Quality inspection apparatus, quality inspection method, and program

Abstract

To provide a quality inspection device, a quality inspection method, and a program capable of more precisely inspecting the quality of a freeze-dried preparation or a powdery medicine.SOLUTION: Quality inspection apparatus 1 is a quality inspection apparatus that inspects the quality of an inspection target sample that is a freeze-dried preparation or a powdered pharmaceutical filled in transparent container B, and includes illuminator 13 that illuminates the bottom surface of transparent container B, imager 12 that images the side surface of transparent container B, an acquirer (controller 21) that acquires the light scattering characteristic based on the imaging result by imager 12, and a detector (controller 21) that detects the internal state of the inspection target sample based on the light scattering characteristic acquired by the acquirer.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a quality inspection device, a quality inspection method, and a program. [Background technology]

[0002] In the production of freeze-dried or powdered pharmaceuticals, if the preparation is not sufficiently dried and moisture remains, the moisture and active ingredient may undergo a hydrolysis reaction, which may affect the storage stability of the preparation. Therefore, it is necessary to produce the preparation so that the moisture content is sufficiently low.

[0003] When manufacturing freeze-dried preparations or powdered pharmaceuticals, there is a need to test the components of the preparation, such as the water content. In the production of freeze-dried formulations or powdered pharmaceuticals, there are cases where the moisture content of some products does not match the design due to factors such as the increase in size of the formulation manufacturing equipment (freeze-drying chamber). Also, there may be variations in the moisture content between products. Therefore, there is a need for non-destructive 100% inspection during the production of such formulations. Insufficient drying of freeze-dried or powdered pharmaceuticals can lead to problems with the internal structure, such as collapse and meltback, and / or problems with the appearance of the formulation. Therefore, there is a need to inspect the internal structure of the formulation, which cannot be inspected by visual inspection. There is a need to inspect freeze-dried preparations or powdered pharmaceuticals for unintentional contamination with foreign matter such as rubber, resin, and glass. Patent Documents 1 and 2 disclose techniques for inspecting freeze-dried preparations or pharmaceuticals. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] Patent No. 3351910 [Patent Document 2] International Publication No. 2007 / 063840 Summary of the Invention [Problem to be solved by the invention]

[0005] However, in the past, inspection of the internal state of freeze-dried preparations or pharmaceuticals during their manufacture was generally carried out by random destructive testing, which raised concerns about whether all defective products could be detected.On the other hand, with conventional non-destructive visual inspection, it was difficult to directly measure the internal state of freeze-dried preparations or pharmaceuticals. The production of freeze-dried or powdered pharmaceuticals requires rigorous testing of the quality of the formulation.

[0006] Therefore, in order to solve the above problems, an object of the present invention is to provide a quality inspection device, a quality inspection method, and a program that can inspect the quality of freeze-dried preparations or powdered pharmaceuticals more precisely. [Means for solving the problem]

[0007] The quality inspection device according to claim 1 comprises: A quality inspection device for inspecting the quality of a sample to be inspected, which is a freeze-dried preparation or a powdered pharmaceutical product filled in a transparent container, an illumination unit that illuminates the bottom surface of the transparent container; an imaging unit that images a side surface of the transparent container; an acquisition unit that acquires light scattering characteristics based on an imaging result by the imaging unit; and a detection unit that detects the internal state of the inspection target sample based on the light scattering characteristics acquired by the acquisition unit.

[0008] The invention described in claim 2 is the quality inspection device described in claim 1, The detection unit detects an internal defect of the inspection target sample as an internal state of the inspection target sample.

[0009] The invention described in claim 3 is the quality inspection device described in claim 2, The detection unit detects the internal defects by comparing the light scattering characteristics of a reference sample measured in advance with the light scattering characteristics of the inspection target sample.

[0010] The invention described in claim 4 is the quality inspection device described in claim 2, The detection unit detects the internal defect by detecting a deviation from an exponential decay characteristic in the light scattering characteristic.

[0011] The invention described in claim 5 is the quality inspection device described in claim 1, The detection unit evaluates the amorphous structure of the freeze-dried preparation as the internal state of the test sample.

[0012] The invention described in claim 6 is the quality inspection device described in claim 5, The detection unit compares the light scattering characteristics of a reference sample measured in advance with the light scattering characteristics of the test sample to evaluate the amorphous structure of the freeze-dried preparation.

[0013] The invention described in claim 7 is the quality inspection device described in claim 5, the imaging unit acquires spectral information by imaging, The detection unit evaluates the amorphous structure of the freeze-dried preparation based on the attenuation coefficient or scattering coefficient calculated based on the light scattering characteristics including the spectral information.

[0014] The invention described in claim 8 is the quality inspection device described in claim 1, The detection unit evaluates the uniformity of components contained in the test sample as the internal state of the test sample.

[0015] The invention described in claim 9 is the quality inspection device described in claim 8, the imaging unit acquires spectral information by imaging, the acquiring unit acquires the intensity of the transmitted diffused light including the spectral information based on the imaging result by the imaging unit; The detection unit evaluates the uniformity of components contained in the test sample based on the distribution of the intensity of the transmitted diffused light or the absorption spectrum distribution calculated based on the intensity of the transmitted diffused light.

[0016] The invention described in claim 10 is the quality inspection device described in claim 1, The detection unit detects foreign matter inside the inspection target sample as an internal state of the inspection target sample.

[0017] The invention described in claim 11 is the quality inspection device described in claim 10, the acquiring unit acquires the intensity of the transmitted diffused light based on the image capturing result by the image capturing unit; The detection unit detects the foreign matter based on the distribution of the intensity of the transmitted diffused light or the absorption spectrum distribution calculated based on the intensity of the transmitted diffused light.

[0018] The invention described in claim 12 is the quality inspection device described in claim 11, The detection unit estimates the foreign matter based on the absorption spectrum distribution.

[0019] The invention described in claim 13 is the quality inspection device according to any one of claims 1 to 12, the imaging unit captures images at a plurality of points in a vertical direction from a bottom surface of the transparent container, The acquisition unit acquires the light scattering characteristics based on the intensities of the transmitted diffused light at the plurality of points.

[0020] The quality inspection method according to claim 14 comprises: A quality inspection device for inspecting the quality of a sample to be inspected, which is a freeze-dried preparation or a powdered pharmaceutical product filled in a transparent container, an illumination unit that illuminates the bottom surface of the transparent container; A quality inspection method performed by a quality inspection device including an imaging unit that images a side surface of the transparent container, an acquisition step of acquiring light scattering characteristics based on the imaging result by the imaging unit; and a detecting step of detecting an internal state of the inspection target sample based on the light scattering characteristics acquired in the acquiring step.

[0021] The program according to claim 15 comprises: A quality inspection device for inspecting the quality of a sample to be inspected, which is a freeze-dried preparation or a powdered pharmaceutical product filled in a transparent container, an illumination unit that illuminates the bottom surface of the transparent container; an imaging unit that images the side surface of the transparent container; an acquisition unit that acquires light scattering characteristics based on the image capture result by the image capture unit; The light scattering characteristic is acquired by the acquisition unit, and the light scattering characteristic is then made to function as a detection unit that detects the internal state of the inspection target sample based on the light scattering characteristic acquired by the acquisition unit. [Effects of the Invention]

[0022] According to the present invention, the quality of freeze-dried preparations or powdered pharmaceuticals can be inspected more precisely. [Brief explanation of the drawings]

[0023] [Figure 1] 1 is a block diagram of a quality inspection device according to an embodiment of the present invention. [Figure 2] FIG. 2 is a perspective view of an inspection unit. [Figure 3] FIG. 2 is a diagram showing the configuration of an inspection unit. [Figure 4] FIG. 10 is a diagram illustrating an example of light scattering characteristics. [Figure 5] 10 is a flowchart illustrating an example of the flow of a quality inspection process. [Figure 6] 10 is a flowchart showing the flow of an absorption spectrum calculation process. [Figure 7] FIG. 10 is a diagram illustrating an example of an evaluation position. [Figure 8] FIG. 10 is a diagram showing an example of an absorption spectrum. [Figure 9] 10A and 10B are diagrams illustrating an example of matching the light scattering characteristics of a reference sample with the light scattering characteristics of a test sample. [Figure 10] FIG. 10 is a diagram showing an example of the ratio of the light scattering characteristics of a reference sample to the light scattering characteristics of a test sample. [Figure 11] 1 is a diagram showing the light scattering characteristics and exponential decay characteristics of a sample to be inspected; [Figure 12] 10A and 10B are diagrams illustrating an example of matching the light scattering characteristics of a reference sample with the light scattering characteristics of a test sample. [Figure 13] 10A and 10B are diagrams illustrating an example of the difference between the light scattering characteristics of a reference sample and the light scattering characteristics of a test sample. [Figure 14] FIG. 10 is a diagram showing the scattering coefficient of the light scattering characteristics of a reference sample and the scattering coefficient of the light scattering characteristics of a test sample. [Figure 15] FIG. 10 is a diagram showing an example of imaging data based on the intensity of diffused light transmitted through a sample to be inspected. [Figure 16] FIG. 10 is a diagram showing an example of imaging data including a foreign object. [Figure 17] 10A and 10B are diagrams illustrating an example in which the illumination range of the illumination unit is enlarged. [Figure 18] 10A and 10B are diagrams illustrating an example in which the illumination range of the illumination unit is reduced. DETAILED DESCRIPTION OF THE INVENTION

[0024] [Configuration example of quality inspection device 1] 1 is a block diagram of a quality inspection device 1 according to this embodiment. The quality inspection device 1 is a device for inspecting the quality of an inspection target sample, which is a freeze-dried preparation or a powdered pharmaceutical product. As shown in Fig. 1, the quality inspection device 1 includes an inspection unit 10 and a processing device 20. Fig. 2 is a perspective view of the inspection unit 10, and Fig. 3 is a diagram showing the configuration of the inspection unit 10. In Figs. 2 and 3, the X-axis direction and the Y-axis direction are two horizontal directions that are perpendicular to each other, and the vertical direction that is perpendicular to the X-axis and Y-axis is the Z-axis direction.

[0025] The inspection unit 10 includes a rotating unit 11, an imaging unit 12, an illumination unit 13, and the like. The rotating unit 11 rotates a sample stage 111 on a horizontal plane (XY plane) by driving a motor or the like (not shown), on which a transparent container B filled with a sample S is placed. The sample S is a freeze-dried preparation or a powdered pharmaceutical product to be inspected by the quality inspection device 1. In this embodiment, the quality inspection device 1 is installed in a production line (in-line) that produces a freeze-dried preparation or a powdered medicine. The inspection unit 10 includes a transport mechanism that transports the transparent container B to the sample stage 111. However, the quality inspection device 1 may be installed as a benchtop offline device in a laboratory, etc. In this case, the inspection unit 10 does not need to include a transport mechanism for transporting the transparent container B to the sample stage 111.

[0026] The imaging unit 12 is, for example, a hyperspectral camera. The imaging unit 12 is placed on the sample stage 111 and captures an image of the side surface of the transparent container B rotated by the rotation unit 11. In this embodiment, the image capturing unit 12 captures images of the sample S while rotating it once, so the spectroscopic principle of the hyperspectral camera serving as the image capturing unit 12 is optimally a push-broom type. However, the spectroscopic principle of the hyperspectral camera may also be a wavelength scanning type such as a Fabry-Perot type, or a snapshot type. If the wavelength resolution of the image capturing unit 12 is not required to be high, the image capturing unit 12 may also be a multispectral camera.

[0027] The imaging unit 12 captures an image of the range of one frame for one full rotation of the sample S. The imaging unit 12 separates the wavelength of light into multiple wavelength bands and captures the image. Specifically, the imaging unit 12 generates a data cube consisting of two-dimensional planar image images of the Y-axis and Z-axis of the sample S, which is the image target, stacked in layers for each dispersed wavelength region. The imaging unit 12 acquires spectral information by capturing (imaging) the sample S. As a result, the imaging unit 12 measures the intensity and light scattering characteristics of the transmitted diffused light generated by irradiating the sample S with illumination light from the illumination unit 13 in all directions of the sample S. The imaging unit 12 outputs the measurement results of the intensity and light scattering characteristics of the transmitted diffused light to the processing device 20. Figure 4 shows the details of the light scattering characteristics obtained by capturing images of one complete rotation of sample S. In the example shown in Figure 4, the horizontal axis represents pixels (px) in the Z-axis direction within one frame, and the vertical axis represents the intensity of the measured transmitted diffused light. As shown in Figure 4, the light scattering characteristics peak at a specific position (Area 0). On the positive Z-axis side of Area 0, the light scattering characteristics gradually attenuate as the light moves in the positive Z-axis direction due to the scattering and absorption characteristics of sample S. The light scattering characteristics vary depending on the formulation type and manufacturing process of sample S, etc.

[0028] 2 and 3, the inspection unit 10 is provided with one imaging unit 12, but the inspection unit 10 may be provided with two or more imaging units 12. In this case, multiple images of the samples S can be taken simultaneously by the multiple imaging units 12. This makes it possible to improve the takt time and inspection speed in the quality inspection process for inspecting the quality of the samples S. The imaging wavelength range of the imaging unit 12 preferably includes a near-infrared region, which has relatively high transmittance and can acquire characteristic absorption peaks of components such as active ingredients, excipients, and water contained in the sample S. In this embodiment, the imaging wavelength range of the imaging unit 12 is 900 to 1700 nm.

[0029] The illumination unit 13 includes an illumination light 131, a light source 132, etc., and irradiates the bottom surface of the transparent container B in which the sample S is filled with illumination light. The illumination light 131 is configured by bundling multiple optical fibers, and guides illumination light emitted from a light source 132 to the tip side (bottom side of the transparent container B) of the illumination light 131. The illumination light 131 irradiates illumination light from the tip surface toward the bottom side of the transparent container B. The light source 132 is preferably configured as a halogen lamp that has a broad wavelength range and a relatively high light intensity, but may also be configured as an LED (Light Emitting Diode).

[0030] The processing device 20 is, for example, a personal computer, etc. The processing device 20 is connected to the rotating unit 11 and the imaging unit 12 of the inspection unit 10 via wiring (not shown), and controls the operations of the rotating unit 11 and the imaging unit 12. The processing device 20 may also be connected to the illumination unit 13 via wiring, and control the operation of the illumination unit 13. The processing device 20 includes a control unit 21 , a storage unit 22 , a communication unit 23 , an operation unit 24 , and a display unit 25 .

[0031] The control unit 21 includes, for example, a processor such as a CPU (Central Processing Unit) or an MPU (Micro Processing Unit) and a memory such as a RAM (Random Access Memory). The control unit 21 executes a program 22a stored in a memory such as the RAM, a storage unit 22, etc., to realize various processes including quality inspection processes for the sample S.

[0032] The storage unit 22 includes any storage module, such as a hard disk drive (HDD), a solid state drive (SSD), a read only memory (ROM), and a RAM. The storage unit 22 stores, for example, system programs, application programs, various data, etc. Specifically, the storage unit 22 stores a program 22a for executing quality inspection processing of the sample S, etc.

[0033] The communication unit 23 includes, for example, a communication module including a NIC (Network Interface Card), a receiver, and a transmitter, etc. The communication unit 23 communicates various types of information with external devices connected via a network such as the Internet.

[0034] The operation unit 24 includes, for example, a mouse, a keyboard, switches, buttons, etc. The operation unit 24 may be, for example, a touch panel integrally combined with the display unit 25, or an interface that accepts voice input. The operation unit 24 accepts instructions corresponding to various input operations from the user, converts the accepted instructions into operation signals, and outputs the operation signals to the control unit 21.

[0035] The display unit 25 is, for example, a liquid crystal display, an organic EL (Electro Luminescence) display, etc. The display unit 25 performs display based on display data output from the control unit 21.

[0036] By configuring the quality inspection device 1 as described above, it is possible to easily incorporate the quality inspection device 1 into an existing visual inspection device. For example, there are space limitations when incorporating a diffuse reflectance measurement benchtop spectroscopic analyzer in-line. On the other hand, by using the imaging unit 12 and the lighting unit 13 as a replacement for the machine vision camera of the existing visual inspection device, it is possible to easily incorporate the quality inspection device 1 into the existing visual inspection device.

[0037] [Quality Inspection Device 1 Operation] Next, the operation of the quality inspection device 1 according to this embodiment will be described. Fig. 5 is a flowchart showing an example of the flow of a quality inspection process in which the quality inspection device 1 inspects the quality of the sample S.

[0038] (Quality inspection processing) The user blocks light and captures an image using the imaging unit 12 of the quality inspection device 1. This causes the imaging unit 12 to perform a dark measurement and output dark data, which is the measurement result, to the processing device 20 (step S1). Next, the user photographs a sample that serves as a reference in the quality inspection (hereinafter referred to as the reference sample) using the imaging unit 12. As a result, the imaging unit 12 measures the reference sample and outputs the measurement data of the reference sample to the processing device 20 (step S2). During imaging, the imaging unit 12 captures an image based on the signal intensity acquired through the optical path to the imaging unit 12, where absorption and scattering occur within the sample due to illumination light irradiated from the illumination unit 13. Therefore, when measuring a reference sample, signals from an object whose absorption and scattering characteristics are known may be acquired in advance and used as reference values. The reference sample may be a standard white plate such as PTFE (polytetrafluoroethylene), or a predetermined sample similar to the sample to be measured. The measurement of the reference sample in step S2 includes calibration of the imaging unit 12 when it is started up.

[0039] Next, the user uses the imaging unit 12 to capture an image of the sample S, which is the sample to be inspected and placed on the sample stage 111, for one full rotation. As a result, the imaging unit 12 measures the intensity and light scattering characteristics of the transmitted diffused light for one full rotation of the sample to be inspected, and outputs the measurement data to the processing device 20 (step S3). In step S3, the imaging unit 12 may measure only one frame of the test sample, or any range of the test sample, instead of measuring the entire rotation of the test sample. In this case, the intensity of the transmitted diffused light can be measured from the measurement results for one frame, making it possible to calculate the absorption spectrum from the measurement data of the transmitted diffused light intensity in step S4, which will be described later. If a crack has occurred in the test sample, it may be impossible to measure the intensity and light scattering characteristics of the transmitted diffused light at the location where the crack has occurred. Therefore, it is preferable to exclude the location where the crack has occurred from the target range of the detection process in step S6, which will be described later. Next, the control unit 21 of the processing device 20 acquires the measurement data output from the imaging unit 12. That is, the control unit 21 acquires the light scattering characteristics of the inspection target sample based on the imaging results by the imaging unit 12. The control unit 21 functions as an acquisition unit. Step S3 is an acquisition step. Next, the control unit 21 executes the absorption spectrum calculation process shown in FIG. 6 based on the acquired measurement data of the test sample (step S4).

[0040] (Absorption spectrum calculation process) The control unit 21 executes a dark correction process (step S11). Specifically, the control unit 21 subtracts the dark data measured in step S1 from the acquired measurement data of the inspection target sample. This makes it possible to remove noise due to the dark current of the imaging unit 12 from the measurement data of the inspection target sample. Next, the control unit 21 calculates the diffuse transmittance of the inspection target sample based on the measurement data of the inspection target sample after the dark correction process in step S11 (step S12). Two methods for calculating the diffuse transmittance of the inspection target sample will be described below.

[0041] (Method 1 for calculating diffuse transmittance) In method 1 for calculating diffuse transmittance, in step S3, the user uses the imaging unit 12 to capture images of the test sample at two or more measurement points in the Z-axis direction (the vertical direction of the transparent container B). That is, the imaging unit 12 captures images at multiple measurement points in the vertical direction from the bottom surface of the transparent container B. The control unit 21 of the processing device 20 acquires the light scattering characteristics of the test sample based on the intensities of the transmitted diffuse light at the multiple measurement points.

[0042] The control unit 21 performs the following calibration process on the light scattering characteristics, which are measurement data measured at two or more measurement points. Specifically, the control unit 21 sets px, which indicates a peak, as in Area 0 shown in FIG. 4, as the calibration point. The control unit 21 divides the intensity of the transmitted diffused light at other measurement points by the intensity of the transmitted diffused light at the calibration point. The other measurement points are, for example, Areas 1, 2, and 3 shown in FIG. 4. Alternatively, the control unit 21 may divide the intensity of the transmitted diffused light at other measurement points by the average value of the intensity of the transmitted diffused light in a predetermined range including the calibration point. The control unit 21 performs this calibration process for each frame captured by the imaging unit 12. The measurement data after the calibration process is data indicating the diffuse transmittance of the sample to be inspected. By performing the calibration process, the control unit 21 normalizes the overall diffuse transmittance by setting the average value of the diffuse transmittance in a predetermined range including the calibration point to 1.

[0043] By performing the above calibration process, the influence of the light source 132 on the diffuse transmittance of the test sample can be removed. As a result, in the detection process in step S6 described below, evaluation can be performed focusing only on the absorption of illumination light by the test sample between the calibration point (reference position) and other measurement points (evaluation positions). Figure 7 shows the reference position A0 and the positions of evaluation positions A1 to A3. As shown in Figure 7, the distance from reference position A0 to evaluation position A1 is Δd1, the distance from reference position A0 to evaluation position A2 is Δd2, and the distance from reference position A0 to evaluation position A3 is Δd3. In this case, the diffuse transmittance Tn at a predetermined evaluation position An can be calculated using the following formula (1) (Beer-Lambert law):

number

[0044] As shown in the above formula (1), the influence (I0) of the light source 132 on the diffuse transmittance Tn of the test sample can be removed. This allows evaluation to be performed in the detection process of step S6, which will be described later, focusing on the influence of the components and / or concentration of the test sample. In the detection process of step S6, evaluation can be performed in the detection process of step S6, focusing on a predetermined evaluation position An on the test sample. As described above, when calculating the diffuse transmittance of the inspection sample by Method 1, the measurement of the reference sample in step S2 may be omitted.

[0045] (Diffuse transmittance calculation method 2) In the diffuse transmittance calculation method 2, the control unit 21 calculates the diffuse transmittance Tn at a predetermined evaluation position An using the measurement data of the reference sample measured in step S2 as W in the above formula (1). In this case, the detection process in step S6, which will be described later, can be performed based on the reference sample, making it possible to detect abnormalities in the sample to be inspected. In the above formula (1), measurement data of a predetermined sample or measurement data at another evaluation position on the sample to be inspected may be used as W.

[0046] Alternatively, the quality inspection device 1 may include a reference light receiving unit (not shown) that measures the amount of light emitted by the light source 132 of the illumination unit 13. In this case, in the method 2 for calculating the diffuse transmittance, the control unit 21 calculates the diffuse transmittance Tn at the predetermined evaluation position An using the amount of light received by the light source 132 measured by the reference light receiving unit as W in the above formula (1).

[0047] Next, the control unit 21 calculates the absorbance of the test sample based on the diffuse transmittance of the test sample calculated in step S12. The control unit 21 calculates the absorbance at each wavelength of the transmitted diffused light to calculate the absorption spectrum (step S13), and ends the absorption spectrum calculation process. Below, two methods for calculating the absorbance of the test sample will be described.

[0048] (Method 1 for calculating absorbance) In the absorbance calculation method 1, the control unit 21 calculates the absorbance Abs at a predetermined evaluation position An for the test sample using the following formula (2): n Calculate.

number

[0049] As shown in the above formula (2), the absorbance Abs of the test sample n This allows the effect of the average scattering distance to be removed, making it possible to perform evaluation focusing on a predetermined evaluation position An on the inspection target sample in the detection process in step S6, which will be described later. An example of an absorption spectrum calculated based on the diffuse transmittance of the test sample is shown in Figure 8. In the example shown in Figure 8, the horizontal axis represents the measured wavelength of the transmitted diffuse light, and the vertical axis represents the calculated absorbance.

[0050] (Method 2 for calculating absorbance) In the absorbance calculation method 2, the control unit 21 calculates the absorbance of the test sample based on the light scattering characteristics of each wavelength of the transmitted diffused light. In the above formula (1), εcΔd n is unknown in the measurement data acquired in step S3. However, the light attenuation characteristics of the diffuse transmittance Tn can be acquired from the measurement data acquired in step S3. Therefore, the control unit 21 estimates εc by fitting the light attenuation characteristics of the diffuse transmittance Tn with an exponential function. This makes it possible to calculate the unit absorption spectrum Abs. Alternatively, the control unit 21 may n The attenuation characteristic of the above equation (2) may be linearly approximated to estimate εc.

[0051] Alternatively, the control unit 21 may estimate the scattering coefficient and the absorption coefficient using an arbitrary model such as a light diffusion theory based on the measurement approach of spatially resolved spectroscopy (SRS). When the light diffusion theory is used, the control unit 21 acquires a plurality of spatially different spectral information (intensity of transmitted diffused light) by the SRS method. Next, the control unit 21 substitutes the light attenuation characteristics of the spectral information into the light diffusion equation and solves the simultaneous equations to obtain the scattering coefficient μ s ′ and absorption coefficient μ a This calculates the scattering coefficient μ s ' and absorption coefficient μ a Since the internal state of the sample to be inspected can be precisely detected in the detection process in step S6 described below, the internal state of the sample to be inspected can be precisely detected. According to the principle of multiple scattering of light, the scattering direction is randomized at a certain depth Z0 in the scattering medium, which generates a virtual light source. The light diffusion equation R(ρ) at the isodiametric distance (average scattering distance) ρ is shown in the following equation (3). The effective attenuation coefficient μ eff is shown in the following formula (4).

number

[0052] The control unit 21 calculates the scattering coefficient μ s ′ and absorption coefficient μ a By calculating the above, fitting to the diffusion theory model shown in the following formulas (5) to (9) is performed.

number

[0053] 5, the control unit 21 performs preprocessing on the absorption spectrum of the test sample calculated in step S4 (step S5). The preprocessing includes, for example, noise processing, normalization, correction processing (baseline correction processing, etc.), SNV (Standard Normal Variate) processing, smoothing by the Savitzky-Golay method, differentiation processing, etc.

[0054] Next, the control unit 21 executes a detection process for detecting the internal state of the inspection target sample (step S6). The control unit 21 functions as a detection unit. Step S6 is a detection step. Four examples of detecting the internal state of a specimen to be inspected will be described below.

[0055] (Detection Processing Example 1) In the first embodiment of the detection process, the control unit 21 detects an internal defect of the inspection target sample as the internal state of the inspection target sample. Specifically, the control unit 21 compares the light scattering characteristics of a reference sample measured in advance with the light scattering characteristics of the sample to be inspected to detect internal defects in the sample to be inspected. The light scattering characteristics of the sample to be inspected are the measurement data after the dark correction process in step S11. In this case, the control unit 21 may omit steps S12 and S13. The dashed line in Fig. 9 represents the light scattering characteristics of a reference sample stored in, for example, memory unit 22. The solid line in Fig. 9 represents the light scattering characteristics of the sample to be inspected. In the example shown in Fig. 9, the horizontal axis represents pixels (px) in the Z-axis direction, and the vertical axis represents the intensity of transmitted diffused light. In the example shown in Fig. 9, the reference sample is a normal sample with no internal defects, and the sample to be inspected is a sample with internal defects.

[0056] Next, the control unit 21 calculates the difference between the light scattering characteristics of the reference sample and the light scattering characteristics of the inspection target sample. Next, if the calculated difference exceeds a predetermined threshold, the control unit 21 determines that an internal defect has occurred in the inspection target sample in the portion exceeding the predetermined threshold.

[0057] Alternatively, the control unit 21 calculates the ratio of the light scattering characteristics of the reference sample to the light scattering characteristics of the inspection target sample. Next, if the calculated ratio exceeds a predetermined threshold, the control unit 21 determines that an internal defect has occurred in the inspection target sample. The solid line in Fig. 10 represents the ratio of the light scattering characteristics of the reference sample to the light scattering characteristics of the sample under test. The dashed line in Fig. 10 represents a predetermined threshold for this ratio. In the example shown in Fig. 10, the horizontal axis represents pixels (px) in the Z-axis direction, and the vertical axis represents the ratio of the light scattering characteristics of the reference sample to the light scattering characteristics of the sample under test. In the example shown in FIG. 10, the control unit 21 determines that an internal defect has occurred in a portion of the inspection target sample where the above ratio exceeds the threshold value.

[0058] Alternatively, the control unit 21 detects internal defects in the sample based on the discrepancy between the light scattering characteristics of the sample and the exponential decay characteristics. The light scattering characteristics of the sample are the measurement data after the dark correction process in step S11. In this case, the control unit 21 may omit steps S12 and S13. The solid line in Fig. 11 represents the light scattering characteristics of the sample under test. The dotted line in Fig. 11 represents the exponential decay characteristics. In the example shown in Fig. 11, the horizontal axis represents pixels (px) in the Z-axis direction, and the vertical axis represents the intensity of the transmitted diffused light. The control unit 21 calculates a coefficient of determination of the fitting result between the light scattering characteristics of the inspection target sample after the dark correction process in step S11 and the exponential attenuation characteristics. Next, if the calculated coefficient of determination is less than a predetermined threshold (e.g., 0.94), the control unit 21 determines that an internal defect has occurred in the inspection target sample. That is, the control unit 21 detects deviations from the exponential attenuation characteristics in the light scattering characteristics of the inspection target sample, and detects internal defects in the inspection target sample.

[0059] (Detection Process Example 2) In Example 2 of the detection process, the control unit 21 evaluates the amorphous structure of a freeze-dried preparation as the internal state of the sample to be inspected. A freeze-dried preparation has an amorphous (non-crystalline) pore structure due to its manufacturing method. If a problem occurs in the freeze-drying process during the manufacturing process of a freeze-dried preparation, the amorphous pore structure and / or size of the freeze-dried preparation will be in a defective state that differs from a normal state. In this case, a difference will occur in the light scattering characteristics of a sample with a defective amorphous pore structure and a sample with a normal amorphous pore structure. Therefore, the control unit 21 compares the light scattering characteristics of a reference sample measured in advance with the light scattering characteristics of the test sample to evaluate the amorphous structure of the freeze-dried preparation. The light scattering characteristics of the test sample are the measurement data after the dark correction process in step S11. In this case, the control unit 21 may omit steps S12 and S13. The dashed line in Fig. 12 represents the light scattering characteristics of a reference sample stored in, for example, memory unit 22. The solid line in Fig. 12 represents the light scattering characteristics of the test sample. In the example shown in Fig. 12, the horizontal axis represents pixels (px) in the Z-axis direction, and the vertical axis represents the intensity of transmitted diffused light. In the example shown in Fig. 12, the reference sample is a sample with a normal amorphous pore structure, and the test sample is a sample with a defective amorphous pore structure.

[0060] Next, the control unit 21 calculates the difference between the light scattering properties of the reference sample and the light scattering properties of the test sample. If the calculated difference exceeds a predetermined threshold, the control unit 21 determines that a problem has occurred in the freeze-drying process and that the amorphous pore structure is in a poor state. The difference between the light scattering characteristics of a reference sample and the light scattering characteristics of a test sample is shown in Fig. 13. In the example shown in Fig. 13, the horizontal axis represents pixels (px) in the Z-axis direction, and the vertical axis represents the difference between the light scattering characteristics of the reference sample and the light scattering characteristics of a test sample. In the example shown in FIG. 13, the control unit 21 determines that the amorphous pore structure is in a poor state in a portion of the sample to be inspected where the difference exceeds a predetermined threshold value.

[0061] Alternatively, the control unit 21 calculates the ratio of the light scattering characteristics of the reference sample to the light scattering characteristics of the test sample. Next, if the calculated ratio exceeds a predetermined threshold, the control unit 21 determines that a problem has occurred in the freeze-drying process and that the amorphous pore structure is in a poor state.

[0062] Alternatively, the control unit 21 fits the light scattering characteristics of the transmitted and diffused light of the test sample at each wavelength with an exponential function. This allows the control unit 21 to calculate the attenuation coefficient of the light scattering characteristics of the transmitted and diffused light of the test sample at each wavelength. The control unit 21 then evaluates the amorphous structure of the freeze-dried preparation based on the calculated attenuation coefficient. Specifically, the control unit 21 calculates the difference from the reference sample at each wavelength, and determines that the amorphous pore structure is defective in areas of the test sample where the difference exceeds a predetermined threshold. For example, the control unit 21 determines that an internal defect has occurred in the test sample when the average value of the calculated difference spectrum in the wavelength direction is equal to or greater than a predetermined threshold (e.g., 0.02).

[0063] Alternatively, the control unit 21 calculates the scattering coefficient of the light scattering characteristics at each wavelength of the transmitted diffused light of the test sample using an arbitrary model such as light diffusion theory based on the measurement approach of the SRS method, in the same manner as in method 2 of calculating absorbance. The dashed line in Fig. 14 represents the scattering coefficient of the light scattering characteristics at each wavelength of a reference sample stored in, for example, memory unit 22. The solid line in Fig. 14 represents the scattering coefficient of the light scattering characteristics at each wavelength of the test sample. In the example shown in Fig. 14, the horizontal axis represents the wavelength of the transmitted diffused light, and the vertical axis represents the scattering coefficient. In the example shown in Fig. 14, the reference sample is a sample with a normal amorphous pore structure, and the test sample is a sample with a defective amorphous pore structure. Next, the control unit 21 evaluates the amorphous structure of the freeze-dried preparation based on the calculated scattering coefficient. Specifically, the control unit 21 calculates the difference from the reference sample at each wavelength, and determines that the amorphous pore structure is defective in a portion of the test sample where the difference exceeds a predetermined threshold. For example, the control unit 21 determines that an internal defect has occurred in the test sample when the average value of the calculated difference spectrum in the wavelength direction is equal to or greater than a predetermined threshold (e.g., 0.02).

[0064] (Detection Process Example 3) In Example 3 of the detection process, the control unit 21 evaluates the uniformity of components contained in the test sample as the internal state of the test sample. The components contained in the test sample include a desired active pharmaceutical ingredient (API), excipients, water, etc.

[0065] Specifically, the control unit 21 generates imaging data, which is a distribution of the intensity of the transmitted diffused light, based on the intensity of the transmitted diffused light for one complete rotation of the test sample. The intensity of the transmitted diffused light for one complete rotation of the test sample is the measurement data after the dark correction process in step S11. In this case, the control unit 21 may omit steps S12 and S13. FIG. 15 shows an example of imaging data. In the example shown in FIG. 15, the horizontal axis represents the rotation angle in the circumferential direction of the transparent container B. Next, the control unit 21 evaluates the uniformity of the components contained in the test sample using the generated imaging data. The imaging data reflects the absorption characteristics of the components contained in the test sample. Therefore, by evaluating the uniformity of the components contained in the test sample using the imaging data, it is possible to detect local component bias in the test sample. The control unit 21 may generate imaging data that is a distribution of the absorption spectrum based on the absorption spectrum after preprocessing in step S5, instead of the intensity of the diffused light transmitted through the inspection target sample.

[0066] The control unit 21 performs, for example, the following evaluation to evaluate the uniformity of the components contained in the test sample. Specifically, the control unit 21 divides the imaging data into arbitrary areas. Next, the control unit 21 evaluates the uniformity of the components by calculating the rate of variation of the intensity of transmitted diffused light for each divided area relative to the average value of the intensity of transmitted diffused light for the entire imaging data. The control unit 21 may also calculate the rate of variation of the absorption spectrum for each divided area relative to the average value of the absorption spectrum for the entire imaging data.

[0067] (Detection Process Example 4) In the fourth embodiment of the detection process, the control unit 21 detects foreign matter inside the test sample as an internal state of the test sample. The foreign matter is rubber, resin, glass, etc. that is not intended in the test sample.

[0068] Specifically, the control unit 21 generates imaging data that is a distribution of the intensity of the transmitted diffused light based on the intensity of the transmitted diffused light for one complete rotation of the test sample. The intensity of the transmitted diffused light for one complete rotation of the test sample is the measurement data after the dark correction process in step S11. In this case, the control unit 21 may omit steps S12 and S13. FIG. 16 shows an example of imaging data based on the intensity of the transmitted diffused light of the test sample containing foreign matter. In the example shown in FIG. 16, the horizontal axis represents the rotation angle in the circumferential direction of the transparent container B. Next, the control unit 21 detects a location in the generated imaging data where the intensity of the transmitted diffused light changes locally as a location containing a foreign object. For example, if the rate of change between the intensity of the transmitted diffused light at a specific location in the imaging data and the average value of the intensity of the transmitted diffused light in 10 pixels adjacent to the specific location is equal to or greater than a specific threshold, the control unit 21 determines that the specific location contains a foreign object.

[0069] The control unit 21 may generate imaging data that is a distribution of the absorption spectrum based on the absorption spectrum after preprocessing in step S5, instead of the intensity of the transmitted diffused light of the inspection target sample. In this case, the control unit 21 detects a location in the generated imaging data where the absorption spectrum changes locally as a location containing a foreign substance. The control unit 21 estimates the presence of a foreign substance based on the absorption spectrum of a portion of the imaging data that is determined to contain the foreign substance. Specifically, the control unit 21 compares the absorption spectra of multiple types of foreign substances created in advance with the absorption spectrum of the portion of the imaging data that is determined to contain the foreign substance. Next, the control unit 21 estimates the presence of the foreign substance based on the match rate of the absorption spectra. This makes it possible to detect contamination during the manufacturing process of the sample to be inspected, thereby contributing to the manufacturing of highly safe samples.

[0070] In the above quality inspection process, by measuring the transmitted and diffused light using the imaging unit 12, it is possible to measure information about the inside of the sample, rather than measuring only components on or near the surface of the sample as in the case of reflected light measurement, which allows for more precise inspection of the quality of the sample.

[0071] [others] During measurements in steps S2 and S3 of the quality inspection process, the illumination range of the illumination unit 13 illuminating the bottom surface of the transparent container B may be adjusted. In this embodiment, the illumination range can be adjusted to the entire bottom surface of the transparent container B or only the center of the transparent container B. Specifically, as shown in FIG. 17 , the illumination range can be increased by increasing the distance from the tip of the illumination light 131 to the bottom surface of the transparent container B. On the other hand, as shown in FIG. 18 , the illumination range can be reduced by reducing the distance from the tip of the illumination light 131 to the bottom surface of the transparent container B. Alternatively, the illumination range can be increased by guiding the illumination light through all of the optical fibers of the illumination light 131 and irradiating it onto the bottom surface of the transparent container B. On the other hand, the illumination range can be reduced by guiding the illumination light through only the optical fibers located in the center of the optical fibers of the illumination light 131 and irradiating it onto the bottom surface of the transparent container B. The length of the optical path F of the illumination light passing through the sample S can be adjusted by adjusting the illumination range of the illumination unit 13 that illuminates the bottom surface of the transparent container B. This makes it possible to set the length of the optical path F appropriate for the absorbance of the sample S. For example, if the absorption of the illumination light by the sample S is significantly small, the amount of illumination light absorbed by the sample S can be increased by increasing the length of the optical path F of the illumination light.

[0072] [effect] The quality inspection device 1 of this embodiment is a quality inspection device that inspects the quality of an inspection target sample, which is a freeze-dried preparation or a powdered pharmaceutical product filled in a transparent container B. The quality inspection device 1 includes an illumination unit 13 that illuminates the bottom surface of the transparent container B. The quality inspection device 1 includes an imaging unit 12 that images the side surface of the transparent container B. The quality inspection device 1 includes an acquisition unit (control unit 21) that acquires light scattering characteristics based on the imaging results obtained by the imaging unit 12. The quality inspection device 1 includes a detection unit (control unit 21) that detects the internal state of the inspection target sample based on the light scattering characteristics acquired by the acquisition unit. Therefore, the internal state of the test sample can be detected without destroying the test sample. This makes it possible to inspect all freeze-dried preparations or pharmaceuticals during their production. In other words, the quality of freeze-dried preparations or powdered pharmaceuticals can be inspected more precisely.

[0073] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) detects internal defects of the inspection target sample as the internal state of the inspection target sample. Therefore, internal defects in the inspection target sample can be detected without destroying the inspection target sample.

[0074] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) detects internal defects by comparing the light scattering characteristics of a reference sample measured in advance with the light scattering characteristics of the sample to be inspected. Therefore, by comparing the light scattering characteristics, internal defects in the sample to be inspected can be precisely detected.

[0075] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) detects deviations from the exponential decay characteristics in the light scattering characteristics to detect internal defects. Therefore, by detecting deviations from the exponential decay characteristics, internal defects in the sample to be inspected can be precisely detected.

[0076] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) evaluates the amorphous structure of the freeze-dried preparation as the internal state of the sample to be inspected. Therefore, the amorphous structure of a freeze-dried formulation can be evaluated without destroying the freeze-dried formulation.

[0077] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) compares the light scattering characteristics of a reference sample measured in advance with the light scattering characteristics of the sample to be inspected to evaluate the amorphous structure of the freeze-dried preparation. Therefore, by checking the light scattering properties, the amorphous structure of a freeze-dried preparation can be precisely evaluated.

[0078] In the quality inspection device 1 of this embodiment, the imaging unit 12 acquires spectral information by imaging. The detection unit (control unit 21) evaluates the amorphous structure of the freeze-dried preparation based on the attenuation coefficient or scattering coefficient calculated based on the light scattering characteristics including the spectral information. Therefore, the amorphous structure of a freeze-dried formulation can be precisely evaluated based on the attenuation or scattering coefficient.

[0079] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) evaluates the uniformity of the components contained in the inspection target sample as the internal state of the inspection target sample. Therefore, the uniformity of the components contained in the test sample can be evaluated without destroying the freeze-dried preparation.

[0080] In the quality inspection device 1 of this embodiment, the imaging unit 12 acquires spectral information by imaging. The acquisition unit (control unit 21) acquires the intensity of the transmitted diffused light including the spectral information based on the image capturing result by the image capturing unit 12. The detection unit (control unit 21) evaluates the uniformity of the components contained in the test sample based on the distribution of the intensity of the transmitted diffused light or the absorption spectrum distribution calculated based on the intensity of the transmitted diffused light. Therefore, the uniformity of the components contained in the test sample can be precisely evaluated based on the distribution of the intensity of the transmitted diffused light or the absorption spectrum distribution calculated based on the intensity of the transmitted diffused light.

[0081] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) detects foreign matter inside the inspection target sample as the internal state of the inspection target sample. Therefore, foreign matter inside the sample to be inspected can be detected without destroying the freeze-dried preparation.

[0082] In the quality inspection device 1 of this embodiment, the acquisition unit (control unit 21) acquires the intensity of the transmitted diffused light based on the image capturing result by the image capturing unit 12. The detection unit (control unit 21) detects foreign matter based on the distribution of the intensity of the transmitted diffused light or the absorption spectrum distribution calculated based on the intensity of the transmitted diffused light. Therefore, foreign matter can be precisely detected based on the distribution of the intensity of the transmitted diffused light or the absorption spectrum distribution calculated based on the intensity of the transmitted diffused light. This makes it possible to detect contamination during the manufacturing process of the sample to be inspected, thereby contributing to the manufacturing of highly safe samples.

[0083] In the quality inspection device 1 of this embodiment, the detection unit (control unit 21) estimates the presence of foreign matter based on the absorption spectrum distribution. Therefore, unknown foreign objects can be identified.

[0084] In the quality inspection device 1 of this embodiment, the imaging unit 12 captures images of the transparent container B at a plurality of points in the vertical direction from the bottom surface thereof. The acquisition unit (control unit 21) acquires the light scattering characteristics based on the intensities of the transmitted diffused light at a plurality of points. Therefore, the internal state of the inspection target sample can be detected at a plurality of points in the vertical direction from the bottom surface of the transparent container B.

[0085] While the preferred embodiments of the present disclosure have been described in detail above with reference to the accompanying drawings, the technical scope of the present disclosure is not limited to such examples. Furthermore, various modifications and improvements made by those skilled in the art will naturally fall within the scope of the technical ideas described in the claims. [Explanation of symbols]

[0086] 1. Quality inspection equipment 10 Inspection Unit 11 Rotating part 12 Imaging unit 13 Lighting Department 131 Lighting 132 Light source 20 Processing equipment 21 Control unit (acquisition unit, detection unit) 22 Memory section 22a Program 23 Communications Department 24 Control section 25 Display section B Transparent container

Claims

1. A quality inspection device for inspecting the quality of a sample to be inspected, which is a freeze-dried preparation or a powdered pharmaceutical product filled in a transparent container, an illumination unit that illuminates the bottom surface of the transparent container; an imaging unit that images a side surface of the transparent container; an acquisition unit that acquires light scattering characteristics based on an imaging result by the imaging unit; a detection unit that detects an internal state of the inspection target sample based on the light scattering characteristics acquired by the acquisition unit.

2. The quality inspection device according to claim 1 , wherein the detection unit detects an internal defect of the inspection target sample as the internal state of the inspection target sample.

3. 3. The quality inspection device according to claim 2, wherein the detection unit detects the internal defects by comparing the light scattering characteristics of the inspection target sample with the light scattering characteristics of a reference sample that has been measured in advance.

4. The quality inspection device according to claim 2 , wherein the detection unit detects the internal defect by detecting a deviation from an exponential decay characteristic in the light scattering characteristic.

5. The quality inspection device according to claim 1 , wherein the detection unit evaluates the amorphous structure of the freeze-dried preparation as the internal state of the inspection target sample.

6. 6. The quality inspection device according to claim 5, wherein the detection unit evaluates the amorphous structure of the freeze-dried preparation by comparing the light scattering characteristics of a reference sample measured in advance with the light scattering characteristics of the test sample.

7. the imaging unit acquires spectral information by imaging, The quality inspection device according to claim 5 , wherein the detection unit evaluates the amorphous structure of the freeze-dried preparation based on an attenuation coefficient or a scattering coefficient calculated based on the light scattering characteristics including the spectral information.

8. The quality inspection device according to claim 1 , wherein the detection unit evaluates the uniformity of components contained in the inspection target sample as the internal state of the inspection target sample.

9. the imaging unit acquires spectral information by imaging, the acquiring unit acquires the intensity of the transmitted diffused light including the spectral information based on the imaging result by the imaging unit; 9. The quality inspection device according to claim 8, wherein the detection unit evaluates the uniformity of the components contained in the test sample based on the distribution of the intensity of the transmitted diffused light or an absorption spectrum distribution calculated based on the intensity of the transmitted diffused light.

10. The quality inspection device according to claim 1 , wherein the detection unit detects a foreign substance inside the inspection target sample as the internal state of the inspection target sample.

11. the acquiring unit acquires the intensity of the transmitted diffused light based on the image capturing result by the image capturing unit; The quality inspection device according to claim 10 , wherein the detection unit detects the foreign matter based on a distribution of the intensity of the transmitted diffused light or an absorption spectrum distribution calculated based on the intensity of the transmitted diffused light.

12. The quality inspection device according to claim 11 , wherein the detection unit estimates the foreign matter based on the absorption spectrum distribution.

13. the imaging unit captures images at a plurality of points in a vertical direction from a bottom surface of the transparent container, The quality inspection device according to claim 1 , wherein the acquisition unit acquires the light scattering characteristics based on the intensities of the transmitted diffused light at the plurality of points.

14. A quality inspection device for inspecting the quality of a sample to be inspected, which is a freeze-dried preparation or a powdered pharmaceutical product filled in a transparent container, an illumination unit that illuminates the bottom surface of the transparent container; A quality inspection method performed by a quality inspection device including an imaging unit that images a side surface of the transparent container, an acquisition step of acquiring light scattering characteristics based on the imaging result by the imaging unit; a detecting step of detecting an internal state of the inspection target sample based on the light scattering characteristics acquired in the acquiring step.

15. A quality inspection device for inspecting the quality of a sample to be inspected, which is a freeze-dried preparation or a powdered pharmaceutical product filled in a transparent container, an illumination unit that illuminates the bottom surface of the transparent container; an imaging unit that images the side surface of the transparent container; an acquisition unit that acquires light scattering characteristics based on the image capture result by the image capture unit; a program that causes the detector to function as a detector that detects the internal state of the inspection target sample based on the light scattering characteristics acquired by the acquirer.

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