Mass spectrometry system, processing apparatus, and abnormality detection method

Abstract

To enable abnormality in a liquid chromatograph mass spectrometry system to be easily detected.SOLUTION: A mass spectrometry system comprises: a liquid chromatography having a plurality of passages, a mass spectrometry device 110, and a processing device 2 for acquiring a signal intensity from the mass spectrometry device 110 as a measurement result of a substance. Each of the plurality of passages is provided with a separation column 105, and the plurality of passages being arranged so as to be in parallel to one another. A passage to be connected to the mass spectrometry device 110 is selected from the plurality of passages by a selector valve 106. For each of the plurality of passages, a prescribed substance is circulated together with a solution. The prescribed substance is measured by the mass spectrometry device 110. For the processing device 2 and each of the plurality of passages, LC / MS1 abnormality is assessed on the basis of the signal intensity obtained as the result of measurement by the mass spectrometry device 110, and a result of the assessment is output to an output device.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to technologies of a mass spectrometry system, a processing device, and an abnormality detection method in a liquid chromatography mass spectrometer (LC / MS) having a plurality of flow paths passing through a separation column.

Background Art

[0002] A mass spectrometer is a device that separates ions by the mass-to-charge ratio (m / z) of molecular ions in a vacuum. According to the mass spectrometer, it is possible to separate and detect ions with high sensitivity and high precision. In addition, the mass spectrometer is generally used as a detector of a liquid chromatograph (LC), and an analysis method called liquid chromatography mass spectrometry (LC / MS) is often used.

[0003] Here, LC is an analysis method in which a mobile phase is pressurized by a liquid feed pump and passed through a separation column, and a sample is separated and detected by the difference in the interaction (adsorption, partitioning, etc.) between the stationary phase of the separation column and the mobile phase. In the analysis using a separation column, the higher the flow rate through the separation column, the shorter the time required for separation. On the other hand, the higher the flow rate through the separation column, the higher the required liquid feed pressure, so it is necessary to apply a high pressure with the liquid feed pump. Also, in the case of LC / MS, the ionization efficiency decreases as the flow rate increases. For this reason, the throughput is limited in LC analysis using a single flow path. Therefore, Patent Document 1 discloses a method for achieving high throughput by performing analysis in parallel with a plurality of flow paths each having a separation column.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] In an LC / MS having a plurality of flow paths as in the technique described in Patent Document 1, there are multiple factors contributing to a decrease in sensitivity, such as the mobile phase, the ion source, contamination of the flow paths, errors in solution mixing in the liquid delivery pump, etc. There is a problem that it is difficult to identify the contaminated location. Although it is necessary to identify the cause of such a decrease in sensitivity, Patent Document 1 does not disclose a method for identifying the contaminated location.

[0006] In view of such a background, the present invention has been made, and an object of the present invention is to easily detect abnormalities in a liquid chromatograph mass spectrometer.

Means for Solving the Problems

[0007] To solve the above-described problems, the present invention includes a liquid chromatography having a plurality of flow paths, a mass spectrometer, and a processing device that acquires a signal intensity, which is a measurement result of a substance, from the mass spectrometer. Each of the plurality of flow paths is provided with a separation column, the plurality of flow paths are arranged in parallel with each other, a flow path connected to the mass spectrometer is selected by a selector valve, for each of the plurality of flow paths, a predetermined substance is caused to flow together with a solution, the predetermined substance is measured by the mass spectrometer, and the processing device determines an abnormality in the liquid chromatography and the mass spectrometer based on the signal intensity obtained as a result of the measurement by the mass spectrometer for each of the plurality of flow paths, and outputs the determination result to an output unit. Other means for solving the problem will be described as appropriate in the embodiments.

Effects of the Invention

[0008] According to the present invention, it is possible to easily detect an abnormality in a liquid chromatograph mass spectrometer.

Brief Description of the Drawings

[0009]

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Figure 13B

Mode for Carrying Out the Invention

[0010] Next, a mode for carrying out the present invention (referred to as "embodiment") will be described in detail with appropriate reference to the drawings.

[0011] [First Embodiment] First, the first embodiment will be described with reference to FIGS. 1 to 6. (System Configuration) FIG. 1 is a diagram showing a configuration example of the LC / MC system Z. The LC / MC system Z includes an LC / MS (liquid chromatograph mass spectrometer) 1 and a processing device 2. The LC / MS 1 includes a plurality of solution tanks 101, a plurality of liquid feed pumps 102, an injector 103, a plurality of injection valves 104, a plurality of separation columns 105, a selector valve 106, and a mass spectrometer 110. Each configuration in the LC / MS 1 will be described later. Further, the processing device 2 acquires the result of analyzing the sample from the mass spectrometer 110, and further controls the switching of the liquid feed pump 102, the injection valve 104, and the selector valve 106. In FIG. 1, for ease of viewing the figure, the processing device 2 is connected to one liquid feed pump 102 and injection valve 104, but actually controls all the liquid feed pumps 102 and injection valves 104.

[0012] Different types of solutions are stored in each of the solution tanks 101. In the example shown in FIG. 1, two types of solutions are stored in two solution tanks 101a and 101b, respectively. In the present embodiment, the solution stored in the solution tank 101a is referred to as the first solution, and the solution stored in the solution tank 101b is referred to as the second solution. The liquid feed pump 102 pressurizes and feeds the solution stored in the solution tank 101. The liquid delivery pump 102 performs liquid delivery with sufficient pressure so as to obtain a flow rate for delivering liquid to the mass spectrometer 110 even when the separation column 105 with low conductance is arranged. Typically, a liquid delivery pump 102 that can deliver liquid in a pressure range of about 0.1 to 100 MPa is used. Note that the separation column 105 will be described later.

[0013] In the example shown in FIG. 1, the pipes 121a and 121b connected to the respective solution tanks 101a and 101b branch into three respectively. The liquid delivery pump 102 is provided in each of the pipes 122a and 122b that have branched into three. The first solution flows through the pipe 122a, and the second solution flows through the pipe 122b. Downstream of the liquid delivery pump 102, the solutions delivered from the liquid delivery pump 102 merge, and the pipes 123 (123a to 123c) through which the solutions flow are arranged. In the example shown in FIG. 1, a set of pipes 122a and 122b merge into each of the pipes 123. Therefore, in the example shown in FIG. 1, since three pipes 122a and 122b are installed respectively, three pipes 123 (123a to 123c) will be installed.

[0014] The first solution and the second solution delivered from the liquid delivery pump 102 merge and are mixed in the pipe 123. The mixed solution of the first solution and the second solution is delivered in parallel in the pipes 123a to 123c.

[0015] Note that the liquid delivery pump 102 delivers liquid from the solution tank 101 to which it is connected using a low-pressure gradient. By doing so, a mixed solution with a gradient applied at an arbitrary ratio of the mixing rate can be delivered.

[0016] The injector 103 injects the sample solution from a vial or the like into the sample loop 124. Then, by switching the injection valve 104 by the processing device 2, the sample loop 124 into which the sample is injected is connected to any one of the pipes 123a to 123c. Each of the pipes 123 (123a to 123c) is connected to one separation column 105 (105a to 105c). With such a configuration, the sample is injected into the separation column 105. The mixed solution of the first solution and the second solution into which the sample is injected is appropriately referred to as the sample solution.

[0017] Pipes 125 (125a to 125c) are connected downstream of each of the separation columns 105. That is, the sample solution that has passed through each separation column 105 flows through the pipes 125a to 125.

[0018] Then, by the selector valve 106, any one of the pipes 123a to 123c is connected to the pipe 126 that leads to the mass spectrometer 110. That is, by the selector valve 106, the connection destination of the pipe 126 connected to the mass spectrometer 110 is switched to any one of the pipes 125a to 125c provided downstream of the separation column 105.

[0019] In this embodiment, the system of the pipe 123a, the separation column 105a, and the pipe 125a is appropriately referred to as the first flow path. Similarly, the system of the pipe 123b, the separation column 105b, and the pipe 125b is appropriately referred to as the second flow path. Further, the system of the pipe 123c, the separation column 105c, and the pipe 125c is appropriately referred to as the third flow path. Also, the first flow path to the third flow path are collectively referred to as the flow path as appropriate. As shown in FIG. 1, the sample solution flows in parallel in each of the first flow path to the third flow path.

[0020] Among the pipes 125a to 125c, the flow paths not connected to the mass spectrometer 110 by the selector valve 106 are connected to a waste liquid tank not shown in the figure. Thereby, it is possible to prevent the sample solution from flowing out to the outside.

[0021] As described above, a plurality of pipes 125 (125a to 125c) passing through the respective independent separation columns 105 are connected to the mass spectrometer 110 via the selector valve 106. In the example shown in FIG. 1, an example with three flow paths is shown, but the method of this embodiment can be applied as long as the number of flow paths is two or more.

[0022] The mass spectrometer 110 has an ion source 111 and a capillary 112. The mass spectrometer 110 ionizes the sample with the ion source 111 and separates the sample for each mass-to-charge ratio (m / z) using an electric field or a magnetic field, thereby measuring the components of the sample. The measurement result is output in the form of signal intensity and input to the processing device 2. As the ion source 111 for ionizing the sample, for example, an electrospray ionization ion source, an atmospheric pressure chemical ionization ion source, an atmospheric pressure photoionization ion source, etc. can be used. In any ion source 111, the solution containing the sample is sprayed into the ion source 111 by the capillary 112 provided in the thin mass spectrometer 110.

[0023] (Processing device 2) FIG. 2 is a functional block diagram showing the configuration of the processing device 2 in the first embodiment. Refer to FIG. 1 as appropriate. The processing device 2 is composed of a PC (Personal Computer) or the like and has a CPU (Central Processing Unit) 201. Further, the processing device 2 has a storage device 202 composed of an HD (Hard Disk), an SSD (Solid State Drive), or the like. Furthermore, the processing device 2 has a communication device 203 for transmitting a control instruction for controlling the LC / MS1 to the LC / MS1 and receiving a signal from the mass spectrometer 110. And the processing device 2 has an input device 204 such as a keyboard and an output device 205 such as a display. Also, the processing device 2 includes a memory 210 composed of a RAM (Random Access Memory) or the like. A program stored in the storage device 202 is loaded into the memory 210. Then, by executing the loaded program by the CPU 201, an acquisition unit 211, a determination processing unit 212, and a control unit 213 are embodied.

[0024] The acquisition unit 211 acquires a measurement result (signal intensity) from the mass spectrometer 110. The determination processing unit 212 makes a determination for specifying a contaminated location based on the measurement result (signal intensity) acquired from the mass spectrometer 110. The control unit 213 controls the liquid feed pump 102, the injection valve 104, and the selector valve 106. Also, the storage device 202 stores a threshold value TH1 used when the determination processing unit 212 specifies a contaminated location.

[0025] (Flowchart) A method for specifying a contaminated location according to this embodiment will be described. FIG. 3 shows the procedure of the threshold setting process in the first embodiment. Refer to FIGS. 1 and 2 as appropriate. First, in a non-contaminated state, a standard sample of a known concentration is flowed from the injector 103 into each flow path (the first flow path to the third flow path) and measured by the mass spectrometer 110 (S101). The non-contaminated state means that the solution tank 101, the pipes 121a, 121b, 122a, 122b, 123, 125, 126, the sample loop 124, the separation column 105, the mass spectrometer 110, etc. are not contaminated. The measurement results are acquired by the acquisition unit 211 of the processing device 2 as the signal intensity of the mass spectrometer 110 and stored in the storage device 202 of the processing device 2. Then, a threshold value TH1 is set based on, for example, the average value of the signal intensities of the standard samples acquired from each of the first to third flow paths (S102). The threshold value TH1 is determined and set by the user. However, the processing device 2 may also calculate and set the threshold value TH1. The set threshold value TH1 is stored in the storage device 202. Note that one type of standard sample may be used in the first embodiment.

[0026] (Contamination location determination process) FIG. 4 is a flowchart showing the procedure of the contamination location identification process performed in the first embodiment. Refer to FIGS. 1 and 2 as appropriate. The details of each process in FIG. 4 will be described later. The process shown in FIG. 4 is performed after a predetermined period (for example, one month) has elapsed from the process shown in FIG. 3. Further, the process shown in FIG. 4 is performed at regular intervals (for example, every month). First, a standard sample having the same conditions as those used in the process of FIG. 3 is flowed into each flow path (the first flow path to the third flow path). The same conditions mean having the same type, the same concentration, and the same measurement conditions. Then, the mass spectrometer 110 measures the standard sample for each of the first to third flow paths (S201). The measurement is performed such that each of the first to third flow paths is connected to the mass spectrometer 110 one by one by the selector valve 106 and measured each time.

[0027] Then, the determination processing unit 212 of the processing device 2 compares the measurement result (signal intensity of the mass spectrometer 110) obtained by the processing in step S201 with the set threshold value TH1. The signal intensity depends on measurement conditions such as the temperature of the separation column 105, the conditions of the mobile phase, the conditions of the gradient, and the electrode voltage setting of the mass spectrometer 110. Also, the mobile phase corresponds to the pipes 122a, 122b to 126 in FIG. 1. And the conditions of the mobile phase are the temperature conditions and the like in the mobile phase.

[0028] Then, the determination processing unit 212 determines whether the signal intensity is greater than the threshold value TH1 in all the flow paths (all of the first to third flow paths) (S202). If the signal intensity is greater than the threshold value TH1 in all the flow paths (S202 → Yes), the determination processing unit 212 determines that there is no contamination and outputs the determination result to the output device 205 (S203).

[0029] Also, if there is a flow path in which the signal intensity is lower than the threshold value TH1 (S202 → No), the determination processing unit 212 determines whether the signal intensity is less than or equal to the threshold value TH1 in all the flow paths (S211). If the signal intensity is not less than or equal to the threshold value TH1 in all the flow paths (S211 → No), the determination processing unit 212 determines that the flow path (specific flow path) is contaminated and outputs the determination result to the output device 205 (S212). That the flow path is contaminated means that any of the pipes 122a, 122b, 123, 125, the sample loop 124, the liquid delivery pump 102, and the separation column 105 constituting the flow path is contaminated.

[0030] If the signal intensity is less than or equal to the threshold value TH1 in all the flow paths (S211 → Yes), the determination processing unit 212 determines that any of the common part, the solution, and the ion source 111 is contaminated and outputs the determination result to the output device 205 (S213). The common part is the selector valve 106, the pipe 126, the injector 103, and the capillary 112 of the mass spectrometer 110.

[0031] (Details of the determination process) Next, with reference to FIGS. 5A and 5B, the details of the process of FIG. 4 will be described. FIGS. 5A and 5B are diagrams showing the signal intensity of the mass spectrometer 110 of the standard sample measured for each flow path. In FIGS. 5A and 5B, the horizontal axis indicates the time (retention time) required from when the sample is injected into the LC column until it elutes. And the vertical axis is the signal intensity of the ions of the standard sample separated and detected by the mass spectrometer 110 (that is, the measurement result of the sample (standard sample in this embodiment)). Incidentally, the retention time of LC and the m / z of the ions generated by the ion source 111 are values specific to the substances constituting the sample (standard sample in this embodiment).

[0032] In FIG. 5A, the signal intensity 301 in the graph 300A shows the result measured in the first flow path. Also, the signal intensity 302 in the graph 300B shows the result measured in the second flow path. Furthermore, the signal intensity 303 in the graph 300C shows the result measured in the third flow path. In the result shown in FIG. 5A, only for a specific flow path (graph 300B: the second flow path in the example shown in FIG. 5A), the signal intensity 302 of the standard sample is below the threshold TH1. And in the others (graphs 300A, 300C: the first flow path, the third flow path), the signal intensities 301, 303 are greater than the threshold TH1. Such measurement results indicate that the flow path (the second flow path in the example of FIG. 5A) where the signal intensity is below the threshold TH is contaminated, and the signal intensity of the standard sample has decreased due to ion suppression by the contaminants eluted from the contaminated part. As described above, that the flow path is contaminated means that any of the pipes 122a, 122b, 123, 125, the sample loop 124, the liquid feed pump 102, and the separation column 105 constituting the flow path is contaminated.

[0033] Therefore, when measurement results (signal intensity) as shown in FIG. 5A are obtained, the determination processing unit 212 determines that contamination has occurred in a specific flow path (the second flow path in the example of FIG. 5A) (step S212 in FIG. 4). That is, FIG. 5A corresponds to the result of selecting "No" in step S202 → "No" in step S211 in the process shown in FIG. 4. Thus, by making a determination based on the measurement results shown in FIG. 5A, contamination of a specific flow path can be easily detected.

[0034] Next, FIG. 5B will be described. In FIG. 5B, the signal intensity 311 in the graph 310A indicates the result measured in the first flow path. The signal intensity 312 in the graph 310B indicates the result measured in the second flow path. Further, the signal intensity 313 in the graph 310C indicates the result measured in the third flow path. In the example shown in FIG. 5B, the signal intensity of the mass spectrometer 110 has decreased to the same extent in the measurements of all flow paths and is below the threshold value TH1. That is, as shown in the graphs 310A to 310C, all of the signal intensities 311 to 313 obtained in the first to third flow paths are lower than the threshold value TH1. Such a result indicates that either the common part, the solution, or the ion source 111 is contaminated. That is, in the example shown in FIG. 5B, it shows that the signal intensity has decreased due to ion suppression by contaminants eluted from the contaminated part or charge-up of the electrodes inside the mass spectrometer 110. As described above, the common part includes the selector valve 106, the pipe 126, the injector 103, and the capillary 112 of the mass spectrometer 110. Incidentally, the result shown in FIG. 5B corresponds to step S213 in FIG. 4. That is, FIG. 5B corresponds to the result of selecting "No" in step S202 → "Yes" in step S211 in the process shown in FIG. 4.

[0035] Thus, by making a determination based on the measurement results shown in FIG. 5B, contamination of the common part, the solution, and the ion source 111 can be easily detected.

[0036] Note that even when the pipes 122a, 122b, 123, 125 that make up all the flow paths, the sample loop 124, the liquid delivery pump 102, and the separation column 105 are contaminated to the same extent at the same time, the signal intensity decreases in the measurement of all the flow paths, similar to Figure 5B. However, since contamination of the flow paths generally occurs independently one by one, the probability that the pipe 122a in all the flow paths is contaminated at the same time is low. The same applies to the pipes 122b, 123, 125, the sample loop 124, the liquid delivery pump 102, and the separation column 105. Therefore, by performing the measurement for identifying the contamination location at a sufficiently high frequency, the possibility that all the flow paths are contaminated at the same time can be kept low.

[0037] (Summary of the First Embodiment) The determination of the contamination location in the first embodiment is summarized in the table shown in Figure 6. Refer to Figures 1 and 2 as appropriate. As shown in Figure 6, when the signal intensity is lower than the threshold value TH1 in all the flow paths, the determination processing unit 212 determines that contamination has occurred in either the common part, the solution, or the ion source 111 (step S213 in Figure 4, Figure 5B). Also, when the signal intensity is lower than the threshold value TH1 only in a specific flow path, the determination processing unit 212 determines that the flow path is contaminated. Specifically, it is determined that any one of the pipes 122a, 122b, 123, 125, the sample loop 124, the liquid delivery pump 102, and the separation column 105 in the flow path with a low signal intensity is contaminated (step S212 in Figure 4, Figure 5A).

[0038] As described above, in the first embodiment, by comparing the signal intensity of each flow path with the threshold value TH1, it is possible to discriminate the contamination state of at least any one of the mobile phase and the mass spectrometer 110 (ion source 111, capillary 112).

[0039] According to the first embodiment, the contaminated location is identified based on the signal intensity acquired from the mass spectrometer 110. This enables the identification of the contaminated location without adding a special device. Also, by identifying the contaminated location based on the signal intensity acquired from the mass spectrometer 110, it becomes possible to identify the contaminated location regardless of the instrumental differences of the LC / MS1.

[0040] [Second Embodiment] Next, with reference to FIGS. 7 to 12, a second embodiment of the present invention will be described. In the second embodiment, a mixed sample of a plurality of components with different ionization efficiencies is used as the standard sample. In the second embodiment, it is assumed that a standard sample containing two types of components (referred to as the first component and the second component) is used. Note that in the second embodiment, since the configuration of the LC / MS system Z is the same as that in FIG. 1, the description thereof is omitted here.

[0041] (Processing device 2a) FIG. 7 is a functional block diagram showing a configuration example of the processing device 2a in the second embodiment. In FIG. 7, the same components as those in FIG. 2 are denoted by the same reference numerals, and the description thereof is omitted. In the processing device 2a shown in FIG. 7, the storage device 202a stores the signal intensity threshold TH11A of the first component, the signal intensity threshold TH11B of the second component, the upper limit value TH12U of the signal intensity ratio threshold TH12, and the lower limit value TH12L of the signal intensity ratio threshold TH12. The signal intensity threshold TH11A of the first component, the signal intensity threshold TH11B of the second component, the upper limit value TH12U of the signal intensity ratio threshold TH12, and the lower limit value TH12L of the signal intensity ratio threshold TH12 will be described later. Hereinafter, the signal intensity threshold TH11A of the first component and the signal intensity threshold TH11B of the second component are collectively referred to as the signal intensity threshold TH11 as appropriate. Also, the upper limit value TH12U of the signal intensity ratio threshold TH12 and the lower limit value TH12L of the signal intensity ratio threshold TH12 are collectively referred to as the signal intensity ratio threshold TH12 as appropriate.

[0042] In the second embodiment, the signal intensity of each component in the standard sample is compared with a signal intensity threshold TH11 (the signal intensity threshold TH11A for the first component and the signal intensity threshold TH11B for the second component). Further, in the second embodiment, the ratio of the signal intensities (signal intensity ratio) obtained from the mass spectrometer 110 for each component of the standard sample is calculated for each flow path. Then, the signal intensity ratio is compared with a signal intensity ratio threshold TH12. Specifically, as will be described later, the signal intensity ratio is compared with the upper limit value TH12U of the signal intensity ratio threshold TH12 and the lower limit value TH12L of the signal intensity ratio threshold TH12.

[0043] Also, as will be described later, the signal intensity threshold TH11 and the signal intensity ratio threshold TH12 are determined and set in advance by the user by measuring a standard sample with a known concentration in a state where the mass spectrometer 110 is not contaminated. The set signal intensity threshold TH11 and signal intensity ratio threshold TH12 are stored in the storage device 202a of the processing device 2a.

[0044] (Flowchart) FIG. 8 is a flowchart showing the procedure of the setting process of various thresholds in the second embodiment. First, in a non-contaminated state, a standard sample with a known concentration is flowed from the injector 103 into each flow path (the first flow path to the third flow path) and measured by the mass spectrometer 110 (S301). The non-contaminated state means a state where the solution tank 101, the pipes 121a, 121b, 122a, 122b, 123, 125, 126, the sample loop 124, the separation column 105, the mass spectrometer 110, etc. are not contaminated. At this time, a standard sample, which is a mixed sample having the first component and the second component, is flowed into the first flow path to the third flow path. Then, the flow path connected to the mass spectrometer 110 is sequentially switched by the selector valve 106, and the first component and the second component are measured by the mass spectrometer 110 for each of the first flow path to the third flow path. Since the times for the first component and the second component to pass through the separation column 105 are different, the measurements of the respective components are performed with a time difference.

[0045] Next, the user sets a signal intensity threshold TH11 based on the signal intensity for each component obtained in step S301 (measurement of the standard sample in a non-contaminated state) (S302). That is, the user sets a signal intensity threshold TH11A for the first component based on, for example, the average value of the signal intensities obtained from each of the first to third flow paths for the first component. Similarly, the user sets a signal intensity threshold TH11B for the second component based on, for example, the average value of the signal intensities obtained from each of the first to third flow paths for the second component.

[0046] Subsequently, the user sets a signal intensity ratio threshold TH12 based on the signal intensity obtained in step S301 (S303). That is, for each component, the user sets an upper limit value TH12U and a lower limit value TH12L of the signal intensity ratio threshold TH12 based on, for example, the average value of the signal intensities obtained from each of the first to third flow paths. The set signal intensity threshold TH11 and signal intensity ratio threshold TH12 are stored in the storage device 202a. Note that the signal intensity threshold TH11 and signal intensity ratio threshold TH12 may be calculated and set by the user, or may be calculated and set by the processing device 2.

[0047] (Contamination location determination process) FIG. 9 is a flowchart showing the procedure of the contamination location identification process performed in the second embodiment. Refer to FIGS. 1 and 7 as appropriate. Details of each process in FIG. 9 will be described later. The process shown in FIG. 9 is performed after a predetermined period (for example, one month) has elapsed from the process shown in FIG. 8. Further, the process shown in FIG. 9 is performed at regular intervals (for example, every month). First, the standard sample used in FIG. 8 is flowed through each flow path (first to third flow paths). As described above, in the example of FIG. 8, since the standard sample, which is a mixed sample having two components (first component and second component), is flowed through each of the first to third flow paths, the standard sample is flowed under the same conditions in this process. At this time, the conditions (concentration, measurement conditions, etc.) under which the standard sample is flowed are made the same as the measurement in step S301 of FIG. 8.

[0048] Then, the mass spectrometer 110 measures the standard sample for each component and each flow path (S401). The measurement is performed such that each flow path is connected to the mass spectrometer 110 one by one by the selector valve 106, and each time, the mass spectrometer 110 measures the standard sample for each flow path. This measurement is performed for each component (the first component and the second component in this embodiment). Since the times for the first component and the second component to pass through the separation column 105 are different as described above, the signal intensities of each component are measured with a time difference.

[0049] Subsequently, the determination processing unit 212 of the processing device 2a determines whether the condition W11 is satisfied (S402). Here, the condition W11 is whether the signal intensity ratio is outside the range of the signal intensity ratio threshold TH12 in any of the flow paths. The range of the signal intensity ratio threshold TH12 is the range between the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold TH12 (the signal intensity ratio threshold range TH12R in FIGS. 10A to 10C).

[0050] When the condition W11 is satisfied (S402→Yes), the determination processing unit 212 determines which of the conditions W21 and W22 is satisfied (S411). The conditions W21 and W22 are as follows. (Condition W21) The signal intensity is equal to or less than the signal intensity threshold TH11 in all flow paths, and the signal intensity ratio is outside the range of the signal intensity ratio threshold TH12 in all flow paths. (Condition W22) The signal intensity is equal to or less than the signal intensity threshold TH11 in a specific flow path, and the signal intensity ratio is outside the range of the signal intensity ratio threshold TH12 in the said flow path.

[0051] When the condition W21 is satisfied in step S411 (S411→W21), the determination processing unit 212 determines which of the conditions W31 and W32 is satisfied (S412). The conditions W31 and W32 are as follows. (Condition W31) The decrease width of the signal intensity in the component with low ionization efficiency is larger than that in the component with high ionization efficiency, and X / X0 in the component with low ionization efficiency is lower than that in the component with high ionization efficiency. Here, X is the signal intensity measured in step S401, and X0 is the signal intensity measured in step S301 of FIG. 8. Note that the ionization efficiency refers to the ease of ionization in the ion source 111 of the mass spectrometer 110. The higher the ionization efficiency, the easier it is to ionize in the ion source 111. The definition of the decrease width will be described later. (Condition W32) The decrease width of the signal intensity in the component with high ionization efficiency is larger than that in the component with low ionization efficiency, and X / X0 of the component with high ionization efficiency is lower than X / X0 of the component with low ionization efficiency. The definition of the decrease width will be described later.

[0052] When condition W31 is satisfied in step S412 (S412→W31), the determination processing unit 212 determines that contamination has occurred in the common part or the solution (S413), and outputs the determination result from the output device 205 (S431). Note that by increasing the frequency of performing this process as described later, the possibility of solution contamination in step S413 can be reduced. Also, the common part is the selector valve 106, the pipe 126, the injector 103, and the capillary 112 of the mass spectrometer 110, as in the first embodiment. When condition W32 is satisfied in step S412 (S412→W32), the determination processing unit 212 determines that the solution is contaminated (S414), and outputs the determination result from the output device 205 (S431).

[0053] When condition W22 is satisfied in step S411 (S411→W22), the determination processing unit 212 determines that contamination has occurred in the flow path (specific flow path) where condition W22 is satisfied (S415), and outputs the determination result to the output device 205 (S431).

[0054] When condition W11 is not satisfied in step S402 (S402→No), the determination processing unit 212 determines whether condition W41 is satisfied (S421). Condition W41 is as follows. (Condition W41) The signal intensity is lower than the signal intensity threshold TH11 for all components and all flow paths.

[0055] When condition W41 is satisfied in step S421 (S421 → Yes), the determination processing unit 212 determines that contamination or deterioration has occurred in the mass spectrometer 110 (S422), and outputs the determination result from the output device 205 (S431). When condition W41 is not satisfied in step S421 (S421 → No), the determination processing unit 212 determines that there is no abnormality (S423), and outputs the determination result from the output device 205 (S431).

[0056] (Details of the determination process) Next, with reference to FIGS. 10A to 10C and FIGS. 11A to 11B, the determination in each process of FIG. 9 will be described in detail. FIGS. 10A to 10C are diagrams showing the signal intensity of the mass spectrometer 110 of the standard samples (first component, second component) measured for each flow path. In the upper part of FIGS. 10A to 10C, the horizontal axis represents the retention time of LC. The vertical axis is the signal intensity of the ions related to the components contained in the standard sample separated and detected by the mass spectrometer 110 at m / z. Since the relationship between the retention time and the m / z of the ions is a value unique to the substance, it generally differs for each component. In addition, in each of FIGS. 10A to 10C, the signal intensity ratio in each flow path is shown in the lower part. Assuming that the signal intensity of the first component is XA and the signal intensity of the second component is XB, the signal intensity ratio is defined as XA / XB. In the following description, it is assumed that the ionization efficiency of the second component is higher than that of the first component.

[0057] First, the case where the measurement result shown in FIG. 10A is obtained will be described. In FIG. 10A, in the upper part (graphs 400A to 400C), the signal intensities of the first component and the second component in each flow path are shown. In FIG. 10A, in the graphs of 400A to 400C, graph 400A shows the measurement result in the first flow path, graph 400B shows the measurement result in the second flow path, and graph 400C shows the measurement result in the third flow path. Also, in graph 400A, signal intensity 401A is the signal intensity regarding the first component, and signal intensity 401B is the signal intensity regarding the second component. Similarly, in graph 400B, signal intensity 402A is the signal intensity regarding the first component, and signal intensity 402B is the signal intensity regarding the second component. Further, in graph 400C, signal intensity 403A is the signal intensity regarding the first component, and signal intensity 403B is the signal intensity regarding the second component. As described above, since the first component and the second component pass through the separation column 105 at different times, as shown in graphs 400A to 400C, the signal intensities 401A to 403A of the first component and the signal intensities 401B to 403B of the second component are measured with a time difference.

[0058] Also, as shown in graphs 400A to 400C of FIG. 10A, a signal intensity threshold TH11A of the first component and a signal intensity threshold TH11B of the second component are set.

[0059] Then, regarding the lower part (graph 400D) of FIG. 10A, signal intensity ratio 404A shows the signal intensity ratio in the first flow path, signal intensity ratio 404B shows the signal intensity ratio in the second flow path, and signal intensity ratio 404C shows the signal intensity ratio in the third flow path. Furthermore, as shown in graph 400D, an upper limit value TH12U and a lower limit value TH12L of the signal intensity ratio threshold TH12 are set. Further, a signal intensity ratio threshold range TH12R is set as the range of the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold TH12. Also, in graph 400D, the signal intensity ratio R indicates the signal intensity ratio in the case of no contamination. The signal intensity ratio R in the case of no contamination has been measured in advance (step S401 in FIG. 8). As described above, the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold TH12 are set based on this signal intensity ratio R. Note that what is meant by the case of no contamination is explained in step S301 of FIG. 8.

[0060] In FIG. 10A, as shown in graphs 400B and 400D, a specific flow path (in the example shown in FIG. 10A, the second flow path: hereinafter, the specific flow path will be described as the second flow path) satisfies the following conditions W22a and W22b. (Condition W22a) As shown in graph 400B, the signal intensities 402A and 402B of both the first component and the second component have decreased and are respectively below the signal intensity thresholds TH11A and TH11B. (Condition W22b) As shown in graph 400D, the signal intensity ratio 404B of the second flow path has also changed from the signal intensity ratio R in the state of no contamination and is below the lower limit value TH12L of the signal intensity ratio threshold TH12 or above the upper limit value TH12U of the signal intensity ratio threshold TH12. That is, only the signal intensity ratio 404B of the second flow path is located outside the signal intensity ratio threshold range TH12R. Note that in the present embodiment, "the signal intensity ratio changes from the signal intensity ratio R in the state of no contamination" means that originally the signal intensity ratio was in the state of the signal intensity ratio R in the state of no contamination, but the signal intensity ratio has changed and decreased due to contamination. Also, conditions W22a and W22a correspond to condition W22 in FIG. 9. That is, FIG. 10A corresponds to step S411: W22 → step S415 in FIG. 9.

[0061] The case shown in FIG. 10A indicates that the flow path (the second flow path in the example shown in FIG. 10A) satisfying conditions W22a and W22b is contaminated. That the flow path is contaminated means that any of the pipes 122a, 122b, 123, 125, the sample loop 124, the liquid feed pump 102, and the separation column 105 constituting the flow path is contaminated. That is, the case shown in FIG. 10A indicates that the signal intensity of the standard sample has decreased due to ion suppression by contaminants eluted from the contaminated portion in the second flow path. Since the ionization efficiency of the first component is lower than that of the second component, the influence of ion suppression by contaminants is large. Therefore, in the graph 400B of FIG. 10A, the signal intensity 402A of the first component has decreased more significantly than the signal intensity 402B of the second component. Further, as the signal intensity 402A of the first component decreases more significantly than the signal intensity 402B of the second component, the signal intensity ratio 404B also changes significantly. Thus, by making a determination based on the measurement results shown in FIG. 10A, contamination in a specific flow path can be easily detected.

[0062] Next, FIG. 10B will be described. In FIG. 10B, in the upper row (graphs 410A to 410C), the signal intensities of the first component and the second component in each flow path are shown. In FIG. 10B, graph 410A shows the measurement results in the first flow path, graph 410B shows the measurement results in the second flow path, and graph 410C shows the measurement results in the third flow path. Also, in graph 410A, the signal intensity 411A is the signal intensity regarding the first component, and the signal intensity 411B is the signal intensity regarding the second component. Similarly, in graph 410B, the signal intensity 412A is the signal intensity regarding the first component, and the signal intensity 412B is the signal intensity regarding the second component. Further, in graph 410C, the signal intensity 413A is the signal intensity regarding the first component, and the signal intensity 413B is the signal intensity regarding the second component.

[0063] Then, regarding the lower part of FIG. 10B (graph 410D), signal intensity ratio 414A indicates the signal intensity ratio in the first flow path, signal intensity ratio 414B indicates the signal intensity ratio in the second flow path, and signal intensity ratio 414C indicates the signal intensity ratio in the third flow path. Furthermore, as shown in graph 410D, an upper limit value TH12U and a lower limit value TH12L of the signal intensity ratio threshold TH12 are set. Furthermore, a signal intensity ratio threshold range TH12R is set as the range of the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold TH12. Also, in graph 410D of FIG. 10B, signal intensity ratio R indicates the signal intensity ratio in the case of no contamination. The signal intensity ratio R in the case of no contamination has been measured in advance (step S301 in FIG. 8). As described above, the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold range TH12R are set based on this signal intensity ratio R. Note that what is meant by the case of no contamination is explained in step S301 of FIG. 8.

[0064] Also, in FIG. 10B, the signal intensity threshold TH11A of the first component, the signal intensity threshold TH11B of the second component, the upper limit value TH12U of the signal intensity ratio threshold range TH12R, and the lower limit value TH12L are the same values as in FIG. 10A.

[0065] Then, in the example shown in FIG. 10B, the following conditions W21a and W21b are satisfied. (Condition W21a) As shown in graphs 410A to 410C, for all flow paths (the first flow path to the third flow path) and all components (the first component, the second component), the signal intensity is equal to or lower than the signal intensity threshold TH11. Specifically, all of signal intensities 411A to 413A are lower than the signal intensity threshold TH11A of the first component. Similarly, all of signal intensities 411B to 413B are lower than the signal intensity threshold TH11B of the second component. (Condition W21b) As shown in graph 410D, in all flow paths (the first to the third flow paths), the signal intensity ratios 414A to 414C are equal to or less than the lower limit value TH12L or equal to or higher than the upper limit value TH12U of the signal intensity ratio threshold range TH12R. That is, the signal intensity ratios in all flow paths are located outside the signal intensity ratio threshold range TH12R. In FIG. 10B, cases are shown where, in all flow paths, the signal intensity ratios 414A to 414C of all components are lower than the lower limit value TH12L of the signal intensity ratio threshold range TH12R. However, there may also be cases where the signal intensity ratios 414A to 414C of all components are higher than the upper limit value TH12U of the signal intensity ratio threshold range TH12R. The satisfaction of condition W21a and condition W21b corresponds to the satisfaction of condition W21 in FIG. 9 (step S411: W21).

[0066] In the case of the situation shown in FIG. 10B, it can be seen that the signal intensity has decreased due to contamination of the solution or ion suppression due to contamination of the common part. Here, the common part refers to the selector valve 106, the pipe 126, the injector 103, and the capillary 112 of the mass spectrometer 110.

[0067] As described above, in the case of the situation shown in FIG. 10B, contamination of the solution or contamination of the common part is conceivable. Therefore, when the case of FIG. 10B occurs, the case is further divided by FIGS. 11A and 11B.

[0068] FIGS. 11A and 11B are diagrams showing the relationship between the concentration of impurities and the retention time, and the relationship between the signal intensity of the mass spectrometer 110 and the LC retention time.

[0069] First, the case where the solution is contaminated will be described with reference to FIG. 11A. In FIG. 11A, the time change of the impurity concentration is shown as graph 500A in the upper part. Also, the signal intensity for each component is shown as graph 500B in the middle part. And the X / X0 for each component is shown as graph 500C in the lower part. Here, X represents the signal intensity measured in step S401 of FIG. 9, and X0 is the signal intensity (initial signal intensity value) measured in step S301 of FIG. 8.

[0070] And in graph 500B, signal intensity 501A indicates the signal intensity of the first component, and signal intensity 501B indicates the signal intensity of the second component. Also, in graph 500C, signal intensity / signal intensity initial value 502A is the signal intensity / signal intensity initial value (X / X0) of the first component, and signal intensity / signal intensity initial value 502B is the signal intensity / signal intensity initial value (X / X0) of the second component. The signal intensity initial value is the signal intensity measured in step S301 of FIG. 8. Note that in graph 500C, XA is the signal intensity of the first component measured in step S401 of FIG. 9 (the same value as signal intensity 501A). Also, XB is the signal intensity of the second component measured in step S401 of FIG. 9 (the same value as reference sign 501B). Further, in graph 500C, XA0 is the signal intensity of the first component measured in step S301 of FIG. 8 (the signal intensity initial value). And XB0 is the signal intensity of the second component measured in step S301 of FIG. 8 (the signal intensity initial value).

[0071] Here, the process shown in FIG. 11A may be performed by paying attention to any one of the first to third flow paths. In FIG. 11A, it is assumed that attention is paid to the first flow path. That is, graphs 500A to 500C shown in FIG. 11A relate to the first flow path. Also, although the shape of graph 500B in FIG. 11A is different from the shape of graph 410A in FIG. 10B, this is because the result shown in FIG. 11A satisfies the above-described conditions W21a and W21b but shows an example different from FIG. 10B. Note that times ta and tb will be described later. Also, the signal intensity threshold TH11A of the first component and the signal intensity threshold TH11B of the second component are the same as those in FIG. 10B.

[0072] In the case where the solution is contaminated, contaminants in the solution also pass through the separation column 105 together with the standard sample. In particular, when a gradient is applied to the mixing ratio of the solution, the contaminant concentration changes depending on the retention time of the separation column 105 (graph 500A). For this reason, the influence of ion suppression also changes depending on the retention time. This will be described in detail below. Incidentally, the contaminant concentration can be known from the measurement results of the mass spectrometer 110.

[0073] Suppose that contaminants are mixed in the second solution. And suppose that the second solution is gradually mixed with the first solution. In this case, as shown in graph 500A of FIG. 11A, the contaminant concentration increases with the retention time.

[0074] And as shown in graph 500B, it is assumed that the signal intensity 501A regarding the first component is measured at time ta and the signal intensity 501B regarding the second component is measured at time tb.

[0075] The influence of ion suppression by contaminants is greater for the second component measured at time tb with a higher contaminant concentration than for the first component measured at time ta with a lower contaminant concentration. Therefore, as shown in graph 500B of FIG. 11A, the signal intensity 501B of the second component has decreased more significantly than the signal intensity 501A of the first component. That is, the decrease width of the signal intensity 411B of the second component with respect to the signal intensity threshold TH11B is greater than the decrease width of the signal intensity 411A of the first component with respect to the signal intensity threshold TH11A.

[0076] Furthermore, the signal intensity 501B of the second component measured at time tb when the contaminant concentration in the solution is high decreases more significantly than the signal intensity 501A of the first component measured at time ta when the contaminant concentration is low. Here, the decrease is with respect to the initial value of the signal intensity in each component. Therefore, as shown in graph 500C of FIG. 11A, XA / XA0 > XB / XB0. Here, XA / XA0 corresponds to the signal intensity / signal intensity initial value 502A in FIG. 10B, and XB / XB0 corresponds to the signal intensity / signal intensity initial value 502B in FIG. 10B.

[0077] When the impurity concentration is high at the retention time of the second component and low at the retention time of the first component in this way, the signal intensity of the second component with a high ionization efficiency decreases more significantly than that of the first component with respect to the initial value of the signal intensity. As a result, as shown in the graph 500C of FIG. 11A, XA / XA0 > XB / XB0.

[0078] Note that when the contamination relationship of the solution is reversed (when the first solution is contaminated), results opposite to those shown in FIG. 11A are obtained. In this case, results similar to the graphs 510B and 510C in FIG. 11B described later are obtained. Therefore, it is desirable to perform the measurement with the gradient of the solution reversed, that is, with the gradient pattern of the first solution → the second solution and the gradient pattern of the second solution → the first solution.

[0079] The measurement results detected in FIG. 11A can be considered to be the case where the following conditions W32a and W32b are satisfied. (Condition W32a) The decrease width of the signal intensity in the component with a high ionization efficiency is larger than the decrease width of the signal intensity in the component with a low ionization efficiency. Here, the decrease width is the decrease width with respect to the signal intensity thresholds TH11A and TH11B in each component. Hereinafter, the decrease width shall be the decrease width according to this definition. (Condition W32b) X / X0 in the component with a high ionization efficiency is lower than the value of X / X0 in the component with a low ionization efficiency. In this way, when the following conditions W32a and W32b are satisfied, the determination processing unit 212 determines that the solution is contaminated. The case where Condition W32a and Condition W32b are satisfied corresponds to the case where Condition W32 in FIG. 9 is satisfied. That is, when the state of FIG. 11A is detected, it corresponds to the case where the process of step S412: W32 → step S414 in FIG. 9 is performed.

[0080] In this way, by making a determination based on the measurement results shown in FIGS. 10B and 11A, it is possible to easily detect the contamination of the solution.

[0081] Next, refer to FIG. 11B. In FIG. 11B, the time change of the impurity concentration is shown as graph 510A in the upper part. Also, the signal intensity for each component is shown as graph 510B in the middle part. And the X / X0 for each component is shown as graph 510C in the lower part.

[0082] And in graph 510B, signal intensity 511A indicates the signal intensity of the first component, and signal intensity 511B indicates the signal intensity of the second component. Also, in graph 510C, signal intensity / signal intensity initial value 512A is the signal intensity / signal intensity initial value (X / X0) of the first component, and signal intensity / signal intensity initial value 512B is the signal intensity / signal intensity initial value (X / X0) of the second component. Note that in graph 510C, XA is the signal intensity of the first component measured in step S401 of FIG. 9 (the same value as signal intensity 511A). Also, XB is the signal intensity of the second component measured in step S401 of FIG. 9 (the same value as signal intensity 511B). Further, in graph 510C, XA0 is the signal intensity of the first component measured in step S301 of FIG. 8 (the signal intensity initial value). And XB0 is the signal intensity of the second component measured in step S301 of FIG. 8 (the signal intensity initial value).

[0083] Here, the process shown in FIG. 11B may be performed by paying attention to any one of the first flow paths ~ C. In FIG. 11B, it is assumed that attention is paid to the first flow path. That is, graphs 510A to 510C shown in FIG. 11B relate to the first flow path. Also, although the shape of graph 510B in FIG. 11B is different from the shape of graph 410A in FIG. 10B, this is because the result shown in FIG. 11B satisfies the above-mentioned conditions W21a and W21b, but shows an example different from FIG. 10B. Note that times ta and tb will be described later. Also, the signal intensity threshold TH11A of the first component and the signal intensity threshold TH11B of the second component are the same as those in FIG. 10B.

[0084] In the graph 510B of FIG. 11B, the signal intensity 511A indicates the signal intensity of the first component measured at time ta. Similarly, the signal intensity 511B indicates the signal intensity of the second component measured at time tb. In the case of contamination of the common part, contamination will exist in the latter stage of the separation column 105. Therefore, the dependence on the retention time due to impurities is small. Thus, as shown in the graph 510A of FIG. 11B, the impurities are eluted at a substantially constant concentration throughout the retention time. The common part is the selector valve 106, the pipe 126, the injector 103, and the capillary 112 of the mass spectrometer 110 as described above.

[0085] In such a state, since all components uniformly contain impurities, the signal intensity is more strongly affected by ion suppression for components with lower ionization efficiency. That is, samples with lower ionization efficiency are more strongly suppressed.

[0086] As described above, in this embodiment, the first component has a lower ionization efficiency than the second component. Therefore, when contamination occurs in the common part, as shown in the graph 510B of FIG. 11B, the decrease width of the signal intensity 511A of the first component is larger than the decrease width of the signal intensity 511B of the second component. That is, the decrease in the signal intensity of the first component 511A is larger than that of the second component 511B.

[0087] When contamination occurs in the common part, ion suppression occurs more strongly in the first component with lower ionization efficiency than in the second component with higher ionization efficiency as described above. Therefore, XA / XA0 which is X / X0 of the first component becomes smaller than the value of XB / XB0 which is X / X0 of the second component. That is, XB / XB>XA / XA0. XA / XA0 corresponds to the signal intensity / signal intensity initial value 512A in FIG. 11B, and XB / XB0 corresponds to the signal intensity / signal intensity initial value 512B in FIG. 11B.

[0088] Therefore, the measurement results shown in FIG. 11B are in a state where the following conditions W31a and W31b are satisfied. (Condition W31a) The decrease width of the signal intensity in the component with low ionization efficiency is larger than that in the component with high ionization efficiency. (Condition W31b) X / X0 in the component with low ionization efficiency is lower than X / X0 in the component with high ionization efficiency. Thus, when the following Condition W31a and Condition W31b are satisfied, the determination processing unit 212 determines that contamination of the common part has occurred.

[0089] However, even when contamination has occurred in all solutions (both the first solution and the second solution in the example of FIG. 11B), the state of FIG. 11B, that is, Condition W31a and Condition W31b are satisfied. Therefore, when Condition W31a and Condition W31b are satisfied, in addition to contamination of the common part, the possibility of solution contamination is also considered. However, since the probability that all solutions are contaminated simultaneously is low, by performing this contamination determination frequently, when Condition W31a and Condition W31b are satisfied, it is possible to specify that it is contamination of the common part.

[0090] Note that the case where Condition W31a and Condition W31b are satisfied corresponds to the case where Condition W31 in FIG. 9 is satisfied. Therefore, when the state of FIG. 11B is detected, it corresponds to step S412: W31 → step S413 in FIG. 9. Thus, by performing the determination based on the measurement results shown in FIGS. 10B and 11B, it is possible to easily detect the contamination of the common part.

[0091] Next, the state of FIG. 10C will be described. In FIG. 10C, in the upper part (graphs 420A to 420C), the signal intensities of the first component and the second component in each flow path are shown. In FIG. 10C, graph 420A shows the measurement result in the first flow path, graph 420B shows the measurement result in the second flow path, and graph 420C shows the measurement result in the third flow path. Also, in graph 420A, signal intensity 421A is the signal intensity related to the first component, and signal intensity 421B is the signal intensity related to the second component. Similarly, in graph 420B, signal intensity 422A is the signal intensity related to the first component, and signal intensity 422B is the signal intensity related to the second component. Further, in graph 420C, signal intensity 423A is the signal intensity related to the first component, and signal intensity 423B is the signal intensity related to the second component.

[0092] And regarding the lower part (graph 420D) of FIG. 10C, signal intensity ratio 424A indicates the signal intensity ratio in the first flow path, signal intensity ratio 424B indicates the signal intensity ratio in the second flow path, and signal intensity ratio 424C indicates the signal intensity ratio in the third flow path. Furthermore, as shown in graph 420D, the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold TH12 are set. Further, a signal intensity ratio threshold range TH12R is set as the range of the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold TH12. Also, in graph 420D of FIG. 10C, signal intensity ratio R indicates the signal intensity ratio in the case of no contamination. The signal intensity ratio R in the case of no contamination has been measured in advance (step S401 in FIG. 8). As described above, the upper limit value TH12U and the lower limit value TH12L of the signal intensity ratio threshold TH12 are set based on this signal intensity ratio R. Note that the case of no contamination is explained in step S401 of FIG. 8.

[0093] Also, in FIG. 10C, the signal intensity threshold TH11A of the first component, the signal intensity threshold TH11B of the second component, the upper limit value TH12U of the signal intensity ratio threshold TH12, and the lower limit value TH12L are the same values as in FIGS. 10A and 10B.

[0094] In the example shown in FIG. 10C, the following conditions W41 and condition W11N are satisfied. (Condition W41) As shown in graphs 420A to 420C in FIG. 10C, the signal intensities 421A to 423A and 421B to 423B decrease in all flow paths and are equal to or lower than the signal intensity threshold TH11. Specifically, all of the signal intensities 421A to 423A of the first component are lower than the signal intensity threshold TH11A of the first component. Further, all of the signal intensities 421B to 423B of the second component are lower than the signal intensity threshold TH11B of the second component. Condition W41 is the same as condition W41 in FIG. 9 (step S421: Yes in FIG. 9). (Condition W11N) In all flow paths, the signal intensity ratios 424A to 424C are less than the upper limit value TH12U of the signal intensity ratio threshold TH12 and greater than the lower limit value TH12L. In other words, in all flow paths, the signal intensity ratios 424A to 424C are within the signal intensity ratio threshold range TH12R. Condition W11N is the case where condition W11 in FIG. 9 is not satisfied (step S402: No in FIG. 9). Both condition W41 and condition W11N are caused by contamination or deterioration of the electrode of the ion source 111 inside the mass spectrometer 110 that is not affected by the ionization efficiency. Therefore, when both condition W41 and condition W11N are satisfied, the determination processing unit 212 determines that contamination or deterioration has occurred in the mass spectrometer 110 (specifically, the ion source 111).

[0095] As described above, the establishment of condition W41 is equivalent to the establishment of condition W41 in FIG. 9. Further, the establishment of condition W11N is equivalent to the establishment of "No" in condition W11 in FIG. 9. That is, the detection of the state of FIG. 10C is equivalent to the processing of step S402: No → step S421: Yes → step S422 in FIG. 9.

[0096] In this way, by making a determination based on the measurement results shown in FIG. 10C, contamination of the mass spectrometer 110 (particularly the ion source 111) can be easily detected.

[0097] (Summary) Figure 12 summarizes the contamination determination in the third embodiment. In Figure 12, "W11", "W21", "W22", "W31", "W32", and "W41" correspond to the conditions W11, W21, W22, W31, W32, and W41 in Figure 9. First, the following conditions may hold. · The signal intensity ratio threshold TH12 is outside the signal intensity ratio threshold range (outside the signal intensity ratio threshold range TH12R) in any of the channels (Condition W11 in Figure 9: Yes). · The signal intensity is lower than the signal intensity threshold TH11 in all channels, and the signal intensity ratio is outside the signal intensity ratio threshold range (outside the signal intensity ratio threshold range TH12R: when Condition W21 in Figure 9 is satisfied) in all channels. · The decrease in the signal intensity (X) of the component with low ionization efficiency is greater than that of the component with high ionization efficiency, and X / X0 of the component with low ionization efficiency is lower than that of the component with high ionization efficiency (when Condition W31 in Figure 9 is satisfied). In Figure 12, X and X0 are the same as X and X0 in Figures 9, 11A, and 11B.

[0098] When such conditions hold, it corresponds to the case where the states in Figures 10B and 11B are detected. Therefore, the determination processing unit 212 determines that contamination of the common part or contamination of the solution has occurred. However, as described above, by increasing the frequency of determining the contaminated location, the possibility of solution contamination can be reduced, so it is marked as "△" in Figure 12.

[0099] Next, the following conditions may hold. · The signal intensity ratio threshold TH12 is outside the signal intensity ratio threshold range (outside the signal intensity ratio threshold range TH12R) in any of the channels (Condition W11 in Figure 9: Yes). · The signal intensity is lower than the signal intensity threshold TH11 in all channels, and the signal intensity ratio is outside the signal intensity ratio threshold range (outside the signal intensity ratio threshold range TH12R: when Condition W21 in Figure 9 is satisfied) in all channels. · When the component with high ionization efficiency has a greater decrease in signal intensity (X) than the component with low ionization efficiency, and X / X0 of the component with high ionization efficiency is lower than X / X0 of the component with low ionization efficiency (when condition W32 in Fig. 9 is satisfied). When such a condition is satisfied, it corresponds to the case where the states in Figs. 10B and 11A are detected. Therefore, the determination processing unit 212 determines that the solution is contaminated.

[0100] Next, there may be cases where the following conditions are satisfied. · In any flow path, the signal intensity ratio threshold TH12 is outside the signal intensity ratio threshold range (outside the signal intensity ratio threshold range TH12R) (condition W11: Yes in Fig. 9). · In a specific flow path, the signal intensity of the flow path is lower than that of other flow paths, and the signal intensity ratio of the flow path is outside the signal intensity ratio threshold range (outside the signal intensity ratio threshold range TH12R) (when condition W22 in Fig. 9 is satisfied). When such a condition is satisfied, it corresponds to the case where the state in Fig. 10A is detected. Therefore, the determination threshold determines that contamination has occurred in the flow path (specific flow path) that satisfies the above conditions.

[0101] Subsequently, there may be cases where the following conditions are satisfied. · In all flow paths, the signal intensity ratio is within the signal intensity ratio threshold range (within the signal intensity ratio threshold range TH12R) (condition W11: No in Fig. 9). · In all flow paths, the signal intensity is lower than the signal intensity threshold TH11 (condition W41: Yes in Fig. 9). When such a condition is satisfied, it corresponds to the case where the state in Fig. 10C is detected. Therefore, the determination processing unit 212 determines that contamination or deterioration has occurred in the mass spectrometer 110 (specifically, the ion source 111).

[0102] In a state where it is determined that "the signal intensity ratios in all channels are within the signal intensity ratio threshold range", a state where "the signal intensity in a specific channel is lower than the signal intensity threshold TH11" is not detected (indicated by hatching in FIG. 12). In the process of FIG. 9, in a state where it is determined that "the signal intensity ratios in all channels are within the signal intensity ratio threshold range" (S402: No), when the condition that "the signal intensity in all channels is lower than the signal intensity threshold TH11" (S421) is determined to be "No", the determination processing unit 212 determines that there is no abnormality.

[0103] The signal intensity varies due to factors other than the influence of contamination, such as the ionization state in the ion source 111 and the pulsation of the liquid delivery pump 102. Therefore, when determining the contaminated location only based on the value (absolute value) of the signal intensity as in the first embodiment, it is necessary to set the threshold TH1 (see FIGS. 5A and 5B) low to reduce the sensitivity of the determination and prevent false determination. That is, when specifying the contaminated location based on the value (absolute value) of the signal intensity, it is necessary to consider the fluctuations due to the ionization state in the ion source 111 and the pulsation of the liquid delivery pump 102, and set the threshold TH1 low.

[0104] In the second embodiment, in addition to the signal intensity, by referring to the change in the signal intensity ratio, it is possible to determine contamination without being affected by the variation (fluctuation) of the signal intensity due to factors other than contamination. For this reason, compared with the first embodiment, even if the threshold (signal intensity threshold TH11) is set high in the contamination determination based on the value (absolute value) of the signal intensity, the probability of false determination can be reduced, and high-sensitivity determination becomes possible.

[0105] Also, in the second embodiment, it is possible to specify contaminated locations in more detail than in the first embodiment, such as distinguishing the contamination state between solution contamination and common parts. Thereby, the accuracy of abnormality determination can be improved. Note that the number of components included in the mixed sample may be two or more, and the determination can be similarly performed even if there are three or more. In that case, it is sufficient to obtain the signal intensity ratio using any two specific components.

[0106] [Third Embodiment] 13A and 13B are diagrams showing a method for identifying the cause of contamination in the third embodiment. In Fig. 13A and Fig. 13B, the time series data of the signal intensity when measuring the contaminated part of the flow path is stored in the storage device 202, and the judgment processing unit 212 compares the signal intensity along the time series. For example, when the signal intensity gradually (continuously) decreases as in the time series 601 of the signal intensity shown in Fig. 13A, accumulation of contamination in the pipes 121a, 121b, 122a, 122b, 123, 125, or deterioration of consumable parts such as the capillary 112 may be considered. On the other hand, when the signal intensity decreases discontinuously (discontinuously) as in the time series 602 of the signal intensity shown in Fig. 13B, it is suspected that dust or the like (foreign matter) is mixed into the solution or the standard sample, or that the contamination occurs due to the replacement work. When the judgment in Fig. 13A and Fig. 13B is combined with information such as the cleaning history of the separation column 105, the capillary 112, and the replacement of the solution, the accuracy of identifying the contaminated part can be further improved. According to the third embodiment, it is possible to determine the location of contamination with higher accuracy than when the determination is made based on a single measurement.

[0107] If the contaminated location is identified by the method shown in the first to third embodiments, the contamination can be removed by performing recovery operations such as cleaning the identified contaminated location or replacing parts. After the recovery operation, the contaminated location identification process shown in FIG. 4 is performed again. If the signal strength in all flow paths becomes equal to or greater than the threshold value TH1, the user determines that the contamination has been removed. In this state, normal measurement can be performed. Incidentally, normal measurement is not a measurement for identifying contaminated locations as in FIG. 3, FIG. 4, FIG. 8, and FIG. 9, but rather a measurement of an arbitrary sample.

[0108] In addition, when the contaminated part is a specific flow path, the capillary 112 of the ion source 111, or the separation column 105, cleaning is performed by sending a cleaning solution to the contaminated part. The solution suitable for cleaning varies depending on the type of contamination. Pure water is suitable for removing inorganic substances such as salts. Also, an organic solution such as isopropanol is suitable for removing polymer substances. If the signal intensity does not recover after cleaning, consumables such as the separation column 105 and the capillary 112 of the ion source 111 are replaced.

[0109] In the first to third embodiments, the identification of the contaminated part may be notified by an alarm or the like. Also, the cleaning of the contaminated part may be performed by automatic cleaning.

[0110] The present invention is not limited to the above-described embodiments, and includes various modifications. For example, the above-described embodiments have been described in detail for easy understanding of the present invention, and are not necessarily limited to those having all the configurations described. Also, a part of the configuration of one embodiment can be replaced with the configuration of another embodiment, and the configuration of another embodiment can be added to the configuration of one embodiment. Also, for a part of the configuration of each embodiment, addition, deletion, or replacement with other configurations is possible.

[0111] In addition, each of the above-described configurations, functions, each part 211 to 213, the storage devices 202, 202, etc. may be realized in hardware by designing a part or all of them, for example, by an integrated circuit. Also, as shown in FIG. 2 and FIG. 7, each of the above-described configurations, functions, etc. may be realized in software by a processor such as the CPU 201 interpreting and executing a program for realizing each function. Information such as a program, a table, a file, etc. for realizing each function can be stored not only in the HD but also in a recording device such as the memory 210 or an SSD, or a recording medium such as an IC (Integrated Circuit) card, an SD (Secure Digital) card, or a DVD (Digital Versatile Disc). Also, in each embodiment, the control lines and information lines show those considered necessary for explanation, and not necessarily all control lines and information lines are shown on the product. In reality, it may be considered that almost all components are interconnected.

Explanation of Signs

[0112] 1 LC / MS (Liquid Chromatograph Mass Spectrometer) 2, 2a Processing Device 101, 101a, 101b Solution Tank (where the solution is stored 102 Liquid Delivery Pump (Liquid Chromatography 103 Injector (Liquid Chromatography 104 Injection Valve (Liquid Chromatography 105, 105a~105c Separation Column (Liquid Chromatography 106 Selector Valve (Liquid Chromatography, common part in each flow path 110 Mass Spectrometer 111 Ion Source 112 Capillary (common part in each flow path 121a, 121b Pipe (Liquid Chromatography, 122a, 122b Pipe (Liquid Chromatography, multiple flow paths, where the solution flows, components constituting the flow path 123, 123a~123c Pipe (Liquid Chromatography, multiple flow paths, where the solution flows, components constituting the flow path 124 Sample Loop (Liquid Chromatography, where a predetermined substance flows, where the mixed sample flows, components constituting the flow path 125, 125a~125c Pipe (Liquid Chromatography, multiple flow paths, where the solution and the mixed sample flow, components constituting the flow path 126 Pipe (Liquid Chromatography, flow path connected to the mass spectrometer, common part in each flow path 205 Output Device (Output Unit) Signal intensities of 301~303, 311~313, 401A~403A, 401B~403B, 411A~413A, 411B~413B, 421A~423A, 421B~423B, 501A, 501B, 511A, 511B Signal intensity ratios of 404A~404C, 414A~414C, 424A~424C Signal intensity / initial signal intensity (ratio of signal intensity to pre-measured signal intensity) of 502A, 502B, 512A, 512B Time series of 601, 602 R Signal intensity ratio Measurement of standard sample in an uncontaminated state (pre-measurement, pre-measured signal intensity can be obtained) of S101, S301 Threshold value TH1 Signal intensity threshold values of TH11, TH11A, TH11B Signal intensity ratio threshold value TH12 Upper limit value TH12U Lower limit value TH12L Signal intensity ratio threshold range TH12R Z LC / MS system (mass spectrometry system)

Claims

1. A liquid chromatography having a plurality of flow paths, a mass spectrometer, and a processing device that acquires a signal intensity which is a measurement result of a substance from the mass spectrometer, Each of the plurality of flow paths is provided with a separation column, and the plurality of flow paths are arranged in parallel with each other, A flow path connected to the mass spectrometer is selected by a selector valve from the plurality of flow paths, For each of the plurality of flow paths, a predetermined substance is circulated together with a solution, and the predetermined substance is measured by the mass spectrometer, The processing device, For each of the plurality of flow paths, based on the signal intensity obtained as a result of the measurement by the mass spectrometer, an abnormality of the liquid chromatography and the mass spectrometer is determined, The result of the determination is output to an output unit A mass spectrometry system characterized by the above.

2. In a state where no contamination occurs in the liquid chromatography and the mass spectrometer, the predetermined substance is flowed through each of the plurality of flow paths, and a pre-measurement is performed by the mass spectrometer. Based on the pre-measurement signal intensity obtained as a result of the pre-measurement, a threshold value of the signal intensity is preset for each flow path, The processing device, By comparing the signal intensity acquired in the measurement performed after the pre-measurement with the threshold value, an abnormality of the liquid chromatography and the mass spectrometer is determined The mass spectrometry system according to claim 1, characterized by the above.

3. The processing device, Among the plurality of flow paths, when the signal intensity is lower than the threshold value in a predetermined flow path and the signal intensity is higher than the threshold value in other flow paths, it is determined that contamination has occurred in the components constituting the flow path where the signal intensity is lower than the threshold value The mass spectrometry system according to claim 2, characterized by the above.

4. When the signal intensity is lower than the threshold value in all of the plurality of flow paths, it is determined that contamination has occurred in any one of a common location in each flow path, the solution, and an ion source provided in the mass spectrometer among the plurality of flow paths. The mass spectrometry system according to claim 2, characterized in that.

5. As the predetermined substance, a mixed sample having a plurality of components with different ionization efficiencies is used. The processing device is Calculate the signal intensity ratio, which is the ratio of the signal intensity of the mixed sample, for each flow path. Based on the signal intensity and the signal intensity ratio in each flow path, determine the abnormalities of the liquid chromatography and the mass spectrometer. The mass spectrometry system according to claim 1, characterized in that.

6. Preliminary measurement is performed on the mixed sample having known component concentrations in a state where each part constituting the liquid chromatography and the mass spectrometer is not contaminated. Based on the preliminary measurement signal intensity obtained as a result of the preliminary measurement, a signal intensity threshold value, which is the threshold value of the signal intensity, is set for each component, and Based on the preliminary measurement signal intensity obtained as a result of the preliminary measurement, a signal intensity ratio threshold value range, which is a range in which the threshold value of the signal intensity ratio can be taken, is set. After the preliminary measurement, measurement is performed on the mixed sample. The processing device is Compare the plurality of signal intensities obtained as a result of the measurement with the signal intensity threshold value, and By comparing the signal intensity ratio calculated from the plurality of signal intensities obtained as a result of the measurement with the signal intensity ratio threshold value range, detect abnormalities in the liquid chromatography and the mass spectrometer. The mass spectrometry system according to claim 5, characterized in that.

7. The processing device is In a specific flow path, when the signal intensity for all components is lower than the signal intensity threshold and the signal intensity ratio is outside the signal intensity ratio threshold range, contamination has occurred in any of the components constituting the flow path The mass spectrometry system according to claim 6, characterized in that

8. The processing device In all flow paths, when the signal intensity for all components is lower than the signal intensity threshold and in all flow paths, the signal intensity ratio is within the signal intensity ratio threshold range, it is determined that at least one of contamination and deterioration of the mass spectrometer has occurred The mass spectrometry system according to claim 6, characterized in that

9. The processing device In all flow paths, the signal intensity for all components is lower than the signal intensity threshold and in all flow paths, the signal intensity ratio is outside the signal intensity ratio threshold range Furthermore, for the component with a higher ionization efficiency among the components with different ionization efficiencies included in the mixed sample, the decrease width of the signal intensity with respect to the signal intensity threshold is larger than that of the component with a lower ionization efficiency, and the ratio of the signal intensity related to the component with a higher ionization efficiency to the pre-measured signal intensity is lower than the ratio of the signal intensity related to the component with a lower ionization efficiency to the pre-measured signal intensity, it is determined that contamination of the solution has occurred The mass spectrometry system according to claim 6, characterized in that

10. The processing device In all flow paths, the signal intensity for all components is lower than the signal intensity threshold and in all flow paths, the signal intensity ratio is outside the signal intensity ratio threshold range Further, among the components with different ionization efficiencies included in the mixed sample, for the component with a low ionization efficiency, the decrease width of the signal intensity with respect to the signal intensity threshold is larger than that of the component with a high ionization efficiency, and the ratio of the signal intensity related to the component with a low ionization efficiency to the pre-measured signal intensity is lower than the ratio of the signal intensity related to the component with a high ionization efficiency to the pre-measured signal intensity. When the condition is satisfied, it is determined that contamination has occurred at least at a common location in each flow path. The mass spectrometry system according to claim 6, characterized in that.

11. When the time series of the signal intensity decreases discontinuously, it is determined that at least one of foreign matter contamination and contamination associated with the replacement operation of the liquid chromatography and the mass spectrometer has occurred. The mass spectrometry system according to claim 1, characterized in that.

12. When the time series of the signal intensity decreases continuously, it is determined that at least one of the accumulation of contamination in the piping constituting the liquid chromatography and the deterioration of the components constituting the mass spectrometer has occurred. The mass spectrometry system according to claim 1, characterized in that.

13. A processing device that acquires a signal intensity, which is a measurement result of a substance, from a mass spectrometer of a liquid chromatography mass spectrometer having a liquid chromatography with a plurality of flow paths and a mass spectrometer, Each of the plurality of flow paths is provided with a separation column, and the plurality of flow paths are arranged in parallel with each other. A flow path connected to the mass spectrometer is selected by a selector valve for the plurality of flow paths. For each of the plurality of flow paths, a predetermined substance is circulated together with a solution, and the predetermined substance is measured by the mass spectrometer. The processing device is For each of the plurality of flow paths, based on the signal intensity obtained as a result of the measurement by the mass spectrometer, an abnormality of the liquid chromatography and the mass spectrometer is determined, and the result of the determination is output to an output unit. A processing device characterized by the above.

14. An abnormality detection method in a mass spectrometry system including a liquid chromatography having a plurality of flow paths, a mass spectrometer, and a processing device that acquires a signal intensity which is a measurement result of a substance from the mass spectrometer, wherein each of the plurality of flow paths is provided with a separation column, and the plurality of flow paths are arranged in parallel with each other, a flow path connected to the mass spectrometer is selected by a selector valve for the plurality of flow paths, for each of the plurality of flow paths, a predetermined substance is circulated together with a solution, and the predetermined substance is measured by the mass spectrometer the processing device, for each of the plurality of flow paths, based on the signal intensity obtained as a result of the measurement by the mass spectrometer, an abnormality of the liquid chromatography and the mass spectrometer is determined, and the result of the determination is output to an output unit. An abnormality detection method characterized by the above.

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