Quantitatively measuring method, analysis system and program

Abstract

To provide a technique for quantitatively measuring a specific component in mixture with high speed and high accuracy.SOLUTION: A method for quantitatively measuring a specific component contained in a measurement sample is provided. The method includes the steps of: analyzing the measurement sample using chromatograph to obtain measurement spectrum at each of a plurality of time points; applying filtering for extracting a specific component on the measurement spectrum at each of the plurality of time points to thereby derive an index value at each of the plurality of time points; arranging one or more index values at each of the plurality of time points in time direction to obtain chromatogram; and quantitatively measuring the specific component from a peak in the chromatogram.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] TECHNICAL FIELD This disclosure relates to analyzing the measurement output of a measurement instrument. [Background technology]

[0002] International Publication No. 2020 / 225864 discloses that a measurement sample is analyzed by chromatography to obtain absorption spectra at multiple time points, and the sum of the intensities of the absorption spectra at each time point is arranged in the time direction to obtain a chromatogram, and the components corresponding to the peaks in the chromatogram are quantified. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] International Publication No. 2020 / 225864 Summary of the Invention [Problem to be solved by the invention]

[0004] Conventionally, to accurately quantify a specific component in a mixture, it was necessary to set a long separation time, for example by supplying the mobile phase at a slow rate, so that the peaks of other components would not overlap.

[0005] The present disclosure has been made in view of the above circumstances, and its purpose is to provide a technique for rapidly and accurately quantifying a specific component in a mixture. [Means for solving the problem]

[0006] A quantitative method according to one aspect of the present disclosure is a method for quantifying a specific component contained in a measurement sample, and includes the steps of: analyzing the measurement sample using chromatography to obtain a measured spectrum at each of a plurality of time points; applying a filter to the measured spectrum at each of the plurality of time points to extract the specific component, thereby deriving an index value at each of the plurality of time points; obtaining a chromatogram by arranging one or more index values ​​at each of the plurality of time points in the time direction; and quantifying the specific component from the peak of the chromatogram.

[0007] An analytical system according to one aspect of the present disclosure includes a measuring instrument connected to a reaction apparatus that produces a product by chemically changing one or more precursors, and that measures the spectrum of a measurement sample extracted from the product produced in the reaction apparatus, and an analytical apparatus that analyzes the output of the measuring instrument, and the analytical apparatus performs the above-mentioned quantitative method on the measurement sample extracted from the product.

[0008] A program according to an aspect of the present disclosure, when executed by a computer, causes the computer to carry out the above-described quantification method. [Effects of the Invention]

[0009] According to one aspect of the present disclosure, there is provided a technique for rapidly and accurately quantifying a specific component in a mixture. [Brief explanation of the drawings]

[0010] [Figure 1] FIG. 1 is a diagram illustrating a configuration of a generation system according to an embodiment of the present disclosure. [Figure 2] FIG. 2 is a block diagram showing the configuration of a control device 100 in FIG. [Figure 3] FIG. 1 shows a chromatogram obtained by chromatography of a typical mixture performed at a first flow rate. [Figure 4] FIG. 4 shows a chromatogram obtained by chromatography of the mixture of FIG. 3 carried out at a second flow rate. [Figure 5] FIG. 4 shows the chromatogram of FIG. 3 together with a waveform processed using a filter. [Figure 6] FIG. 5 shows the chromatogram of FIG. 4 together with a waveform processed using a filter. [Figure 7] 7 is a diagram showing the measurement results when the mixtures mentioned in FIGS. 3 to 6 are introduced into a measuring instrument 340 without passing through a separation column 330. FIG. [Figure 8] FIG. 1 is a diagram schematically showing an example of a measurement result of a general sample. [Figure 9] FIG. 10 is a diagram illustrating an example of a reference spectrum. [Figure 10] 1 is a flowchart of a process performed by the analytical device 300 to provide information for monitoring the manufacturing process in the reactor 200. [Figure 11] 10 is a flowchart of a subroutine of step S20. [Figure 12] 10 is a flowchart of a subroutine of step S40. DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, embodiments of the present disclosure will be described in detail with reference to the drawings. In the drawings, the same or corresponding parts are designated by the same reference numerals, and description thereof will not be repeated.

[0012] [Generation system configuration] A production system according to an embodiment of the present disclosure will be described in detail below with reference to the drawings. Fig. 1 is a diagram showing the configuration of a production system according to one embodiment of the present disclosure. As shown in Fig. 1, the production system 500 includes a control device 100, a reaction device 200, and an analysis device 300. The analysis device 300 includes a separation column for a liquid chromatograph that separates a sample using an eluent.

[0013] The control device 100 is configured by, for example, a computer, and includes a CPU (Central Processing Unit) and a memory. The control device 100 acquires various measurement results from the reaction device 200 and also acquires measurement results from the analysis device 300, and controls the operation of the reaction device 200 based on the acquired results. Details of the control device 100 will be described later.

[0014] The reactor 200 has the function of continuously manufacturing a product, for example, in the pharmaceutical, food or chemical industries.

[0015] The analysis device 300 uses a filter described below to analyze the measurement results of the target solution generated during continuous production in the reaction device 200, thereby providing information for monitoring the manufacturing process in the reaction device 200.

[0016] Reaction apparatus 200 includes liquid delivery units 210, 220 and reactor 230. A first liquid raw material and a second liquid raw material are supplied to liquid delivery units 210, 220, respectively, from factory equipment or the like. The first liquid raw material includes a first precursor for the product. The second liquid raw material includes a second precursor for the product. Liquid delivery units 210, 220 are, for example, liquid delivery pumps, which pump the first and second liquid raw materials to reactor 230, respectively, through flow path 501. Flow path 501 is provided with flow rate sensors 211, 221 that measure the amounts of the first and second liquid raw materials delivered, respectively.

[0017] The reactor 230 includes, for example, a CSTR (continuous tank reactor) or a plug flow reactor, and continuously produces a predetermined product (hereinafter referred to as a reaction product) by reacting a first liquid raw material with a second liquid raw material. The reactor 230 is provided with a temperature regulator 231 that adjusts the internal temperature, and a pressure regulating valve 232 that adjusts the internal pressure. The reactor 230 is also provided with a temperature sensor 233 and a pressure sensor 234 that measure the internal temperature and pressure, respectively.

[0018] An evaluation value indicating the quality, such as the yield or purity, of the reaction product produced by the reactor 230 varies depending on the residence time of the first liquid raw material, the residence time of the second liquid raw material, the reaction temperature, or the reaction pressure in the reactor 230. The residence time of the first liquid raw material in the reactor 230 is determined by the amount of the first liquid raw material fed and the flow path shape (volume) of the reactor 230. Similarly, the residence time of the second liquid raw material in the reactor 230 is determined by the amount of the second liquid raw material fed and the flow path shape of the reactor 230.

[0019] A flow path 502 including a main pipe 502a and branch pipes 502b and 502c is connected to the downstream portion of the reactor 230. Most of the reaction products produced in the reactor 230 are sent as finished products or semi-finished products to the downstream of the factory production line through branch pipe 502b branching from the main pipe 502a. On the other hand, a portion of the reaction products produced in the reactor 230 is guided as a sample to be analyzed to the analyzer 300 through branch pipe 502c branching from the main pipe 502a. A pump may be provided to guide the reaction products from the reactor 230 to the flow path 502.

[0020] In this embodiment, the cross-sectional area of ​​channel 501 through which the first or second liquid raw material flows and the cross-sectional area of ​​channel 502 through which the reaction product flows are larger than the cross-sectional area of ​​channel 503 (described below) through which the eluent flows in analyzer 300. In this case, reaction device 200 can produce a large amount of reaction product and send the produced reaction product downstream. Meanwhile, analyzer 300 can suppress the sample from diffusing in channel 503, thereby improving the sample separation performance.

[0021] The analytical device 300 includes an eluent supply unit 310, a sample supply unit 320, a separation column 330, a measuring instrument 340, and a processing unit 350. The analytical device 300 may be installed in the same factory as the reaction device 200, or may be installed in a research facility or the like different from the factory where the reaction device 200 is installed. A display device 351 and an input device 352 are connected to the processing unit 350. If the control device 100 has the same function as the processing unit 350, the analytical device 300 does not need to be provided with the processing unit 350.

[0022] The eluent supply unit 310 includes bottles 311 and 312, liquid delivery units 313 and 314, and a mixing unit 315. The bottles 311 and 312 store, for example, an aqueous solution and an organic solvent as eluents, respectively. The liquid delivery units 313 and 314 are, for example, liquid delivery pumps, and pressure-feed the eluents stored in the bottles 311 and 312, respectively, through a flow path 503. The mixing unit 315 is, for example, a gradient mixer. The mixing unit 315 mixes the eluents pressure-feed by the liquid delivery units 313 and 314 at an arbitrary ratio and supplies the mixed eluent while changing the mixing ratio.

[0023] The sample supply unit 320 is, for example, an autosampler, and includes a flow vial 321 and a sampling needle 322. The sample generated by the reaction device 200 is introduced into the flow vial 321 through a flow path 502 and then discarded in a waste liquid unit (not shown). The sampling needle 322 aspirates the sample in the flow vial 321 and injects the aspirated sample into the separation column 330 together with the eluent supplied by the eluent supply unit 310. The sampling needle 322 is an example of a sample extraction unit. The sample injected into the separation column 330 may be diluted as appropriate in the sample supply unit 320.

[0024] The separation column 330 is housed in a column thermostatic bath (not shown) and is maintained at a predetermined constant temperature. The separation column 330 separates the sample injected by the sample supply unit 320 into components based on differences in chemical properties or composition. The measuring instrument 340 includes, for example, an absorptiometer or an RI (Refractive Index) measuring instrument, and detects the components of the sample separated by the separation column 330. If the measuring instrument 340 is an absorptiometer, the measuring instrument 340 may be configured as a single absorptiometer capable of measuring absorbance at multiple wavelengths, or may be configured as multiple absorptiometers capable of measuring absorbance at different wavelengths. The sample that has passed through the measuring instrument 340 is discarded. If it is acceptable for the eluent to be mixed into the reaction device 200, the sample that has passed through the measuring instrument 340 may be returned to the reaction device 200. The measuring instrument 340 may be a mass spectrometer or a refractometer.

[0025] The processing unit 350 includes hardware elements such as a CPU and memory or a microcomputer, and controls the operations of the eluent supply unit 310, the sample supply unit 320, the separation column 330 (column thermostatic bath), and the measuring instrument 340. The processing unit 350 also processes the measurement results from the measuring instrument 340 to create processing results such as a chromatogram showing the relationship between the retention time and the measured intensity of each component. When GPC (gel permeation chromatography) analysis is performed, the processing unit 350 may calculate the average molecular weight of the reaction product by analyzing the created chromatogram.

[0026] [Control device] 2 is a block diagram showing the configuration of the control device 100 of FIG. 1. As shown in FIG. 2, the control device 100 includes, as its functions, a reference value acquisition unit 10, an allowable range setting unit 20, a result acquisition unit 30, a search unit 40, a determination unit 50, and a reaction control unit 60. Each function may be realized, for example, by the CPU of the control device 100 executing a generation and analysis program stored in memory. The control device 100 also includes a database storage device 110. Some or all of the functions of the control device 100 may be realized by hardware such as an electric circuit.

[0027] The database storage device 110 includes a large-capacity data server or the like that stores a database. The database may include past measurement results of the reaction product. The past measurement results may include past measurement results obtained by the analytical device 300 of FIG. 1, or past measurement results obtained by other analytical devices and published in literature. The database may also include a design space that indicates the relationship between an evaluation value indicating the quality of the reaction product and a combination of the residence time of the first liquid raw material, the residence time of the second liquid raw material, the reaction temperature, and the reaction pressure.

[0028] The reference value acquiring unit 10 repeatedly acquires a reference value at a predetermined time interval from the chromatogram created by the processing unit 350. Here, the user can specify conditions for identifying a desired peak in the chromatogram to the reference value acquiring unit 10. The reference value may be the magnitude of the specified peak. The magnitude of the peak may be the area of ​​the peak or the height of the peak. The same applies to the following description.

[0029] The reference value may be the ratio of the magnitude of the designated peak to the magnitude of another peak. The other peak may be a peak adjacent to the designated peak. Alternatively, the other peak may also be designated by the user. The reference value may also be the average molecular weight calculated by the processing unit 350. The average molecular weight includes any or all of the number average molecular weight, weight average molecular weight, and Z average molecular weight.

[0030] The tolerance setting unit 20 sets upper and lower limit values ​​for the reference value acquired by the reference value acquiring unit 10. The user can specify in the tolerance setting unit 20 the upper and lower limit values ​​for the reference value that should be set so that the reaction product satisfies a predetermined quality.

[0031] The result acquiring unit 30 acquires past measurement results for the specified reaction product from the database storage device 110. A user can specify a desired reaction product in the result acquiring unit 30. If the control device 100 is connected to the Internet or the like, the result acquiring unit 30 may acquire past measurement results for the specified reaction product from an external server or the like.

[0032] The result acquiring unit 30 may present to the user the peak to be specified in the chromatogram based on the analysis conditions or the type of reaction product in the acquired past measurement results. In this case, the user can easily specify the desired peak in the chromatogram in the reference value acquiring unit 10. Alternatively, the result acquiring unit 30 may present to the user the upper and lower limit values ​​to be specified for the reference value based on the acquired past measurement results. In this case, the user can easily specify the appropriate upper and lower limit values ​​for the reference value in the tolerance range setting unit 20.

[0033] The search unit 40 searches for a design space related to a specified reaction product on the database storage device 110. A user can specify a desired reaction product in the search unit 40. If the control device 100 is connected to the Internet or the like, the search unit 40 may search for a design space related to the specified reaction product on an external server or the like.

[0034] Determination unit 50 acquires the flow rate of the first liquid raw material, the flow rate of the second liquid raw material, the reaction temperature, and the reaction pressure from flow rate sensor 211, flow rate sensor 221, temperature sensor 233, and pressure sensor 234. Determination unit 50 also calculates the residence times of the first and second liquid raw materials in reactor 230 based on the flow rates of the first and second liquid raw materials.

[0035] Furthermore, the determination unit 50 determines at least one control object to be changed by the reaction control unit 60 from among the residence time of the first liquid raw material, the residence time of the second liquid raw material, the reaction temperature, and the reaction pressure in the reactor 230. Here, the control object may be determined based on at least one of the measurement results acquired by the result acquisition unit 30 and the design space searched by the search unit 40. Alternatively, the control object may be determined based on an algorithm set by the user.

[0036] Reaction control unit 60 dynamically changes the control target determined by determination unit 50 so that the reference value acquired by reference value acquisition unit 10 falls between the upper and lower limit values ​​set by tolerance range setting unit 20. Reaction control unit 60 can change the residence time of the first liquid raw material, the residence time of the second liquid raw material, the reaction temperature, and the reaction pressure by controlling liquid delivery unit 210, liquid delivery unit 220, temperature adjustment device 231, and pressure adjustment valve 232, respectively.

[0037] [Extraction of measurement values ​​corresponding to specific components] Figure 3 shows a chromatogram obtained by chromatography of a typical mixture performed at a first flow rate (flow rate per unit time of mobile phase). In Figure 3, the horizontal axis represents retention time (minutes) in the separation column 330. The vertical axis represents absorbance at a given wavelength. That is, in the example of Figure 3, an absorptiometer is used as the measuring instrument 340.

[0038] In Figure 3, line L10 has many peaks, including peaks P11 and P12. Each of these peaks is thought to correspond to one of the components contained in the mixture. As shown in Figure 3, the chromatogram can adequately separate the components contained in the mixture when an appropriate flow rate is used.

[0039] FIG. 4 shows a chromatogram obtained by chromatography of the mixture of FIG. 3 performed at a second flow rate. The second flow rate is greater than the first flow rate mentioned in FIG. 3 . That is, the example of FIG. 4 corresponds to a chromatogram of chromatography performed at a higher speed than the example of FIG. 3 . In the example of FIG. 4 , the components of the mixture are introduced into the measuring instrument 340 without sufficient separation in time, as compared to the example of FIG. 3 . As a result, the peaks that are separated in line L10 of FIG. 3 overlap in line L20 of FIG. 4 . More specifically, each peak in line L20 appears to represent a group of peaks among the many peaks included in line L10 of FIG. 3 .

[0040] 3 and 4 provide insight that when analyzing a mixture, shortening the chromatographic processing time shortens the measurement time, but the measurement results do not adequately separate the multiple components contained in the mixture.

[0041] Therefore, in this embodiment, when a component of interest in a mixture is identified in advance, the processing unit 350 creates a filter for extracting a measurement value of the component of interest using a chromatogram of the mixture that has been subjected to a separation process under first separation conditions. The processing unit 350 then applies the filter to the results of a measurement performed on a mixture that has not been subjected to a separation process under the first separation conditions, thereby extracting a measurement value corresponding to the amount of the component of interest from the measurement results of the mixture that has not been subjected to a separation process according to the first separation conditions. This extraction of measurement values ​​will be described in more detail with reference to FIGS. 5 to 7. Note that a measurement performed on a mixture that has not been subjected to a separation information processing device under first separation conditions refers to, for example, an analysis that has been subjected to a separation process under second separation conditions, an analysis that has been performed under non-separation conditions that do not separate each component, or an analysis that has not been subjected to a separation process.

[0042] FIG. 5 shows the chromatogram of FIG. 3 together with a waveform processed using a filter. In FIG. 5, line L10, like line L10 in FIG. 3, represents a chromatogram of a mixture at a first flow rate. Line L11 represents a waveform created by applying a filter to line L10. The filter is created to extract peaks P11 and P12 (see FIG. 3). The method for creating the filter will be described later with reference to FIGS. 8 and 9.

[0043] In line L11, peaks K11 and K12 correspond to peaks P11 and P12, respectively. Line L11 does not include any noticeable peaks other than peaks K11 and K12. In other words, by applying a filter to line L10 to extract peaks P11 and P12, a waveform can be created that has peaks K11 and K12, corresponding to peaks P11 and P12, as main peaks, as shown by line L11.

[0044] As explained with reference to FIG. 5, creating a new waveform by applying a filter to a chromatogram may be referred to herein as "processing the measurement results."

[0045] FIG. 6 shows the chromatogram of FIG. 4 together with a waveform processed using the above-described filter. In FIG. 6, line L20, like line L20 in FIG. 4, represents the measurement result when a mixture is introduced into the measuring instrument 340 without passing through the separation column 330. Line L21 represents a waveform created by applying a filter to line L20. In other words, line L21 is a waveform created by processing line L20 using a filter. While line L20 has multiple peaks in the range of elapsed times 0.16 to 0.22, line L21 has peak K21. Peak K21 is considered to be a peak extracted as a peak corresponding to peaks K11 and K12 in FIG. 5 by applying the above-described filter.

[0046] The ratio of the sum of the peak areas of peaks K11 and K12 in FIG. 5 to the area of ​​the entire chromatogram indicated by line L11 is 0.0901. On the other hand, the ratio of the peak area of ​​peak K21 in FIG. 6 to the area of ​​the chromatogram indicated by line L21 is 0.0910. The two ratios are close. From this, it can be said that peak K21 in FIG. 6 is a peak corresponding to peaks K11 and K12 in FIG. 5.

[0047] FIG. 7 shows the measurement results when the mixture mentioned in FIGS. 3 to 6 is introduced into the measuring instrument 340 without passing through the separation column 330. In FIG. 7, line L30 represents a chromatogram generated based on the measurement results from the measuring instrument 340. The horizontal axis represents the elapsed time (minutes) since the introduction of the mixture into the measuring instrument 340 began, and the vertical axis represents the absorbance at a given wavelength, as in FIG. 3. In FIG. 7, line L31 represents a waveform generated by processing line L30 using the filter. Line L31 includes peak K31. Like peak K21 in FIG. 6, peak K31 is also considered to be a peak extracted as a peak corresponding to peaks K11 and K12 in FIG. 5.

[0048] The ratio of the sum of the peak areas of peaks K11 and K12 in FIG. 5 to the area of ​​the entire chromatogram indicated by line L11 is 0.0901. On the other hand, the ratio of the peak area of ​​peak K31 in FIG. 7 to the area of ​​the chromatogram indicated by line L31 is also 0.0901. The ratios are the same. From this, it can be said that peak K31 in FIG. 7 corresponds to peaks K11 and K12 in FIG. 5.

[0049] As described above with reference to FIGS. 3 to 7, in this embodiment, a chromatogram (first chromatogram) of a mixture that has been subjected to a separation process according to first separation conditions is prepared. Furthermore, a peak corresponding to a component of interest is specified in the first chromatogram. Then, a filter for extracting a measurement value of the component of interest is created using the first chromatogram. By applying the filter to a chromatogram (second chromatogram) of a mixture that has not been subjected to a separation process according to the first separation conditions, a measurement value of the component of interest is extracted from the second chromatogram, as shown by peak K21 in FIG. 6 and peak K31 in FIG. 7.

[0050] In this embodiment, if a filter for extracting a measurement value of a component of interest is created using the measurement results of the measuring instrument 340 for a mixture that has been subjected to a separation process according to the first separation conditions, a value corresponding to the amount of the component of interest can be extracted from the measurement results of the measuring instrument 340 for a mixture that has not been subjected to a separation process according to the first separation conditions. This eliminates the need to perform a separation process according to the first separation conditions, which takes a long time, in order to obtain a value corresponding to the amount of the component of interest in a product manufacturing process. Furthermore, both the creation of the filter and the acquisition of the value corresponding to the amount of the component of interest are based on the measurement results of a common measuring instrument (measuring instrument 340). This ensures that the value obtained without performing a separation process according to the first separation conditions corresponds to the value obtained by performing a separation process according to the first separation conditions. This facilitates the operation of monitoring the product manufacturing process and facilitates the examination of the validity of the monitoring.

[0051] An example of "separation processing according to the first separation conditions is not being performed" may be that chromatography is performed at a higher speed than under the first separation conditions, or that chromatography itself is not being performed.

[0052] According to this embodiment, the component of interest can be quantified quickly and with high accuracy by performing chromatography at a higher speed than under the first separation conditions, or without performing chromatography.

[0053] As an alternative method for rapidly quantifying a target component without performing chromatography, it is possible to use the output values ​​of a measuring device with a fast response speed, such as an infrared spectrophotometer, turbidity meter, thermometer, or pH meter (for example, a soft sensor such as that disclosed in "Development of an adaptive soft sensor method that takes into account the predictive reliability of a model" (https: / / www.jstage.jst.go.jp / article / jccj / 11 / 1 / 11_24 / _pdf)).

[0054] However, in the case of soft sensors, it is generally difficult to find a relationship between the output of the measuring device and the estimated value, and there is also a known phenomenon called "model degradation," in which the model becomes incompatible due to changes in the environment.

[0055] Furthermore, with software sensors, variables obtained by methods that are difficult to measure are estimated using measurement results from methods that are easy to measure, but advanced know-how is required to establish a relationship between variables obtained by the former method and measurement results from the latter method. Furthermore, with software sensors, advanced know-how is required to determine which method to use as the "latter method." To begin with, with software sensors, the relationship between variables obtained by the former method and measurement results from the latter method is a black box, and advanced know-how is required to examine the validity of that relationship.

[0056] On the other hand, the method of this embodiment uses information extracted from the output of the same detector in the time direction (chromatogram) and information extracted in the wavelength or mass direction (spectrum), making it less likely to suffer from the inconveniences that occur with soft sensors.

[0057] Furthermore, with regard to pharmaceutical manufacturing, as described in the "Concepts for Introducing Continuous Manufacturing of Pharmaceuticals (Tentative Draft)" (https: / / www.pmda.go.jp / files / 000223711.pdf), a method known as "Continuous Manufacturing" is being considered, in which raw materials or mixtures thereof are continuously supplied to the manufacturing process while the manufacturing process is in operation, thereby producing the product continuously.

[0058] This literature points out that in continuous manufacturing, raw materials or their mixtures are continuously supplied to the manufacturing process and the product is continuously extracted. Therefore, without proper manufacturing control, fluctuations that may occur during the process may result in the temporary production of a product that does not meet the desired quality. To ensure that a product of the desired quality is consistently produced throughout the entire operating time of the process, it is necessary not only to control each unit operation (e.g., blending, granulation, tableting, etc.) that constitutes the manufacturing process, as in batch manufacturing, but also to understand the dynamic characteristics within unit operations (e.g., within the granulation process) and between unit operations (e.g., between the blending and granulation processes). State control in continuous manufacturing is also discussed as a "state of control" in "Latest Information on Continuous Manufacturing in Japan" (https: / / www.pmda.go.jp / files / 000239490.pdf).

[0059] Furthermore, "The Evolution of Pharmaceutical Manufacturing and Quality Assurance through Quality by Design" (https: / / www.jstage.jst.go.jp / article / faruawpsj / 53 / 5 / 53_411 / _pdf / -char / ja) discloses the "Quality by Design" method as a method for assuring the quality of manufactured pharmaceuticals. In the "Quality by Design" method, each manufacturing process is managed by monitoring using chemical analysis to ensure the quality of the manufactured pharmaceuticals.

[0060] In the monitoring described in the above document, in order to analyze the sample to be monitored more precisely, it is preferable to separate the components of the sample using chromatography before introducing the sample into an analytical device. However, chromatographic separation generally requires a long time. On the other hand, for process monitoring, the measurement results of the sample need to be obtained in a short time.

[0061] In this regard, the method of the present embodiment can perform chromatography at a higher speed than under the first separation conditions, or can perform quantitative determination of the target component at high speed and with high accuracy without performing chromatography.

[0062] Create a filter In one implementation example, a filter for extracting the measurement value of the component of interest is created to have the function of canceling out the measurement values ​​of components other than the component of interest. As an example of creating a filter, an embodiment using a vector representation of the measurement results by the measuring instrument 340 will be described below.

[0063] In this example, a spectrum is assumed as the measurement result of the measuring instrument 340. The spectrum may be in any form, such as an absorption spectrum or a mass spectrum. In the following description, an absorption spectrum is used as an example of a spectrum.

[0064] First, a waveform corresponding to the peaks other than the peak corresponding to the component of interest is created from the spectrum obtained as a measurement result. The created waveform is composed of the distribution of absorbance in a predetermined wavelength range. The created waveform is then regarded as a collection of absorbance data at each discrete wavelength within the predetermined wavelength range and described as a vector VC[a(λ1), a(λ2), a(λ3), ..., a(λn)] in n-dimensional space, where a(λm) represents the absorbance at wavelength m (m = 1 to n). A vector orthogonal to the above vector VC in n-dimensional space is then created as a filter.

[0065] In one implementation, a filter is created using the measurement results of a reference mixture. The spectrum obtained as a result of the measurement of the solution to be analyzed is then converted into a vector representation, and the dot product of the vector representation obtained by the conversion and the filter is calculated. In the resulting dot product vector, elements of the vector representation corresponding to components other than the component of interest are canceled out. Therefore, the dot product yields a measurement value corresponding to the component of interest, as shown by peak K21 in Figure 6.

[0066] [Example of creating a filter] Next, a specific example of how to create the filter will be described. First, a reference mixture is prepared. The reference mixture contains a component of interest. The reference mixture may be extracted as a product from the reactor 200, which is controlled under ideal conditions.

[0067] Next, the reference mixture is subjected to a separation process using the separation column 330 according to the first separation conditions, and then introduced into the measuring instrument 340, and a spectrum is obtained as a result of analysis using the measuring instrument 340. The first separation conditions may include a flow rate in column chromatography.

[0068] FIG. 8 is a diagram showing an example of the measurement results of a typical sample. (a) of FIG. 8 shows three-dimensional chromatogram data obtained as a result of a separation process using a separation column 330. The three-dimensional chromatogram data is a collection of absorption spectra at each of a plurality of measurement times. A chromatogram such as that shown in (b) of FIG. 8 is created by extracting absorbance data at a specific wavelength (e.g., λ0) from the three-dimensional chromatogram data of (a) of FIG. 8. The chromatogram of (b) of FIG. 8 shows the relationship between the measurement time (i.e., retention time) and absorbance at the wavelength λ0. The three-dimensional chromatogram data of (a) of FIG. 8 and the wavelength chromatogram of (b) of FIG. 8 share the same axes representing time and absorbance. If absorbance data at another wavelength (for example, λ1) is extracted from the three-dimensional chromatogram data of FIG. 8(a), a wavelength chromatogram different from that shown in FIG. 8(b) can be created.

[0069] When three-dimensional chromatogram data is obtained for a reference mixture, a chromatogram created by extracting absorbance data at a specific wavelength from the three-dimensional chromatogram data constitutes an example of a "reference spectrum" in this embodiment.

[0070] Fig. 9 is a diagram showing an example of a reference spectrum. The chromatogram in Fig. 9 includes six peaks 91 to 96. A selection of a peak corresponding to a component of interest from among these peaks is accepted. In response to this selection, a waveform is created from the chromatogram in Fig. 9 with the selected peak removed.

[0071] An example of removing a selected peak is to identify the peak position (e.g., the position of the peak top) and peak width of the selected peak, and then remove data in the measurement time region corresponding to the identified peak position and peak width. To identify the peak width, for example, the tangent method, half-width method, area height method, or EMG (Exponential Modified Gaussian) method, as described in "Formula for Calculating the Number of Theoretical Plates" (https: / / www.an.shimadzu.co.jp / service-support / technical-support / analysis-basics / hplc / faq / data / lctalk-34tec / index.html), may be used.

[0072] A vector representation of the waveform that has been "removed from selected peaks" as described above is then prepared, and a vector orthogonal to the prepared vector representation is specified as the filter.

[0073] The filter may be identified by other methods. That is, the reference spectrum may be modified so that the peak area of ​​the peak to be deleted becomes zero, and a filter vector may be identified as the "filter" by using optimization to increase the area of ​​each peak in the modified spectrum (a spectrum including peaks other than the peak to be deleted). In this way, a filter that is robust to noise may be identified as the "filter."

[0074] A more specific example of the above-mentioned "filter" specification will be described. Let us assume that a multidimensional vector to be processed, which represents the spectrum to be processed at a certain measurement point in time as a vector, is represented by "vector I," a multidimensional vector representing the spectrum of the target component (the component corresponding to the above-mentioned "selected peak," i.e., the component of interest) as a vector, is represented by vector A, and a multidimensional vector representing the spectrum of impurities (components other than the component corresponding to the above-mentioned "selected peak") as a vector, is represented by vector B. Then, vector I can be expressed by vector calculation using the following equation (1).

[0075] I=A+B …(1) Consider vector B by decomposing it into vector Ba, which is dependent on vector A, and vector Bo, which is perpendicular to vector A. Also consider multidimensional vector F, which is perpendicular to vector A. Since the dot product of mutually perpendicular vectors is 0, the dot product of vector F and vector Ba is also 0. Therefore, the dot product of the multidimensional vector I to be processed and vector F is equal to the dot product of vector Bo and vector F. In other words, the following equation (2) holds true.

[0076] I·F=Bo·F …(2) Since the length of vector Bo is proportional to the length of vector B, Bo·F on the right side of the above equation (2) is proportional to the length of vector B. Therefore, the vector dot product I·F on the left side of equation (2) is proportional to the length of vector B, which represents the spectrum of the impurity. Therefore, the vector dot product I·F can be used as an index value u that represents the amount of impurity. Therefore, in this embodiment, the processing unit 350 calculates vector F that is orthogonal to vector A (which represents the spectrum of the target component) and specifies this as a filter for impurity extraction.

[0077] In this example, vector I represents the spectrum to be processed, which is obtained from (or derived from) the three-dimensional chromatogram data. Then, processing unit 350 calculates the dot product of vector I and vector F, which is a filter, and determines whether or not an impurity is present based on the calculation result.

[0078] In a typical embodiment, the processing unit 350 calculates the dot product of a vector I representing each spectrum to be processed obtained at each measurement time point over time and a vector F representing a filter. The processing unit 350 then observes changes in the value of the dot product over time. The processing unit 350 can be configured to determine that impurities other than the target component are present in the sample corresponding to the spectrum to be processed when a waveform resembling a chromatogram peak appears in the change in the dot product value.

[0079] Furthermore, if multiple types of impurities are present in the sample corresponding to the spectrum to be processed, signals from multiple spectra will be mixed in the sub-vector (vector F), which is the impurity extraction filter at each measurement time. In such a case, calculating a simple average may not adequately represent the presence of impurities. Therefore, as yet another embodiment, the filter creation unit may be configured to calculate a clustering average of multiple vectors, which are impurity extraction filters obtained at each measurement time, and the impurity inclusion information acquisition unit may use the vector obtained by the clustering average to calculate an inner product for each vector representing the spectrum to be processed at each measurement time.

[0080] The clustering average can be calculated using the K-means method, the mean shift method, etc. In addition, a smoothing filter that takes into account time-series fluctuations, such as a moving average, a bilateral filter, a Kalman filter, or a particle filter, can also be used.

[0081] The number of components (constituents) of interest may be one or more. In one embodiment, if there is one, the number of peaks selected for the chromatogram shown in FIG. 9 is "1." If there are multiple components, multiple peaks are selected for the chromatogram shown in FIG. 9. For example, in a manufacturing process for a product, when the total amount of multiple components that are intermediate products is managed, a solution containing the multiple components is used as a reference mixture, and multiple peaks corresponding to each of the multiple components are selected for the reference spectrum. In this case, the multiple components of interest constitute an example of "multiple types of constituents" in the present disclosure.

[0082] [Processing flow] 10 is a flowchart of a process performed by the analytical device 300 to provide information for monitoring the manufacturing process in the reaction device 200. In one implementation example, the process of FIG. 10 is realized by the CPU of the processing unit 350 executing a given program (for example, an analytical program).

[0083] Referring to FIG. 10, in step S10, processing unit 350 determines whether or not an instruction to carry out preparation for analysis has been input.

[0084] An instruction to carry out preparations for analysis is input to the processing unit 350, for example, by the user operating the input device 352. More specifically, the user prepares a reference mixture related to the manufacturing process in the reaction device 200, sets the reference mixture to be supplied to the separation column 330 via the sampling needle 322, and then inputs an instruction to carry out the above preparations to the input device 352. The reference mixture contains components that are to be monitored in the manufacturing process.

[0085] If processing unit 350 determines that a preparation instruction has been input (YES in step S10), it proceeds to step S20, and if not (NO in step S10), it proceeds to step S30.

[0086] In step S20, the processing unit 350 performs preparation. Fig. 11 is a flowchart of the subroutine of step S20. The contents of step S20 will be described with reference to Fig. 11.

[0087] In step S202, the processing unit 350 acquires the measurement result of the reference mixture. An example of the measurement result is three-dimensional chromatogram data as shown in (a) of Fig. 8. The measurement result may also be a mass spectrum.

[0088] More specifically, the reference mixture is subjected to a separation process (liquid chromatography using a separation column 330) and then introduced into a measuring instrument 340. Then, based on the output of the measuring instrument 340, a measurement result of the reference mixture is obtained.

[0089] In step S204, the processing unit 350 displays the measurement results acquired in step S202 on the display device 351.

[0090] If the measurement result is three-dimensional chromatogram data, the measurement result displayed in step S202 may be the three-dimensional chromatogram data itself, or an absorption spectrum at a given wavelength (created from the three-dimensional chromatogram data). In the latter case, the user may use the input device 352 to specify the wavelength of the absorption spectrum to be displayed. The processing unit 350 extracts the absorbance at the specified wavelength from the three-dimensional chromatogram data, and displays the absorption spectrum at the specified wavelength on the display device 351.

[0091] In step S206, the processing unit 350 acquires a designation of a peak corresponding to a component of interest in the measurement results displayed in step S204. In one implementation example, the user designates a peak using the input device 352 for the measurement results displayed in step S204.

[0092] In step S208, processing unit 350 creates a filter. The filter is for canceling peaks other than the peak designated in step S206 (or for increasing the peak area of ​​the designated peak), and is created in the manner described with reference to FIGS. 3 to 9, for example.

[0093] In step S210, the processing unit 350 stores the filter created in step S208 in memory. After that, the processing unit 350 returns the control to FIG.

[0094] 10, in step S30, processing unit 350 determines whether or not an instruction to monitor the manufacturing process in reaction device 200 has been input. If processing unit 350 determines that an instruction to monitor has been input (YES in step S30), it proceeds to step S40, and if not (NO in step S30), it returns control to step S10.

[0095] 12 is a flowchart of the subroutine of step S40. The contents of step S40 will be described with reference to FIG.

[0096] In step S402, the processing unit 350 performs measurement of the product of the reaction apparatus 200. In this measurement, the product is subjected to a separation process (liquid chromatography using the separation column 330) and then introduced into the measuring instrument 340. The flow rate of the separation process in step S402 may be different from the flow rate of the separation process for filter creation in step S202. More specifically, the flow rate in step S402 may be higher than the flow rate in step S202 (for example, about 11 times the flow rate in step S202). This may shorten the processing time of the separation process for monitoring compared to the processing time of the separation process for filter creation. Furthermore, in the measurement in step S402, the product may be introduced into the measuring instrument 340 without being subjected to a separation process, i.e., without passing through the separation column 330 (so that the sampling needle 322 directly introduces the product into the measuring instrument 340). The measuring instrument 340 then performs measurement of the product and outputs the measurement results.

[0097] In one implementation example, the measurement in step S402 creates an absorption spectrum for the wavelength that is the target of the absorption spectrum on which the filter is created in step S208 (the absorption spectrum for which the target peak is specified in step S206). The absorption spectrum created in this way is an example of a "measured spectrum."

[0098] In step S404, processing unit 350 processes the measurement results of the object acquired in step S402 using a filter. More specifically, processing unit 350 creates a vector expression representing the measurement results of the object, calculates the dot product of the vector expression and the filter created in step S208, and creates an index value. That is, in step S404, processing unit 350 processes the measurement results of the object acquired in step S402 to create the above-mentioned index value.

[0099] The value of the peak in the index value described above corresponds to the amount of the component in the target object to which the peak designated in step S206 corresponds, as shown as peak K21 in Fig. 6. That is, the value of the peak in the index value described above (for example, the absorbance value) is an example of an output value corresponding to the amount of a specific component.

[0100] In step S406, the processing unit 350 displays the processing result in step S404, that is, the created index value, on the display device 351. Thereafter, the processing unit 350 returns the control to FIG.

[0101] In the present embodiment described above, the measurement results for the product (measurement sample) in the reaction apparatus 200 are analyzed. More specifically, as described with reference to FIG. 11 , a filter is created to extract output values ​​corresponding to the amounts of one or more specific components contained in the reference mixture using a reference spectrum derived from the measurement results by the measuring instrument 340 of a reference mixture corresponding to the measurement sample. The reference spectrum is derived for a reference mixture that has been processed according to first separation conditions using the separation column 330 (separation unit). Then, as described with reference to FIG. 12 , an actual measurement spectrum is derived as the measurement result by the measuring instrument of a measurement sample that has not been subjected to separation processing according to the first separation conditions. Then, a filter is applied to the actual measurement spectrum to derive the measurement results that have been processed as described above. Peaks in the processed measurement results are extracted as output values ​​corresponding to the amounts of the one or more specific components contained in the measurement sample.

[0102] In this embodiment, the analytical device 300 displays the processing results in step S406, thereby providing information necessary for monitoring the production of a product in the reaction device 200. The production of a product in the reaction device 200 is not limited to a chemical reaction between a first raw material (first precursor) and a second raw material (second precursor). The production of a product may be the application of a catalyst to one or more precursors of the product. Furthermore, the one or more precursors may be radical molecules.

[0103] In this embodiment, monitoring may be performed through a single separation process or multiple separation processes. For example, a first filter may be created based on measurement results obtained through a separation process using a first mobile phase on a reference mixture, and a second filter may be created based on measurement results obtained through a separation process using a second mobile phase on the reference mixture. The flow rates of the separation processes when the first and second filters are created are set to a first flow rate (first separation conditions). Then, in monitoring, the product is sent to measuring instrument 340 through a separation process using the first mobile phase, and measurement results are obtained. The first filter is applied to the measurement results, thereby creating a first processed result and providing it to the user. In monitoring, the product is further sent to measuring instrument 340 through a separation process using a second mobile phase, and measurement results are obtained. The second filter is applied to the measurement results, thereby creating a first processed result and providing it to the user. The flow rate of the separation process during monitoring is set to a second flow rate (second separation conditions). The first and second mobile phases differ from each other, for example, in pH and / or temperature.

[0104] When the concentration of the target component in the target object is high, linearity may not be sufficiently ensured in the measurement results of the absorptiometer or mass spectrometer, and artifact noise may occur. To avoid the occurrence of artifact noise, a stray light correction algorithm may be applied to the measurement results, or a restriction may be applied to the range of the measurement results of the measuring instrument 340 (for example, the wavelength region of the peak when the measuring instrument 340 is absorptiometer, or the m / z range when the measuring instrument 340 is a mass spectrometer) used to create and apply a filter.

[0105] It is also possible to set a retention time range that is excluded from the analysis target in the measuring instrument 340. For example, the injection shock portion at the start of flow from the separation column 330 to the measuring instrument 340 may be excluded from the analysis target.

[0106] Furthermore, peaks that are significantly separated in the retention time direction from the target peak in the chromatogram may also be excluded from the analysis.

[0107] Furthermore, very large peaks in the chromatogram (peaks whose detected values ​​exceed a given threshold) may be excluded from the analysis.

[0108] In this embodiment, an example in which the sample is in a liquid phase has been described. However, the present invention is not limited to this, and the sample may be in a gas phase. In this case, gas chromatography is performed instead of liquid chromatography. Furthermore, supercritical chromatography may be performed on a liquid phase sample.

[0109] In this embodiment, an example has been described in which the second separation condition, which is faster than the first separation condition, is realized by increasing the flow rate of the mobile phase. However, the present invention is not limited to this, and speedup may be achieved by changing to a shorter column, increasing the column temperature, or changing the solvent of the mobile phase (e.g., changing methanol to acetonitrile) instead of or in addition to increasing the flow rate of the mobile phase.

[0110] [Variations] In the embodiment described above, a vector orthogonal to the prepared vector representation is determined, and the vector is used to obtain a measurement value corresponding to the component of interest. The process for obtaining a measurement value corresponding to the component of interest can also be described as follows. In the following description, it is assumed that the sample contains n components (non-specific components) in addition to the component of interest (specific component).

[0111] A chromatogram is created by extracting absorbance data at specific wavelengths from the analysis results (three-dimensional chromatogram data). In the chromatogram, n spectra (i.e., n spectra to be removed) are identified for each of the n peaks other than the peak of the component of interest. Each of the n peaks corresponds to one of the above n components. An observation vector V is then generated from the chromatogram.

[0112] Then, for the above observation vector V, among the n spectra to be removed (spectra to be removed SP1 to SPn: n is an integer equal to or greater than 1), the first spectrum SP1 to be removed is first subjected to calculation using the following equation (3) using a vector D1 converted from spectrum SP1.

[0113] R1=V-(V·D1)D1 [· is the dot product symbol] …(3) In the above formula (3), the vector D1 component is removed from the vector V to obtain the vector R1, which is orthogonalized to the vector D1.

[0114] Next, for the second removal target spectrum SP2, the following equation (4) is executed using vector D2 converted from spectrum SP2 and vector R1 obtained for the previous removal target. Note that before executing equation (4), vector D2 is processed so that it contains only components orthogonal to vector D1. The process of converting to contain only orthogonal components is, for example, compression using SVD (singular value decomposition).

[0115] R2 = R1 - (R1 D2) D2 … (4) In the above formula (4), the vector R2 is obtained by removing the vector D2 component from the vector R1 and thereby orthogonalizing the vector R2 with respect to the vector D2.

[0116] Here, as described above, vector R1 is a vector obtained from vector V and is orthogonalized to vector D1. From this, it can be said that vector R2 is a vector obtained from vector V and is orthogonalized to vectors D1 and D2.

[0117] Similarly, for n=3 and onward, vector Rn is sequentially obtained using vector Dn converted from spectrum SPn and vector Rn-1. Vector Rn is a vector obtained from vector V, and can be said to be a vector orthogonalized to vectors D1 to Dn.

[0118] As described above, in this modification, the vector Rn is calculated from the vector V, which is the observation vector, as described above, and the intensity sum (integrated value) of the vector Rn is arranged in the time direction to obtain the spectrum of the component of interest. In this modification, the vectors D1 to Dn function as a filter for extracting the specific component (component of interest).

[0119] Now, consider calculating the dot product of an appropriate filter vector F and observed data V. For example, if all elements of vector F are 1, the dot product will be an integrated value in the spectrum direction.

[0120] Let us consider a case where the vector F happens to be orthogonal to all of the above-mentioned vectors D1 to Dn.

[0121] When vector V is separated into vector Rn that is orthogonal to vectors D1 to Dn and dependent components, the inner product of vector V and vector F can be found according to the following equation (5).

[0122]

number

[0123] That is, the dot product of vector V and vector F is equivalent to the dot product of vector F and vector Rn, which is orthogonal to vectors D1 to Dn.

[0124] The SN ratio of Rn·F is maximized when Rn and F are similar in shape, since the norm of F is restricted to 1 if the noise level at each wavelength is assumed to be the same (the same logic as a matched filter). Therefore, from the perspective of SN, the ideal value of F is the true spectral value of the remaining peaks orthogonalized with D1 to Dn.

[0125] [Aspect] It will be appreciated by those skilled in the art that the exemplary embodiments described above are examples of the following aspects.

[0126] (Item 1) A quantitative method according to one embodiment is a method for quantifying a specific component contained in a measurement sample, and may include the steps of: analyzing the measurement sample using chromatography to obtain a measured spectrum at each of a plurality of time points; applying a filter to the measured spectrum at each of the plurality of time points to extract the specific component, thereby deriving an index value at each of the plurality of time points; arranging one or more index values ​​at each of the plurality of time points in the time direction to obtain a chromatogram; and quantifying the specific component from a peak in the chromatogram.

[0127] The quantitative determination method described in item 1 provides a technique for rapidly and accurately determining the amount of a specific component in a mixture.

[0128] (Item 2) The quantitative method according to item 1 may further comprise a step of obtaining a reference spectrum corresponding to the specific component by analyzing a reference substance by chromatography under first separation conditions.

[0129] According to the quantitative method described in paragraph 2, a spectrum suitable as a reference spectrum can be obtained.

[0130] (Item 3) In the quantitative method described in item 2, the measurement sample may be analyzed by chromatography under second separation conditions in which analysis is performed faster than the first separation conditions, or under non-separation conditions in which separation of individual components is not performed.

[0131] According to the quantitative method described in item 3, in monitoring, separation processing can be performed at high speed or can be omitted, thereby shortening the time required for monitoring.

[0132] (Item 4) In the quantitative method according to item 3, the second separation conditions may include a flow rate of a mobile phase in the chromatographic separation that is greater than that of the first separation conditions.

[0133] According to the quantitative method described in item 4, the time required for monitoring can be reliably shortened. (Item 5) In the quantitative method according to any one of items 2 to 4, the filter may be a vector orthogonal to the vector representation of the reference spectrum.

[0134] According to the quantification method described in paragraph 5, the filter can be appropriately produced. (Item 6) The quantitative method according to item 5 may further comprise the step of creating the filter by calculating a vector orthogonal to a vector representation of the reference spectrum.

[0135] According to the quantification method described in paragraph 6, it is not necessary for the filter to be prepared in advance.

[0136] (Item 7) In the quantitative method described in any one of Items 1 to 6, the measurement sample may contain non-specific components different from the specific components, and the filter may utilize a vector representation of one or more spectra to be removed that correspond to the non-specific components.

[0137] The quantification method described in item 7 makes it easy to prepare filters. (Item 8) In the quantitative method described in any one of Items 1 to 7, the specific component may include multiple types of constituents, and the filter may be configured to extract output values ​​corresponding to the amounts of each of the multiple types of constituents contained in the measurement sample.

[0138] According to the quantification method described in item 8, each of the multiple types of constituents contained in the measurement sample can be quantified.

[0139] (Item 9) In the quantitative method described in any one of Items 2 to 6, in the step of obtaining the chromatogram, intermittent or continuous sampling may be performed on the flow of the measurement sample, and in the step of quantifying the specific component, a filter created from the reference spectrum may be applied to each of the measurement samples that are the subject of each sampling.

[0140] According to the quantification method described in paragraph 9, an appropriate filter can be applied to each measurement sample that is the subject of each sampling.

[0141] (Item 10) In the quantitative determination method according to any one of items 1 to 9, the measurement sample may be a product obtained by successively chemically changing one or more precursors.

[0142] According to the quantitative determination method described in item 10, the products obtained by successively chemically changing one or more precursors can be used as measurement samples.

[0143] (Item 11) In the method for quantifying according to item 10, the chemical change of the one or more precursors may be a chemical reaction between a first precursor and a second precursor.

[0144] According to the quantification method described in item 11, for one or more precursors produced by a chemical reaction between a first precursor and a second precursor, the products obtained by successively chemically changing the one or more precursors can be used as measurement samples.

[0145] (Item 12) An analytical system according to one embodiment is connected to a reaction device that produces a product by chemically changing one or more precursors, and includes a measuring instrument that measures the measurement spectrum of a measurement sample extracted from the product produced in the reaction device, and an analytical device that analyzes the output of the measuring instrument, and the analytical device may perform the quantification method described in any one of items 1 to 11 on the measurement sample extracted from the product.

[0146] The analytical system described in item 12 provides a technique for rapidly and accurately quantifying a specific component in a mixture.

[0147] (Item 13) In the analysis system according to item 12, the measuring instrument may include at least one of an absorptiometer, a mass spectrometer, and a refractometer.

[0148] According to the analysis system described in paragraph 13, the measurement results are derived from at least one of an absorptiometer, a mass spectrometer, and a refractometer.

[0149] (Item 14) The program according to one aspect may be executed by a computer to cause the computer to carry out the quantification method according to any one of items 1 to 11.

[0150] The program described in item 14 provides a technology for rapidly and accurately quantifying a specific component in a mixture.

[0151] The embodiments disclosed herein should be considered to be illustrative in all respects and not restrictive. The scope of the present disclosure is defined by the claims, not by the description of the above embodiments, and is intended to include all modifications within the meaning and scope of the claims. Furthermore, it is intended that each technique in the embodiments can be implemented alone or, if necessary, in combination with other techniques in the embodiments to the extent possible. [Explanation of symbols]

[0152] 10 Reference value acquisition unit, 20 Tolerance range setting unit, 30 Result acquisition unit, 40 Search unit, 50 Determination unit, 60 Reaction control unit, 91, 96, K11, K12, K21, K31, P11, P12 Peak, 100 Control device, 110 Database storage device, 200 Reaction device, 210, 220, 313, 314 Solution delivery unit, 211, 221 Flow sensor, 230 Reactor, 231 Temperature control device, 232 Pressure adjustment valve, 233 Temperature sensor, 234 Pressure sensor, 300 Analytical device, 310 Eluent supply unit, 311, 312 Bottle, 315 Mixing unit, 320 Sample supply unit, 321 Flow vial, 322 Sampling needle, 330 Separation column, 340 Measuring instrument, 350 Processing unit, 351 Display device, 352 Input device, 500 Generation system, 501, 502, 503 Flow path.

Claims

1. A method for quantifying a specific component contained in a measurement sample, comprising: analyzing the measurement sample using chromatography to obtain a measurement spectrum at each of a plurality of time points; deriving an index value at each of the plurality of time points by applying a filter for extracting the specific component to the measured spectrum at each of the plurality of time points; obtaining a chromatogram by arranging one or more index values ​​at each of the plurality of time points in a time direction; and quantifying the specific component from the peak of the chromatogram.

2. The method of claim 1 , further comprising the step of chromatographically analyzing a reference substance under first separation conditions to obtain a reference spectrum corresponding to the specific component.

3. 3. The quantitative method according to claim 2, wherein in the step of acquiring the measurement spectrum, the measurement sample is analyzed by chromatography under second separation conditions in which analysis is performed faster than the first separation conditions, or under non-separation conditions in which separation of components is not performed.

4. The quantitative method according to claim 3 , wherein the second separation conditions include a flow rate of a mobile phase in the chromatographic separation that is greater than that of the first separation conditions.

5. The method of claim 2 , wherein the filter is a vector orthogonal to the vector representation of the reference spectrum.

6. The method of claim 5 , further comprising the step of creating the filter by computing a vector orthogonal to a vector representation of the reference spectrum.

7. the measurement sample contains a non-specific component different from the specific component, 3. The quantitative determination method according to claim 1, wherein a vector representation of one or more spectra to be removed corresponding to the non-specific components is used as the filter.

8. The specific component includes a plurality of types of constituents, 3. The quantification method according to claim 1, wherein the filter is configured to extract an output value corresponding to the amount of each of the plurality of types of constituents contained in the measurement sample.

9. In the step of obtaining the chromatogram, intermittent or continuous sampling is performed on the flow of the measurement sample; The quantitative determination method according to claim 2 , wherein in the step of quantifying the specific component, a filter created from the reference spectrum is applied to each of the measurement samples that are the subject of sampling.

10. 3. The method according to claim 1, wherein the measurement sample is a product obtained by successive chemical reactions of one or more precursors.

11. The method for quantifying the amount of a compound according to claim 10 , wherein the chemical change of the one or more precursors is a chemical reaction between a first precursor and a second precursor.

12. a measuring instrument connected to a reactor that produces a product by chemically changing one or more precursors, and that measures a measurement spectrum of a measurement sample extracted from the product produced in the reactor; an analysis device that analyzes the output of the measuring device, The analytical system is configured to perform the quantitative determination method according to claim 1 or 2 on a measurement sample extracted from the product.

13. The analytical system of claim 12 , wherein the measuring instrument includes at least one of an absorptiometer, a mass spectrometer, and a refractometer.

14. A program that, when executed by a computer, causes the computer to carry out the quantification method according to claim 1 or 2.

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