Probe unit for spectroscopic analysis

Abstract

A probe unit for spectroscopic analysis comprises: a probe that includes a built-in first optical system for irradiating, with measurement light, a substance subject to measurement of physical property data by a spectroscopic analysis device and capturing return light from the substance subject to measurement, the probe being attachable to and detachable from a measurement head of the spectroscopic analysis device that includes a built-in second optical system; and a displacement restricting member that restricts, in a state in which the probe is disposed in a container of a fluid containing the substance subject to measurement and the orientation of the probe is aligned in a direction corresponding to a flow of the fluid, displacement of the probe with respect to the container.

Description

Spectroscopic Probe Unit

[0001] The technology of the present disclosure relates to a probe unit for spectroscopic analysis.

[0002] The spectroscopic analyzer has a measurement head. The tip of the measurement head 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. JP-T 2023-510210 A describes a configuration in which the tip (referred to as a sample optical system in JP-T 2023-510210 A) is detachable from the measurement head (referred to as a probe head in JP-T 2023-510210 A). In JP-T 2023-510210 A, the measurement head is attached to the tip by fixing the tip to the measurement head with a screw.

[0003] The tip portion of the measurement head is placed, for example, in a container of a fluid containing a substance to be measured. Depending on the measurement head, it may be necessary to align the tip portion with the direction corresponding to the fluid flow and maintain that state in order to accurately measure physical property data. For example, if the container is a flow cell having a fluid flow path and the tip portion also has a fluid flow path, it is necessary to maintain the tip portion oriented in a direction such that the fluid flow direction in the flow path of the tip portion coincides with the fluid flow direction in the flow path of the flow cell. However, JP-A 2023-510210 does not disclose a configuration for maintaining the tip portion oriented in a direction corresponding to the fluid flow.

[0004] One embodiment of the technique of the present disclosure provides a spectroscopic probe unit that can contribute to accurate measurement of physical property data.

[0005] The spectroscopic analysis probe unit of the present disclosure is a probe incorporating a first optical system for irradiating measurement light onto a substance to be measured for physical property data of the spectroscopic analysis device and capturing return light from the substance to be measured, and is equipped with a probe that is detachable from a measurement head of the spectroscopic analysis device incorporating a second optical system, and a displacement control member that controls displacement of the probe relative to the container while the probe is placed in a container of a fluid containing the substance to be measured and is oriented in a direction corresponding to the flow of the fluid.

[0006] The container is preferably a flow cell having a first flow path through which a fluid flows.

[0007] The probe preferably has a second flow path through which the fluid flows.

[0008] The probe is preferably oriented so that the direction of fluid flow in the second flow path coincides with the direction of fluid flow in the first flow path.

[0009] The second flow path preferably has an inlet and an outlet for the fluid, the inlet and outlet being surrounded by a wall surface.

[0010] It is preferable to have a connecting member that detachably connects the measuring head and the probe.

[0011] It is preferable that the first optical axis of the first optical system and the second optical axis of the second optical system are aligned by fitting the probe to the connecting member.

[0012] The connecting member is preferably detachable from the measuring head.

[0013] It is preferable that the probe is an inner cylinder, the displacement restricting member is an outer cylinder, and a connecting member is inserted into the space between the probe and the displacement restricting member.

[0014] It is preferable that an insertion hole is formed in the displacement control member, and a screw hole that looks into the outer surface of the probe is formed at the position of the connecting member corresponding to the insertion hole, and the tip of a bolt that is inserted into the insertion hole and screwed into the screw hole is pressed against the outer surface of the probe, thereby fixing the probe and the connecting member.

[0015] The displacement restricting member preferably restricts rotation of the probe around the first optical axis of the first optical system.

[0016] The probe is an inner tube and the displacement control member is an outer tube, and a flange portion is formed on the outer surface of the probe to abut the bottom surface of the mounting hole formed in the container, and it is preferable that the rotation of the probe is controlled by pressing the end of the displacement control member against the flange portion.

[0017] The probe preferably has a facing wall surface facing the emission surface of the measurement light from the first optical system, and at least a part of the surface of the facing wall surface is preferably made of metal.

[0018] 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.

[0019] The physical property data is preferably Raman spectrum data.

[0020] The fluid is preferably any one of a cell culture medium, a culture supernatant, a purified liquid, and a medium.

[0021] The first optical system preferably includes a lens having positive refractive power.

[0022] The first optical system is preferably composed of lenses only.

[0023] The lens has an exit surface for the measurement light that contacts the fluid, and the exit surface is preferably flat.

[0024] The first optical system includes, in addition to the lens, an optical element having an exit surface for the measurement light that comes into contact with the fluid, and the exit surface is preferably a flat surface.

[0025] The lens is preferably one of a hemispherical lens, a ball lens, a cylindrical lens, and an aspherical lens.

[0026] According to the technique of the present disclosure, it is possible to provide a spectroscopic probe unit that can contribute to accurate measurement of physical property data.

[0027] 1 is a diagram showing how Raman spectral data of antibodies and the like in culture supernatant fluid obtained in a cell culture section is measured by a measurement system. It is a diagram showing excitation light and Raman scattered light. It is an exploded perspective view of a flow cell, a spectroscopic analysis probe unit, and a measurement head. It is an exploded cross-sectional view of a flow cell, a spectroscopic analysis probe unit, and a measurement head. It is a cross-sectional view of a flow cell, a spectroscopic analysis probe unit, and a measurement head. It is a diagram showing an optical system built into the measurement head. It is a diagram showing the relationship between the area of ​​metal on the opposing wall surface and the area irradiated with excitation light on the opposing wall surface. It is a flowchart showing the procedure for attaching a spectroscopic analysis probe unit. It is a diagram showing how the probe is rotated around its optical axis to align the direction of the probe so that the flow direction of the culture supernatant fluid in the flow channel of the probe coincides with the flow direction of the culture supernatant fluid in the flow channel of the flow cell. It is a diagram showing how a rotation restricting member is attached to a mounting hole of a flow cell and the tip of the rotation restricting member is pressed against the flange of the probe to restrict the rotation of the probe. It is a diagram showing how a connecting member is inserted into the space between the probe and the rotation restricting member to align the optical axis of the optical system built into the probe with the optical axis of the optical system built into the measurement head. FIG. 1 is a diagram showing how the probe and the connecting member are fixed by inserting a screw into the insertion hole of the rotation restricting member, screwing the screw into the threaded hole of the connecting member, and pressing the tip of the bolt against the bottom surface of the groove of the probe. FIG. 2 is a diagram showing a modified example in which a spectroscopic analysis probe unit is arranged in a storage tank for culture supernatant liquid. FIG. 3 is a diagram showing an optical system including a ball lens. FIG. 4 is a diagram showing another example of an optical system including a ball lens. FIG. 5 is a diagram showing an optical system including a cylindrical lens. FIG. 6 is a diagram showing an optical system including a plano-convex lens with an aspherical entrance surface. FIG. 7 is a diagram showing an optical system composed of only hemispherical lenses.

[0028] As an example, as shown in FIG. 1 , the 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, for example, a manufacturing system for active pharmaceutical ingredients for biopharmaceuticals. The cell culture unit 12 has 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.

[0029] 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.

[0030] 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. 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, and viruses are also examples of the "measurement target substance" according to the technology of the present disclosure. The cell removal filter 14 may be an alternating tangential flow filtration (ATF) filter.

[0031] The flow cell 10 is connected to a first outlet path 18 downstream of the cell removal filter 14. The culture supernatant 15A flows through the flow cell 10 from the first outlet path 18 at a preset flow rate. 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.

[0032] 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.

[0033] 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.

[0034] Returning to Figure 1, the Raman spectrometer 11 is composed of a measurement head 25 and an analyzer 26. The measurement head 25 is connected to the analyzer 26 via a cable 27. The measurement head 25 is attached to the flow cell 10. In the following description, the measurement head 25 side will be referred to as the "top" or "base end," and the flow cell 10 side will be referred to as the "bottom," "bottom," or "tip."

[0035] The analyzer 26 incorporates a light source that emits excitation light EL. The excitation light EL emitted from the light source is guided to the measurement head 25 via a cable 27. The measurement head 25 emits the excitation light EL from its tip. The excitation light EL is irradiated onto the culture supernatant 15A flowing within 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 measurement head 25 receives the Raman scattered light RSL. The Raman scattered light RSL received by the measurement head 25 is output to the analyzer 26 via the cable 27.

[0036] 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 28. The Raman spectrum data 28 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 28 is －１ ~1800cm －１ The intensity values ​​of the Raman scattered light RSL in the range from 1 cm －１ The graph shown below the Raman spectrum data 28 is obtained by plotting the intensity values ​​of the Raman spectrum data 28 for each wavenumber and connecting them with a line. The Raman spectrum data 28 is an example of "physical property data" according to the technology of the present disclosure.

[0037] 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 measurement head 25, thereby measuring Raman spectrum data 28 of the antibodies 17 and the like in the culture supernatant 15A.

[0038] The Raman spectrum data 28 is used to predict the state of the substance to be measured, such as the concentration of antibody 17 in the culture supernatant 15A. In this case, for example, a machine learning model that outputs the concentration of antibody 17 in response to input of the Raman spectrum data 28 is utilized. Note that the concentration of aggregates in the culture supernatant 15A may also be predicted as the state of the substance to be measured. Furthermore, instead of or in addition to the concentration, density or the like may also be predicted.

[0039] As shown in Figures 3, 4, and 5 as an example, the flow cell 10 is a rectangular parallelepiped member having a linear flow path 30 with a circular cross section at its center. The flow path 30 is an example of a "first flow path" according to the technology of the present disclosure. The flow cell 10 is made of a metal such as Hastelloy. Alternatively, the flow cell 10 may be made of a resin such as a polyolefin resin. If made of a resin, the flow cell 10 may be single-use.

[0040] A cylindrical boss-shaped first connector 31 and a second connector 32 are provided on opposing end surfaces 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 FD1 of the culture supernatant 15A in the flow path 30. The flow direction FD1 is an example of the "flow direction of the fluid in the first flow path" according to the technology of the present disclosure.

[0041] The first feed path 18 and the first connecting portion 31 are liquid-tightly connected by a ferrule joint. The ferrule joint is composed of ferrules (not shown) formed at one end of the first feed path 18 and one end of the first connecting portion 31, a gasket (not shown) sandwiched in a groove of the ferrule, and a first clamp 35 that secures one end of the first feed path 18 and one end of the first connecting portion 31. The second feed path 19 and the second connecting portion 32 are similarly liquid-tightly connected by a ferrule joint including a second clamp 36. Note that a parallel thread or a tapered thread may be used to connect the first feed path 18 and the first connecting portion 31 to the second feed path 19 and the second connecting portion 32.

[0042] An attachment hole 37 is provided in the center of the top surface of the flow cell 10. The attachment hole 37 is a circular hole for detachably attaching a spectroscopic probe unit (hereinafter simply referred to as unit) 38 to the flow cell 10, and has a thread 39 on its inner wall surface. The attachment hole 37 is connected to a fitting hole 40 (see Figures 4 and 5). The fitting hole 40 is also a circular hole, and its center coincides with that of the attachment hole 37. The fitting hole 40 has a diameter slightly smaller than that of the attachment hole 37. The fitting hole 40 penetrates into the flow path 30.

[0043] The unit 38 is composed of a probe 45, a rotation restricting member 46, and a connecting member 47. The unit 38 is made of metal, such as Hastelloy. Alternatively, the unit 38 may be made of resin, such as polyolefin resin. If made of resin, the unit 38 may be single-use. The rotation restricting member 46 is an example of a "displacement restricting member" according to the technology of the present disclosure.

[0044] The probe 45 is a cylindrical member having a diameter that matches the diameter of the fitting hole 40. The operator of the measurement system 2 inserts the probe 45 into the mounting hole 37 and fits it into the fitting hole 40. This positions the probe 45 within the flow cell 10. When the rotation restricting member 46 is not attached to the mounting hole 37, but the probe 45 is simply inserted into the mounting hole 37 and fitted into the fitting hole 40, the probe 45 can rotate 360° in the circumferential direction. Here, "match" refers to not only perfect match, but also match that includes 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. The error here is preferably ±10%, and more preferably ±5%.

[0045] The probe 45 has a main body 48 and a tip 49. The main body 48 has a linear, circular optical path 50 at its center. The excitation light EL and the Raman scattered light RSL pass through the optical path 50. The excitation light EL passes through the optical path 50 from the measurement head 25 and the main body 48 toward the tip 49. Conversely, the Raman scattered light RSL passes through the optical path 50 from the tip 49 toward the main body 48 and ultimately the measurement head 25.

[0046] A radially recessed groove 51 is formed around the entire outer periphery of the upper outer periphery of the main body 48. The tip of a bolt 53 is pressed against a bottom surface 52 of the groove 51 (see FIGS. 5 and 12 ). The bottom surface 52 of the groove 51 is an example of the “outer periphery of the probe” according to the technology of the present disclosure.

[0047] Furthermore, a flange 54 that protrudes radially is formed around the entire outer periphery of the central portion of the main body 48. When the probe 45 is inserted through the mounting hole 37 and fitted into the fitting hole 40, the lower surface of the flange 54 abuts against the bottom surface 55 (see FIGS. 4 and 5 ) of the mounting hole 37. In other words, the flange 54 functions as a stopper that prevents the main body 48 of the probe 45 above the flange 54 from slipping below the bottom surface 55.

[0048] A circular groove 56 (see FIGS. 4 and 5) is formed on the underside of the flange 54. An O-ring 57 is fitted into the groove 56. The O-ring 57 is made of elastic rubber. The O-ring 57 is compressed between the bottom surface 55 of the mounting hole 37 and the groove 56, thereby preventing the culture supernatant 15A flowing through the flow path 30 from leaking to the outside. Although not shown, O-rings for preventing leakage of the culture supernatant 15A are also disposed between the main body 48 and the tip 49, etc.

[0049] An optical system 60 is built into the lower part of the main body 48. The optical system 60 is disposed at a position where its optical axis OA1 (see FIGS. 4 and 5) coincides with the center of the optical path 50. The optical system 60 is an example of a "first optical system" according to the technology of the present disclosure. The optical axis OA1 is also an example of a "first optical axis" according to the technology of the present disclosure.

[0050] The optical system 60 is composed of a hemispherical lens 61 and a transparent plate 62. The hemispherical lens 61 is literally a hemispherical lens and is made of, for example, sapphire glass or quartz glass. The hemispherical lens 61 has a hemispherical entrance surface for the excitation light EL and a flat exit surface for the excitation light EL. The hemispherical lens 61 is an example of a "lens with positive refractive power" according to the technology of the present disclosure.

[0051] The transparent plate 62 is a circular plate having an incident surface and an exit surface 63 for the excitation light EL that are parallel to each other (see FIGS. 4, 5, and 7), and is made of, for example, sapphire glass or quartz glass. The transparent plate 62 is an example of an "optical element" according to the technology of the present disclosure. The exit surface 63 of the transparent plate 62 is also an example of an "exit surface of the measurement light of the first optical system" and an "exit surface of the measurement light that contacts the fluid" according to the technology of the present disclosure. Here, "parallel" refers not only to perfect parallelism but also to parallelism that includes 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. The error here is preferably ±10%, more preferably ±5%.

[0052] The curvature of the exit surface of the hemispherical lens 61 and the curvature of the entrance surface of the transparent plate 62 are the same (0 in this case). The exit surface of the hemispherical lens 61 and the entrance surface of the transparent plate 62 may be fixedly joined with an adhesive or the like, or may be held at the tip portion 49 in a state where the surfaces are simply joined together without using an adhesive or the like. Here, "same" refers to not only complete sameness, but also sameness in the sense of including 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. The error here is preferably ±10%, more preferably ±5%.

[0053] The tip portion 49 has a cylindrical container shape, with an open upper side connected to the main body portion 48, a flat bottom plate 64 (see FIGS. 4, 5, and 7), and a peripheral plate extending upward from the bottom plate 64. An inlet 65 and an outlet 66 for the culture supernatant 15A are formed at positions 180° symmetrical about the center of the peripheral plate. The inlet 65 and the outlet 66 are rectangular, or more precisely, square, and surrounded by a wall. The inlet 65 and the outlet 66, together with the space formed by the bottom plate 64 and the peripheral plate, form a flow path 67 (see FIGS. 4 and 5) through which the culture supernatant 15A flows. The direction parallel to the flow path 67 from the inlet 65 to the outlet 66 is the flow direction FD2 of the culture supernatant 15A in the flow path 67. The flow path 67 is an example of a "second flow path" according to the technology disclosed herein. Furthermore, the flow direction FD2 is an example of the "flow direction of the fluid in the second flow path" according to the technology of the present disclosure.

[0054] The mounting hole 37 is formed to a depth such that the center of the flow channel 30 coincides with the center of the flow channel 67 when the flange 54 abuts against its bottom surface 55. The probe 45, with the rotation restricting member 46 not attached to the mounting hole 37, is rotated around the optical axis OA1 by an operator to orient the probe 45 so that the flow direction FD2 coincides with the flow direction FD1 (see FIG. 9 ). Since the centers of the flow channels 30 and 67 are aligned and the flow directions FD1 and FD2 are aligned, the line L1 connecting the center of the inlet 33 of the flow channel 30 and the center of the outlet 34 of the flow channel 67 coincides with the line L2 connecting the center of the inlet 65 of the flow channel 67 and the center of the outlet 66 of the flow channel 67 (see FIG. 5 ). The term "alignment" as used herein refers not only to perfect alignment but also to an alignment that includes an error generally acceptable in the technical field to which the technology of the present disclosure pertains and that does not deviate from the spirit of the technology of the present disclosure. The error is preferably ±10%, more preferably ±5%. More specifically, the line L1 and the line L2 being aligned means that an angular deviation of, for example, ±3° is permitted. Note that the centers of the flow channels 30 and 67 do not necessarily have to be aligned.

[0055] The rotation restricting member 46 has a large diameter portion 70 on the base end side and a small diameter portion 71 on the tip end side. A circular insertion hole 72 is formed in the center of the interior of the rotation restricting member 46. The insertion hole 72 is slightly larger in diameter than the probe 45. The diameter of the insertion hole 72 is smaller at the boundary between the large diameter portion 70 and the small diameter portion 71. The probe 45 is inserted into the insertion hole 72. Therefore, the probe 45 serves as an inner cylinder, and the rotation restricting member 46 serves as an outer cylinder.

[0056] A screw 73 is formed in the small diameter portion 71. The screw 73 is threadedly engaged with the screw 39 of the mounting hole 37. The screw 39 and the screw 73 allow the rotation restricting member 46 to be attached to and detached from the flow cell 10.

[0057] When the rotation restricting member 46 is attached to the flow cell 10 via the mounting hole 37, the tip 74 (see FIGS. 4 and 5) of the small diameter portion 71 of the rotation restricting member 46 is pressed against the flange 54 (see FIGS. 5 and 10). The flange 54 is sandwiched between the bottom surface 55 of the mounting hole 37 and the tip 74 of the small diameter portion 71 of the rotation restricting member 46. In this way, the rotation restricting member 46 restricts the rotation of the probe 45 around the optical axis OA1. The tip 74 is an example of an "end of a displacement restricting member" according to the technology of the present disclosure.

[0058] An insertion hole 75 is formed in the large diameter portion 70 at a position corresponding to the groove 51 of the probe 45. The diameter of the insertion hole 75 is larger than the diameter of the bolt 53. The bolt 53 is inserted into the insertion hole 75.

[0059] The connecting member 47 has, in order from the proximal end, a large diameter portion 80, a medium diameter portion 81, and a small diameter portion 82. The diameter of the large diameter portion 80 is larger than the diameter of the insertion hole 72 in the large diameter portion 70 of the rotation restricting member 46. The diameter of the medium diameter portion 81 is slightly smaller than the diameter of the insertion hole 72 in the large diameter portion 70 of the rotation restricting member 46. The diameter of the small diameter portion 71 is also slightly smaller than the diameter of the insertion hole 72, which is one step smaller at the boundary between the large diameter portion 70 and the small diameter portion 71. For this reason, the connecting member 47 is inserted into the space 115 (see FIG. 10 ) between the probe 45 and the rotation restricting member 46 with some backlash occurring between the connecting member 47 and the rotation restricting member 46. When the connecting member 47 is inserted into the space 115 between the probe 45 and the rotation restricting member 46, the medium diameter portion 81 faces the large diameter portion 70 of the rotation restricting member 46 in the radial direction, and the small diameter portion 82 faces the small diameter portion 71 of the rotation restricting member 46.

[0060] A circular mounting hole 83 is formed in the center of the interior of the connecting member 47. A thread 84 is cut into the inner wall surface of the mounting hole 83. The mounting hole 83 is connected to a fitting hole 85 (see FIGS. 4 and 5). The fitting hole 85 is also a circular hole, and its center coincides with that of the mounting hole 83. The diameter of the fitting hole 85 is slightly smaller than that of the mounting hole 83.

[0061] The diameter of the fitting hole 85 matches the diameter of the probe 45, and the probe 45 is fitted into the fitting hole 85. More specifically, the diameter of the probe 45 and the fitting hole 85 is, for example, 12.1 mm (φ12.1). The fit tolerance of the probe 45 is, for example, H7 (0 to +18 μm), and the fit tolerance of the fitting hole 85 is, for example, G6 (+6 μm to +17 μm). By fitting the probe 45 into the fitting hole 85, in other words, by fitting the probe 45 to the connecting member 47, the optical axis OA1 of the optical system 60 and the optical axis OA2 of the optical system 100 built into the measurement head 25 (both see FIG. 6 ) are aligned (see FIG. 11 ). The optical system 100 is an example of a "second optical system" according to the technology of the present disclosure. The optical axis OA2 is also an example of a "second optical axis" according to the technology of the present disclosure.

[0062] A screw hole 86 is formed in the medium diameter portion 81 at a position corresponding to the groove 51 of the probe 45 and the insertion hole 75 of the rotation restricting member 46. The screw hole 86 is a through-hole that exposes the bottom surface 52 of the groove 51 of the probe 45 when the probe 45 is fitted to the connecting member 47. A screw 87 cut into the tip of a bolt 53 is threaded into the screw hole 86. A hexagonal hole is formed in the head of the bolt 53 for inserting a hexagonal wrench. After the probe 45 is fitted to the connecting member 47, the operator inserts the bolt 53 into the insertion hole 75 and threads the screw 87 into the screw hole 86. At this time, the tip of the bolt 53 is pressed against the bottom surface 52 of the groove 51 of the probe 45, thereby fixing the probe 45 and the connecting member 47. The bolt 53 may be made of metal or resin.

[0063] The fitting hole 85 has approximately the same length as the length of the main body 48 of the probe 45 above the flange 54. When the connecting member 47 is inserted into the space 115 between the probe 45 and the rotation restricting member 46 and the probe 45 is fitted to the connecting member 47, the tip of the medium diameter portion 81 abuts against the bottom surface of the insertion hole 72 in the large diameter portion 70 of the rotation restricting member 46. The tip of the small diameter portion 71 abuts against the upper surface of the flange 54.

[0064] The measurement head 25 has a linear, circular optical path 90 at its center. Like the optical path 50 of the probe 45, the excitation light EL and the Raman scattered light RSL pass through the optical path 90. The center of the optical path 90 coincides with the optical axis OA2 of the optical system 100 built into the measurement head 25.

[0065] The measuring head 25 has a main body 91 and a tip 92. The tip 92 has a smaller diameter than the main body 91. The diameter of the tip 92 matches the diameter of the mounting hole 83 of the connecting member 47. A thread 93 is formed in the tip 92. The thread 93 screws into the thread 84 of the mounting hole 83 of the connecting member 47. The thread 84 and the thread 93 allow the connecting member 47, and therefore the unit 38, to be attached to and detached from the measuring head 25.

[0066] 6, the measurement head 25 includes an optical system 100. The optical system 100 includes a collimating lens 101, a mirror 102, a dichroic filter 103, and a condenser lens 104.

[0067] The collimating lens 101 is provided at a position facing the excitation light optical fiber 105 laid in the cable 27. The excitation light EL guided from the analyzer 26 by the excitation light optical fiber 105 is incident on the collimating lens 101. The collimating lens 101 collimates the excitation light EL and outputs it to the mirror 102. The mirror 102 reflects the collimated excitation light EL toward the dichroic filter 103.

[0068] The dichroic filter 103 reflects the excitation light EL from the mirror 102 toward the optical system 60 of the probe 45. The excitation light EL passes through the optical system 60 and is focused at a focusing position FP. The focal length is determined by the diameter and refractive index of the hemispherical lens 61, 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 63 of the transparent plate 62 and the inner wall surface 110 of the bottom plate 64 of the tip portion 49 (see FIG. 7). Ideally, the focusing position FP coincides with the point where the exit surface 63 of the transparent plate 62 intersects with the optical axis OA1. In other words, the focusing position FP is located at the exit surface 63 of the transparent plate 62.

[0069] The dichroic filter 103 transmits the Raman scattered light RSL taken in by the optical system 60 and outputs it to the condenser lens 104. The condenser lens 104 is provided in a position facing the optical fiber 106 for Raman scattered light laid in the cable 27. The condenser lens 104 condenses the Raman scattered light RSL from the dichroic filter 103 into the optical fiber 106 for Raman scattered light. The optical axis OA2 of the optical system 100 is a line passing through the centers of the dichroic filter 103 and the condenser lens 104.

[0070] 7 , the excitation light EL that has passed through the focusing position FP spreads conically from the focusing position FP toward the inner wall surface 110 of the bottom plate 64 of the tip portion 49, and is ultimately irradiated onto the inner wall surface 110. Reference numeral 111 denotes the irradiation area of ​​the excitation light EL on the inner wall surface 110. The irradiation area 111 is a circle centered on the optical axis OA1. The diameter of this irradiation area 111 is smaller than the diameter of the inner wall surface 110. In other words, the area of ​​the metal on the inner wall surface 110 is larger than the irradiation area of ​​the excitation light EL on the inner wall surface 110 (area of ​​the metal on the inner wall surface 110 > irradiation area of ​​the excitation light EL on the inner wall surface 110).

[0071] Next, the operation of the above configuration will be described with reference to the flowchart shown in Fig. 8 and the state diagrams shown in Fig. 9 to Fig. 12. In Fig. 9 to Fig. 12, to avoid complication, only components relevant to the description are labeled with reference numerals.

[0072] First, as shown in step ST100 of Fig. 8, the operator inserts the probe 45 into the mounting hole 37 of the flow cell 10 and fits the probe 45 into the fitting hole 40, thereby placing the probe 45 inside the flow cell 10. The lower surface of the flange 54 of the probe 45 abuts against the bottom surface 55 of the mounting hole 37. This causes the centers of the flow channels 30 and 67 to coincide.

[0073] 8 and 9, the operator rotates the probe 45 around the optical axis OA1 to orient the probe 45 so that the flow direction FD2 of the culture supernatant 15A in the flow path 67 of the probe 45 coincides with the flow direction FD1 of the culture supernatant 15A in the flow path 30 of the flow cell 10. By performing the procedures of steps ST100 and ST110, a line L1 connecting the center of the inlet 33 and the center of the outlet 34 of the flow path 30 coincides with a line L2 connecting the center of the inlet 65 and the center of the outlet 66 of the flow path 67.

[0074] 8 and 10, the operator screws the threads 73 of the small diameter portion 71 of the rotation restricting member 46 into the threads 39 of the mounting hole 37 of the flow cell 10, thereby attaching the rotation restricting member 46 to the mounting hole 37. At this time, the tip 74 of the small diameter portion 71 of the rotation restricting member 46 is pressed against the flange 54 of the probe 45, thereby restricting rotation of the probe 45 around the optical axis OA1.

[0075] When the rotation restricting member 46 is attached to the flow cell 10, a space 115 is formed between the probe 45 and the rotation restricting member 46. As shown in step ST130 of FIG. 8 and in FIG. 11 , the operator inserts the connecting member 47 into this space 115. This causes the main body 48 of the probe 45 above the flange 54 to fit into the fitting hole 85 of the connecting member 47. By fitting the probe 45 into the connecting member 47 in this manner, the optical axes OA1 of the optical system 60 and OA2 of the optical system 100 are aligned.

[0076] 8 and 12, the operator inserts the bolt 53 into the insertion hole 75 of the rotation restricting member 46. The operator also screws the thread 87 of the bolt 53 into the threaded hole 86 of the connecting member 47. At this time, the tip of the bolt 53 is pressed against the bottom surface 52 of the groove 51 of the probe 45, thereby fixing the probe 45 and the connecting member 47 together.

[0077] Finally, as shown in step ST150 of FIG. 8 , the operator attaches the measuring head 25 to the connecting member 47 by threading the screw 93 on the tip 92 of the measuring head 25 into the screw 84 in the mounting hole 83 of the connecting member 47. The operator also connects the first outlet path 18 to the first connecting portion 31, and the second outlet path 19 to the second connecting portion 32. This allows the measuring system 2, consisting of the flow cell 10 and the Raman spectrometer 11, to be incorporated into the cell culture unit 12. The measuring head 25 may be attached to the connecting member 47 before step ST130. The operator may also connect the first outlet path 18 to the first connecting portion 31, and the second outlet path 19 to the second connecting portion 32 before step ST100.

[0078] 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 and the flow path 67 of the probe 45. Within the tip 49, the culture supernatant 15A is irradiated with excitation light EL that has passed through the cable 27, the optical system 100, the optical path 90, the optical path 50, and the optical system 60. The excitation light EL is focused by the optical system 60 at a focusing position FP.

[0079] Raman scattered light RSL is generated by the interaction between the excitation light EL and the antibodies 17 and the like in the culture supernatant 15A. The Raman scattered light RSL is captured by the optical system 60, passes through the optical path 50, the optical path 90, the optical system 100, and the cable 27, and is output to the analyzer 26. The analyzer 26 converts the Raman scattered light RSL into Raman spectrum data 28.

[0080] As described above, the unit 38 includes a probe 45 and a rotation restricting member 46. The probe 45 incorporates an optical system 60. The optical system 60 irradiates the antibodies 17 and other substances in the culture supernatant 15A, which are the measurement target substances for the Raman spectrum data 28, with excitation light EL and captures Raman scattered light RSL from the antibodies 17 and other substances. The probe 45 is detachable from the measurement head 25 of the Raman spectrometer 11, which incorporates an optical system 100. The probe 45 is disposed in a flow cell 10, which is a container for the culture supernatant 15A containing the antibodies 17 and other substances. The rotation restricting member 46 restricts the rotation of the probe 45 relative to the flow cell 10 while the probe 45 is oriented in a direction corresponding to the flow of the culture supernatant 15A. This allows the probe 45 to be oriented in a direction corresponding to the flow of the culture supernatant 15A and maintain that state, even when separated from the measurement head 25, which is difficult to handle. This contributes to accurate measurement of the Raman spectrum data 28.

[0081] 1 and other figures, the container in which the probe 45 is placed is a flow cell 10 having a flow path 30 through which the culture supernatant 15A flows. Therefore, the Raman spectrum data 28 of the culture supernatant 15A can be easily measured without modifying the culture tank 13, such as providing an attachment portion for the probe 45.

[0082] 3 and other figures, the probe 45 has a flow path 67 through which the culture supernatant 15A flows. Therefore, it is more necessary to maintain the orientation of the probe 45 in accordance with the flow of the culture supernatant 15A. This makes it possible to more effectively maintain the orientation of the probe 45 in accordance with the flow of the culture supernatant 15A.

[0083] 5, step ST110 in FIG. 8, and FIG. 9, the probe 45 is oriented so that the flow direction FD2 of the culture supernatant 15A in the flow path 67 of the probe 45 coincides with the flow direction FD1 of the culture supernatant 15A in the flow path 30 of the flow cell 10. This allows the culture supernatant 15A to flow smoothly through the flow paths 30 and 67 without causing pressure loss, reducing damage to the antibodies 17 and the like in the culture supernatant 15A. This allows for more accurate measurement of the Raman spectrum data 28.

[0084] 3 and other figures, the flow path 67 has an inlet 65 and an outlet 66 for the culture supernatant 15A, which are surrounded by a wall. This stabilizes the flow of the culture supernatant 15A near the focusing position FP of the excitation light EL. This reduces the concentration of components in the culture supernatant 15A near the focusing position FP, thereby improving the measurement stability of the Raman spectrum data 28.

[0085] 3 and other figures, the unit 38 has a connecting member 47 that detachably connects the measuring head 25 and the probe 45. Therefore, the measuring head 25 and the probe 45 can be easily attached and detached.

[0086] 11, by fitting the probe 45 into the connecting member 47, the optical axis OA1 of the optical system 60 and the optical axis OA2 of the optical system 100 are aligned. This allows the optical axis OA1 and the optical axis OA2 to be easily aligned. This prevents a decrease in the S / N ratio of the Raman spectrum data 28 due to misalignment of the optical axes.

[0087] In this example, to facilitate the handling of the probe 45, which needs to be oriented in a direction corresponding to the flow of the culture supernatant 15A, the probe 45 is detachable from the measurement head 25. However, if the probe 45 is detachable from the measurement head 25, it becomes necessary to align the optical axes OA1 of the optical system 60 and OA2 of the optical system 100 when attaching the unit 38 to the flow cell 10. For this reason, in this example, the probe 45 and the connecting member 47 are fitted together, allowing for easy optical axis alignment.

[0088] 3 and other figures, the connecting member 47 is detachable from the measuring head 25. Therefore, the orientation of the probe 45 can be adjusted in accordance with the flow of the culture supernatant 15A, and the optical axes OA1 and OA2 can be aligned, with the unit 38, and therefore the probe 45, detached from the measuring head 25, which is difficult to handle.

[0089] 3 to 5, 10, and 11, the probe 45 is an inner cylinder, the rotation restricting member 46 is an outer cylinder, and the connecting member 47 is inserted into the space 115 between the probe 45 and the rotation restricting member 46. Therefore, the connecting member 47 can be attached to the probe 45 simply and stably.

[0090] As shown in Fig. 3 and other drawings, an insertion hole 75 is formed in the rotation restricting member 46. Furthermore, a screw hole 86 that looks into the bottom surface 52 of the groove 51 of the probe 45 is formed at a position of the connecting member 47 that corresponds to the insertion hole 75. Then, as shown in Fig. 12, the tip of the bolt 53 that is inserted into the insertion hole 75 and screwed into the screw hole 86 is pressed against the bottom surface 52, thereby fixing the probe 45 and the connecting member 47. This makes it possible to fix the probe 45 and the connecting member 47 easily.

[0091] 10 , the rotation restricting member 46 restricts the rotation of the probe 45 around the optical axis OA1 of the optical system 60. This makes it possible to maintain the orientation of the probe 45 aligned with the flow of the culture supernatant 15A, thereby contributing to accurate measurement of the Raman spectrum data 28.

[0092] 3 and other figures, a flange 54 is formed on the outer circumferential surface of the probe 45, which abuts against the bottom surface 55 of the mounting hole 37 formed in the flow cell 10. Then, as shown in Fig. 10, the tip 74 of the rotation restricting member 46 is pressed against the flange 54, thereby restricting the rotation of the probe 45. Therefore, the rotation of the probe 45 can be easily restricted.

[0093] 7, the probe 45 has an inner wall surface 110 that faces the exit surface 63 of the transparent plate 62. The probe 45 is made of metal. That is, metal is disposed on at least a portion of the surface of the inner wall surface 110. This reduces the risk that the 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 the Raman spectrum data 28.

[0094] The area of ​​the metal on the inner wall surface 110 is larger than the area of ​​the inner wall surface 110 that is irradiated with the excitation light EL. Therefore, it is possible to more reliably reduce the risk that the excitation light EL is irradiated onto the resin, and Raman scattered light RSL generated by the interaction between the excitation light EL and the resin is captured and adversely affects the Raman spectrum data 28.

[0095] If the probe 45 is made of resin, a metal film of aluminum, copper, gold, or the like may be formed by plating on all or part of the inner wall surface 110. Furthermore, a metal film may be formed by plating on all or part of the inner wall surface of the periphery of the tip portion 49. If the probe 45 is made of resin, the effect of reducing the risk of Raman scattered light RSL generated by the interaction between the excitation light EL and the resin being captured and adversely affecting the Raman spectrum data 28 can be more effectively achieved.

[0096] Raman scattered light RSL is likely to reflect information derived from the functional groups of amino acids in proteins. Therefore, by using Raman spectrum data 28 as the physical property data as in this example, it is possible to obtain physical property data that better reflects the physical properties, such as the concentration of antibody 17, which is a protein.

[0097] 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.

[0098] 3 and other figures, the optical system 60 includes a hemispherical lens 61. The hemispherical lens 61 has a relatively high refractive power, and can shorten the distance between the exit surface of the hemispherical lens 61 from which the excitation light EL is emitted and the focusing position FP. This allows the thickness of the transparent plate 62 in the direction of the optical axis OA1 to be reduced accordingly, which can contribute to the miniaturization of the flow cell 10.

[0099] As shown in FIG. 3 and other figures, the optical system 60 includes, in addition to the hemispherical lens 61, a transparent plate 62 having a flat exit surface 63 for the excitation light EL that contacts the culture supernatant 15A. This allows the distance from the exit surface 63 to the focusing position FP to be shortened (set to zero in this example). This reduces the risk of the excitation light EL being attenuated by the culture supernatant 15A. This also reduces the risk of the excitation light EL being insufficient to obtain Raman spectrum data 28 that is strong enough for analysis. This allows the S / N ratio of the Raman spectrum data 28 resulting from 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 to be maintained at a high level.

[0100] In the above embodiment, the flow cell 10 is exemplified as a fluid container, but this is not limiting. For example, as shown in Fig. 13, the unit 38 may be applied to a storage tank 120 for a culture supernatant 15A.

[0101] The storage tank 120 has a mounting portion 121 for the unit 38. The mounting portion 121 is formed with a mounting hole 122 corresponding to the mounting hole 37 of the flow cell 10, and a fitting hole 123 corresponding to the fitting hole 40 of the flow cell 10.

[0102] The storage tank 120 is installed, for example, between the cell culture unit 12 and the purification unit. A flow path for supplying the culture supernatant 15A from the cell culture unit 12 and a flow path for supplying the culture supernatant 15A to the purification unit (both not shown) are connected to the storage tank 120. Because the storage tank 120 receives the culture supernatant 15A from the cell culture unit 12 and delivers the culture supernatant 15A to the purification unit, a flow of the culture supernatant 15A from top to bottom, as indicated by the arrow and symbol FD3, occurs in the storage tank 120. In this example, as in the above embodiment, the probe 45 is oriented so that the flow direction FD3 coincides with the flow direction FD2 of the culture supernatant 15A in the flow path 67.

[0103] The container may be a culture tank 13. In this case, the fluid is a cell culture solution 15. In this case, a mounting part is provided in the culture tank 13, and the unit 38 is mounted on the mounting part. When the container is a 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.

[0104] The connecting member 47 may be attached non-detachably to the measuring head 25. In other words, the measuring head 25 and the connecting member 47 may be integrated.

[0105] The method for restricting the rotation of the probe 45 around the optical axis OA1 is not limited to the exemplified method of pressing the tip 74 of the rotation restricting member 46 against the flange 54 of the probe 45. For example, a method in which protrusions formed on the tip 74 of the rotation restricting member 46 are fitted into two or more fitting holes formed in the flange 54 may be used. Furthermore, the method for fixing the probe 45 and the connecting member 47 is not limited to the method in which the tip of the bolt 53 is pressed against the bottom surface 52 of the groove 51 of the probe 45. A method using a stopper having a tip that can be protruded and retracted by spring bias may also be used.

[0106] Although screw fastening is used to connect the flow cell 10 and the rotation restricting member 46, and the measuring head 25 and the connecting member 47, etc., the present invention is not limited to this. Connections may also be made using leaf spring-like claws that engage with the lower edges of holes.

[0107] The flow path 67 of the probe 45 is not limited to the example having an inlet 65 and an outlet 66 surrounded by a wall. It may also be a probe having a tip with an L-shaped cross section, as shown in Figures 13 and 19 of Japanese Patent Application Laid-Open No. 2021-048872. Alternatively, the probe may not have a flow path 67, but may have a component that affects the flow of the culture supernatant 15A at the tip 49 or a portion other than the tip 49, and must be oriented in a direction corresponding to the flow of the culture supernatant 15A. In short, any probe may be used as long as it has directionality relative to the direction of fluid flow.

[0108] The inlet 65 and the outlet 66 are not limited to a rectangular shape but may be circular, elliptical, or the like. Furthermore, the tip 49 is not limited to the exemplified cylindrical container shape but may be a square or hexagonal cylindrical container shape. Therefore, the bottom plate 64 is also not limited to the exemplified circular shape but may be a rectangular or hexagonal shape. Furthermore, the peripheral plate is also not limited to the exemplified curved surface but may be a flat surface.

[0109] The bottom plate 64, and in turn the inner wall surface 110 of the bottom plate 64, may be a downwardly convex curved surface that follows the shape of the flow channel 30 of the flow cell 10. If the inner wall surface 110 is a downwardly convex curved surface, the inner wall surface 110 serves as a reflective surface that directs the Raman scattered light RSL toward the optical system 60. This makes it possible to further increase the S / N ratio of the Raman spectrum data 28. The downwardly convex curved surface may be in the shape of a parabolic antenna.

[0110] The lens constituting the optical system 60 is not limited to the illustrated hemispherical lens 61. For example, the optical system 130 shown in FIG. 14 and the optical system 135 shown in FIG. 15 may be a spherical ball lens 131. The optical systems 130 and 135 are examples of the "first optical system" according to the technology of the present disclosure. The ball lens 131 is an example of the "lens having positive refractive power" according to the technology of the present disclosure.

[0111] 14 includes a ball lens 131 and a transparent plate 133 having flat entrance and exit surfaces 132 for excitation light EL. The ball lens 131 and the transparent plate 133 are held in contact with each other without the use of adhesive or the like. The transparent plate 133 is an example of an "optical element" according to the technology of the present disclosure. The exit surface 132 of the transparent plate 133 is an example of an "exit surface of measurement light of the first optical system" and an "exit surface of measurement light that contacts a fluid" according to the technology of the present disclosure. The ball lens 131 and the transparent plate 133 may be spaced apart from each other rather than being in contact with each other.

[0112] 15 is composed of a ball lens 131 and an optical element 138 having an incident surface 136 for excitation light EL that is shaped like the ball lens 131, and a flat exit surface 137 for excitation light EL. The curvature of the incident surface 136 is the same as the curvature of the ball lens 131. The ball lens 131 and the optical element 138 are either fixed and bonded together with an adhesive or the like, or are simply held in a state where their surfaces are aligned without using an adhesive. The exit surface 137 of the optical element 138 is an example of the "exit surface of the measurement light of the first optical system" and the "exit surface of the measurement light that comes into contact with the fluid" according to the technology disclosed herein.

[0113] Ball lens 131 has a refractive power even higher than that of hemispherical lens 61. This allows the distance between the exit surface of ball lens 131 for the excitation light EL and the focusing position FP to be further shortened, and the thickness of transparent plate 133 or optical element 138 in the direction of optical axis OA1 to be further reduced. As a result, this can greatly contribute to the miniaturization of the flow cell.

[0114] As an example, as shown in FIG. 16 , a cylindrical lens 141 may be used as a lens having positive refractive power. The optical system 140 includes a transparent plate 142 in addition to the cylindrical lens 141. The cylindrical lens 141 is a lens having a crescent-shaped cross section formed by vertically splitting a cylinder. The cylindrical lens 141 has an entrance surface 143 for the excitation light EL, which is a spherical convex surface, and an exit surface 144 for the excitation light EL. The exit surface 144 is a rectangular flat surface. The optical system 140 is an example of a "first optical system" according to the technology of the present disclosure. The cylindrical lens 141 is also an example of a "lens having positive refractive power" according to the technology of the present disclosure. The entrance surface 143 of the cylindrical lens 141 may be aspherical.

[0115] The transparent plate 142 is a rectangular plate having an incident surface 145 and an exit surface 146 for the excitation light EL that are parallel to each other. The exit surface 144 of the cylindrical lens 141 and the incident surface 145 of the transparent plate 142 have the same curvature (0 in this case), and the exit surface 144 and the incident surface 145 are bonded together. The transparent plate 142 is an example of an "optical element" according to the technology of the present disclosure. Furthermore, the exit surface 146 of the transparent plate 142 is an example of an "exit surface of the measurement light of the first optical system" and an "exit surface of the measurement light that contacts the fluid" according to the technology of the present disclosure.

[0116] While the hemispherical lens 61 and the ball lens 131 etc. focus the excitation light EL in a point shape, the cylindrical lens 141 focuses the excitation light EL in a line shape. For example, the cylindrical lens 141 focuses the excitation light EL in a line shape parallel to the flow directions FD1 and FD2. Alternatively, the cylindrical lens 141 focuses the excitation light EL in a line shape perpendicular to the flow directions FD1 and FD2.

[0117] When the excitation light EL is focused in a line parallel to the flow directions FD1 and FD2, the temporal changes in the culture supernatant 15A flowing through the flow path 67 can be reflected in the Raman spectrum data 28. On the other hand, when the excitation light EL is focused in a line perpendicular to the flow directions FD1 and FD2, the spatial changes in the culture supernatant 15A flowing through the flow path 67 can be reflected in the Raman spectrum data 28. In either case, the measurement stability of the Raman spectrum data 28 can be improved compared to when the excitation light EL is focused in a point shape.

[0118] 17 shows an example of an optical system 150 that may use a plano-convex lens 151 as a lens with positive refractive power. The optical system 150 includes a transparent plate 152 in addition to the plano-convex lens 151. The plano-convex lens 151 is a lens in which an entrance surface 153 for the excitation light EL is an aspherical convex surface and an exit surface 154 for the excitation light EL is flat. The plano-convex lens 151 focuses the excitation light EL in a point shape. The plano-convex lens 151 is an example of a "lens with positive refractive power" and an "aspherical lens" according to the technology of the present disclosure.

[0119] Like the transparent plate 62, the transparent plate 152 is a circular plate having an incident surface 155 and an exit surface 156 for the excitation light EL that are parallel to each other. The exit surface 154 of the plano-convex lens 151 and the incident surface 155 of the transparent plate 152 have the same curvature (0 in this case), and the exit surface 154 and the incident surface 155 are cemented together. The transparent plate 152 is an example of an "optical element" according to the technology of the present disclosure. The exit surface 156 of the transparent plate 152 is an example of an "exit surface of the measurement light of the first optical system" and an "exit surface of the measurement light that contacts the fluid" according to the technology of the present disclosure.

[0120] Since the incident surface 153 of the plano-convex lens 151 is aspherical, spherical aberration can be reduced compared to a plano-convex lens with a spherical incident surface. A plano-convex lens with a spherical incident surface may also be used. A biconvex lens may also be used as a lens with positive refractive power.

[0121] Instead of forming an optical system by cementing a lens and a transparent plate, the lens and the transparent plate may be integrally formed as one lens.

[0122] As an example, as shown in FIG. 18 , the transparent plate may not be necessary, and the optical system may be configured using only lenses. The optical system 160 shown in FIG. 18 is configured using only a hemispherical lens 161. The hemispherical lens 161 has a hemispherical entrance surface for the excitation light EL and a planar exit surface 162 for the excitation light EL. The hemispherical lens 161 is an example of a "lens with positive refractive power" according to the technology of the present disclosure. Furthermore, the exit surface 162 of the hemispherical lens 161 is an example of an "exit surface of the measurement light of the first optical system" and an "exit surface of the measurement light that comes into contact with the fluid" according to the technology of the present disclosure.

[0123] In this way, optical system 160 may be composed of only hemispherical lens 161. This allows for a simpler configuration than optical system 60, which is combined with an optical element such as transparent plate 62. Note that the optical system may be composed of only ball lens 131 shown in FIGS. 14 and 15, or may be composed of only cylindrical lens 141 shown in FIG. 16. Furthermore, the optical system may be composed of only plano-convex lens 151 shown in FIG. 17.

[0124] The first connecting portion 31 and the second connecting portion 32 may be disposed on the underside of the flow cell 10, making the flow path 30 U-shaped. The shape of the flow cell 10 is not limited to a rectangular parallelepiped, but may also be a cylindrical or rectangular tube. The cross-sectional shape of the flow path 30 is also not limited to a circular shape, but may also be an elliptical or rectangular shape. Furthermore, the flow cell 10, the unit 38, etc. may be formed from a composite material such as carbon fiber reinforced resin.

[0125] The substance to be measured is not limited to the antibody 17, etc. Other substances than the antibody 17 may include proteins, peptides, nucleic acids (DNA, RNA (Ribonucleic Acid)), lipids, viruses, virus subunits, virus-like particles, etc.

[0126] 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.

[0127] The physical property data is not limited to the Raman spectrum data 28. 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.

[0128] The fluid is not limited to the culture supernatant 15A. It may be the cell culture fluid 15 before the cells are removed by the cell removal filter 14. It may be a cell culture fluid (so-called culture medium) that does not contain cell products before being supplied to the culture tank 13. It may be a purified liquid obtained by purifying the culture supernatant 15A using a chromatography device in the purification unit. The fluid is not limited to a liquid related to cell culture, and 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.

[0129] From the above description, the technology described in the following supplementary paragraphs can be understood.

[0130] [Supplementary Item 1] A spectroscopic probe unit comprising: a probe incorporating a first optical system for irradiating measurement light onto a measurement target substance for physical property data of a spectroscopic analyzer and capturing return light from the measurement target substance, the probe being detachable from a measurement head of the spectroscopic analyzer incorporating a second optical system; and a displacement restriction member for restricting displacement of the probe relative to a container for a fluid containing the measurement target substance, the probe being disposed in the container and oriented in accordance with the flow of the fluid. [Supplementary Item 2] The spectroscopic probe unit according to Supplementary Item 1, wherein the container is a flow cell having a first flow path through which the fluid flows. [Supplementary Item 3] The spectroscopic probe unit according to Supplementary Item 2, wherein the probe has a second flow path through which the fluid flows. [Supplementary Item 4] The spectroscopic probe unit according to Supplementary Item 3, wherein the probe is oriented so that the flow direction of the fluid in the second flow path coincides with the flow direction of the fluid in the first flow path. [Supplementary Item 5] The spectroscopic probe unit according to Supplementary Item 3 or Supplementary Item 4, wherein the second flow path has an inlet and an outlet for the fluid surrounded by a wall. [Supplementary Item 6] The spectroscopic probe unit according to any one of Supplementary Items 1 to 5, including a connecting member that detachably connects the measurement head and the probe. [Supplementary Item 7] The spectroscopic probe unit according to Supplementary Item 6, wherein the optical axes of a first optical system and a second optical system are aligned by fitting the probe into the connecting member. [Supplementary Item 8] The spectroscopic probe unit according to Supplementary Item 6 or Supplementary Item 7, wherein the connecting member is detachable from the measurement head. [Supplementary Item 9] The spectroscopic probe unit according to any one of Supplementary Items 6 to 8, wherein the probe is an inner tube and the displacement restricting member is an outer tube, and the connecting member is inserted into a space between the probe and the displacement restricting member.[Supplementary Item 10] The spectroscopic probe unit according to Supplementary Item 9, wherein an insertion hole is formed in the displacement restricting member, and a screw hole that looks into the outer circumferential surface of the probe is formed in the connecting member at a position corresponding to the insertion hole, and the probe and the connecting member are fixed by pressing a tip of a bolt that is inserted into the insertion hole and screwed into the screw hole against the outer circumferential surface of the probe. [Supplementary Item 11] The spectroscopic probe unit according to any one of Supplementary Items 1 to 10, wherein the displacement restricting member restricts rotation of the probe about a first optical axis of the first optical system. [Supplementary Item 12] The spectroscopic probe unit according to Supplementary Item 11, wherein the probe is an inner tube and the displacement restricting member is an outer tube, and a flange that abuts against a bottom surface of a mounting hole formed in the container is formed on the outer circumferential surface of the probe, and rotation of the probe is restricted by pressing an end of the displacement restricting member against the flange. [Supplementary Item 13] The spectroscopic analysis probe unit according to any one of Supplementary Items 1 to 12, wherein the probe has an opposing wall surface facing the emission surface of the measurement light of the first optical system, and a metal is arranged on at least a portion of the surface of the opposing wall surface. [Supplementary Item 14] The spectroscopic analysis probe unit according to Supplementary Item 13, wherein the area of ​​the metal on the opposing wall surface is larger than the area of ​​the opposing wall surface irradiated with the measurement light. [Supplementary Item 15] The spectroscopic analysis probe unit according to any one of Supplementary Items 1 to 14, wherein the physical property data is Raman spectrum data. [Supplementary Item 16] The spectroscopic analysis probe unit according to any one of Supplementary Items 1 to 15, wherein the fluid is any one of a cell culture medium, a culture supernatant, a purified solution, and a culture medium. [Supplementary Item 17] The spectroscopic analysis probe unit according to any one of Supplementary Items 1 to 16, wherein the first optical system includes a lens having a positive refractive power. [Supplementary Item 18] The spectroscopic analysis probe unit according to Supplementary Item 17, wherein the first optical system is composed of only the lens. [Supplementary Item 19] The spectroscopic analysis probe unit according to Supplementary Item 18, wherein the lens has an exit surface of the measurement light that comes into contact with the fluid, and the exit surface is flat.[Supplementary Item 20] The spectroscopic analysis probe unit according to Supplementary Item 17, wherein the first optical system includes, in addition to the lens, an optical element having an exit surface for the measurement light that comes into contact with the fluid, and the exit surface is flat. [Supplementary Item 21] The spectroscopic analysis probe unit according to any one of Supplementary Items 17, 18, and 20, wherein the lens is any one of a hemispherical lens, a ball lens, a cylindrical lens, and an aspherical lens.

[0131] The technology of the present disclosure can be appropriately combined with the various embodiments and / or various modified examples described above. Furthermore, it is needless to say that the technology is not limited to the above-described embodiments, and various configurations can be adopted as long as they do not deviate from the gist of the present disclosure.

[0132] 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.

[0133] 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."

[0134] 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 spectroscopic analysis probe unit comprising: a probe incorporating a first optical system for irradiating measurement light onto a substance to be measured for physical property data of a spectroscopic analyzer and capturing return light from the substance to be measured, the probe being detachable from a measurement head of the spectroscopic analyzer incorporating a second optical system; and a displacement control member for controlling displacement of the probe relative to a container in which a fluid including the substance to be measured is placed and the orientation of the probe is aligned according to the flow of the fluid.

2. A spectroscopic probe unit according to claim 1, wherein said container is a flow cell having a first flow path through which said fluid flows.

3. The spectroscopic probe unit according to claim 2, wherein the probe has a second flow path through which the fluid flows.

4. A spectroscopic probe unit according to claim 3, wherein the probe is oriented so that the flow direction of the fluid in the second flow path coincides with the flow direction of the fluid in the first flow path.

5. A spectroscopic probe unit according to claim 3, wherein said second flow path has an inlet and an outlet for said fluid, the inlet and outlet being surrounded by a wall.

6. A spectroscopic probe unit according to claim 1, further comprising a connecting member for detachably connecting said measuring head and said probe.

7. A spectroscopic probe unit as claimed in claim 6, wherein the first optical axis of the first optical system and the second optical axis of the second optical system are aligned by fitting the probe into the connecting member.

8. The spectroscopic analysis probe unit according to claim 6, wherein the connection member is detachable from the measurement head.

9. A spectroscopic probe unit according to claim 6, wherein the probe is an inner cylinder, the displacement restriction member is an outer cylinder, and the connecting member is inserted into the space between the probe and the displacement restriction member.

10. A spectroscopic probe unit as described in claim 9, wherein an insertion hole is formed in the displacement control member, and a screw hole is formed in the connecting member at a position corresponding to the insertion hole, looking into the outer peripheral surface of the probe, and the probe and the connecting member are fixed by pressing the tip of a bolt inserted into the insertion hole and screwed into the screw hole against the outer peripheral surface of the probe.

11. The spectroscopic analysis probe unit according to claim 1, wherein the displacement regulating member regulates rotation of the probe around a first optical axis of the first optical system.

12. A spectroscopic probe unit as described in claim 11, wherein the probe is an inner tube and the displacement regulating member is an outer tube, a flange portion is formed on the outer peripheral surface of the probe to abut against a bottom surface of a mounting hole formed in the container, and rotation of the probe is regulated by pressing an end of the displacement regulating member against the flange portion.

13. A spectroscopic probe unit according to claim 1, wherein the probe has an opposing wall surface facing the emission surface of the measurement light of the first optical system, and a metal is arranged on at least a portion of the surface of the opposing wall surface.

14. The spectroscopic analysis probe unit according to claim 13, 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.

15. The spectroscopic probe unit according to claim 1, wherein the physical property data is Raman spectrum data.

16. The spectroscopic probe unit according to claim 1, wherein the fluid is any one of a cell culture medium, a culture supernatant, a purified liquid, and a culture medium.

17. The spectroscopic analysis probe unit according to claim 1, wherein the first optical system includes a lens having a positive refractive power.

18. A spectroscopic probe unit according to claim 17, wherein the first optical system is composed of only the lens.

19. A spectroscopic probe unit according to claim 18, wherein the lens has an exit surface for the measurement light that contacts the fluid, and the exit surface is a flat surface.

20. A spectroscopic probe unit as described in claim 17, wherein the first optical system includes, in addition to the lens, an optical element having an exit surface for the measurement light that contacts the fluid, and the exit surface is a flat surface.

21. The spectroscopic probe unit according to claim 17, wherein the lens is any one of a hemispherical lens, a ball lens, a cylindrical lens, and an aspherical lens.

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