Sensor portion of spectroscopic analysis device, measuring system, and measuring method

Abstract

This sensor portion for a spectroscopic analysis device is provided with a tip end portion equipped internally with an optical system for emitting measurement light onto a measurement target substance of which physical property data are to be measured, and capturing returned light from the measurement target substance, the tip end portion being fitted into a container for a fluid that includes the measurement target substance, wherein the tip end portion includes: an opposing wall surface that opposes an emission surface of the measurement light of the optical system; and a holding portion that projects from the emission surface side toward the opposing wall surface side, and that holds the opposing wall surface in a state in which a space through which the fluid flows is provided between the emission surface and the opposing wall surface, the holding portion including an inflow port and outflow port for the fluid, and side wall surfaces disposed on both sides in a direction of flow of the fluid.

Description

Sensor section of spectroscopic analyzer, measurement system, and measurement method

[0001] The technology of the present disclosure relates to a sensor unit of a spectroscopic analyzer, a measurement system, and a measurement method.

[0002] The spectroscopic analyzer has a sensor unit. The tip of the sensor unit has a built-in optical system for irradiating a measurement light onto a substance to be measured for physical property data and capturing return light from the substance to be measured. As described in JP-A-2020-511635, the tip may be attached to a flow cell. The flow cell has a flow path through which a fluid containing the substance to be measured flows. The flow cell is a type of container for a fluid containing the substance to be measured. JP-A-2020-511635 describes flow cells with various flow path diameters.

[0003] Japanese Patent Application Laid-Open No. 2021-048872 describes a sensor unit having an L-shaped leg at the end of an optical system (transparent element). The leg has an end that faces the emission surface of the measurement light of the optical system at a fixed interval.

[0004] As described in JP-A-2020-511635, flow cell flow path diameters vary widely. Therefore, the distance between the focusing position of the measurement light from the optical system and the wall surface of the flow path facing the exit surface of the measurement light from the optical system varies depending on the flow path diameter. As a result, even when the same substance to be measured is measured, the physical property data will differ depending on the flow path diameter of the flow cell. Specifically, when the flow path diameter of the flow cell is relatively large and the distance between the focusing position and the wall surface of the flow path facing the exit surface is relatively wide, the intensity value of the physical property data will be lower overall than when the flow path diameter of the flow cell is relatively small and the distance between the focusing position and the wall surface of the flow path facing the exit surface is relatively narrow.

[0005] In Japanese Patent Application Laid-Open No. 2021-048872, a leg having an end facing the emission surface of the measurement light of the optical system at a fixed distance is provided. The leg in Japanese Patent Application Laid-Open No. 2021-048872 has an L-shaped cross section and is open except for the portion connected to the end. For this reason, if the flow cell contains a resin, for example, measurement light leaking from the open portion of the leg is irradiated onto the resin of the flow cell, and the returned light is taken in through the open portion, causing a new problem of adversely affecting physical property data.

[0006] One embodiment of the technique of the present disclosure provides a sensor unit of a spectroscopic analyzer, a measurement system, and a measurement method that can reduce the risk of adversely affecting physical property data.

[0007] The sensor unit of the spectroscopic analysis device of the present disclosure is a tip portion incorporating an optical system for irradiating a substance to be measured for physical property data with measurement light and capturing return light from the substance to be measured, and is a sensor unit of a spectroscopic analysis device having a tip portion to be attached to a container for a fluid containing the substance to be measured, and the tip portion has an opposing wall surface that faces the emission surface of the measurement light of the optical system, and a holding portion that protrudes from the emission surface side to the opposing wall surface side and holds the opposing wall surface with a space provided between the emission surface and the opposing wall surface through which the fluid flows, and includes an inlet and outlet for the fluid, and side wall surfaces arranged on both sides in the direction of fluid flow.

[0008] The container is preferably a flow cell having a channel through which a fluid flows.

[0009] The tip is preferably attached to a flow cell containing a resin.

[0010] The tip is preferably attached to a plurality of types of flow cells having different flow channel diameters.

[0011] It is preferable that at least a part of the surface of the opposing wall is made of metal.

[0012] The area of ​​the metal on the opposing wall surface is preferably larger than the area of ​​the opposing wall surface that is irradiated with the measurement light.

[0013] The surface roughness of the opposing wall surface is preferably 1.6 μm or less.

[0014] The opposing wall surface is preferably flat.

[0015] When the light exit surface side is the upper side and the opposing wall side is the lower side, it is preferable that the opposing wall surface be a curved surface that is convex downward.

[0016] It is preferable to have a body portion that includes a resin.

[0017] The inlet and outlet are preferably circular or rectangular.

[0018] The position where the measurement light is collected by the optical system is preferably between the exit surface and the opposing wall surface.

[0019] The optical system preferably includes a lens with positive refractive power.

[0020] It is preferable that the optical system further includes an optical element having a flat exit surface for the measurement light.

[0021] The thickness of the optical element in the optical axis direction is preferably at least half the distance between the point where the exit surface of the lens intersects with the optical axis and the focusing position of the measurement light, but not more than that distance.

[0022] It is preferable that a metal be disposed on at least a portion of the surface of the side wall.

[0023] It is preferable that the distance between the light exit surface and the opposing wall surface is fixed.

[0024] The physical property data is preferably Raman spectrum data.

[0025] The turbidity of the fluid is preferably 250 NTU or more and 1000 NTU or less.

[0026] Preferably, the fluid is a cell culture medium.

[0027] A measurement system according to the present disclosure includes a sensor unit of any of the spectroscopic analyzers described above, and a container into which the tip is attached.

[0028] When the container is a flow cell and the tip is attached to the flow cell, the flow path through which the fluid flows is preferably present inside and outside the tip.

[0029] When the container is a flow cell and the tip is attached to the flow cell, it is preferable that the line connecting the centers of the inlet and outlet be parallel to the flow direction.

[0030] The measurement method of the present disclosure measures physical property data using a sensor unit of any of the above-described spectroscopic analyzers.

[0031] According to the technology of the present disclosure, it is possible to provide a sensor unit of a spectroscopic analyzer, a measurement system, and a measurement method that can reduce the risk of adversely affecting physical property data.

[0032] 1 is a diagram showing how Raman spectrum data of a substance to be measured in a cell culture solution obtained from a culture tank during culture is measured using a measurement system. FIG. 1 is a diagram showing excitation light and Raman scattered light. FIG. 2 is an exploded perspective view of a flow cell. FIG. 3 is an exploded perspective view of a sensor unit. FIG. 4 is a cross-sectional view of a flow cell and a sensor unit. FIG. 5 is a diagram showing the positional relationship between the flow channel of the flow cell and the inlet and outlet of the tip. FIG. 6 is a diagram showing an example of a tip attached to a flow cell having a relatively small flow channel diameter. FIG. 7 is a diagram showing an example of a tip attached to a flow cell having a medium flow channel diameter. FIG. 8 is a diagram showing an example of a tip attached to a flow cell having a relatively large flow channel diameter. FIG. 9 is an explanatory diagram of the focusing position of excitation light and the thickness of an optical element in the optical axis direction. FIG. 10 is a diagram showing the relationship between the area of ​​metal on an opposing wall surface and the area irradiated with excitation light on the opposing wall surface. FIG. 11 is a diagram showing an opposing wall surface that is curved convex downward. FIG. 12 is a diagram showing a circular inlet and outlet. FIG. 13 is a diagram showing an information processing device. FIG. 14 is a block diagram of a computer constituting an information processing device. FIG. 15 is a block diagram showing the processing unit of a CPU of the information processing device. FIG. 16 is a diagram showing the formation of a dataset group. FIG. 17 is a diagram showing processing in the learning phase of a concentration prediction model. FIG. 1 is a diagram showing a state in which Raman spectrum data measured using a flow cell with a medium flow path diameter is applied to a concentration prediction model and a concentration prediction result is output from the concentration prediction model. FIG. 2 is a diagram showing a state in which Raman spectrum data measured using a flow cell with a relatively large flow path diameter is applied to a concentration prediction model and a concentration prediction result is output from the concentration prediction model. FIG. 3 is a diagram showing a Raman spectrum analysis screen. FIG. 4 is a diagram showing a Raman spectrum analysis screen on which a concentration prediction result is displayed. FIG. 5 is a flowchart showing a processing procedure in the learning phase of the concentration prediction model. FIG. 6 is a flowchart showing a processing procedure of an information processing device.

[0033] [First Embodiment] As shown in FIG. 1 as an example, a measurement system 2 includes a flow cell 10 and a Raman spectrometer 11. The measurement system 2 is incorporated into a cell culture unit 12 in a manufacturing system for active pharmaceutical ingredients of biopharmaceuticals, for example. The cell culture unit 12 includes a culture tank 13 and a cell removal filter 14. A cell culture solution 15 is stored in the culture tank 13. The flow cell 10 is an example of a "container" according to the technology of the present disclosure. The Raman spectrometer 11 is an example of a "spectroscopic analysis device" according to the technology of the present disclosure. The cell removal filter 14 may be an alternating tangential flow filtration (ATF) filter.

[0034] Antibody-producing cells 16 are seeded in the culture vessel 13, and the antibody-producing cells 16 are cultured in a cell culture solution 15. The antibody-producing cells 16 are cells established by incorporating an antibody gene into host cells such as Chinese hamster ovary cells (CHO cells). The antibody-producing cells 16 produce immunoglobulins, i.e., antibodies 17, during the culture process. Therefore, not only the antibody-producing cells 16 but also the antibodies 17 are present in the cell culture solution 15. The antibodies 17 are, for example, monoclonal antibodies, and are the active ingredients of biopharmaceuticals. The antibodies 17 are an example of a "substance to be measured" according to the technology of the present disclosure.

[0035] A first delivery path 18 is connected to the culture vessel 13. A cell removal filter 14 is disposed in the first delivery path 18. The cell removal filter 14 captures antibody-producing cells 16 in the cell culture solution 15 using a filter membrane (not shown), for example, by tangential flow filtration (TFF), thereby removing the antibody-producing cells 16 from the cell culture solution 15. The cell removal filter 14 also allows antibodies 17 to pass through. Therefore, the cell culture solution 15 containing mainly antibodies 17 flows downstream of the cell removal filter 14 in the first delivery path 18. The cell culture solution 15 from which the antibody-producing cells 16 have been removed by the cell removal filter 14 is referred to as a culture supernatant 15A. Hereinafter, the cell culture solution 15 from which the antibody-producing cells 16 have been removed by the cell removal filter 14 will be referred to as a culture supernatant 15A. The culture supernatant 15A is an example of a "fluid" according to the technology disclosed herein.

[0036] The turbidity of the culture supernatant 15A is 250 NTU (Nephelometric Turbidity Unit) or more and 1000 NTU or less. NTU is a unit of turbidity of a liquid based on a formazin standard solution. In addition to the antibody 17, the culture supernatant 15A also contains cell-derived proteins, cell-derived DNA (deoxyribonucleic acid), aggregates of the antibody 17, viruses, etc. These cell-derived proteins, cell-derived DNA, aggregates of the antibody 17, viruses, etc. are also examples of the "measurement target substance" according to the technology of the present disclosure.

[0037] The flow cell 10 is connected to a first outlet path 18 downstream of the cell removal filter 14. As indicated by arrow FD, culture supernatant 15A flows from the first outlet path 18 at a preset flow rate through the flow cell 10. A delivery pump (not shown) is provided on the first outlet path 18 downstream of the cell removal filter 14 (between the cell removal filter 14 and the flow cell 10). The delivery pump delivers the culture supernatant 15A toward the flow cell 10 at a flow rate of 200 cc / min or more, for example, 300 cc / min.

[0038] A second outlet path 19 is also connected to the flow cell 10. The culture supernatant 15A that flows into the flow cell 10 from the first outlet path 18 flows out to the second outlet path 19. The second outlet path 19 is connected to a purification unit that purifies the antibody 17 from the culture supernatant 15A using, for example, a chromatography device, and sends the culture supernatant 15A from the flow cell 10 to the purification unit.

[0039] As an example, as shown in FIG. 2 , a Raman spectrometer 11 is an instrument that evaluates a substance M by utilizing the characteristics of Raman scattered light RSL. When excitation light EL is irradiated onto the substance M, the excitation light EL interacts with the substance M, generating Raman scattered light RSL having a wavelength different from that of the excitation light EL. The wavelength difference between the excitation light EL and the Raman scattered light RSL corresponds to the energy of the molecular vibrations of the substance M. Therefore, Raman scattered light RSL with different wavenumbers can be obtained between substances M with different molecular structures. The excitation light EL is an example of the "measurement light" according to the technology of the present disclosure. The Raman scattered light RSL is an example of the "return light" according to the technology of the present disclosure. Of the Stokes line and the anti-Stokes line, it is preferable to use the Stokes line for the Raman scattered light RSL.

[0040] Returning to FIG. 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 excitation light EL from its tip. The excitation light EL is irradiated onto the culture supernatant 15A flowing through the flow cell 10. Raman scattered light RSL is generated by the interaction between this excitation light EL and the antibodies 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.

[0041] The analyzer 26 resolves the Raman scattered light RSL into wavenumbers and derives the intensity value of the Raman scattered light RSL for each wavenumber, thereby generating Raman spectrum data 27. The Raman spectrum data 27 is data in which the intensity value of the Raman scattered light RSL for each wavenumber is registered. In FIG. 1 , the Raman spectrum data 27 is －１ ~1800cm －１ The intensity values ​​of the Raman scattered light RSL in the range from 1 cm －１The graph shown below the Raman spectrum data 27 is obtained by plotting the intensity values ​​of the Raman spectrum data 27 for each wavenumber and connecting them with a line. The Raman spectrum data 27 is an example of "physical property data" according to the technology of the present disclosure.

[0042] In this way, the measurement system 2 causes the culture supernatant 15A obtained from the culture tank 13 in which antibody-producing cells 16 are being cultured to flow through the flow cell 10. Then, the culture supernatant 15A flowing through the flow cell 10 is irradiated with excitation light EL via the sensor unit 25, thereby measuring Raman spectrum data 27 of the antibodies 17 and the like in the culture supernatant 15A.

[0043] As an example, as shown in FIG. 3 , the flow cell 10 is a cylindrical member having a linear flow path 30 with a circular cross section at its center. The flow cell 10 contains a resin. The resin content in the flow cell 10 is 95% or more, for example, 99%. Alternatively, the resin content is 100%, and the flow cell 10 is formed entirely of resin. In other words, the flow cell 10 is made of resin. The resin is, for example, a polyolefin-based resin. In this case, the flow cell 10 may be single-use. The flow cell 10 may also be made of metal.

[0044] A cylindrical boss-shaped first connector 31 and a second connector 32 are provided at the center of both end faces of the flow cell 10. The first connector 31 has an inlet 33 of the flow path 30, and the second connector 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" according to the technology of the present disclosure.

[0045] The first connecting portion 31 and the second connecting portion 32 are parallel threads or tapered threads. A sterile connector 35 provided at one end of the first delivery path 18 is liquid-tightly attached to the first connecting portion 31. A sterile connector 36 provided at one end of the second delivery path 19 is liquid-tightly attached to the second connecting portion 32. Ferrules may be used to connect the first connecting portion 31 and the second connecting portion 32 to the sterile connectors 35 and 36.

[0046] An attachment portion 37 is provided at the center of the peripheral plate of the flow cell 10. The attachment portion 37 is a cylindrical hole for detachably attaching the sensor portion 25 to the flow cell 10, and has a thread 38 on its inner wall surface. The attachment portion 37 is provided up to just before the flow path 30. A part of the sensor portion 25 is housed in the attachment portion 37.

[0047] The sensor unit 25 includes a main body 39 and a tip 40. The main body 39 is a cylindrical member having a linear optical path 41 with a circular cross section at its center. 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 tip 40. Conversely, the Raman scattered light RSL passes through the optical path 41 from the tip 40 toward the main body 39 and, ultimately, the analyzer 26. Similar to the flow cell 10, the main body 39 contains a resin. The resin content of the main body 39 is 95% or more, for example, 99%. Alternatively, the resin content may be 100%, and the main body 39 may be entirely made of resin. In other words, the main body 39 is made of resin. Similar to the flow cell 10, the resin may be, for example, a polyolefin-based resin.

[0048] As shown in FIG. 4 as an example, the main body 39 has, in order from the base end, a large diameter section 45, a medium diameter section 46, and a small diameter section 47. The large diameter section 45 is the section of the main body 39 with the largest diameter. The medium diameter section 46 has a diameter smaller than that of the large diameter section 45 but larger than that of the small diameter section 47. A thread 48 is formed in the medium diameter section 46. The thread 48 is threadedly engaged with the thread 38 of the mounting section 37. In other words, the main body 39, and therefore the sensor section 25, are detachably attached to the mounting section 37 via the medium diameter section 46. Therefore, the medium diameter section 46 and the tip section 40 and small diameter section 47, which are the portions of the sensor section 25 beyond the medium diameter section 46, are housed within the flow cell 10. The small diameter section 47 is the section of the main body 39 with the smallest diameter. The small diameter section 47 is threaded with the thread 49.

[0049] The tip portion 40 has an optical system 55, an inner shell portion 56, and an outer shell portion 57. The optical system 55 is located between the small diameter portion 47 of the main body portion 39 and the inner shell portion 56, and is held within the outer shell portion 57. The optical system 55 includes a hemispherical lens 58 and a transparent plate 59. The hemispherical lens 58 is literally a hemispherical lens and is made of, for example, quartz glass. The hemispherical lens 58 has an exit surface 60 from which the excitation light EL is emitted. The exit surface 60 is flat. The hemispherical lens 58 is an example of a "lens with positive refractive power" according to the technology of the present disclosure.

[0050] The transparent plate 59 is a circular plate having an exit surface 61 and an entrance surface 62 for the excitation light EL that are parallel to each other, and is made of, for example, quartz glass. The exit surface 60 of the hemispherical lens 58 and the entrance surface 62 of the transparent plate 59 have the same curvature (0 in this case). The exit surface 60 and the entrance surface 62 may be fixed and joined with an adhesive or the like, or may simply be held in a mated state without using an adhesive or the like. The transparent plate 59 is an example of an "optical element" according to the technology of the present disclosure. The exit surface 61 of the transparent plate 59 is also an example of an "exit surface of measurement light of an optical system" according to the technology of the present disclosure.

[0051] If the main body 39 side (the side of the exit surface 61 of the transparent plate 59) is defined as the upper side and the tip 40 side (the side of the inner wall surface 63A of the bottom plate 63 of the inner shell portion 56) as the lower side (see also FIG. 5 ), both the inner shell portion 56 and the outer shell portion 57 have the shape of a cylindrical container that is open at the top and closed at the bottom by the flat bottom plates 63 and 64. The inner shell portion 56 has a peripheral plate 65, and the outer shell portion 57 has a peripheral plate 66. The peripheral plate 65 extends upward from the bottom plate 63 and forms a cylindrical space 67 together with the bottom plate 63. Similarly, the peripheral plate 66 extends upward from the bottom plate 64 and forms a cylindrical space 68 together with the bottom plate 64.

[0052] The height of peripheral plate 65 is lower than that of peripheral plate 66. In other words, the height of inner shell portion 56 is lower than that of outer shell portion 57. Inner shell portion 56 is slightly smaller overall than outer shell portion 57, and is housed tightly within space 68 of outer shell portion 57 (see also FIG. 5 ).

[0053] The inner shell 56 is made of metal, for example, Hastelloy. On the other hand, the outer shell 57 contains resin, similar to the flow cell 10. The resin content in the outer shell 57 is 95% or more, for example, 99%. Alternatively, the resin content is 100%, and the entire outer shell 57 is made of resin. In other words, the outer shell 57 is made of resin. The resin is, for example, a polyolefin-based resin, similar to the flow cell 10.

[0054] A thread 69 is formed on the upper side of an inner wall surface 66A of the peripheral plate 66 of the outer shell portion 57. The thread 69 is threadedly engaged with the thread 49 of the small diameter portion 47. This allows the outer shell portion 57, and therefore the tip portion 40, to be integrated with the main body portion 39.

[0055] Rectangular notches 70A and 71A are formed on the upper side of the peripheral plate 65 at positions 180° symmetrical to each other. Rectangular holes 70B and 71B are formed in the center of the peripheral plate 66 at positions 180° symmetrical to each other. More precisely, the holes 70B and 71B are square-shaped. The notches 70A and 71A and the holes 70B and 71B have the same size. The notch 70A corresponds to the hole 70B, and the notch 71A corresponds to the hole 71B. The notch 70A and the hole 70B function as an inlet 70 for the culture supernatant fluid 17. The notch 71A and the hole 71B function as an outlet 71 for the culture supernatant fluid 17.

[0056] 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 facing the excitation light EL (downstream in the irradiation direction of the excitation light EL), and the excitation light EL is irradiated onto the inner wall surface 63A (see FIGS. 10 and 11 ). The inner wall surface 63A faces the exit surface 61 of the transparent plate 59. In other words, the inner wall surface 63A is an example of an "opposing wall surface" according to the technology of the present disclosure. When the optical system 55 and the inner shell portion 56 are housed in the space 68 of the outer shell portion 57 and the thread 69 of the outer shell portion 57 is threadedly engaged with the thread 49 of the small-diameter portion 47 to integrate the tip portion 40 with the main body portion 39, the distance between the exit surface 61 and the inner wall surface 63A is fixed.

[0057] The surface roughness (arithmetic mean roughness) Ra of the inner wall surface 63A is greater than 0 and not greater than 6.4 μm (0<Ra≦6.4 μm), preferably not greater than 1.6 μm (0<Ra≦1.6 μm). Although not shown, the surface roughness Ra of the inner wall surface 65A is also greater than 0 and not greater than 6.4 μm, preferably not greater than 1.6 μm. The inner wall surfaces 63A and 65A are subjected to a smoothing process such as polishing to achieve a target surface roughness Ra. The surface roughness Ra is a value measured in accordance with JIS B 0601-2001, as defined by the Japanese Industrial Standards.

[0058] When viewed from above, the inner wall surface 65A of the peripheral plate 65 of the inner shell portion 56 protrudes from the exit surface 61 of the transparent plate 59 toward the inner wall surface 63A. The inner wall surface 65A supports the inner wall surface 63A, creating a space 67 between the exit surface 61 and the inner wall surface 65A, through which the culture supernatant fluid 17 flows. The inner wall surfaces 65A are arranged on both sides of the direction FD, blocking both sides of the direction FD. That is, the inner wall surfaces 65A are an example of a "side wall surface" according to the technology of the present disclosure, and the inner shell portion 56 is an example of a "retaining portion" according to the technology of the present disclosure. As can be seen from the inner shell portion 56, the functions of the "opposing wall surface" and the "retaining portion" according to the technology of the present disclosure may be performed by a single component. The reference numeral 64A denotes the inner wall surface of the bottom plate 64 of the outer shell portion 57.

[0059] As shown in FIG. 5 as an example, the optical system 55 is sandwiched and held between the tip 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 emission surface 61 of the transparent plate 59 is flush with the upper edges of the inlet 70 and the outlet 71. A circular groove 80 is formed in the mounting portion 37 where it contacts the medium-diameter portion 46 of the main body 39. An O-ring 81 is fitted into the groove 80. The O-ring 81 is made of elastic rubber and is compressed between the medium-diameter portion 46 and the bottom plate of the groove 80 when the main body 39 is fastened to the mounting portion 37 with the screws 38 and 48. The O-ring 81 is compressed between the medium-diameter portion 46 and the bottom plate of the groove 80 to prevent the culture supernatant 15A flowing through the flow path 30 from leaking out of the mounting portion 37. Although not shown, O-rings for preventing leakage of the culture supernatant 15A 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.

[0060] 5, when the tip 40 is attached to the flow cell 10, a 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 channel 30. Here, "parallel" refers to parallelism in the sense of including, in addition to perfect parallelism, an error that is generally acceptable in the technical field to which the technology of the present disclosure belongs and that does not contradict the spirit of the technology of the present disclosure.

[0061] 6, when the tip 40 is attached to 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 coincide. Here, "coincidence" refers to a perfect coincidence, as well as a coincidence that includes an error that is generally acceptable in the technical field to which the technology of the present disclosure pertains and that does not contradict the spirit of the technology of the present disclosure. The error here is preferably ±10%, more preferably ±5%.

[0062] As can be seen from FIG. 6 , when the tip portion 40 is attached to the flow cell 10, the flow path through which the culture supernatant 15A flows exists on both the inside and outside of the tip portion 40. In other words, the culture supernatant 15A flows on both the inside and outside of the tip portion 40. The flow path inside the tip portion 40 is defined by the inlet 70 and 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 tip 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. The areas of the inlet 70 and outlet 71 are preferably ½ or less, more preferably ¼ or less, and even more preferably ⅛ or less of the area of ​​the peripheral plate 65 of the inner shell portion 56.

[0063] As an example, as shown in FIGS. 7 to 9, the tip 40 is attached to multiple types of flow cells 10 with different flow path diameters. Specifically, as shown in FIG. 7, the tip 40 is attached to a flow cell 10S having a flow path 30S with a flow path diameter φS. As shown in FIG. 8, the tip 40 is attached to a flow cell 10M having a flow path 30M with a flow path diameter φM. As shown in FIG. 9, the tip 40 is attached to a flow cell 10L having a flow path 30L with a flow path diameter φL. The flow path diameters φS, φM, and φL have a relationship of φS < φM < φL. In other words, the flow cell 10S has a relatively small flow path diameter φ, the flow cell 10M has a medium flow path diameter φ, and the flow cell 10L has a relatively large flow path diameter φ. Note that the flow rate of the culture supernatant 15A is always the same regardless of the type of flow cell 10.

[0064] Here, when the tip portion 40 is attached to any 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 parallel to the direction FD. Furthermore, when the tip portion 40 is attached to any 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 the same. Note that although three types of flow cells 10S, 10M, and 10L are exemplified here, the number of types of flow cells 10 to which the tip portion 40 is attached may be two, four, or more.

[0065] 10 , the excitation light EL emitted from the exit surface 61 of the transparent plate 59 is focused at a focusing position FP located within the inner shell portion 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. In this case, the focusing position FP is point-like. 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 portion 56.

[0066] If the thickness of the transparent plate 59 in the direction of the optical axis OA is Th and the distance between the first point P1 intersecting the optical axis OA on the exit surface 60 of the hemispherical lens 58 and the focusing position FP is d, the thickness Th is greater than or equal to half the distance d and less than or equal to the distance d (d / 2≦Th≦d). More preferably, the thickness Th is the same as the distance d, i.e., Th=d. When Th=d, the focusing position FP coincides with the second point P2 intersecting the optical axis OA on the exit surface 61 of the transparent plate 59. Note that "the thickness Th and the distance d" being "the same" refers not only to being completely the same, but also to including an error that is generally acceptable in the technical field to which the technology of the present disclosure pertains and that does not contradict the spirit of the technology of the present disclosure. The error here is preferably ±10%, more preferably ±5%.

[0067] 11 , the excitation light EL that has passed through the focusing position FP spreads conically from the focusing position FP toward the inner wall surface 63A, and is ultimately irradiated onto the inner wall surface 63A. Reference numeral 90 indicates the irradiation area of ​​the excitation light EL on the inner wall surface 63A. The irradiation area 90 is a circle centered on the optical axis OA. The diameter of this irradiation area 90 is smaller than the diameter of the inner wall surface 63A. In other words, the area of ​​the metal on the inner wall surface 63A is larger than the irradiation area of ​​the excitation light EL on the inner wall surface 63A (area of ​​the metal on the inner wall surface 63A > irradiation area of ​​the excitation light EL on the inner wall surface 63A).

[0068] Next, the operation of the above configuration will be described. The measurement system 2, consisting of the flow cell 10 and the Raman spectrometer 11, is incorporated into the cell culture unit 12. The flow cell 10 has a first connection 31 connected to the first outlet path 18 and a second connection 32 connected to the second outlet path 19. The sensor unit 25 (tip 40) of the Raman spectrometer 11 attached to the flow cell 10 via an attachment unit 37. A culture supernatant 15A obtained from a culture tank 13 in which antibody-producing cells 16 are being cultured flows through the flow path 30 of the flow cell 10. The culture supernatant 15A flows into the tip 40 of the sensor unit 25 through the inlet 70 and exits the tip 40 through the outlet 71. Within the tip 40, the culture supernatant 15A is irradiated with excitation light EL that has passed through the light path 41 and the optical system 55. The excitation light EL is focused at a focusing position FP by the optical system 55.

[0069] The interaction between the excitation light EL and the antibodies 17 and the like in the culture supernatant 15A generates Raman scattered light RSL. The Raman scattered light RSL is captured by the optical system 55, passes through the optical path 41, and is output from the sensor unit 25 to the analyzer 26. The analyzer 26 converts the Raman scattered light RSL into Raman spectrum data 27.

[0070] The tip portion 40 has an inner wall surface 63A and an inner shell portion 56. The inner wall surface 63A is a wall surface facing the exit surface 61 of the transparent plate 59. The inner shell portion 56 protrudes from the exit surface 61 side toward the inner wall surface 63A side and holds the inner wall surface 63A with a space 67 provided between the exit surface 61 and the inner shell portion 56 through which the culture supernatant fluid 15A flows. The inner shell portion 56 includes an inlet 70 and an outlet 71 for the culture supernatant fluid 15A, as well as inner wall surfaces 65A arranged on both sides in the direction FD. This inner wall surface 65A can reduce the risk of adversely affecting the Raman spectrum data 27 compared to the sensor portion described in JP 2021-048872 A, which is open on one side in the fluid flow direction. For example, it is possible to reduce the risk that Raman scattered light RSL generated by the interaction between the excitation light EL and the resin of the flow cell 10 is captured when the excitation light EL is irradiated onto a resin flow cell 10, and that this adversely affects the Raman spectrum data 27. Even if the flow cell 10 is not made of resin, it is possible to reduce the risk that Raman scattered light from the flow cell 10 due to leakage of the excitation light EL will adversely affect the Raman spectrum data 27.

[0071] 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. For this reason, in the case of the sensor unit described in JP 2021-048872 A, the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin of the flow cell 10 drowns out the Raman scattered light RSL that should be measured, which is generated by the interaction between the excitation light EL and the antibodies 17 and the like in the culture supernatant 15A. In other words, the S / N ratio of the Raman spectrum data 27 generated by the Raman scattered light RSL generated by the interaction between the excitation light EL and the antibodies 17 and the like in the culture supernatant 15A is significantly reduced.

[0072] However, with the technology disclosed herein, by providing inner wall surfaces 65A disposed on both sides in the direction FD, there is little risk that the Raman scattered light RSL that should be measured, which is generated by the interaction between the excitation light EL and the antibodies 17 and the like in the culture supernatant 15A, will be drowned out by the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin of the flow cell 10. In other words, the S / N ratio of the Raman spectrum data 27 generated by the Raman scattered light RSL generated by the interaction between the excitation light EL and the antibodies 17 and the like in the culture supernatant 15A can be maintained at a higher level.

[0073] Furthermore, compared to the sensor unit described in JP 2021-048872 A, the presence of the inner wall surfaces 65A arranged on both sides of the direction FD can stabilize the flow of the culture supernatant 15A near the focusing position FP of the excitation light EL within the inner shell portion 56. This reduces the bias of components in the culture supernatant 15A near the focusing position FP, thereby improving the measurement stability of the Raman spectrum data 27.

[0074] If a branch flow path of a preset flow path diameter is provided in the first delivery path 18 and the flow cell 10 is connected to the branch flow path, it is possible to measure Raman spectrum data 27 using a flow cell 10 of the same diameter regardless of the flow path diameter of the first delivery path 18. However, this requires providing a branch flow path each time, which is time-consuming. In contrast, the technology disclosed herein does not require such time-consuming work.

[0075] Furthermore, as will be described in detail later in a second embodiment, the sensor unit 25 generates a concentration prediction model 126 (see FIG. 16 ) that predicts the concentration of antibody 17 contained in the culture supernatant 15A based on the Raman spectrum data 27 only from the Raman spectrum data 27 measured using one type of flow cell 10, and the generated concentration prediction model 126 can be shared by multiple types of flow cells 10. This saves the effort of preparing a concentration prediction model 126 for each of the multiple types of flow cells 10.

[0076] 1 and other figures, the container to which the tip 40 is attached is a flow cell 10 having a flow path 30 through which the culture supernatant 15A flows. Therefore, the Raman spectrum data 27 of the culture supernatant 15A can be easily measured without modifying the culture tank 13, such as providing an attachment portion for the tip 40.

[0077] 3, the tip 40 is attached to the flow cell 10 containing a resin. This significantly reduces the risk that the excitation light EL will be irradiated onto the resin of the flow cell 10 and the resulting Raman scattered light RSL will be captured and adversely affect the Raman spectrum data 27.

[0078] 7 to 9, tip portion 40 is attached to multiple types of flow cells 10S, 10M, and 10L having different flow path diameters. As described above, tip portion 40 has an inner wall surface 63A facing exit surface 61 of transparent plate 59, and the distance between exit surface 61 of transparent plate 59 and inner wall surface 63A remains constant. Therefore, even when the same substance to be measured is measured, the Raman spectrum data 27 does not differ between multiple types of flow cells 10S, 10M, and 10L having different flow path diameters, and tip portion 40 can be used without any problems with flow cells 10 having a wide variety of flow path diameters.

[0079] 4, inner shell portion 56 is made of metal, and inner wall surfaces 63A and 65A are also made of metal, which further reduces the risk that Raman scattered light RSL generated by the interaction between the excitation light EL and the resin when the excitation light EL is irradiated onto the resin will be captured and adversely affect Raman spectrum data 27.

[0080] 11, the area of ​​the metal on the inner wall surface 63A is larger than the area of ​​the inner wall surface 63A that is irradiated with the excitation light EL. Therefore, it is possible to more reliably reduce the risk that the Raman scattered light RSL generated by the interaction between the excitation light EL and the resin when the resin is irradiated with the excitation light EL will be captured and adversely affect the Raman spectrum data 27.

[0081] 4, 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.

[0082] 4 and other figures, the inner wall surface 63A is a flat surface, which makes it possible to easily manufacture the inner wall surface 63A, and therefore the inner shell portion 56.

[0083] 3, the main body 39 contains resin, which allows the main body 39 to be manufactured inexpensively and can be easily disposed of.

[0084] 4 and other figures, the inlet 70 and the outlet 71 are rectangular. This allows the culture supernatant 15A to flow stress-free toward the focusing position FP of the excitation light EL within the inner shell 56. This reduces the bias of components in the culture supernatant 15A near the focusing position FP, thereby improving the measurement stability of the Raman spectrum data 27.

[0085] 10, the focusing position FP of the excitation light EL by the optical system 55 is located between the exit surface 61 of the transparent plate 59 and the inner wall surface 63A. Therefore, the Raman spectrum data 27 of the culture supernatant fluid 15A flowing inside the inner shell portion 56 can be reliably measured.

[0086] 4 and other figures, 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 relatively close to the exit surface 61 of the transparent plate 59, thereby reducing the risk of the excitation light EL being attenuated by the culture supernatant fluid 15A.

[0087] 4 and other figures, the optical system 55 further includes a transparent plate 59 having a flat exit surface 61 for the excitation light EL, which further reduces the risk of the excitation light EL being attenuated by the culture supernatant 15A.

[0088] 10 , the thickness Th of the transparent plate 59 in the direction of the optical axis OA is equal to or greater than half the distance d between a first point P1, where the exit surface 60 of the hemispherical lens 58 intersects with the optical axis OA, and the focusing position FP of the excitation light EL, but is equal to or less than the distance d. If the thickness Th is equal to or greater than half the distance d, the effect of reducing the risk of the excitation light EL being attenuated by the culture supernatant 15A can be more effectively achieved. If the thickness Th is equal to or less than the distance d, the focusing position FP can be ensured to be outside the transparent plate 59.

[0089] The distance between the exit surface 61 of the transparent plate 59 and the inner wall surface 63A is fixed. Therefore, even when measuring the same substance to be measured, the Raman spectrum data 27 will not differ between the flow cells 10S, 10M, and 10L, which have different flow path diameters, and the flow cells 10 can be used without any problems with a wide variety of flow path diameters.

[0090] Raman scattered light RSL easily reflects information derived from the functional groups of amino acids in proteins. Therefore, by using Raman spectrum data 27 as the physical property data in this example, it is possible to obtain physical property data that accurately reflects the physical properties, such as the concentration of antibody 17, which is a protein.

[0091] 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 by the culture supernatant 15A is greater. Therefore, by using a hemispherical lens 58 with positive refractive power or a transparent plate 59 with a flat exit surface 61 for the excitation light EL, it is possible to significantly reduce the risk of the excitation light EL being attenuated by the culture supernatant 15A.

[0092] Biopharmaceuticals containing antibody 17, which is a cell product, are called antibody drugs and are widely used to treat chronic diseases such as cancer, diabetes, and rheumatoid arthritis, as well as rare diseases such as hemophilia and Crohn's disease. Therefore, according to this example, in which culture supernatant 15A, which is the source of antibody drugs obtained from culture tank 13 in which antibody-producing cells 16 are cultured, is used as the fluid, it is possible to promote the development of antibody drugs that are widely used to treat various diseases.

[0093] The fluid used is culture supernatant 15A obtained from culture tank 13 during culture. Therefore, Raman spectrum data 27 can be measured while continuing to culture antibody-producing cells 16 in culture tank 13. Furthermore, culture supernatant 15A is obtained by removing antibody-producing cells 16. Therefore, Raman spectrum data 27 of cell products such as antibodies 17 can be measured with high accuracy.

[0094] 6 and other figures, when the tip 40 is attached to the flow cell 10, the flow path through which the culture supernatant 15A flows exists inside and outside the tip 40. Therefore, Raman spectrum data 27 of the culture supernatant 15A can be measured within the tip 40 (inner shell 56). Furthermore, the tip 40 does not impede the flow of the culture supernatant 15A in the flow cell 10.

[0095] 5, when the tip 40 is attached to the flow cell 10, the line LIO connecting the centers CI and CO of the inlet 70 and outlet 71 is parallel to the direction FD. This allows the culture supernatant 15A to flow stress-free toward the focusing position FP of the excitation light EL within the inner shell 56. This reduces the bias of components in the culture supernatant 15A within the inner shell 56, thereby improving the measurement stability of the Raman spectrum data 27.

[0096] (Variation 1) As an example, the tip portion 100 may be as shown in Fig. 12. The tip portion 100 has an inner shell portion 101. A bottom plate 102 of the inner shell portion 101, and hence an inner wall surface 102A of the bottom plate 102, is a curved surface that is convex downward and follows the shape of the flow channel 30 of the flow cell 10. The inner wall surface 102A is an example of an "opposing wall surface" according to the technology of the present disclosure.

[0097] By making the inner wall surface 102A a curved surface that is convex downward in this way, the inner wall surface 102A serves as a reflecting surface that directs the Raman scattered light RSL toward the optical system 55. This makes it possible to further increase the S / N ratio of the Raman spectrum data 27. The curved surface that is convex downward may be in the shape of a parabolic antenna.

[0098] 13 shows an example of a tip portion 105. The tip portion 105 has a circular inlet 106 and an outlet 107. In this way, the shapes of the inlet and outlet are not limited to rectangular shapes like the inlet 70 and outlet 71, but may be circular like the inlet 106 and outlet 107.

[0099] The inner shell portion 56 is not limited to the illustrated cylindrical container shape. It may be a square or hexagonal cylindrical container shape, etc. Therefore, the bottom plate 63 is not limited to the illustrated circular shape, but may be a rectangular or hexagonal shape, etc. Furthermore, the peripheral plate 66 is not limited to the illustrated curved surface, but may be a flat surface.

[0100] Second Embodiment In the second embodiment, the state of a measurement target substance such as an antibody 17 contained in a culture supernatant 15A is predicted based on Raman spectrum data 27.

[0101] 14, the Raman spectrometer 11 is connected to an information processing device 110 via a computer network such as a local area network (LAN) so as to be able to communicate with each other. The Raman spectrometer 11 transmits 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.

[0102] 15 , as an example, a computer constituting an information processing device 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 interconnected via a bus line 121.

[0103] The storage 115 is a hard disk drive built into a computer constituting the information processing device 110 or connected via a cable or network. Alternatively, the storage 115 is a disk array consisting of multiple hard disk drives. The storage 115 stores control programs such as an operating system, various application programs, and various data associated with these programs. Note that a solid state drive may be used instead of a hard disk drive.

[0104] The memory 116 is a work memory for the CPU 117 to execute processing. The CPU 117 loads programs stored in the storage 115 into the memory 116 and executes processing in accordance with the programs. In this way, the CPU 117 comprehensively controls each part of the computer. The memory 116 may be built into the CPU 117.

[0105] The communication unit 118 is a network interface that controls the transmission of various types of information via a LAN or the like. The display 119 displays various screens. The various screens are provided with an operation function using a GUI (Graphical User Interface). The computer that constitutes the information processing device 110 accepts input of operation instructions from an input device 120 via the various screens. The input device 120 is a keyboard, a mouse, a touch panel, a microphone for voice input, etc.

[0106] 16 as an example, an operating program 125 is stored in the storage 115 of the information processing device 110. The operating program 125 is an application program for causing a computer to function as the information processing device 110. In addition to the operating program 125, the storage 115 also stores a concentration prediction model 126. The concentration prediction model 126 is a machine learning model configured by, for example, a neural network. Note that the model is not limited to a neural network, and may be a decision tree, a random forest, a naive Bayes, a gradient boosting decision tree, or the like.

[0107] When the operating program 125 is started, the CPU 117 of the computer constituting the information processing device 110 works in cooperation 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.

[0108] The acquiring unit 130 acquires the Raman spectrum data 27 from the Raman spectrometer 11. The acquiring unit 130 outputs the Raman spectrum data 27 to the RW control unit 131.

[0109] The RW control unit 131 controls the storage of various data in the storage 115 and the reading of various data stored in the storage 115. The RW control unit 131 stores the Raman spectrum data 27 from the acquisition unit 130 in the storage 115. The RW control unit 131 also reads the Raman spectrum data 27 and the concentration prediction model 126 from the storage 115, and outputs the read Raman spectrum data 27 and the concentration prediction model 126 to the prediction unit 132. The RW control unit 131 also outputs the Raman spectrum data 27 to the display control unit 133.

[0110] The prediction unit 132 applies the Raman spectrum data 27 to the concentration prediction model 126, and causes the concentration prediction model 126 to output a concentration prediction result 135. In this case, the concentration prediction result 135 is a result of predicting the concentration of antibody 17 in culture supernatant 15A. The prediction unit 132 outputs the concentration prediction result 135 to the display control unit 133.

[0111] The display control unit 133 controls the display of various screens on the display 119. For example, the display control unit 133 controls the display of a Raman spectrum analysis screen 150 (see FIG. 21 etc.) on the display 119.

[0112] 17 , a data set 140 is a set of a learning intensity value 141 and a correct concentration 142. A data set group 140G, which is a collection of these data sets 140, is prepared for the learning phase of the concentration prediction model 126.

[0113] The learning intensity value 141 is a copy of the intensity value of the Raman spectrum data 27S measured using a flow cell 10S having a flow path 30S with a flow path diameter φS shown in Figure 7. The correct concentration 142 is calculated based on the amount of antibody 17 in the culture supernatant 15A from which the Raman spectrum data 27S was measured and the volume of the flow path 30S. The amount of antibody 17 is measured using, for example, a high-performance liquid chromatography device.

[0114] 18 , in the learning phase of the concentration prediction model 126, a learning intensity value 141 from a data set 140 is input to the concentration prediction model 126, and a learning concentration prediction result 135L is output from the concentration prediction model 126. Next, a loss calculation is performed for the concentration prediction model 126 using a loss function based on the result of comparison between the learning concentration prediction result 135L and a correct concentration 142. Then, update settings are made for the coefficients of the concentration prediction model 126 according to the result of the loss calculation, and the concentration prediction model 126 is updated according to the update settings.

[0115] In the learning phase of the concentration prediction model 126, the above series of processes, including input of the learning intensity value 141 to the concentration prediction model 126, output of the learning concentration prediction result 135L from the concentration prediction model 126, loss calculation, update setting, and update of the concentration prediction model 126, are repeated while changing the data set 140. The repetition of the above series of processes is terminated when the prediction accuracy of the learning concentration prediction result 135L for the correct concentration 142 reaches a predetermined set level. The concentration prediction model 126 whose prediction accuracy has thus reached the set level is stored in the storage 115 and used by the prediction unit 132. Note that learning may be terminated when the above series of processes have been repeated a set number of times, regardless of the prediction accuracy of the learning concentration prediction result 135L for the correct concentration 142.

[0116] The concentration prediction model 126 may be trained in the information processing device 110 or in a device other than the information processing device 110. Furthermore, the concentration prediction model 126 may continue to be trained even after it is stored in the storage 115.

[0117] The prediction unit 132 applies Raman spectrum data 27 measured using multiple types of flow cells 10, different from the flow cell 10S, each having a flow path 30 with a flow path diameter φ different from the flow path diameter φS, to the concentration prediction model 126. The prediction unit 132 then outputs a concentration prediction result 135 from the concentration prediction model 126. More specifically, as shown in FIG. 19 as an example, the prediction unit 132 inputs the intensity values ​​of Raman spectrum data 27M measured using a flow cell 10M having a flow path 30M with the flow path diameter φM shown in FIG. 8 into the concentration prediction model 126. The prediction unit 132 then outputs the concentration prediction result 135 from the concentration prediction model 126. Also, as shown in FIG. 20 as an example, the prediction unit 132 inputs the intensity values ​​of Raman spectrum data 27L measured using a flow cell 10L having a flow path 30L with the flow path diameter φL shown in FIG. 9 into the concentration prediction model 126. The prediction unit 132 then outputs the concentration prediction result 135 from the concentration prediction model 126. Although not shown in the figure, the prediction unit 132 inputs the intensity value of the Raman spectrum data 27S measured using a flow cell 10S having a flow path 30S with a flow path diameter φS into the concentration prediction model 126, and outputs a concentration prediction result 135 from the concentration prediction model 126.

[0118] 21 on the display 119. The Raman spectrum analysis screen 150 displays a graph of the Raman spectrum data 27.

[0119] 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, a concentration prediction instruction is accepted by the CPU 117 of the information processing device 110. In response to the concentration prediction instruction, the CPU 117 causes the prediction unit 132 to perform the processes shown in Figures 19 and 20 and output a concentration prediction result 135 from the concentration prediction model 126.

[0120] When the concentration prediction result 135 is input from the prediction unit 132, the display control unit 133 changes the display of the Raman spectrum analysis screen 150 as shown in Fig. 22, for example. In Fig. 22, the Raman spectrum analysis screen 150 displays the concentration prediction result 135 together with a graph of the Raman spectrum data 27.

[0121] Next, the operation of the second embodiment will be described with reference to the flowcharts shown in FIGS. 23 and 24 as an example.

[0122] First, the concentration prediction model 126 is trained as shown in FIG. 18 using the data set 140 shown in FIG. 17. Specifically, training intensity values ​​141, which are copies of the intensity values ​​of Raman spectrum data 27S measured using a flow cell 10S having a flow path 30S with a flow path diameter φS, are input to the concentration prediction model 126, and the concentration prediction model 126 outputs a training concentration prediction result 135L (step ST100 in FIG. 23). Next, the concentration prediction model 126 is updated based on the comparison result between the training concentration prediction result 135L and the correct concentration 142 (step ST110). The processes of steps ST100 and ST110 are repeatedly performed while the data set 140 is being changed (step ST130) until the prediction accuracy of the training concentration prediction result 135L relative to the correct concentration 142 reaches a predetermined set level (NO in step ST120). When the prediction accuracy of the learning concentration prediction result 135L for the correct concentration 142 reaches the set level (YES in step ST120), the learning of the concentration prediction model 126 is terminated. The concentration prediction model 126 for which the learning has been completed is stored in the storage 115 of the information processing device 110.

[0123] As shown in FIG. 16, the CPU 117 of the information processing device 110 functions as an acquisition unit 130, a RW control unit 131, a prediction unit 132, and a display control unit 133 when the operating program 125 is started.

[0124] A concentration prediction model 126 is stored in the storage 115 of the information processing device 110. The concentration prediction model 126 is read from the storage 115 by the RW control unit 131 and output to the prediction unit 132.

[0125] In the information processing device 110, the Raman spectrum data 27 is acquired by the acquisition unit 130 from the Raman spectrometer 11 (step ST200 in FIG. 24). The Raman spectrum data 27 is stored in the storage 115 by the RW control unit 131 (step ST210).

[0126] The Raman spectrum data 27 is read from the storage 115 by the RW control unit 131 (step ST220) and output to the prediction unit 132 and the display control unit 133. Then, as shown in Fig. 21, the display control unit 133 displays a Raman spectrum analysis screen 150 on the display 119 (step ST230).

[0127] 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 antibody 17 in the culture supernatant 15A from which the Raman spectrum data 27, the graph of which is displayed on the Raman spectrum analysis screen 150, has been measured. This causes the concentration prediction instruction to be accepted by the CPU 117 (step ST240).

[0128] 19 and 20, the prediction unit 132 inputs the intensity values ​​of the Raman spectrum data 27 into the concentration prediction model 126, which then outputs a concentration prediction result 135 (step ST250). The prediction unit 132 outputs the concentration prediction result 135 to the display control unit 133, which then displays it on the Raman spectrum analysis screen 150 (step ST260), as shown in FIG.

[0129] The user makes various decisions based on the concentration prediction result 135 displayed on the Raman spectrum analysis screen 150. For example, consider a case where a condition-finding experiment is being conducted using small-scale equipment to determine the culture conditions of antibody-producing cells 16. In this case, if the concentration prediction result 135 is worse than the target value, the user may decide to stop the current experiment and move on to an experiment using new conditions. Also, consider a case where the condition-finding experiment has been completed and mass production is being conducted using large-scale equipment. In this case, if the concentration prediction result 135 is worse than the target value, the user may decide to stop mass production and perform maintenance on the culture tank 13.

[0130] As described above, in the second embodiment, the CPU 117 of the information processing device 110 uses a concentration prediction model 126 that predicts the concentration of the antibody 17 contained in the culture supernatant 15A. The concentration prediction model 126 is generated using only a data set 140 that includes learning intensity values ​​141 that are copies of the intensity values ​​of the Raman spectrum data 27S of the antibody 17, etc., contained in the culture supernatant 15A in the flow cell 10S, and a correct concentration 142 of the antibody 17.

[0131] The acquisition unit 130 acquires Raman spectral data 27M and 27L of the antibody 17, etc., contained in the culture supernatant 15A in a flow cell 10 different from the flow cell 10S, for example, in flow cells 10M and 10L. The prediction unit 132 applies the Raman spectral data 27M and 27L to the concentration prediction model 126, and causes the concentration prediction model 126 to output a concentration prediction result 135 of the antibody 17.

[0132] Concentration prediction model 126 generated solely from Raman spectrum data 27S measured using flow cell 10S can be used to predict the concentration of antibody 17 based on Raman spectrum data 27M and 27L measured using flow cells 10M and 10L that are different from flow cell 10S. This eliminates the need to prepare concentration prediction models 126 for each of multiple types of flow cells 10, such as for flow cell 10S, flow cell 10M, and flow cell 10L.

[0133] All that is required as the learning intensity values ​​141 of the data set 140 are the intensity values ​​of the Raman spectrum data 27S of the antibody 17, etc. contained in the culture supernatant 15A in the flow cell 10S. This makes it possible to easily prepare the data set 140.

[0134] The Raman spectrum data 27S, 27M, and 27L are measured by the sensor unit 25 having the tip portion 40 shown in the first embodiment. Therefore, even if the same measurement target substance is measured, the Raman spectrum data 27S, 27M, and 27L will not differ, and there is no need to correct the Raman spectrum data 27S, 27M, and 27L to eliminate the differences between them.

[0135] The concentration prediction model 126 is not limited to a machine learning model. It may 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 such a model generated by multivariate analysis or statistical analysis, determining the coefficients of a regression equation based on at least two datasets 140 corresponds to "generating a state prediction model" using only datasets, such as in Supplementary Note 25 described below.

[0136] The Raman spectrum data 27 used to generate the data set 140 is not limited to the illustrated Raman spectrum data 27S. The intensity values ​​of the Raman spectrum data 27M or the intensity values ​​of the Raman spectrum data 27L may be used as the learning intensity values ​​141 of the data set 140.

[0137] The flow rate of the culture supernatant 15A may vary depending on the type of flow cell 10. In this case, however, it is preferable to correct for differences in the Raman spectrum data 27 resulting from differences in the flow rate of the culture supernatant 15A before applying the Raman spectrum data 27 to the concentration prediction model 126. If the Raman spectrum data 27 used to generate the dataset 140 is, for example, Raman spectrum data 27S, then correction is performed to treat the Raman spectrum data 27M and 27L as if they were data equivalent to the Raman spectrum data 27S. The correction may be performed using a conversion formula that treats the Raman spectrum data 27M and 27L as data equivalent to the Raman spectrum data 27, or a machine learning model.

[0138] Although the concentration of antibody 17 in culture supernatant 15A is predicted, the present invention is not limited to this. The concentration of aggregates in culture supernatant 15A may also be predicted. Furthermore, instead of or in addition to the concentration, the density or the like may also be predicted.

[0139] The container to which the tip portion 40 is attached is not limited to the flow cell 10. The container to which the tip portion 40 is attached may be, for example, a culture tank 13. In this case, a mounting portion is provided in the culture tank 13, and the tip portion 40 is attached to the mounting portion. When the container is the culture tank 13, the flow direction is the direction in which the cell culture solution 15 flows, which is generated by the rotation of the stirring blades in the culture tank 13.

[0140] Although the inner wall surface 63A of the bottom plate 63 of the inner shell portion 56 is used as the opposing wall surface, this is not limited thereto. The tip portion 40 may be formed only by the outer shell portion 57 without using the inner shell portion 56, with the inner wall surface 64A of the bottom plate 64 of the outer shell portion 57 serving as the opposing wall surface. In this case, the outer shell portion 57 may be made of metal, just like the inner shell portion 56. Alternatively, the outer shell portion 57 may be made of resin, and a metal film such as aluminum, copper, or gold may be formed on the entire or a portion of the inner wall surface 64A by plating. Furthermore, a metal film may also be formed on the entire or a portion of the inner wall surface 66A of the peripheral plate 66 of the outer shell portion 57 by plating. In this manner, it is sufficient that metal is disposed on at least a portion of the surface of the opposing wall surface and at least a portion of the surface of the side wall surface. However, to fully exert the effect of reducing the risk of resin reducing the S / N ratio of the Raman spectrum data 27, it is preferable that metal be disposed on the entire surface of the opposing wall surface and the entire surface of the side wall surface.

[0141] Although the functions of the "opposing wall surface" and "retaining portion" according to the technology of the present disclosure are performed by a single member, inner shell portion 56, this is not limitative. Bottom plate 63 having inner wall surface 63A, which is the opposing wall surface, and other portions of inner shell portion 56 that perform the function of the retaining portion may originally be separate bodies and may be integrated by bonding, welding, or the like.

[0142] The lens having positive refractive power is not limited to the exemplified hemispherical lens 58. It may be a spherical ball lens, a plano-convex lens, a biconvex lens, a cylindrical lens, or the like. Furthermore, the optical element is not limited to the exemplified disc-shaped transparent plate 59 having parallel exit surface 61 and entrance surface 62. It may be a transparent plate having an entrance surface shaped to match the shape of the exit surface of a ball lens, a plano-convex lens, a biconvex lens, or the like, and a flat exit surface.

[0143] Instead of constructing an optical system by cementing a lens having a positive refractive power and an optical element, the lens having a positive refractive power and the optical element may be integrally formed as a single lens. Note that the optical element may not be necessary, and the optical system may be constructed using only a lens having a positive refractive power.

[0144] A mechanism for changing, for example, in stages, the distance between the exit surface of the optical system 55 for the excitation light EL (exit surface 61 of the transparent plate 59) and the opposing wall surface (inner wall surface 63A) may be provided. In this case, the distance between the exit surface of the optical system 55 for the excitation light EL and the opposing wall surface is set to match the flow cell 10 with the smallest flow path diameter φ among the flow cells 10 expected to be used. In other words, the distance between the exit surface of the optical system 55 for the excitation light EL and the opposing wall surface does not need to be fixed.

[0145] The first connecting portion 31 and the second connecting portion 32 may be disposed below the flow cell 10, making the flow path 30 U-shaped. The shape of the flow cell 10 is not limited to a cylindrical shape, but may be a rectangular tube. The cross-sectional shape of the flow path 30 is also not limited to a circular shape, but may be an elliptical shape or a rectangular shape. The flow cell 10 may also be formed from a composite material such as carbon fiber reinforced resin.

[0146] The substance for which the Raman spectrum data 27 is measured is not limited to the antibody 17, etc. Other substances than the antibody 17, such as proteins, peptides, nucleic acids (DNA, RNA (Ribonucleic Acid)), lipids, viruses, virus subunits, and virus-like particles, may also be used.

[0147] The cell product is not limited to antibody 17, etc. It may also be a cytokine (interferon, interleukin, etc.), a hormone (insulin, glucagon, follicle-stimulating hormone, erythropoietin, etc.), a growth factor (IGF (insulin-like growth factor)-1, bFGF (basic fibroblast growth factor), etc.), a blood coagulation factor (factor 7, factor 8, factor 9, etc.), an enzyme (lysosomal enzyme, DNA (deoxyribonucleic acid) degrading enzyme, etc.), an Fc (fragment crystalline) fusion protein, a receptor, albumin, or a protein vaccine. The antibody 17 also includes bispecific antibodies, antibody-drug conjugates, low molecular weight antibodies, sugar chain modified antibodies, and the like.

[0148] The physical property data is not limited to the Raman spectrum data 27. It may be infrared absorption spectrum data, near-infrared absorption spectrum data, nuclear magnetic resonance spectrum data, ultraviolet-visible absorption spectroscopy (UV-Vis) spectrum data, or fluorescence spectrum data.

[0149] The fluid is not limited to the culture supernatant 15A. It may be the cell culture solution 15 before the cells are removed by the cell removal filter 14. It may be a cell culture solution (so-called culture medium) that does not contain cell products before being supplied to the culture tank 13. It may be a purified solution obtained by purifying the culture supernatant 15A using a chromatography device in the purification section. The fluid is not limited to the cell culture solution 15, but may be, for example, river water collected to check for water pollution. It may also be a raw material (e.g., polystyryllithium and an aqueous methanol solution) and / or a product when continuously producing a product such as a monomer or polymer (e.g., polystyrene) by flow synthesis. Furthermore, the fluid is not limited to a liquid and may be a gas.

[0150] When the tip 40 is attached to 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 aligned, but this is not limited to this. When the flow path diameter φ is relatively large, the flow cell 10 and the sensor unit 25 may be designed so that the center CI of the inlet 70 and the center CO of the outlet 71 are positioned above the center CP of the flow path 30. This reduces the amount of protrusion of the tip 40 and the like into the flow path 30, thereby reducing the resistance of the tip 40 and the like to the flow of the culture supernatant fluid 15A. Alternatively, the amount of protrusion of the tip 40 and the like into the flow path 30 may be the same regardless of the type of flow cell 10.

[0151] From the above description, the technology described in the following supplementary paragraphs can be understood.

[0152] [Supplementary Item 1] A sensor unit of a spectroscopic analyzer having a tip portion incorporating an optical system for irradiating a measurement light onto a measurement target substance for physical property data and capturing return light from the measurement target substance, the tip portion being attached to a container for a fluid containing the measurement target substance, wherein the tip portion has: an opposing wall surface facing an exit surface of the measurement light of the optical system; and a holder protruding from the exit surface side to the opposing wall surface and holding the opposing wall surface with a space for the fluid to flow between the exit surface and the opposing wall surface, the holder including an inlet and outlet for the fluid and side wall surfaces arranged on both sides in the direction of the fluid flow. [Supplementary Item 2] The sensor unit of the spectroscopic analyzer according to Supplementary Item 1, wherein the container is a flow cell having a flow path through which the fluid flows. [Supplementary Item 3] The sensor unit of the spectroscopic analyzer according to Supplementary Item 2, wherein the tip portion is attached to the flow cell containing resin. [Supplementary Item 4] The sensor unit of the spectroscopic analyzer according to Supplementary Item 2 or Supplementary Item 3, wherein the tip is attached to a plurality of types of flow cells with different flow path diameters. [Supplementary Item 5] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 4, wherein a metal is arranged on at least a portion of the surface of the opposing wall. [Supplementary Item 6] The sensor unit of the spectroscopic analyzer according to Supplementary Item 5, wherein the area of ​​the metal on the opposing wall is larger than the area of ​​the opposing wall irradiated with the measurement light. [Supplementary Item 7] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 6, wherein the opposing wall has a surface roughness of 1.6 μm or less. [Supplementary Item 8] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 7, wherein the opposing wall is a flat surface. [Supplementary Item 9] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 7, wherein, when the exit surface side is the upper side and the opposing wall side is the lower side, the opposing wall is a curved surface that is convex downward. [Supplementary Item 10] A sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 9, comprising a body containing resin. [Supplementary Item 11] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 10, wherein the inlet and the outlet are circular or rectangular.[Supplementary Item 12] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 11, wherein the focusing position of the measurement light by the optical system is between the exit surface and the opposing wall surface. [Supplementary Item 13] 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 positive refractive power. [Supplementary Item 14] The sensor unit of the spectroscopic analysis device according to Supplementary Item 13, wherein the optical system further includes an optical element having a flat exit surface for the measurement light. [Supplementary Item 15] The sensor unit of the spectroscopic analysis device according to Supplementary Item 14, wherein the thickness of the optical element in the optical axis direction is equal to or greater than half the distance between the point where the exit surface of the lens intersects with the optical axis and the focusing position of the measurement light. [Supplementary Item 16] The sensor unit of the spectroscopic analysis device according to any one of Supplementary Items 1 to 15, wherein a metal is arranged on at least a portion of the surface of the side wall surface. [Supplementary Item 17] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 16, wherein the distance between the exit surface and the opposing wall surface is fixed. [Supplementary Item 18] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 17, wherein the physical property data is Raman spectrum data. [Supplementary Item 19] The sensor unit of the spectroscopic analyzer 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. [Supplementary Item 20] The sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 19, wherein the fluid is a cell culture medium. [Supplementary Item 21] A measurement system comprising: the sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 20; and the container to which the tip portion is attached. [Supplementary Item 22] The measurement system according to Supplementary Item 21, wherein when the container is the flow cell and the tip is attached to the flow cell, a flow path through which the fluid flows is present on both the inside and outside of the tip. [Supplementary Item 23] The measurement system according to Supplementary Item 21 or Supplementary Item 22, wherein when the container is the flow cell and the tip is attached to the flow cell, a line connecting the centers of the inlet and the outlet is parallel to the flow direction.[Supplementary Item 24] A measurement method for measuring the physical property data using a sensor unit of the spectroscopic analyzer according to any one of Supplementary Items 1 to 20.

[0153] Furthermore, from the description of the second embodiment above, the technology described in the following supplementary paragraphs can be understood.

[0154] [Supplementary Item 25] A spectroscopic analyzer comprising a processor, wherein the processor uses a state prediction model that predicts a state of a substance to be measured contained in a fluid, the state prediction model being 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 ground truth data of the state of the substance to be measured, acquires second physical property data of the substance to be measured contained in the fluid in a second container different from the first container, applies the second physical property data to the state prediction model, and causes the state prediction model to output a prediction result of the state of the substance to be measured, the first physical property data and the second physical property data being a tip portion incorporating an optical system for irradiating the substance to be measured with measurement light and capturing return light from the substance to be measured, the sensor portion of the spectroscopic analyzer comprising tip portions attached to the first container and the second container, wherein the tip portion comprises: an opposing wall surface that faces the emission surface of the measurement light of the optical system; an optical fiber cable that connects the optical fiber cable to the optical fiber terminal and the optical fiber cable, and a sensor unit that detects the optical fiber cable and the optical fiber cable, and a holding unit that protrudes from the optical fiber cable to the optical fiber terminal and holds the optical fiber cable while providing a space for the fluid to flow between the optical fiber cable and the optical fiber terminal, the holding unit including an inlet and an outlet for the fluid and side wall surfaces arranged on both sides in a flow direction of the fluid. [Supplementary Item 26] The information processing device according to Supplementary Item 25, wherein the first container is a first flow cell having a first flow path diameter and including a first flow path through which the fluid flows, and the second container is a second flow cell having a second flow path diameter different from the first flow path diameter and including a second flow path through which the fluid flows.[Supplementary Item 27] ​​A state prediction model for predicting a state of a substance to be measured contained in a fluid, the state prediction model being generated using only a data set configured of first physical property data of the substance to be measured contained in the fluid in a first container and ground truth data of the state of the substance to be measured; 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 applying the second physical property data to the state prediction model and outputting a prediction result of the state of the substance to be measured from the state prediction model, wherein the first physical property data and the second physical property data are a sensor unit of a spectroscopic analysis device having a tip portion attached to the first container and the second container, the tip portion comprising: an opposing wall surface facing the emission surface of the measurement light of the optical system; a holding part that protrudes from the exit surface side to the opposing wall surface side and holds the opposing wall surface while leaving a space between the exit surface and the opposing wall surface through which the fluid flows, the holding part including an inlet and outlet for the fluid and side wall surfaces arranged on both sides in the direction of the fluid flow, wherein the holding part is measured by a sensor part of a spectroscopic analysis device.[Supplementary Item 28] An operating program for an information processing device for causing a computer to execute processes including: using a state prediction model for predicting a state of a substance to be measured contained in a fluid, the state prediction model being generated using only a data set configured of first physical property data of the substance to be measured contained in the fluid in a first container and ground truth data of the state of the substance to be measured; 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 applying the second physical property data to the state prediction model and outputting a prediction result of the state of the substance to be measured from the state prediction model, wherein the first physical property data and the second physical property data are represented by a sensor unit of a spectroscopic analyzer having a tip portion attached to the first container and the second container, the tip portion comprising: an opposing wall surface facing the emission surface of the measurement light of the optical system; an operating program for an information processing device, the operating program being measured by a sensor unit of a spectroscopic analysis device, the operating program including: a holding unit that protrudes from the exit surface side to the opposing wall surface side and holds the opposing wall surface while leaving a space between the exit surface and the opposing wall surface through which the fluid flows, the holding unit including an inlet and outlet for the fluid and side wall surfaces arranged on both sides in the flow direction of the fluid.

[0155] Here, the CPU 117 is an example of the "processor." The concentration prediction model 126 is an example of the "state prediction model." The concentration is an example of the "state." The flow cell 10S is an example of the "first container" and "first flow cell." The Raman spectrum data 27S and the learning intensity value 141 are an example of the "first physical property data." The correct concentration 142 is an example of the "correct data."

[0156] The flow cells 10M and 10L are examples of the "second container" and "second flow cell" described above. The Raman spectrum data 27M and 27L are examples of the "second physical property data" described above. The concentration prediction result 135 is an example of the "prediction result" described above.

[0157] In the second embodiment, the following various processors can be used as the hardware structure of processing units that perform various processes, such as the acquisition unit 130, the RW control unit 131, the prediction unit 132, and the display control unit 133. The various processors include the CPU 117, which is a general-purpose processor that executes software (operation program 125) and functions as various processing units, as described above, as well as dedicated electrical circuits that are processors having a circuit configuration specifically designed to perform specific processes, such as a programmable logic device (PLD) that is a processor whose circuit configuration can be changed after manufacture, such as an FPGA (Field Programmable Gate Array), and an ASIC (Application Specific Integrated Circuit).

[0158] A single processing unit may be configured with one of these various processors, or may be configured with a combination of two or more processors of the same or different types (e.g., a combination of multiple FPGAs and / or a combination of a CPU and an FPGA).Furthermore, multiple processing units may be configured with a single processor.

[0159] Examples of configuring multiple processing units with a single processor include, first, a form in which one processor is configured with a combination of one or more CPUs and software, as typified by computers such as client and server, and this processor functions as multiple processing units. Second, a form in which a processor is used to realize the functions of the entire system including multiple processing units with a single IC (Integrated Circuit) chip, as typified by systems on chips (SoCs). In this way, various processing units are configured using one or more of the above-mentioned various processors as a hardware structure.

[0160] Furthermore, more specifically, the hardware structure of these various processors can be an electric circuit (circuitry) that combines circuit elements such as semiconductor elements.

[0161] The technology of the present disclosure can be appropriately combined with the various embodiments and / or various modified examples described above. Furthermore, it is not limited to the above-described embodiments, and various configurations can be adopted without departing from the spirit of the present disclosure. Furthermore, the technology of the present disclosure extends not only to programs but also to storage media that non-temporarily store programs.

[0162] The above-described description and illustrations are a detailed explanation of the parts related to the technology of the present disclosure and are merely an example of the technology of the present disclosure. For example, the above description of the configuration, functions, actions, and effects is an explanation of an example of the configuration, functions, actions, and effects of the parts related to the technology of the present disclosure. Therefore, it goes without saying that unnecessary parts may be deleted, new elements may be added, or replacements may be made to the above-described description and illustrations within the scope of the gist of the technology of the present disclosure. Furthermore, to avoid confusion and facilitate understanding of the parts related to the technology of the present disclosure, the above-described description and illustrations omit explanations of common technical knowledge that do not require particular explanation to enable the implementation of the technology of the present disclosure.

[0163] In this specification, "A and / or B" is synonymous with "at least one of A and B." In other words, "A and / or B" means that it may be only A, only B, or a combination of A and B. Furthermore, in this specification, the same concept as "A and / or B" is also applied when three or more things are expressed by connecting them with "and / or."

[0164] All publications, patent applications, and technical standards mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent application, or technical standard was specifically and individually indicated to be incorporated by reference.

Claims

1. A sensor unit of a spectroscopic analysis device, comprising a tip portion incorporating an optical system for irradiating measurement light onto a substance whose physical properties are to be measured and capturing return light from the substance, the tip portion being attached to a container for a fluid containing the substance to be measured, wherein the tip portion has: an opposing wall surface that faces the emission surface of the measurement light of the optical system; and a holding portion that protrudes from the emission surface side to the opposing wall surface and holds the opposing wall surface with a space formed between the emission surface and the opposing wall surface through which the fluid flows, the holding portion including an inlet and outlet for the fluid and side wall surfaces arranged on both sides in the direction of the flow of the fluid.

2. The sensor unit of the spectroscopic analyzer according to claim 1, wherein the container is a flow cell having a flow path through which the fluid flows.

3. The sensor portion of the spectroscopic analyzer according to claim 2, wherein the tip portion is attached to the flow cell containing a resin.

4. The sensor unit of the spectroscopic analyzer according to claim 2, wherein the tip is attached to a plurality of types of flow cells having different flow path diameters.

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

6. The sensor unit of the spectroscopic analysis device according to claim 5, wherein the area of ​​the metal on the opposing wall is larger than the area of ​​the opposing wall that is irradiated with the measurement light.

7. The sensor unit of the spectroscopic analyzer 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 analyzer according to claim 1, wherein the opposing wall surface is flat.

9. The sensor unit of the spectroscopic analyzer according to claim 1, wherein when the exit surface side is the upper side and the opposing wall side is the lower side, the opposing wall surface is a curved surface that is convex downward.

10. The sensor portion of the spectroscopic analyzer according to claim 1, comprising a body portion containing resin.

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

12. The sensor unit of the spectroscopic analyzer according to claim 1, wherein the position at which the measurement light is focused by the optical system is between the exit surface and the opposing wall surface.

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

14. The sensor unit of the spectroscopic analyzer according to claim 13, wherein the optical system further includes an optical element having a flat exit surface for the measurement light.

15. The sensor unit of a spectroscopic analysis device described in claim 14, wherein the thickness of the optical element in the optical axis direction is at least half the distance between the point where the exit surface of the lens intersects with the optical axis and the focusing position of the measurement light, but is not greater than said distance.

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

17. The sensor unit of the spectroscopic analyzer according to claim 1, wherein the distance between the exit surface and the opposing wall surface is fixed.

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

19. The sensor unit of the spectroscopic analyzer according to claim 1, wherein the turbidity of the fluid is between 250 NTU and 1000 NTU.

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

21. A measurement system comprising: a sensor unit of a spectroscopic analyzer according to any one of claims 1 to 20; and the container in which the tip portion is attached.

22. The measurement system of claim 21, wherein the container is the flow cell, and when the tip is attached to the flow cell, the flow path through which the fluid flows is present inside and outside the tip.

23. The measurement system of claim 21, wherein when the container is the flow cell and the tip 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 measurement method for measuring the physical property data using a sensor unit of a spectroscopic analysis device according to any one of claims 1 to 20.