on a flow cell 10L having a flow path 30L having a flow path diameter φL. The flow path diameters φS, φM, and φL have a relationship of φS<φM<φL. That is, the flow path diameter φ of the flow cell 10S is relatively small, the flow path diameter φ of the flow cell 10M is medium, and the flow path diameter φ of the flow cell 10L is relatively large. In addition, the flow rate of the culture supernatant 15A is always the same regardless of the type of the flow cell 10.

[0091] Here, when the front end portion 40 is mounted on any one of the flow cells 10S, 10M, and 10L, the line LIO connecting the center CI of the inlet 70 and the center CO of the outlet 71 is also parallel to the direction FD. Furthermore, when the front end portion 40 is mounted on any one of the flow cells 10S, 10M, and 10L, the center CI of the inlet 70, the center CO of the outlet 71, and the center CP of the flow path 30 are also consistent. In addition, three types of flow cells 10S, 10M, and 10L are illustrated here, but the flow cells 10 to which the front end portion 40 is mounted may be two types, or may be four or more types.

[0092] As an example, Fig.10 As shown in FIG. 1 , the excitation light EL emitted from the exit surface 61 of the transparent plate 59 is focused at the focusing position FP located in the inner shell 56. The focal length is determined by the diameter and refractive index of the hemispherical lens 58, and the focusing position FP is determined by the focal length. At this time, the focusing position FP is in a point shape. The focusing position FP is located between the exit surface 61 of the transparent plate 59 and the inner wall surface 63A of the bottom plate 63 of the inner shell 56.

[0093] When the thickness of the transparent plate 59 in the direction of the optical axis OA is set to Th and the distance between the first point P1 on the exit surface 60 of the hemispherical lens 58 intersecting the optical axis OA and the focusing position FP is set to d, the thickness Th is more than half of the distance d and less than the distance d (d / 2≤Th≤d). It is more preferred that the thickness Th is the same as the distance d, that is, Th=d. When Th=d, the focusing position FP coincides with the second point P2 on the exit surface 61 of the transparent plate 59 intersecting the optical axis OA. In addition, the thickness Th and the distance d are "the same" in the sense of being the same, in addition to being completely the same, and also including the errors that are generally allowed in the technical field to which the technology of the present invention belongs and the errors that do not violate the technical spirit of the present invention. The error mentioned here is preferably ±10%, and more preferably ±5%.

[0094] As an example, Fig.11As shown, the excitation light EL passing through the focusing position FP expands in a cone shape from the focusing position FP toward the inner wall surface 63A, and finally irradiates the inner wall surface 63A. Symbol 90 represents the irradiation area of ​​the excitation light EL in the inner wall surface 63A. The irradiation area 90 is a circle centered on the optical axis OA. The diameter of the irradiation area 90 is smaller than the diameter of the inner wall surface 63A. In other words, the area of ​​the metal in the inner wall surface 63A is larger than the irradiation area of ​​the excitation light EL in the inner wall surface 63A (the area of ​​the metal in the inner wall surface 63A>the irradiation area of ​​the excitation light EL in the inner wall surface 63A).

[0095] Next, the function of the above-mentioned structure is described. The measurement system 2 including the flow cell 10 and the Raman spectrometer 11 is assembled in the cell culture section 12. In the flow cell 10, the first connection portion 31 is connected to the first conveying path 18, and the second connection portion 32 is connected to the second conveying path 19. The sensor section 25 (front end portion 40) of the Raman spectrometer 11 is mounted on the flow cell 10 via the mounting portion 37. The culture supernatant 15A obtained from the culture tank 13 in which the antibody-producing cells 16 are cultured flows in the flow path 30 of the flow cell 10. The culture supernatant 15A flows into the front end portion 40 of the sensor section 25 from the inlet 70, and flows out of the front end portion 40 from the outlet 71. In the front end portion 40, the culture supernatant 15A is irradiated with the excitation light EL that has passed through the optical path 41 and the optical system 55. The excitation light EL is focused at the focusing position FP by the optical system 55.

[0096] Raman scattered light RSL is generated by the interaction between the excitation light EL and the antibody 17 etc. in the culture supernatant 15A. The Raman scattered light RSL is captured by the optical system 55 and output from the sensor unit 25 to the analyzer 26 through the optical path 41. The Raman scattered light RSL is converted into Raman spectrum data 27 by the analyzer 26.

[0097] The front end portion 40 has an inner wall surface 63A and an inner shell portion 56. The inner wall surface 63A is a wall surface opposite to the exit surface 61 of the transparent plate 59. The inner shell portion 56 protrudes from the exit surface 61 side to the inner wall surface 63A side, and maintains the inner wall surface 63A in a state where a space 67 for the culture supernatant 15A to flow is provided between the inner shell portion 56 and the exit surface 61. The inner shell portion 56 includes an inlet 70 and an outlet 71 for the culture supernatant 15A, and inner wall surfaces 65A arranged on both sides of the direction FD. According to the inner wall surface 65A, compared with the sensor portion described in Japanese Patent Laid-Open No. 2021-048872, which is open on one side of the flow direction of the fluid, the possibility of adversely affecting the Raman spectrum data 27 can be reduced. For example, the excitation light EL is irradiated to the resin flow cell 10, and the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin of the flow cell 10 is captured, so that the possibility of adversely affecting the Raman spectrum data 27 can be reduced. In addition, even if the flow cell 10 is not a resin, the possibility of adversely affecting the Raman spectrum data 27 by the Raman scattered light from the flow cell 10 caused by the leakage of the excitation light EL can be reduced.

[0098] The intensity of the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin of the flow cell 10 is relatively high. Therefore, in the case of the sensor unit described in Japanese Patent Application Laid-Open No. 2021-048872, the Raman scattered light RSL that should be measured due to the interaction between the excitation light EL and the antibody 17 and the like in the culture supernatant 15A is eliminated by the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin of the flow cell 10. That is, the S / N ratio of the Raman spectrum data 27 formed by the Raman scattered light RSL generated by the interaction between the excitation light EL and the antibody 17 and the like in the culture supernatant 15A is significantly reduced.

[0099] However, in the technology of the present invention, since there are inner wall surfaces 65A disposed on both sides of the direction FD, the Raman scattered light RSL to be measured, which is generated by the interaction between the excitation light EL and the antibody 17 and the like in the culture supernatant 15A, is less likely to be eliminated by the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin of the flow cell 10. That is, the S / N ratio of the Raman spectrum data 27 formed by the Raman scattered light RSL generated by the interaction between the excitation light EL and the antibody 17 and the like in the culture supernatant 15A can be maintained at a higher level.

[0100] Furthermore, since there are inner wall surfaces 65A disposed on both sides of the direction FD, the flow of the culture supernatant 15A near the focusing position FP of the excitation light EL in the inner shell portion 56 can be stabilized compared to the sensor portion described in Japanese Patent Application Laid-Open No. 2021-048872. Therefore, the deviation of the components in the culture supernatant 15A near the focusing position FP is reduced, and the measurement stability of the Raman spectrum data 27 can be improved.

[0101] If a branch flow path of a preset flow path diameter is provided on the first conveying path 18, and the flow cell 10 is connected to the branch flow path, the Raman spectrum data 27 can be measured using the flow cell 10 of the same diameter regardless of the flow path diameter of the first conveying path 18. However, the branch flow paths must be provided one by one, which is time-consuming and laborious. In contrast, according to the technology of the present invention, such labor is not required.

[0102] In addition, as will be described in detail in the second embodiment below, the sensor unit 25 can generate a concentration prediction model 126 (see FIG. 1 ) for predicting the concentration of the antibody 17 contained in the culture supernatant 15A based on the Raman spectrum data 27 measured using only one type of flow cell 10. Fig.16 ), and the generated concentration prediction model 126 is shared among the plurality of flow cells 10. The effort of preparing the concentration prediction model 126 for each of the plurality of flow cells 10 can be saved.

[0103] like Figure 1 As shown in the figure, the container to which the front end portion 40 is mounted is a flow cell 10 having a flow path 30 for the culture supernatant 15A to flow. Therefore, the Raman spectrum data 27 of the culture supernatant 15A can be easily measured without making a change such as providing a mounting portion for the front end portion 40 in the culture tank 13.

[0104] like Figure 3 As shown, the tip 40 is attached to the flow cell 10 containing resin. Therefore, the excitation light EL is irradiated to the resin of the flow cell 10 and the Raman scattered light RSL is captured, thereby greatly reducing the possibility of adverse effects on the Raman spectrum data 27.

[0105] like Figure 7 to Figure 9 As shown, the front end portion 40 is mounted on a plurality of flow cells 10S, 10M, and 10L having different flow path diameters. As described above, the front end portion 40 has an inner wall surface 63A facing the emission surface 61 of the transparent plate 59, and the interval between the emission surface 61 of the transparent plate 59 and the inner wall surface 63A is constant. Therefore, even if the same measurement target substance is measured, the Raman spectrum data 27 will not be different in the plurality of flow cells 10S, 10M, and 10L having different flow path diameters, and the Raman spectrum data 27 can be used for the flow cells 10 having various flow path diameters without any problem.

[0106] like Figure 4 As shown, the inner shell 56 is made of metal, and the inner wall surfaces 63A and 65A are formed of metal. Therefore, the excitation light EL is irradiated to the resin and the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin is captured, which can further reduce the possibility of adverse effects on the Raman spectrum data 27.

[0107] like Fig.11 As shown, the area of ​​the metal in the inner wall surface 63A is larger than the irradiation area of ​​the excitation light EL in the inner wall surface 63A. Therefore, the excitation light EL is irradiated to the resin and the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin is captured, thereby more reliably reducing the possibility of adverse effects on the Raman spectrum data 27.

[0108] like Figure 4 As shown in FIG. 1 , the surface roughness Ra of the inner wall surface 63A is 1.6 μm or less. Therefore, the excitation light EL and the Raman scattered light RSL are reflected by the inner wall surface 63A, thereby increasing the intensity value of the Raman spectrum data 27 .

[0109] like Figure 4 As shown in FIG. 1 and FIG. 2 , the inner wall surface 63A is a flat surface. Therefore, the inner wall surface 63A and the inner shell portion 56 can be easily manufactured.

[0110] like Figure 3 As shown, the main body 39 is made of resin. Therefore, the main body 39 can be manufactured at low cost and can be easily discarded.

[0111] like Figure 4 As shown in the figure, the inlet 70 and the outlet 71 are rectangular. Therefore, the culture supernatant 15A can flow without pressure toward the focusing position FP of the excitation light EL in the inner shell 56. The deviation of the components in the culture supernatant 15A near the focusing position FP is reduced, and the measurement stability of the Raman spectrum data 27 can be improved.

[0112] like Fig.10 As shown, the focusing position FP of the excitation light EL by the optical system 55 is located between the emission surface 61 and the inner wall surface 63A of the transparent plate 59. Therefore, the Raman spectrum data 27 of the culture supernatant 15A flowing in the inner shell portion 56 can be measured reliably.

[0113] like Figure 4 As shown in FIG. 1 , the optical system 55 includes a hemispherical lens 58 having a positive refractive power. Therefore, the focusing position FP of the excitation light EL can be set to a position relatively close to the emission surface 61 of the transparent plate 59, and the possibility of the excitation light EL being attenuated in the culture supernatant 15A can be reduced.

[0114] like Figure 4 As shown in FIGS. 1 and 2 , the optical system 55 further includes a transparent plate 59 whose emission surface 61 of the excitation light EL is a flat surface. Therefore, the possibility that the excitation light EL is attenuated in the culture supernatant 15A can be further reduced.

[0115] like Fig.10 As shown in FIG. 1 , the thickness Th of the transparent plate 59 in the direction of the optical axis OA is greater than or equal to half of the distance d between the first point P1 intersecting the optical axis OA on the emission surface 60 of the hemispherical lens 58 and the focusing position FP of the excitation light EL and less than or equal to the distance d. If the thickness Th is greater than or equal to half of the distance d, the possibility of attenuation of the excitation light EL in the culture supernatant 15A can be further reduced. If the thickness Th is less than or equal to the distance d, the focusing position FP can be set outside the transparent plate 59 without fail.

[0116] The interval between the emission surface 61 and the inner wall surface 63A of the transparent plate 59 is fixed. Therefore, even if the same measurement target substance is measured, the Raman spectrum data 27 will not be different in the various flow cells 10S, 10M and 10L having different flow path diameters, and it can be used without any problem in the flow cells 10 having various flow path diameters.

[0117] Raman scattered light RSL easily reflects information on functional groups derived from amino acids of proteins. Therefore, as shown in this example, by using the physical property data as Raman spectrum data 27, physical property data that accurately reflects physical properties such as the concentration of the antibody 17 as a protein can be obtained.

[0118] like Figure 1 As shown in FIG. 1 , the turbidity of the culture supernatant 15A is 250 NTU or more and 1000 NTU or less. In this case, the attenuation of the excitation light EL caused by the culture supernatant 15A becomes greater. Therefore, the following effects can be greatly exerted: using a hemispherical lens 58 with a positive refractive power, or using a transparent plate 59 whose emission surface 61 of the excitation light EL is a flat surface, etc., to reduce the possibility of attenuation of the excitation light EL in the culture supernatant 15A.

[0119] Biopharmaceuticals containing antibodies 17 as cell products are called antibody pharmaceuticals, and are widely used not only for the treatment of chronic diseases such as cancer, diabetes, and rheumatoid arthritis, but also for the treatment of rare diseases such as hemophilia and Crohn's disease. Therefore, according to this example in which the culture supernatant 15A, which is the source of the antibody pharmaceutical obtained from the culture tank 13 in which the antibody-producing cells 16 are cultured, is used as a fluid, the development of antibody pharmaceuticals that are widely used for the treatment of various diseases can be promoted.

[0120] The culture supernatant 15A obtained from the culture tank 13 during culturing is used as a fluid. Therefore, the Raman spectrum data 27 can be measured while the antibody-producing cells 16 are continuously cultured in the culture tank 13. In addition, the antibody-producing cells 16 are removed from the culture supernatant 15A. Therefore, the Raman spectrum data 27 of the antibody 17 or the like, which is a cell product, can be measured with high accuracy.

[0121] like Figure 6 As shown in the figures, when the tip portion 40 is attached to the flow cell 10, the flow path for the culture supernatant 15A to flow exists inside and outside the tip portion 40. Therefore, the Raman spectrum data 27 of the culture supernatant 15A can be measured inside the tip portion 40 (inner shell portion 56). In addition, the tip portion 40 does not hinder the flow of the culture supernatant 15A in the flow cell 10.

[0122] like Figure 5 As shown, when the front end portion 40 is attached to the flow cell 10, the line LIO connecting the centers CI and CO of the inlet 70 and the outlet 71 is parallel to the direction FD. Therefore, the culture supernatant 15A can flow without pressure toward the focusing position FP of the excitation light EL in the inner shell portion 56. The deviation of the components in the culture supernatant 15A in the inner shell portion 56 is reduced, and the measurement stability of the Raman spectrum data 27 can be improved.

[0123] (Variant 1)

[0124] As an example, it can be Fig.12 The front end portion 100 is shown. The front end portion 100 has an inner shell portion 101. The bottom plate 102 of the inner shell portion 101 and the inner wall surface 102A of the bottom plate 102 are curved surfaces convex downwardly in the shape of the flow path 30 of the flow cell 10. The inner wall surface 102A is an example of the "opposing wall surface" involved in the technology of the present invention.

[0125] Thus, if the inner wall surface 102A is formed as a downwardly convex curved surface, the inner wall surface 102A functions as a reflecting surface that directs the Raman scattered light RSL toward the optical system 55. Therefore, it is possible to further improve the S / N ratio of the Raman spectrum data 27. The downwardly convex curved surface may also be in the shape of a parabolic antenna.

[0126] (Variant 2)

[0127] As an example, it can be Fig.13 The front end portion 105 is shown. The front end portion 105 has a circular inlet 106 and an outlet 107. Thus, the shape of the inlet and the outlet is not limited to a rectangular shape like the inlet 70 and the outlet 71, and may be a circular shape like the inlet 106 and the outlet 107.

[0128] In addition, the inner shell 56 is not limited to the cylindrical container shape shown in the example. It can also be a square cylinder container shape, a hexagonal cylinder container shape, etc. Therefore, the bottom plate 63 is not limited to the circular shape shown in the example, and can also be a rectangular, hexagonal, etc. In addition, the peripheral plate 66 is not limited to the curved surface shown in the example, and can also be a flat surface.

[0129] [Second embodiment]

[0130] In the second embodiment, the state of the measurement target substance such as the antibody 17 contained in the culture supernatant 15A is predicted based on the Raman spectrum data 27 .

[0131] As an example, Fig.14 As shown, the Raman spectrometer 11 is connected to the information processing device 110 via a computer network such as a LAN (Local Area Network) so as to be able to communicate with each other. The Raman spectrometer 11 sends the Raman spectrum data 27 to the information processing device 110. The information processing device 110 is, for example, a desktop personal computer, a notebook personal computer, or a tablet terminal.

[0132] As an example, Fig.15 As shown, the computer constituting the information processing apparatus 110 includes a storage 115 , a memory 116 , a CPU (Central Processing Unit) 117 , a communication unit 118 , a display 119 , and an input device 120 . These are connected to each other via a bus 121 .

[0133] The memory 115 is a hard disk drive built into the computer constituting the information processing device 110 or connected via a cable or a network. Alternatively, the memory 115 is a disk array in which a plurality of hard disk drives are connected. The memory 115 stores control programs such as an operating system, various application programs, and various data accompanying these programs. In addition, a solid-state drive may be used instead of a hard disk drive.

[0134] The memory 116 is a working memory for the CPU 117 to execute processing. The CPU 117 loads the program stored in the storage 115 into the memory 116 and executes processing according to the program. Thus, the CPU 117 centrally controls each part of the computer. In addition, the memory 116 can also be built into the CPU 117.

[0135] The communication unit 118 is a network interface that performs transmission control of various information via a LAN or the like. The display 119 displays various screens. Various screens have operation functions based on a GUI (Graphical User Interface). The computer constituting the information processing device 110 receives input of operation instructions from the input device 120 through various screens. The input device 120 is a keyboard, a mouse, a touch panel, a microphone for voice input, and the like.

[0136] As an example, Fig.16 As shown, a working program 125 is stored in the memory 115 of the information processing device 110. The working program 125 is an application for making the computer function as the information processing device 110. In addition to the working program 125, the memory 115 also stores a concentration prediction model 126. The concentration prediction model 126 is, for example, a machine learning model composed of a neural network. In addition, it is not limited to a neural network, and can also be a decision tree, a random forest, a naive Bayes, a gradient boosting decision tree, etc.

[0137] When the operation program 125 is activated, the CPU 117 of the computer constituting the information processing device 110 cooperates with the memory 116 and the like to function as an acquisition unit 130 , a read / write (hereinafter referred to as RW (Read Write)) control unit 131 , a prediction unit 132 , and a display control unit 133 .

[0138] The acquisition unit 130 acquires the Raman spectrum data 27 from the Raman spectrometer 11 . The acquisition unit 130 outputs the Raman spectrum data 27 to the RW control unit 131 .

[0139] The RW control unit 131 controls the storage of various data in the memory 115 and the reading of various data stored in the memory 115. The RW control unit 131 stores the Raman spectrum data 27 from the acquisition unit 130 in the memory 115. In addition, the RW control unit 131 reads the Raman spectrum data 27 and the concentration prediction model 126 from the memory 115, and outputs the read Raman spectrum data 27 and the concentration prediction model 126 to the prediction unit 132. In addition, the RW control unit 131 outputs the Raman spectrum data 27 to the display control unit 133.

[0140] The prediction unit 132 applies the Raman spectrum data 27 to the concentration prediction model 126, and outputs a concentration prediction result 135 from the concentration prediction model 126. The concentration prediction result 135 is a result of predicting the concentration of the antibody 17 in the culture supernatant 15A. The prediction unit 132 outputs the concentration prediction result 135 to the display control unit 133.

[0141] The display control unit 133 controls the display of various screens on the display 119. For example, the display control unit 133 displays the Raman spectrum analysis screen 150 (see Fig.21 etc.) are displayed on the control of the display 119.

[0142] As an example, Fig.17 As shown, the data set 140 is a set of learning intensity values ​​141 and correct concentrations 142. For the training phase of the concentration prediction model 126, a data set group 140G, which is a set of the data sets 140, is prepared.

[0143] The learning intensity value 141 is obtained by copying the intensity value of the Raman spectrum data 27S measured using the flow cell 10S having the flow channel 30S. Figure 7 The correct concentration 142 is calculated based on the amount of the antibody 17 in the culture supernatant 15A for which the Raman spectrum data 27S is measured and the volume of the flow channel 30S. The amount of the antibody 17 is measured using, for example, a high performance liquid chromatography apparatus.

[0144] As an example, Fig.18 As shown, in the learning phase of the concentration prediction model 126, the learning intensity value 141 in the data set 140 is input to the concentration prediction model 126, and the learning concentration prediction result 135L is output from the concentration prediction model 126. Next, based on the comparison result of the learning concentration prediction result 135L and the correct concentration 142, the loss calculation of the concentration prediction model 126 using the loss function is performed. Then, based on the result of the loss calculation, the coefficients of the concentration prediction model 126 are updated and set, and the concentration prediction model 126 is updated according to the updated setting.

[0145] In the learning phase of the concentration prediction model 126, the above-mentioned series of processes, such as inputting the learning intensity value 141 to the concentration prediction model 126, outputting the learning concentration prediction result 135L from the concentration prediction model 126, loss calculation, update setting, and updating of the concentration prediction model 126, are repeated while changing the data set 140. When the prediction accuracy of the learning concentration prediction result 135L relative to the correct concentration 142 reaches a preset setting level, the above-mentioned series of processes are repeated. In this way, the concentration prediction model 126 whose prediction accuracy reaches the set level is stored in the memory 115 and used in the prediction unit 132. In addition, the learning may be terminated when the above-mentioned series of processes are repeated a set number of times, regardless of the prediction accuracy of the learning concentration prediction result 135L relative to the correct concentration 142.

[0146] The concentration prediction model 126 may be learned in the information processing device 110 or in a device different from the information processing device 110. Furthermore, after the data is stored in the memory 115, the concentration prediction model 126 may be continuously learned.

[0147] The prediction unit 132 applies the Raman spectrum data 27 measured using a plurality of flow cells 10 having a flow path 30 different from the flow cell 10S to the concentration prediction model 126. The flow path 30 has a flow path diameter φ different from the flow path diameter φS. Then, the concentration prediction result 135 is output from the concentration prediction model 126. In more detail, as an example, Fig.19 As shown, the prediction unit 132 inputs the intensity value of the Raman spectrum data 27M measured using the flow cell 10M having the flow path 30M into the concentration prediction model 126. Figure 8 Then, the concentration prediction result 135 is output from the concentration prediction model 126. And, as an example, Fig. 20 As shown, the prediction unit 132 inputs the intensity value of the Raman spectrum data 27L measured using the flow cell 10L having the flow path 30L into the concentration prediction model 126. Fig. 9 Then, the concentration prediction result 135 is output from the concentration prediction model 126. In addition, although not shown in the figure, the prediction unit 132 inputs the intensity value of the Raman spectrum data 27S measured using the flow cell 10S having the flow path 30S having the flow path diameter φS into the concentration prediction model 126, and outputs the concentration prediction result 135 from the concentration prediction model 126.

[0148] The display control unit 133 displays, for example, Fig.21 The Raman spectrum analysis screen 150 shown is displayed on the display 119. On the Raman spectrum analysis screen 150, a graph of the Raman spectrum data 27 is displayed.

[0149] A concentration prediction button 151 is provided at the bottom of the Raman spectrum analysis screen 150. When the concentration prediction button 151 is pressed, the CPU 117 of the information processing device 110 receives the concentration prediction instruction. The CPU 117 receives the concentration prediction instruction and causes the prediction unit 132 to perform Fig.19 and Fig. 20 The processing shown is performed, and a concentration prediction result 135 is output from the concentration prediction model 126.

[0150] When the concentration prediction result 135 from the prediction unit 132 is input, the display control unit 133 causes the display of the Raman spectrum analysis screen 150 to be displayed as follows, for example. Fig. 22 As shown in the figure. Fig. 22 In the example, the concentration prediction result 135 is displayed on the Raman spectrum analysis screen 150 together with a graph of the Raman spectrum data 27 .

[0151] Next, as an example, refer to Fig.23 and Fig.24 The flowchart shown explains the operation based on the second embodiment.

[0152] First, use Fig.17 The data set 140 shown, Fig.18 The concentration prediction model 126 is learned as shown. That is, the learning intensity value 141, which is a copy of the intensity value of the Raman spectrum data 27S measured using the flow cell 10S having the flow path 30S having a flow path diameter φS ( Fig.23 ). Next, based on the comparison result of the learning concentration prediction result 135L and the correct concentration 142, the concentration prediction model 126 is updated (step ST110). Before the prediction accuracy of the learning concentration prediction result 135L relative to the correct concentration 142 does not reach a preset set level ("No" in step ST120), the processing of these steps ST100 and ST110 is repeated while changing the data set 140 (step ST130). When the prediction accuracy of the learning concentration prediction result 135L relative to the correct concentration 142 reaches the set level ("Yes" in step ST120), the learning of the concentration prediction model 126 is completed. The concentration prediction model 126 after the learning is completed is stored in the memory 115 of the information processing device 110.

[0153] like Fig.16 As shown, by activating the operation program 125 , the CPU 117 of the information processing device 110 functions as an acquisition unit 130 , an RW control unit 131 , a prediction unit 132 , and a display control unit 133 .

[0154] The concentration prediction model 126 is stored in the memory 115 of the information processing device 110 . The concentration prediction model 126 is read from the memory 115 by the RW control unit 131 and output to the prediction unit 132 .

[0155] In the information processing device 110, the acquisition unit 130 acquires the Raman spectrum data 27 ( Fig.24 The Raman spectrum data 27 is stored in the memory 115 by the RW control unit 131 (step ST210).

[0156] The Raman spectrum data 27 is read from the memory 115 by the RW control unit 131 (step ST220), and output to the prediction unit 132 and the display control unit 133. Fig.21 As shown, the display control unit 133 displays the Raman spectroscopy analysis screen 150 on the display 119 (step ST230 ).

[0157] The user of the information processing device 110 presses the concentration prediction button 151 to cause the concentration prediction model 126 to predict the concentration of the antibody 17 in the culture supernatant 15A for which the Raman spectrum data 27 is measured and displayed as a graph on the Raman spectrum analysis screen 150. The CPU 117 then receives the concentration prediction instruction (step ST240).

[0158] After receiving the concentration forecast indication, if Fig.19 and Fig. 20 As shown in FIG. 2 , in the prediction unit 132, the intensity value of the Raman spectrum data 27 is input to the concentration prediction model 126, thereby outputting the concentration prediction result 135 from the concentration prediction model 126 (step ST250). The concentration prediction result 135 is output from the prediction unit 132 to the display control unit 133, as shown in FIG. Fig. 22 As shown, the display control unit 133 displays it on the Raman spectrum analysis screen 150 (step ST260).

[0159] The user makes various decisions by referring to the concentration prediction result 135 displayed on the Raman spectroscopy analysis screen 150. For example, consider the case where a condition determination experiment such as the culture conditions of the antibody production cell 16 based on a small-scale device is performed. In this case, if the concentration prediction result 135 is worse than the target value, the user makes a decision to terminate the current experiment and transfer to an experiment based on new conditions. In addition, consider the case where the condition determination experiment is completed and mass production based on a large-scale device is performed. In this case, if the concentration prediction result 135 is worse than the target value, the user makes a decision to interrupt mass production and perform maintenance on the culture tank 13.

[0160] Thus, in the second embodiment, the CPU 117 of the information processing device 110 uses the concentration prediction model 126 for predicting the concentration of the antibody 17 contained in the culture supernatant 15A. The concentration prediction model 126 is generated using only the data set 140 consisting of the learning intensity value 141 obtained by copying the intensity value of the Raman spectrum data 27S of the antibody 17 and the like contained in the culture supernatant 15A in the flow cell 10S and the correct concentration 142 of the antibody 17.

[0161] The acquisition unit 130 acquires Raman spectrum data 27M and 27L of the antibody 17 and the like contained in the culture supernatant 15A in the flow cell 10 different from the flow cell 10S, for example, the flow cells 10M and 10L. The prediction unit 132 applies the Raman spectrum data 27M and 27L to the concentration prediction model 126, and outputs a concentration prediction result 135 of the antibody 17 from the concentration prediction model 126.

[0162] The concentration prediction model 126 generated only from the Raman spectrum data 27S measured using the flow cell 10S can be used to predict the concentration of the antibody 17 based on the Raman spectrum data 27M and 27L measured using the flow cells 10M and 10L different from the flow cell 10S. Therefore, the effort of preparing the concentration prediction model 126 for each of the plurality of flow cells 10, such as the flow cell 10S, the flow cell 10M, and the flow cell 10L, can be saved.

[0163] All that is required as the learning intensity value 141 of the data set 140 is the intensity value of the Raman spectrum data 27S of the antibody 17 and the like contained in the culture supernatant 15A in the flow cell 10S. Therefore, the data set 140 can be prepared simply.

[0164] The Raman spectrum data 27S, 27M, and 27L are measured by the sensor unit 25 having the tip portion 40 described in the first embodiment. Therefore, even if the same measurement target substance is measured, the Raman spectrum data 27S, 27M, and 27L will not be different, and there is no need to correct the Raman spectrum data 27S, 27M, and 27L to eliminate the difference between them.

[0165] The concentration prediction model 126 is not limited to a machine learning model. It can also be a model generated by multivariate analysis or statistical analysis. Examples of multivariate analysis and statistical analysis include multiple regression, principal component regression, partial least squares regression, logistic regression, Lasso regression, ridge regression, support vector regression, and Gaussian process regression. In a model generated by such multivariate analysis and statistical analysis, determining the coefficients of the regression equation based on at least two data sets 140 is equivalent to the case of "generating a "state prediction model using only data sets" such as the later-described supplementary item 25.

[0166] The Raman spectrum data 27 used to generate the data set 140 is not limited to the Raman spectrum data 27S shown as an example. The intensity value of the Raman spectrum data 27M or the intensity value of the Raman spectrum data 27L may be used as the learning intensity value 141 of the data set 140 .

[0167] The flow rate of the culture supernatant 15A may differ depending on the type of the flow cell 10. However, in this case, it is preferable to apply the Raman spectrum data 27 to the concentration prediction model 126 after correcting the difference in the Raman spectrum data 27 caused by the difference in the flow rate of the culture supernatant 15A. When the Raman spectrum data 27 used to generate the data set 140 is set to, for example, the Raman spectrum data 27S, correction is performed to set the Raman spectrum data 27M and 27L to data equivalent to the Raman spectrum data 27S. For the correction, a conversion formula or a machine learning model that sets the Raman spectrum data 27M and 27L to data equivalent to the Raman spectrum data 27 can be used.

[0168] The concentration of the antibody 17 in the culture supernatant 15A is predicted, but the method is not limited to this. The concentration of the aggregates in the culture supernatant 15A may be predicted. Furthermore, the density or the like may be predicted instead of or in addition to the concentration.

[0169] The container to which the front end portion 40 is mounted is not limited to the flow cell 10. The container to which the front end portion 40 is mounted may be, for example, a culture tank 13. In this case, a mounting portion is provided in the culture tank 13, and the front end portion 40 is mounted on the mounting portion. When the container is the culture tank 13, the flow direction is the flow direction of the cell culture solution 15 generated by the rotation of the stirring blade in the culture tank 13.

[0170] The inner wall surface 63A of the bottom plate 63 of the inner shell 56 is set as the opposite wall surface, but it is not limited to this. It is also possible to form the front end 40 only by the outer shell 57 without using the inner shell 56, and the inner wall surface 64A of the bottom plate 64 of the outer shell 57 is set as the opposite wall surface. In this case, the outer shell 57 is made of metal in the same way as the inner shell 56. Alternatively, the outer shell 57 is made of resin, and a metal film such as aluminum, copper, gold, etc. is formed on the entire surface or a part of the inner wall surface 64A by plating. Moreover, a metal film is also formed on the entire surface or a part of the inner wall surface 66A of the peripheral plate 66 of the outer shell 57 by plating. In this way, it is sufficient to configure metal on at least a part of the surface of the opposite wall surface and at least a part of the surface of the side wall surface. However, in order to fully exert the effect of reducing the possibility that the S / N ratio of the Raman spectrum data 27 is reduced due to the resin, it is preferred to configure metal on the entire surface of the opposite wall surface and the entire surface of the side wall surface.

[0171] The functions of the "opposing wall" and the "holding part" involved in the technology of the present invention are assumed by one component, i.e., the inner shell 56, but the present invention is not limited thereto. The bottom plate 63 having the opposing wall, i.e., the inner wall 63A, and the other parts of the inner shell 56 that function as the holding part are originally separate bodies, but may be integrated by bonding or welding.

[0172] The lens with positive refractive power is not limited to the hemispherical lens 58 shown in the example. It can also be a sphere, that is, a ball lens, a plano-convex lens, a biconvex lens, or a cylindrical lens. In addition, the optical element is not limited to the circular plate-shaped transparent plate 59 having an exit surface 61 and an incident surface 62 parallel to each other as shown in the example. It can also be a transparent plate having an incident surface that imitates the shape of the exit surface and a planar exit surface, such as a ball lens, a plano-convex lens, and a biconvex lens.

[0173] Instead of joining a lens with positive refractive power and an optical element to form an optical system, a lens with positive refractive power and an optical element may be integrally formed into one lens. Alternatively, the optical system may be formed only of a lens with positive refractive power without an optical element.

[0174] For example, a mechanism may be provided for changing the interval between the exit surface of the excitation light EL of the optical system 55 (the exit surface 61 of the transparent plate 59) and the opposing wall surface (the inner wall surface 63A) in stages. In this case, the interval between the exit surface of the excitation light EL of the optical system 55 and the opposing wall surface is set according to the flow cell 10 having the smallest flow path diameter φ among the flow cells 10 assumed to be used. That is, the interval between the exit surface of the excitation light EL of the optical system 55 and the opposing wall surface may not be fixed.

[0175] The first connection portion 31 and the second connection portion 32 may also be arranged on the lower side of the flow cell 10, and the flow path 30 may be set to a U-shape. The shape of the flow cell 10 is not limited to a cylindrical shape, but may also be a square cylindrical shape. The cross-sectional shape of the flow path 30 is not limited to a circular shape, but may be an elliptical shape or a rectangular shape. Furthermore, the flow cell 10 may also be formed of composite materials such as carbon fiber reinforced resin.

[0176] The object substance for measuring the Raman spectrum data 27 is not limited to the antibody 17 and the like, but may be a protein other than the antibody 17, a peptide, a nucleic acid (DNA, RNA (ribonucleic acid)), a lipid, a virus, a virus subunit, a virus-like particle, and the like.

[0177] Cell products are not limited to antibody 17 and the like. They may also be cytokines (interferons, interleukins, etc.) or hormones (insulin, glucagon, follicle-stimulating hormone, erythropoietin, etc.), growth factors (IGF (Insulin-Like Growth Factor: insulin-like growth factor)-1, bFGF (Basic Fibroblast Growth Factor: basic fibroblast growth factor) and the like), coagulation factors (factor 7, factor 8, factor 9, etc.), enzymes (lysosomal enzymes, DNA (deoxyribonucleic acid) degrading enzymes, etc.), Fc (Fragment Crystallizable: crystallizable segment) fusion proteins, receptors, albumin, protein vaccines. In addition, antibody 17 also includes bispecific antibodies, antibody-drug conjugates, low molecular weight antibodies, sugar chain modified antibodies, and the like.

[0178] The physical property data is not limited to the Raman spectrum data 27, and may be infrared absorption spectrum data, near infrared absorption spectrum data, nuclear magnetic resonance spectrum data, ultraviolet visible spectroscopy (UV-Vis: Ultraviolet Visible Absorption Spectroscopy) spectrum data, or fluorescence spectrum data.

[0179] The fluid is not limited to the culture supernatant 15A. It can also be the cell culture fluid 15 before the cells are removed by the cell removal filter 14. It can also be the cell culture fluid (so-called culture medium) that does not contain cell products before being supplied to the culture tank 13. It can also be a purified solution obtained by purifying the culture supernatant 15A with a chromatographic device in the purification section. The fluid is not limited to the cell culture fluid 15, for example, it can be water from a river collected to investigate water pollution. It can also be a raw material (for example, lithium polystyrene and methanol aqueous solution, etc.) and / or a product when a product such as a monomer or a polymer (for example, polystyrene, etc.) is continuously generated by flow synthesis. In addition, the fluid is not limited to a liquid, but can also be a gas.

[0180] When the front end portion 40 is mounted on the flow cell 10, the center CI of the inlet 70, the center CO of the outlet 71, and the center CP of the flow path 30 are made to coincide with each other, but the present invention is not limited thereto. When the flow path diameter φ is relatively large, the flow cell 10 and the sensor portion 25 may be designed so that the center CI of the inlet 70 and the center CO of the outlet 71 are located above the center CP of the flow path 30. In this way, the amount of the front end portion 40 and the like protruding into the flow path 30 can be reduced, and the resistance of the front end portion 40 and the like to the flow of the culture supernatant 15A can be reduced. Alternatively, the amount of the front end portion 40 and the like protruding into the flow path 30 may be made the same regardless of the type of the flow cell 10.

[0181] Based on the above description, the techniques described in the following supplementary notes can be understood.

[0182] [Supplementary Item 1]

[0183] A sensor unit of a spectroscopic analysis device comprises a front end portion, wherein the front end portion has an optical system built therein for irradiating a measurement light to a measurement target substance of physical property data and capturing return light from the measurement target substance, and the front end portion is mounted on a container containing a fluid containing the measurement target substance, wherein:

[0184] The front end portion has:

[0185] an opposing wall surface facing an emission surface of the measurement light of the optical system; and

[0186] A retaining portion protrudes from the exit surface side to the opposite wall surface side, retains the opposite wall surface in a state where a space for the fluid to flow is provided between the exit surface and the opposite wall surface, and the retaining portion includes an inlet and an outlet for the fluid, and side wall surfaces arranged on both sides of the flow direction of the fluid.

[0187] [Supplementary Item 2]

[0188] The sensor unit of the spectroscopic analysis device according to Supplementary Item 1, wherein the container is a flow cell having a flow path through which the fluid flows.

[0189] [Supplementary Item 3]

[0190] The sensor unit of the spectroscopic analysis device according to Supplementary item 2, wherein the tip portion is attached to the flow cell containing a resin.

[0191] [Supplementary Item 4]

[0192] The sensor unit of the spectroscopic analysis device according to Supplementary Item 2 or Supplementary Item 3, wherein the front end portion is mounted on a plurality of types of flow cells having different flow path diameters.

[0193] [Supplementary Note 5]

[0194] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 4, wherein a metal is disposed on at least a part of a surface of the opposing wall surface.

[0195] [Supplementary Item 6]

[0196] The sensor unit of the spectroscopic analysis device according to Supplementary item 5, wherein an area of ​​the metal in the opposing wall surface is larger than an irradiation area of ​​the measuring light in the opposing wall surface.

[0197] [Supplementary Item 7]

[0198] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 6, wherein the surface roughness of the opposing wall surface is 1.6 μm or less.

[0199] [Supplementary Item 8]

[0200] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 7, wherein the opposing wall surface is a flat surface.

[0201] [Supplementary Item 9]

[0202] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 7, wherein when the emission surface side is set as an upper side and the opposing wall surface side is set as a lower side, the opposing wall surface is a curved surface convex toward the lower side.

[0203] [Supplementary Item 10]

[0204] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 9, comprising a main body portion made of resin.

[0205] [Supplementary Note 11]

[0206] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 10, wherein the inlet and the outlet are circular or rectangular.

[0207] [Supplementary Item 12]

[0208] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 11, wherein a focusing position of the measurement light by the optical system is located between the emission surface and the opposing wall surface.

[0209] [Supplementary Item 13]

[0210] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 12, wherein the optical system includes a lens having a positive refractive power.

[0211] [Supplementary Item 14]

[0212] The sensor unit of the spectroscopic analysis device according to Supplementary Item 13, wherein the optical system further includes an optical element whose emission surface of the measurement light is a flat surface.

[0213] [Supplementary Item 15]

[0214] The sensor unit of the spectroscopic analysis device according to appendix 14, wherein the thickness of the optical element in the optical axis direction is greater than or equal to half of the distance between a point of the emission surface of the lens intersecting the optical axis and a focusing position of the measurement light and the distance less than or equal to the distance.

[0215] [Supplementary Item 16]

[0216] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 15, wherein a metal is disposed on at least a portion of a surface of the side wall surface.

[0217] [Supplementary Item 17]

[0218] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 16, wherein the interval between the emission surface and the opposing wall surface is fixed.

[0219] [Supplementary Item 18]

[0220] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 17, wherein the physical property data is Raman spectrum data.

[0221] [Supplementary Item 19]

[0222] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 18, wherein the turbidity of the fluid is 250 NTU or more and 1000 NTU or less.

[0223] [Supplementary item 20]

[0224] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 19, wherein the fluid is a cell culture fluid.

[0225] [Supplementary item 21]

[0226] A measurement system comprising: a sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 20; and the container to which the front end unit is attached.

[0227] [Supplementary item 22]

[0228] The measurement system according to Supplementary item 21, wherein, when the container is the flow cell and the front end portion is attached to the flow cell, a flow path through which the fluid flows exists inside and outside the front end portion.

[0229] [Supplementary item 23]

[0230] The measuring system according to Supplementary Item 21 or Supplementary Item 22, wherein, when the container is the flow cell and the front end portion is mounted on the flow cell, a line connecting the centers of the inlet and the outlet is parallel to the flow direction.

[0231] [Supplementary item 24]

[0232] A measurement method, comprising measuring the physical property data using a sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 20.

[0233] Furthermore, according to the description of the above-mentioned second embodiment, the techniques described in the following supplementary notes can be understood.

[0234] [Supplementary item 25]

[0235] An information processing device comprises a processor,

[0236] In the processor,

[0237] using a state prediction model that predicts the state of a substance to be measured contained in a fluid and is generated using only a data set consisting of first physical property data of the substance to be measured contained in the fluid in a first container and correct answer data of the state of the substance to be measured,

[0238] acquiring second physical property data of the substance to be measured contained in the fluid in a second container different from the first container,

[0239] applying the second physical property data to the state prediction model, and outputting a prediction result of the state of the measurement target substance from the state prediction model;

[0240] The first physical property data and the second physical property data are measured by a sensor unit of a spectroscopic analyzer.

[0241] The spectroscopic analysis device includes a front end portion, in which an optical system for irradiating the measurement target substance with measurement light and capturing return light from the measurement target substance is built, and the front end portion is mounted on the first container and the second container, wherein:

[0242] The front end portion has:

[0243] an opposing wall surface facing an emission surface of the measurement light of the optical system, and

[0244] A retaining portion protrudes from the exit surface side to the opposite wall surface side, retains the opposite wall surface in a state where a space for the fluid to flow is provided between the exit surface and the opposite wall surface, and the retaining portion includes an inlet and an outlet for the fluid, and side wall surfaces arranged on both sides of the flow direction of the fluid.

[0245] [Supplementary item 26]

[0246] The information processing device according to supplementary item 25, wherein:

[0247] The first container is a first flow cell having a first flow path diameter and a first flow path for the fluid to flow.

[0248] The second container is a second flow cell having a second flow path diameter different from the first flow path diameter and having a second flow path through which the fluid flows.

[0249] [Supplementary item 27]

[0250] A working method of an information processing device comprises the following steps:

[0251] using a state prediction model that predicts the state of a substance to be measured contained in a fluid and is generated using only a data set consisting of first physical property data of the substance to be measured contained in the fluid in a first container and correct answer data of the state of the substance to be measured,

[0252] acquiring second physical property data of the substance to be measured contained in the fluid in a second container different from the first container, and

[0253] applying the second physical property data to the state prediction model, and outputting a prediction result of the state of the measurement target substance from the state prediction model;

[0254] The first physical property data and the second physical property data are measured by a sensor unit of a spectroscopic analyzer.

[0255] The spectroscopic analysis device includes a front end portion, in which an optical system for irradiating the measurement target substance with measurement light and capturing return light from the measurement target substance is built, and the front end portion is mounted on the first container and the second container, wherein:

[0256] The front end portion has:

[0257] an opposing wall surface facing an emission surface of the measurement light of the optical system, and

[0258] A retaining portion protrudes from the exit surface side to the opposite wall surface side, retains the opposite wall surface in a state where a space for the fluid to flow is provided between the exit surface and the opposite wall surface, and the retaining portion includes an inlet and an outlet for the fluid, and side wall surfaces arranged on both sides of the flow direction of the fluid.

[0259] [Supplementary item 28]

[0260] A working program of an information processing device, which is used to make a computer execute a process comprising the following steps:

[0261] using a state prediction model that predicts the state of a substance to be measured contained in a fluid and is generated using only a data set consisting of first physical property data of the substance to be measured contained in the fluid in a first container and correct answer data of the state of the substance to be measured,

[0262] acquiring second physical property data of the substance to be measured contained in the fluid in a second container different from the first container, and

[0263] applying the second physical property data to the state prediction model, and outputting a prediction result of the state of the measurement target substance from the state prediction model;

[0264] The first physical property data and the second physical property data are measured by a sensor unit of a spectroscopic analyzer.

[0265] The spectroscopic analysis device includes a front end portion, in which an optical system for irradiating the measurement target substance with measurement light and capturing return light from the measurement target substance is built, and the front end portion is mounted on the first container and the second container, wherein:

[0266] The front end portion has:

[0267] an opposing wall surface facing an emission surface of the measurement light of the optical system, and

[0268] A retaining portion protrudes from the exit surface side to the opposite wall surface side, retains the opposite wall surface in a state where a space for the fluid to flow is provided between the exit surface and the opposite wall surface, and the retaining portion includes an inlet and an outlet for the fluid, and side wall surfaces arranged on both sides of the flow direction of the fluid.

[0269] Here, CPU 117 is an example of the above-mentioned "processor". Concentration prediction model 126 is an example of the above-mentioned "state prediction model". Concentration is an example of the above-mentioned "state". Circulation cell 10S is an example of the above-mentioned "first container" and "first circulation cell". Raman spectrum data 27S and learning intensity value 141 are examples of the above-mentioned "first physical property data". Correct concentration 142 is an example of the above-mentioned "correct data".

[0270] The flow cells 10M and 10L are examples of the above-mentioned “second container” and “second flow cell.” The Raman spectrum data 27M and 27L are examples of the above-mentioned “second physical property data.” The concentration prediction result 135 is an example of the above-mentioned “prediction result.”

[0271] In the second embodiment described above, for example, as a hardware structure of a processing unit (Processing Unit) that performs various processes such as the acquisition unit 130, the RW control unit 131, the prediction unit 132, and the display control unit 133, various processors (Processor) shown below can be used. As described above, various processors include a general-purpose processor, i.e., the CPU 117, that executes software (the work program 125) to function as various processing units, and processors such as FPGA (Field Programmable Gate Array) whose circuit structure can be changed after manufacturing, i.e., programmable logic devices (PLD), ASIC (Application Specific Integrated Circuit), etc., which have a circuit structure specially designed for performing specific processing, i.e., dedicated circuits, etc.

[0272] A processing unit may be composed of one of these various processors, or a combination of two or more processors of the same or different types (for example, a combination of multiple FPGAs and / or a combination of a CPU and an FPGA). Furthermore, multiple processing units may be composed of one processor.

[0273] As an example of a plurality of processing units being composed of one processor, first, there is a method in which a processor is composed of a combination of one or more CPUs and software, as represented by computers such as clients and servers, and the processor functions as a plurality of processing units. Secondly, there is a method in which a processor is used to implement the overall function of a system including a plurality of processing units by a single IC (Integrated Circuit) chip, as represented by a system on chip (SOC). In this way, various processing units are composed of one or more of the above-mentioned various processors as a hardware structure.

[0274] Furthermore, as the hardware configuration of these various processors, more specifically, a circuit (circuitry) formed by combining circuit elements such as semiconductor elements can be used.

[0275] The technology of the present invention may also appropriately combine the above-mentioned various embodiments and / or various variations. Furthermore, it is not limited to the above-mentioned embodiments, and various structures may be adopted as long as they do not deviate from the main purpose. Furthermore, the technology of the present invention not only relates to programs, but also relates to storage media for non-temporary storage of programs.

[0276] The records and illustrations shown above are detailed descriptions of the parts involved in the technology of the present invention, and are only an example of the technology of the present invention. For example, the description of the above-mentioned structure, function, action and effect is a description of an example of the structure, function, action and effect of the parts involved in the technology of the present invention. Therefore, it is of course possible to delete unnecessary parts, add or replace new elements in the records and illustrations shown above without departing from the main purpose of the technology of the present invention. In addition, in order to avoid complexity and facilitate understanding of the parts involved in the technology of the present invention, in the records and illustrations shown above, descriptions related to technical common sense that does not need to be specifically explained are omitted on the basis of being able to implement the technology of the present invention.

[0277] In this specification, "A and / or B" has the same meaning as "at least one of A and B". That is, "A and / or B" means that it can be only A, only B, or a combination of A and B. Moreover, in this specification, when three or more situations are combined and expressed with "and / or", the same idea as "A and / or B" is also applied.

[0278] All documents, patent applications, and technical standards described in this specification are incorporated herein by reference to the same extent as if each individual document, patent application, or technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. A sensor unit of a spectroscopic analysis device, comprising a front end portion, wherein the front end portion has an optical system built therein for irradiating a measurement light to a measurement target substance of physical property data and capturing return light from the measurement target substance, and the front end portion is mounted on a container containing a fluid containing the measurement target substance, wherein: The front end portion has: an opposing wall surface facing an emission surface of the measurement light of the optical system; as well as A retaining portion protrudes from the exit surface side to the opposite wall surface side, retains the opposite wall surface in a state where a space for the fluid to flow is provided between the exit surface and the opposite wall surface, and the retaining portion includes an inlet and an outlet for the fluid, and side wall surfaces arranged on both sides of the flow direction of the fluid.

2. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The container is a flow cell having a flow path for the fluid to flow.

3. The sensor unit of the spectroscopic analysis device according to claim 2, wherein: The front end portion is mounted on the flow cell containing the resin.

4. The sensor unit of the spectroscopic analysis device according to claim 2, wherein: The front end portion is mounted on a plurality of types of flow cells having different flow path diameters.

5. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: Metal is disposed on at least a portion of the surface of the opposing wall surface.

6. The sensor unit of the spectroscopic analysis device according to claim 5, wherein: An area of ​​the metal on the opposing wall surface is larger than an irradiation area of ​​the measuring light on the opposing wall surface.

7. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The surface roughness of the opposing wall surface is 1.6 μm or less.

8. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The opposing wall surfaces are plane surfaces.

9. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: When the emission surface side is set as the upper side and the opposing wall surface side is set as the lower side, the opposing wall surface is a curved surface convex toward the lower side. 10 . The sensor unit of the spectroscopic analysis device according to claim 1 , comprising a main body portion made of resin.

11. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The inlet and the outlet are circular or rectangular.

12. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: A focusing position of the measurement light by the optical system is located between the emission surface and the opposing wall surface.

13. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The optical system includes a lens having positive refractive power.

14. The sensor unit of the spectroscopic analysis device according to claim 13, wherein: The optical system further includes an optical element whose emission surface of the measurement light is a flat surface.

15. The sensor unit of the spectroscopic analysis device according to claim 14, wherein: The thickness of the optical element in the optical axis direction is not less than half of the distance between a point of the emission surface of the lens intersecting the optical axis and a focusing position of the measurement light and not more than the distance.

16. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: Metal is disposed on at least a portion of the surface of the side wall surface.

17. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The distance between the emission surface and the opposing wall surface is fixed.

18. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The physical property data is Raman spectrum data.

19. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The turbidity of the fluid is greater than or equal to 250 NTU and less than or equal to 1000 NTU.

20. The sensor unit of the spectroscopic analysis device according to claim 1, wherein: The fluid is a cell culture medium.

21. A measurement system comprising: The sensor unit of the spectroscopic analysis device according to any one of claims 1 to 20; and The container having the front end portion is mounted.

22. The assay system according to claim 21, wherein When the container is the flow cell and the tip portion is attached to the flow cell, a flow path through which the fluid flows exists inside and outside the tip portion.

23. The assay system according to claim 21, wherein When the container is the flow cell and the front end portion is attached to the flow cell, a line connecting the centers of the inlet and the outlet is parallel to the flow direction.

24. A determination method, wherein: The physical property data is measured using the sensor unit of the spectroscopic analysis device according to any one of claims 1 to 20.

Images