Mass spectrometry system, processing device, and abnormality detection method

Abstract

To facilitate the detection of anomalies in a liquid chromatograph (LC / MS) quality analysis device, the system comprises: a liquid chromatograph with multiple flow paths; a quality analysis device (110); and a processing device (2) for obtaining the signal intensity of a substance determination result from the quality analysis device (110). Each of the multiple flow paths is equipped with a separation column (105), and the multiple flow paths are arranged in parallel. The multiple flow paths are selected by a selection valve (106) to connect to the quality analysis device (110). For each of the multiple flow paths, a predetermined substance is allowed to flow together with a solution, and the predetermined substance is determined by the quality analysis device (110). For each of the multiple flow paths, the processing device (2) determines an anomaly of the LC / MS (1) based on the signal intensity obtained from the determination result of the quality analysis device (110), and outputs the determination result to an output device.

Description

Technical Field

[0001] This invention relates to the technology of a quality analysis system, processing device, and anomaly detection method in a liquid chromatograph (LC / MS) mass analysis apparatus having multiple flow paths through separation columns. Background Technology

[0002] A mass analyzer is a device that separates ions in a vacuum based on their mass-to-charge ratio (m / z). Furthermore, mass analyzers enable the separation and detection of ions with high sensitivity and precision. Additionally, mass analyzers are commonly used as detectors in liquid chromatography (LC), frequently employing an analytical method known as liquid chromatography-mass analysis (LC / MS).

[0003] Here, LC is an analytical method that uses a pump to pressurize the mobile phase and pass it through a separation column, separating and detecting samples based on the difference in interactions (adsorption, partitioning, etc.) between the stationary and mobile phases. In analyses using separation columns, the higher the flow rate through the column, the shorter the separation time. On the other hand, a higher flow rate requires a higher delivery pressure, thus necessitating the use of a pump to apply higher pressure. Furthermore, in the case of LC / MS, a higher flow rate results in lower ionization efficiency. Therefore, throughput is limited in LC analyses using a single flow path. Therefore, Patent Document 1 discloses a method to achieve high throughput by performing analyses in parallel in multiple flow paths, each equipped with a separation column.

[0004] Existing technical documents

[0005] Patent documents

[0006] Patent Document 1: US Patent No. 6,908,740 Summary of the Invention

[0007] The problem that the invention aims to solve

[0008] In LC / MS with multiple flow paths, as described in Patent Document 1, the decrease in sensitivity can be caused by various factors, including contamination of the mobile phase, ion source, flow paths, and errors in solution mixing in the delivery pump. This presents a challenge in determining the location of contamination. While it is necessary to determine the cause of this sensitivity decrease, Patent Document 1 does not disclose a method for determining the location of contamination.

[0009] The present invention was completed in view of this background, and the subject of the present invention is to easily detect anomalies in a liquid chromatograph quality analysis device.

[0010] Methods for solving problems

[0011] To address the aforementioned issues, the present invention is characterized by comprising: a liquid chromatograph having multiple flow paths; a mass analysis device; and a processing device that obtains signal intensity from the mass analysis device as a measurement result of a substance, wherein each of the multiple flow paths has a separation column and the multiple flow paths are arranged in parallel with each other, the multiple flow paths are selected by a selection valve to connect to the mass analysis device, a predetermined substance is allowed to flow together with a solution for each of the multiple flow paths, the predetermined substance is measured using the mass analysis device, and the processing device, based on the signal intensity obtained from the measurement result of the mass analysis device, determines an anomaly of the liquid chromatograph and the mass analysis device for each of the multiple flow paths, and outputs the determination result to an output unit.

[0012] Other solutions will be appropriately described in the implementation plan.

[0013] Invention Effects

[0014] According to the present invention, anomalies in liquid chromatography quality analysis devices can be easily detected. Attached Figure Description

[0015] Figure 1 This is a diagram illustrating a structural example of an LC / MC system.

[0016] Figure 2 This is a functional block diagram showing the structure of the processing device in the first embodiment.

[0017] Figure 3 This indicates the threshold setting process in the first embodiment.

[0018] Figure 4 This is a flowchart illustrating the steps of determining the contaminated site in the first embodiment.

[0019] Figure 5A This is a graph (one of the graphs) showing the signal intensity of the mass analysis device for measuring standard samples in each flow path.

[0020] Figure 5B This is a graph representing the signal intensity of the mass analyzer used to measure the standard samples in each flow path.

[0021] Figure 6 This is a table summarizing the first implementation method.

[0022] Figure 7 This is a functional block diagram illustrating a structural example of the processing apparatus in the second embodiment.

[0023] Figure 8 This is a flowchart illustrating the steps involved in setting various thresholds in the second embodiment.

[0024] Figure 9 This is a flowchart illustrating the steps of the contaminated site determination process performed in the second embodiment.

[0025] Figure 10A This is a graph (one of the graphs) showing the signal intensity and signal intensity ratio of the standard samples measured for each flow path.

[0026] Figure 10B This is a graph (Part Two) showing the signal intensity and signal intensity ratio of the standard samples measured for each flow path.

[0027] Figure 10C This is a graph (Part Three) showing the signal intensity and signal intensity ratio of the standard samples measured for each flow path.

[0028] Figure 11A It is a graph (one of the graphs) showing the relationship between the concentration of inclusions and the holding time, the signal strength of the mass analysis device 110, and the relationship between the initial value of the signal strength and the holding time of the components.

[0029] Figure 11B The graph (II) shows the relationship between the concentration of inclusions and the holding time, the signal strength of the mass analysis device 110, and the relationship between the initial value of the signal strength and the holding time of the components.

[0030] Figure 12 This is a table summarizing the third implementation method.

[0031] Figure 13A This is a diagram (one of) illustrating the method for determining the cause of pollution in the third embodiment.

[0032] Figure 13B This is a diagram (second one) illustrating the method for determining the cause of pollution in the third embodiment. Detailed Implementation

[0033] Next, the methods for carrying out the present invention (referred to as "implementation methods") will be described in detail with appropriate reference to the accompanying drawings.

[0034] [First Implementation Method]

[0035] First, refer to Figures 1-6 The first implementation method is described below.

[0036] (System Architecture)

[0037] Figure 1 This is a diagram illustrating the structure of an LC / MC system Z.

[0038] The LC / MC system Z has an LC / MC (liquid chromatograph mass analysis device) 1 and a processing device 2.

[0039] The LC / MS1 includes multiple solution tanks 101, multiple delivery pumps 102, ejectors 103, multiple injection valves 104, multiple separation columns 105, a selection valve 106, and a mass analysis device 110. The individual components of the LC / MS1 will be described later.

[0040] Additionally, the processing device 2 obtains the results of sample analysis from the quality analysis device 110 and controls the switching of the liquid delivery pump 102, the injection valve 104, and the selection valve 106. Furthermore, in Figure 1 In the diagram, for easy observation, the processing device 2 is connected to a liquid delivery pump 102 and a jet valve 104, but in reality, it controls all the liquid delivery pumps 102 and jet valves 104.

[0041] Different types of solutions are stored in each solution tank 101. Figure 1 In the example shown, the two solutions are stored in two solution tanks 101a and 101b, respectively. In this embodiment, the solution stored in solution tank 101a is referred to as the first solution, and the solution stored in solution tank 101b is referred to as the second solution.

[0042] The liquid delivery pump 102 pressurizes and delivers the solution stored in the solution tank 101.

[0043] The delivery pump 102 delivers the liquid at sufficient pressure, ensuring a flow rate sufficient to deliver the liquid to the mass analyzer 110 even when the separation column 105 with low conductance is installed. The delivery pump 102 typically uses a pump capable of delivery within a pressure range of approximately 0.1 to 100 MPa. The separation column 105 will be described later.

[0044] exist Figure 1 In the example shown, the pipes 121a and 121b connected to the respective solution tanks 101a and 101b each branch into three. Each of the three branching pipes 122a and 122b is equipped with a delivery pump 102. A first solution flows through pipe 122a, and a second solution flows through pipe 122b. Downstream of the delivery pump 102, pipes 123 (123a to 123c) are arranged to allow the solutions delivered from the delivery pump 102 to merge and flow together. Figure 1 In the example shown, a set of pipes 122a and 122b merges into individual pipes 123. Therefore, in Figure 1 In the example shown, there are three pipes 122a and three pipes 122b, therefore there are three pipes 123 (pipes 123a to 123c).

[0045] The first and second solutions delivered from the delivery pump 102 merge and mix in piping 123. The mixture of the first and second solutions is delivered in parallel in piping 123a to 123c.

[0046] Furthermore, the delivery pump 102 uses a low-pressure gradient to deliver the solution from the solution tank 101 connected to it. This allows for the delivery of mixed solutions with a gradient applied to the mixing ratio in any proportion.

[0047] The injector 103 injects a sample from a vial or similar container into the sample circuit 124. Then, the injection valve 104 is switched by the processing device 2, thereby connecting the sample circuit 124, containing the sample, to any one of the tubing 123a-123c. The tubing 123 (123a-123c) is then connected to a separation column 105 (105a-105c). With this configuration, the sample is injected into the separation column 105. The mixture of the first and second solutions containing the injected sample is appropriately referred to as the sample solution.

[0048] Each of the separation columns 105 is connected to a pipe 125 (125a-125c) downstream. That is, the sample solution that has passed through each separation column 105 flows through the pipes 125a-125c.

[0049] Furthermore, by selecting valve 106, any one of pipes 125a to 125c can be connected to pipe 126 connected to the mass analysis device 110. That is, by selecting valve 106, the connection destination of pipe 126 connected to the mass analysis device 110 can be switched to any one of pipes 125a to 125c located downstream of the separation column 105.

[0050] Furthermore, in this embodiment, the system of piping 123a, separation column 105a, and piping 125a is appropriately referred to as the first flow path. Similarly, the system of piping 123b, separation column 105b, and piping 125b is appropriately referred to as the second flow path. And the system of piping 123c, separation column 105c, and piping 125c is appropriately referred to as the third flow path. In addition, the first flow path to the third flow path is appropriately referred to collectively as a flow path.

[0051] like Figure 1 As shown, the sample solutions flow in parallel in the first to third flow paths.

[0052] Furthermore, the flow paths in piping 125a-125c that are not connected to the mass analysis device 110 via the selector valve 106 are connected to a waste liquid tank (not shown). This prevents the sample solution from flowing out.

[0053] As described above, the mass analysis device 110 is connected via a selector valve 106 through multiple pipes 125 (125a-125c) of each independent separation column 105. Figure 1 The example shown illustrates a structure with three flow paths, but this method can be applied to any structure with two or more flow paths.

[0054] The mass analysis device 110 has an ion source 111 and a capillary tube 112.

[0055] The mass analysis device 110 uses an ion source 111 to ionize the sample and uses electric and magnetic fields to separate the sample according to its mass-to-charge ratio (m / z) to determine the sample composition. The measurement results are output in the form of signal intensity and input to the processing device 2.

[0056] The ion source 111 for ionizing the sample can be, for example, an electrospray ionization source, an atmospheric pressure chemical ionization source, or an atmospheric pressure photoionization source. In any ion source 111, the solution containing the sample is sprayed into the ion source 111 through a fine capillary 112 provided by the mass analysis device 110.

[0057] (Processing device 2)

[0058] Figure 2 This is a functional block diagram showing the structure of the processing device 2 in the first embodiment. Refer to relevant references. Figure 1 .

[0059] The processing device 2 is configured as a PC (Personal Computer) and includes a CPU (Central Processing Unit) 201. It also includes a storage device 202, such as an HD (Hard Disk) or SSD (Solid State Drive). Furthermore, the processing device 2 includes a communication device 203 for sending control instructions to the LC / MS1 or receiving signals from the quality analysis device 110. The processing device 2 also includes an input device 204 such as a keyboard and an output device 205 such as a display. Additionally, the processing device 2 includes a memory 210, such as RAM (Random Access Memory). A program stored in the storage device 202 is loaded into the memory 210. Then, the CPU 201 executes the loaded program to implement the acquisition unit 211, the determination processing unit 212, and the control unit 213.

[0060] The acquisition unit 211 acquires the measurement results (signal strength) from the mass analysis device 110.

[0061] The determination processing unit 212 determines the location of contamination based on the measurement results (signal strength) obtained from the quality analysis device 110.

[0062] The control unit 213 controls the liquid delivery pump 102, the injection valve 104, and the selector valve 106.

[0063] In addition, the storage device 202 stores the threshold TH1 used by the determination processing unit 212 when determining the contaminated area.

[0064] (flow chart)

[0065] The method for determining the contaminated site in this embodiment will be explained.

[0066] Figure 3 This describes the threshold setting process in the first embodiment. See also: Figure 1 and Figure 2 .

[0067] First, in an uncontaminated state, standard samples of known concentrations are flowed from injector 103 into each flow path (first flow path to third flow path), and measured by mass analysis device 110 (S101). An uncontaminated state refers to the uncontaminated state of solution tank 101, piping 121a, 121b, 122a, 122b, 123, 125, 126, sample loop 124, separation column 105, mass analysis device 110, etc.

[0068] The measurement result, which is the signal strength of the quality analysis device 110, is acquired by the acquisition unit 211 of the processing device 2 and stored in the storage device 202 of the processing device 2.

[0069] Then, a threshold TH1 is set based on the average signal strength of the standard samples obtained from the first flow path to the third flow path (S102). The threshold TH1 is determined and set by the user. However, the processing device 2 may also calculate and set the threshold TH1. The set threshold TH1 is stored in the storage device 202. Furthermore, the standard sample used in the first embodiment can be a single type.

[0070] (Identification and treatment of contaminated areas)

[0071] Figure 4 This is a flowchart illustrating the steps of the contaminated site determination process performed in the first embodiment. See also: Figure 1 and Figure 2 Additionally, for Figure 4 The details of each process will be described later.

[0072] Figure 4 The processing shown is from Figure 3 The treatment shown is performed after a predetermined period (e.g., one month). Furthermore, it is performed at fixed intervals (e.g., every month). Figure 4 The processing shown.

[0073] First, possessing and in Figure 3Standard samples under the same conditions are flowed in each flow path (first flow path to third flow path) during the processing. "Same conditions" means having the same type, the same concentration, and the same measurement conditions. Then, the standard samples are measured separately according to the first to third flow paths via the mass analysis device 110 (S201). During the measurement, the first to third flow paths are connected to the mass analysis device 110 one by one via the selector valve 106, and a measurement is performed each time.

[0074] Then, the determination processing unit 212 of the processing device 2 compares the measurement result (signal intensity of the mass analyzer 110) obtained through step S201 with the set threshold TH1. The signal intensity depends on the measurement conditions such as the temperature of the separation column 105, the conditions of the mobile phase, the gradient conditions, and the electrode voltage setting of the mass analyzer 110. Furthermore, the mobile phase is equivalent to... Figure 1 Piping 122a, 122b to 126. Furthermore, the conditions of the mobile phase refer to the temperature conditions, etc., within the mobile phase.

[0075] Then, the determination processing unit 212 determines whether the signal strength in all flow paths (all of the first flow path to the third flow path) is greater than the threshold TH1 (S202).

[0076] If the signal strength in all flow paths is greater than the threshold TH1 (S202 → Yes), the determination processing unit 212 determines that there is no contamination and outputs the determination result to the output device 205 (S203).

[0077] In addition, if there is a flow path with a signal strength lower than the threshold TH1 (S202→No), the determination processing unit 212 determines whether the signal strength in all flow paths is below the threshold TH1 (S211).

[0078] If the signal strength in all flow paths is not below the threshold TH1 (S211→No), the determination processing unit 212 determines that the flow path (the specific flow path) is contaminated and outputs the determination result to the output device 205 (S212). Flow path contamination refers to any one of the pipes 122a, 122b, 123, 125 constituting the flow path, the sample circuit 124, the liquid delivery pump 102, and the separation column 105 being contaminated.

[0079] If the signal strength in all flow paths is below the threshold TH1 (S211 → Yes), the determination processing unit 212 determines that any one 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 piping 126, the ejector 103, and the capillary 112 of the mass analysis device 110.

[0080] (Details of the judgment and handling)

[0081] Next, refer to Figure 5A as well as Figure 5B ,right Figure 4 The details of the handling process will be explained.

[0082] Figure 5A and Figure 5B This is a graph showing the signal strength of the mass analysis device 110 for measuring the standard samples in each flow path.

[0083] exist Figure 5A and Figure 5B In the diagram, the horizontal axis represents the time required from sample injection into the LC column until dissolution (holding time). The vertical axis represents the signal intensity of the ions in the standard sample detected by the mass analyzer 110 based on their m / z (i.e., the measurement result of the sample (in this embodiment, the standard sample)). Furthermore, the holding time of the LC and the m / z of the ions generated by the ion source 111 are inherent values ​​of the substances constituting the sample (in this embodiment, the standard sample).

[0084] exist Figure 5A In the diagram, signal strength 301 in Figure 300A represents the result measured in the first flow path. Similarly, signal strength 302 in Figure 300B represents the result measured in the second flow path. Furthermore, signal strength 303 in Figure 300C represents the result measured in the third flow path.

[0085] exist Figure 5A In the results shown, only specific flow paths (in) Figure 5A In the example shown (Figure 300B: Second Flow Path), the signal intensity 302 of the standard sample is below the threshold TH1. Furthermore, in the others (Figures 300A, 300C: First Flow Path, Third Flow Path), the signal intensities 301 and 303 are greater than the threshold TH1. These measurement results indicate that flow paths with signal intensities below the threshold TH (in...) Figure 5A In the example, the second flow path is contaminated. Due to ion suppression caused by inclusions dissolved from the contaminated site, the signal intensity of the standard sample decreases. As mentioned above, flow path contamination refers to the contamination of any one of the pipes 122a, 122b, 123, 125, sample circuit 124, delivery pump 102, and separation column 105 that constitute the flow path.

[0086] Therefore, after obtaining Figure 5A In the case of the measurement results (signal strength) shown, the determination processing unit 212 determines that in a specific flow path (in Figure 5A In the example, contamination occurred in the second flow path. Figure 4 Step S212). That is, Figure 5A Equivalent to in Figure 4 The process shown selects the result of step S202 "No" → step S211 "No". Thus, based on... Figure 5A The measurement results shown can be used to determine whether contamination in a specific flow path can be easily detected.

[0087] Next, regarding Figure 5B Please provide an explanation.

[0088] exist Figure 5B In the diagram, signal strength 311 in Figure 310A represents the result measured in the first flow path. Signal strength 312 in Figure 310B represents the result measured in the second flow path. Signal strength 313 in Figure 310C represents the result measured in the third flow path.

[0089] exist Figure 5B In the example shown, the signal strength of the mass analyzer 110 decreased to the same extent in all flow path measurements, falling below the threshold TH1. That is, as shown in Figures 310A-310C, the signal strengths 311-313 obtained in the first to third flow paths are all below the threshold TH1. This result indicates that any one of the common components, the solution, or the ion source 111 is contaminated. In other words, in Figure 5B In the example shown, the signal strength decreases due to ion suppression caused by inclusions dissolved from the contaminated area or due to charging of the electrodes inside the mass analysis device 110. As described above, the common components are the selection valve 106, piping 126, injector 103, and capillary 112 of the mass analysis device 110.

[0090] in addition, Figure 5B The result shown is equivalent to Figure 4 Step S213. That is, Figure 5B Equivalent to in Figure 4 The process shown selected the result of step S202 "No" → step S211 "Yes".

[0091] Thus, by using Figure 5B The measurement results shown can be used to determine whether contamination of common parts, solutions, and ion source 111 is possible.

[0092] Furthermore, if the piping 122a, 122b, 123, 125, sample circuit 124, liquid delivery pump 102, and separation column 105 constituting all flow paths are simultaneously and to the same degree contaminated, it will also be similar to Figure 5BSimilarly, the signal strength decreased in all flow path measurements. However, flow path contamination generally occurs independently, one flow path at a time, so the probability of simultaneous contamination of piping 122a in all flow paths is low. The same applies to piping 122b, 123, 125, sample circuit 124, delivery pump 102, and separation column 105. Therefore, by performing measurements to determine the contamination sites at a sufficiently high frequency, the possibility of simultaneous contamination of all flow paths can be suppressed to a low level.

[0093] (Summary of the first implementation method)

[0094] The determination of the contaminated area in the first embodiment is summarized in Figure 6 The table shown is provided for reference. Figure 1 and Figure 2 .

[0095] like Figure 6 As shown, when the signal strength is below the threshold TH1 in all flow paths, the determination processing unit 212 determines that contamination has occurred in any one of the common section, the solution, and the ion source 111 of the mass analysis device 110. Figure 4 Step S213 Figure 5B ).

[0096] Furthermore, if the signal strength is below the threshold TH1 only in a specific flow path, the determination processing unit 212 determines that the flow path is contaminated. Specifically, any one of the following in the flow path where the signal strength is determined to be low is contaminated: piping 122a, 122b, 123, 125, sample circuit 124, liquid delivery pump 102, and separation column 105. Figure 4 Step S212 Figure 5A ).

[0097] As shown above, in the first embodiment, by comparing the signal intensity of each flow path with the threshold TH1, the contamination status of at least one of the mobile phase and the mass analysis device 110 (ion source 111, capillary 112) can be determined.

[0098] Furthermore, according to the first embodiment, the contamination site is determined based on the signal strength obtained from the mass analysis device 110. Therefore, the contamination site can be determined without the need for additional special equipment. In addition, by determining the contamination site based on the signal strength obtained from the mass analysis device 110, it is possible to determine the contamination site regardless of the mechanical error of the LC / MS1.

[0099] [Second Implementation]

[0100] Next, refer to Figures 7-12 The second embodiment of the present invention will now be described.

[0101] In the second embodiment, a mixed sample of multiple components with different ionization efficiencies is used as the standard sample. In the second embodiment, a standard sample containing two components (referred to as the first component and the second component) is used.

[0102] Furthermore, in the second embodiment, the Z-structure of the LC / MS system is similar to... Figure 1 The same applies, therefore the explanation here is omitted.

[0103] (Processing device 2a)

[0104] Figure 7 This is a functional block diagram illustrating a structural example of the processing device 2a in the second embodiment.

[0105] exist Figure 7 In the middle, to and Figure 2 The same structure is labeled with the same symbol, and the explanation is omitted.

[0106] exist Figure 7 In the processing apparatus 2a shown, the storage device 202a stores the signal strength threshold TH11A of the first component (component A), the signal strength threshold TH11B of the second component (component B), the upper limit TH12U of the signal strength ratio threshold TH12, and the lower limit TH12L of the signal strength ratio threshold TH12. The signal strength threshold TH11A of the first component, the signal strength threshold TH11B of the second component, the upper limit TH12U of the signal strength ratio threshold TH12, and the lower limit TH12L of the signal strength ratio threshold TH12 will be described later. Hereinafter, the signal strength threshold TH11A of the first component and the signal strength threshold TH11B of the second component will be collectively referred to as the signal strength threshold TH11. Furthermore, the upper limit TH12U of the signal strength ratio threshold TH12 and the lower limit TH12L of the signal strength ratio threshold TH12 will be appropriately collectively referred to as the signal strength ratio threshold TH12.

[0107] Furthermore, in the second embodiment, the signal intensity of each component of the standard sample is compared with a signal intensity threshold TH11 (signal intensity threshold TH11A for the first component and signal intensity threshold TH11B for the second component). Also in the second embodiment, for each component of the standard sample, the ratio of signal intensities obtained from the mass analyzer 110 is calculated (signal intensity ratio) for each flow path. Then, the signal intensity ratio is compared with a signal intensity ratio threshold TH12. Specifically, as described later, the signal intensity ratio is compared with the upper limit TH12U and the lower limit TH12L of the signal intensity ratio threshold TH12.

[0108] Furthermore, as described later, the signal strength threshold TH11 and the signal strength ratio threshold TH12 are predetermined and set by the user through prior measurement of a standard sample of known concentration in a state where the quality analysis device 110 is uncontaminated. The set signal strength threshold TH11 and signal strength ratio threshold TH12 are stored in the storage device 202a of the processing device 2a.

[0109] (flow chart)

[0110] Figure 8 This is a flowchart illustrating the steps involved in setting various thresholds in the second embodiment.

[0111] First, in an uncontaminated state, a standard sample of known concentration is flowed from the injector 103 into each flow path (first flow path to third flow path), and measured by the mass analysis device 110 (S301). The uncontaminated state refers to the uncontaminated state of the solution tank 101, piping 121a, 121b, 122a, 122b, 123, 125, 126, sample circuit 124, separation column 105, and mass analysis device 110. At this time, the standard sample, as a mixed sample containing a first component and a second component, flows in the first to third flow paths. Then, the flow paths connected to the mass analysis device 110 are sequentially switched by the selector valve 106, and the first and second components are measured in the first to third flow paths respectively by the mass analysis device 110. Furthermore, since the first and second components pass through the separation column 105 at different times, the measurement of each component is performed with a time difference.

[0112] Next, the user sets a signal intensity threshold TH11 (S302) based on the signal intensity of each component obtained in step S301 (determination of the standard sample under uncontaminated conditions). That is, for the first component, the user sets a signal intensity threshold TH11A based on the average signal intensity obtained from the first flow path to the third flow path, etc. Similarly, for the second component, the user sets a signal intensity threshold TH11B based on the average signal intensity obtained from the first flow path to the third flow path, etc.

[0113] Next, the user sets the signal strength ratio threshold TH12 based on the signal strength 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 strength ratio threshold TH12 based on the average value of the signal strength obtained from the first flow path to the third flow path, etc.

[0114] The set signal strength threshold TH11 and signal strength ratio threshold TH12 are stored in the storage device 202a. In addition, the signal strength threshold TH11 and the signal strength ratio threshold TH12 can be calculated and set by the user or by the processing device 2.

[0115] (Identification and treatment of contaminated areas)

[0116] Figure 9 This is a flowchart illustrating the steps of the contaminated site determination process performed in the second embodiment. See also: Figure 1 and Figure 7 Additionally, for Figure 9 The details of each process will be described later. Figure 9 The processing shown is from Figure 8 The process shown is performed after a predetermined period (e.g., one month). Furthermore, it is performed at fixed intervals (e.g., every month). Figure 9 The processing shown.

[0117] first, Figure 8 The standard samples used flowed in each flow path (first to third flow paths). As described above, in Figure 8 In the example, the standard sample, as a mixed sample with two components (a first component and a second component), flows separately in the first to third flow paths. Therefore, in this process, the standard sample also flows through the standard sample under the same conditions. At this time, the conditions for the standard sample to flow (concentration, measurement conditions, etc.) become the same as... Figure 8 The determination is performed under the same conditions as in step S301.

[0118] Then, standard samples are measured in each component and each flow path using the mass analyzer 110 (S401). During the measurement, each flow path is connected to the mass analyzer 110 one by one via the selector valve 106, and standard samples are measured in each flow path using the mass analyzer 110 each time. This measurement is performed for each component (the first component and the second component in this embodiment). Furthermore, as described above, since the first component and the second component pass through the separation column 105 at different times, the signal intensity of each component is measured with a time difference.

[0119] Next, the determination processing unit 212 of the processing device 2a determines whether condition W11 is met (S402). Here, condition W11 is whether the signal strength ratio in any flow path is outside the range of the signal strength ratio threshold TH12. The range of the signal strength ratio threshold TH12 is the range between the upper limit value TH12U and the lower limit value TH12L of the signal strength ratio threshold TH12. Figures 10A to 10C The signal strength ratio in the threshold range TH12R is within the range of TH12R.

[0120] If condition W11 is true (S402 → Yes), the determination processing unit 212 determines which of conditions W21 and W22 is true (S411).

[0121] Conditions W21 and W22 are as follows.

[0122] (Condition W21) The signal strength in all flow paths is below the signal strength threshold TH11, and the signal strength ratio in all flow paths is outside the range of the signal strength ratio threshold TH12.

[0123] (Condition W22) The signal strength in a specific flow path is below the signal strength threshold TH11, and the signal strength ratio in that flow path is outside the range of the signal strength ratio threshold TH12.

[0124] If condition W21 is met in step S411 (S411→W21), the determination processing unit 212 determines which of conditions W31 and W32 is met (S412).

[0125] Conditions W31 and W32 are the following conditions.

[0126] (Condition W31) The signal intensity decreases more significantly for the component with low ionization efficiency than for the component with high ionization efficiency, and the X / X0 ratio of the component with low ionization efficiency is lower than that of the component with high ionization efficiency. Here, X is the signal intensity measured in step S401, and X0 is... Figure 8 The signal intensity is measured in step S301. Furthermore, ionization efficiency is the ease of ionization in the ion source 111 of the mass analysis apparatus 110; the higher the ionization efficiency, the easier it is to ionize in the ion source 111. The definition of the reduction amplitude will be described later.

[0127] (Condition W32) The signal intensity reduction of the component with high ionization efficiency is greater than that of the component with low ionization efficiency, and the X / X0 of the component with high ionization efficiency is lower than that of the component with low ionization efficiency. The definition of the reduction magnitude will be described later.

[0128] If condition W31 is met in step S412 (S412→W31), the determination processing unit 212 determines that contamination of a common part or solution has occurred (S413), and outputs the determination result from the output device 205 (S431). Furthermore, as described later, by increasing the frequency of this process, the possibility of solution contamination in step S413 can be reduced. Additionally, the common part is the same as in the first embodiment, namely the selection valve 106, piping 126, injector 103, and capillary tube 112 of the mass analysis device 110.

[0129] If condition W32 is met 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).

[0130] If condition W22 is met 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 met (S415), and outputs the determination result to the output device 205 (S431).

[0131] If condition W11 is not met in step S402 (S402→No), the determination processing unit 212 determines whether condition W41 is met (S421).

[0132] Condition W41 is the following condition.

[0133] (Condition W41) The signal strength is below the signal strength threshold TH11 in all components and all flow paths.

[0134] If condition W41 is met in step S421 (S421→Yes), the determination processing unit 212 determines that contamination or deterioration has occurred in the quality analysis device 110 (S422), and outputs the determination result from the output device 205 (S431).

[0135] If condition W41 is not met 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).

[0136] (Details of the judgment and handling)

[0137] Next, refer to Figures 10A to 10C as well as Figures 11A-11B ,right Figure 9 The judgments in each process are explained in detail.

[0138] Figures 10A to 10C This is a graph showing the signal intensity of the mass analysis device 110 for measuring the standard samples (first component, second component) in each flow path.

[0139] exist Figures 10A to 10C The upper section, on the horizontal axis, represents the retention time of the LC. The vertical axis represents the signal intensity of ions related to the components contained in the standard sample, detected by the mass analyzer 110 with varying m / z values. The relationship between retention time and ion m / z is inherent to the substance and therefore typically varies depending on the composition.

[0140] In addition, Figures 10A to 10CIn the figures, the signal strength ratio in each flow path is shown in the lower section. Furthermore, if the signal strength of the first component is set as XA and the signal strength of the second component is set as XB, then the signal strength ratio is defined as XA / XB.

[0141] Furthermore, as will be explained later, the second component has a higher ionization efficiency than the first component.

[0142] First, regarding the obtained Figure 10A The results of the measurements shown will be explained.

[0143] Figure 10A The upper section (Figures 400A-400C) shows the signal strengths of the first and second components in each flow path. Furthermore, in Figure 10A In the graphs 400A to 400C, graph 400A represents the measurement results in the first flow path, graph 400B represents the measurement results in the second flow path, and graph 400C represents the measurement results in the third flow path. Furthermore, in graph 400A, signal intensity 401A is the signal intensity related to the first component, and signal intensity 401B is the signal intensity related to the second component. Similarly, in graph 400B, signal intensity 402A is the signal intensity related to the first component, and signal intensity 402B is the signal intensity related to the second component. And in graph 400C, signal intensity 403A is the signal intensity related to the first component, and signal intensity 403B is the signal intensity related to the second component. As described above, since the first and second components 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.

[0144] In addition, such as Figure 10A As shown in Figures 400A to 400C, the signal strength threshold TH11A for the first component and the signal strength threshold TH11B for the second component are set.

[0145] And, regarding Figure 10A In the lower section (Figure 400D), signal strength ratio 404A represents the signal strength ratio in the first flow path, signal strength ratio 404B represents the signal strength ratio in the second flow path, and signal strength ratio 404C represents the signal strength ratio in the third flow path.

[0146] Furthermore, as shown in Figure 400D, an upper limit value TH12U and a lower limit value TH12L for the signal strength ratio threshold TH12 are set. Additionally, a signal strength ratio threshold range TH12R is set as the range between the upper limit value TH12U and the lower limit value TH12L for the signal strength ratio threshold TH12.

[0147] Additionally, in Figure 400D, the signal strength ratio R represents the signal strength ratio under uncontaminated conditions. The signal strength ratio R under uncontaminated conditions is pre-determined. Figure 8 Step S301). Based on the signal strength ratio R, set the upper limit TH12U and lower limit TH12L of the signal strength ratio threshold TH12. Additionally, in Figure 8 Step S301 describes what it means to have no contamination.

[0148] exist Figure 10A As shown in Figures 400B and 400D, a specific flow path (in Figure 10A The example shown is the second flow path: Hereinafter, a specific flow path will be described as the second flow path, satisfying the conditions W22a and W22b shown below.

[0149] (Condition W22a) As shown in Figure 400B, the signal strengths 402A and 402B of the first and second components decrease, respectively, and become below the signal strength thresholds TH11A and TH11B.

[0150] (Condition W22b) As shown in Figure 400D, the signal strength ratio 404B of the second flow path also changes from the signal strength ratio R in the uncontaminated state to below the lower limit TH12L or above the upper limit TH12U of the signal strength ratio threshold TH12. That is, only the signal strength ratio 404B of the second flow path is outside the signal strength ratio threshold range TH12R. Furthermore, in this embodiment, "the signal strength ratio changes from the signal strength ratio R in the uncontaminated state" means that the signal strength ratio was originally in the uncontaminated state of signal strength ratio R, but the signal strength ratio changes or decreases due to contamination. In addition, conditions W22a and W22b are equivalent to Figure 9 Condition W22. That is, Figure 10A Equivalent to Figure 9 Step S411: W22 → Step S415.

[0151] Figure 10A The diagram shows the flow path that satisfies conditions W22a and W22b (in...). Figure 10A The example shown illustrates a contaminated second flow path. Flow path contamination refers to any one of the following components constituting the flow path: piping 122a, 122b, 123, 125; sample circuit 124; delivery pump 102; and separation column 105. That is, Figure 10A The situation shown indicates that the signal strength of the standard sample is reduced due to ion suppression caused by inclusions dissolved from contaminants in the second flow path. Furthermore, since the ionization efficiency of the first component is lower than that of the second component, the effect of ion suppression caused by inclusions is greater. Therefore, in Figure 10A In graph 400B, the signal strength 402A of the first component is significantly lower than the signal strength 402B of the second component. Furthermore, because the signal strength 402A of the first component is significantly lower than the signal strength 402B of the second component, the signal strength ratio 404B also changes significantly.

[0152] Thus, by using Figure 10A The measurement results shown can be used to determine whether contamination in a specific flow path can be easily detected.

[0153] Next, regarding Figure 10B Please provide an explanation.

[0154] Figure 10B The upper section (Figures 410A-410C) shows the signal strengths of the first and second components in each flow path. Furthermore, in Figure 10B In the diagram, Figure 410A represents the measurement results in the first flow path, Figure 410B represents the measurement results in the second flow path, and Figure 410C represents the measurement results in the third flow path. Furthermore, in Figure 410A, signal strength 411A is the signal strength related to the first component, and signal strength 411B is the signal strength related to the second component. Similarly, in Figure 410B, signal strength 412A is the signal strength related to the first component, and signal strength 412B is the signal strength related to the second component. And in Figure 410C, signal strength 413A is the signal strength related to the first component, and signal strength 413B is the signal strength related to the second component.

[0155] Moreover, regarding Figure 10B In the lower section (Figure 410D), signal strength ratio 414A represents the signal strength ratio in the first flow path, signal strength ratio 414B represents the signal strength ratio in the second flow path, and signal strength ratio 414C represents the signal strength ratio in the third flow path.

[0156] Furthermore, as shown in Figure 410D, an upper limit value TH12U and a lower limit value TH12L for the signal strength ratio threshold TH12 are set. Additionally, a signal strength ratio threshold range TH12R is set as the range between the upper limit value TH12U and the lower limit value TH12L for the signal strength ratio threshold TH12.

[0157] In addition, Figure 10B In Figure 410D, the signal strength ratio R represents the signal strength ratio under uncontaminated conditions. The signal strength ratio R under uncontaminated conditions is predetermined. Figure 8 Step S301). As described above, the upper limit TH12U and lower limit TH12L of the signal strength ratio threshold range TH12R are set based on the signal strength ratio R. Furthermore, in Figure 8Step S301 describes what it means to have no contamination.

[0158] In addition, Figure 10B In the above, the signal strength threshold TH11A for the first component, the signal strength threshold TH11B for the second component, the upper limit TH12U for the signal strength ratio threshold range TH12R, and the lower limit TH12L are related to... Figure 10A Same value.

[0159] Furthermore, in Figure 10B In the example shown, the following conditions W21a and W21b are satisfied.

[0160] (Condition W21a) As shown in Figures 410A to 410C, the signal strength in all flow paths (first to third flow paths) and all components (first and second components) is below the signal strength threshold TH11. Specifically, signal strengths 411A to 413A are all lower than the signal strength threshold TH11A of the first component. Similarly, signal strengths 411B to 413B are all lower than the signal strength threshold TH11B of the second component.

[0161] (Condition W21b) As shown in Figure 410D, the signal strength ratios 414A to 414C in all flow paths (first to third flow paths) are below the lower limit TH12L or above the upper limit TH12U of the signal strength ratio threshold range TH12R. That is, the signal strength ratio is outside the signal strength ratio threshold range TH12R in all flow paths. Furthermore, in Figure 10B The diagram shows a case where the signal strength of all components in all flow paths is lower than TH12L (the lower limit of the threshold range TH12R) than 414A to 414C. However, there are also cases where the signal strength of all components is higher than TH12U (the upper limit of the threshold range TH12R) than 414A to 414C.

[0162] Furthermore, the fulfillment of conditions W21a and W21b is equivalent to... Figure 9 The condition W21 is met (step S411: W21).

[0163] exist Figure 10B In such a case, it is known that the signal strength decreases due to ion suppression caused by contamination of the solution or contamination of the common parts. Here, the common parts are the selector valve 106, the piping 126, the ejector 103, and the capillary 112 of the mass analysis device 110.

[0164] As mentioned above, in Figure 10B In that case, consider contamination of the solution or contamination of common areas. Therefore, when contamination occurs... Figure 10B In this situation, further through Figure 11A as well as Figure 11B To categorize the situations.

[0165] Figure 11A and Figure 11B It is a graph showing the relationship between the concentration of inclusions and the holding time, and the relationship between the signal strength of the mass analysis device 110 and the holding time of the LC.

[0166] First, refer to Figure 11A Explain the situation regarding solution contamination.

[0167] exist Figure 11A The upper section, as Figure 500A, shows the time variation of inclusion concentration. Additionally, the middle section, as Figure 500B, shows the signal intensity of each component. Furthermore, the lower section, as Figure 500C, shows the X / X0 for each component. Here, X represents the signal intensity at... Figure 9 The signal intensity measured in step S401, X0 is... Figure 8 The signal strength (initial value of signal strength) measured in step S301.

[0168] Furthermore, in Figure 500B, signal strength 501A represents the signal strength of the first component, and signal strength 501B represents the signal strength of the second component.

[0169] Additionally, in Figure 500C, signal strength / initial signal strength value 502A is the initial signal strength / initial signal strength value (X / X0) of the first component, and signal strength / initial signal strength value 502B is the initial signal strength / initial signal strength value (X / X0) of the second component. The initial signal strength value is... Figure 8 The signal strength measured in step S301. Furthermore, in Figure 500C, XA is... Figure 9 The signal intensity of the first component measured in step S401 (the same value as signal intensity 501A). Additionally, XB is... Figure 9 The signal intensity of the second component measured in step S401 (the same value as in symbol 501B). And, in graph 500C, XA0 is... Figure 8 The signal intensity (initial signal intensity value) of the first component measured in step S301. Furthermore, XB0 is... Figure 8 The signal intensity (initial value of signal intensity) of the second component measured in step S301.

[0170] Here, Figure 11A The processing shown can be performed on any one of the first to third flow paths, but... Figure 11A In this context, the focus is on the first-rate path. That is, Figure 11A The diagrams 500A to 500C shown are related to the first flow path.

[0171] in addition, Figure 11A The shape of chart 500B and Figure 10B The shape of chart 410A is different because although Figure 11A The results shown satisfy the conditions W21a and W21b above, but show a result different from the results shown above. Figure 10B Different examples. Furthermore, the times ta and tb will be discussed later. Additionally, the signal strength thresholds TH11A for the first component and TH11B for the second component are... Figure 10B same.

[0172] When the solution is contaminated, inclusions in the solution pass through the separation column 105 along with the standard sample. In particular, when a gradient in the mixing ratio of the solution occurs, the inclusion concentration varies depending on the holding time of the separation column 105 (Figure 500A). Therefore, the effect of ion suppression also varies depending on the holding time. This will be explained in detail below. Furthermore, the inclusion concentration can be determined from the measurement results of the mass analyzer 110.

[0173] Suppose that there are impurities mixed in the second solution. Then, the second solution gradually mixes with the first solution. At this point, as... Figure 11A As shown in Figure 500A, the inclusion concentration increases along with the holding time.

[0174] Then, as shown in Figure 500B, the signal intensity 501A associated with the first component is measured at time ta, and the signal intensity 501B associated with the second component is measured at time tb.

[0175] Compared to the first component measured at a low inclusion concentration (ta), the second component measured at a high inclusion concentration (tb) exhibits a greater effect of inclusion ion suppression. Therefore, as... Figure 11A As shown in Figure 500B, the signal strength 501B of the second component is significantly lower than that of the signal strength 501A of the first component. That is, the reduction in the signal strength 501B of the second component relative to the signal strength threshold TH11B is greater than the reduction in the signal strength 501A of the first component relative to the signal strength threshold TH11A.

[0176] Furthermore, the signal intensity 501B of the second component measured at the time tb, when the inclusion concentration in the solution is high, is significantly lower than the signal intensity 501A of the first component measured at the time ta, when the inclusion concentration is low. Here, "lower" refers to the decrease in the signal intensity of each component relative to its initial value. Therefore, as... Figure 11A As shown in Figure 500C, XA / XA0 > XB / XB0. Here, XA / XA0 is equivalent to... Figure 10B Signal strength / initial signal strength 502A, XB / XB0 is equivalent to Figure 10BSignal strength / initial signal strength value 502B.

[0177] Thus, when the inclusion concentration is high during the retention time of the second component and low during the retention time of the first component, the signal intensity of the second component, with its higher ionization efficiency, decreases significantly relative to the initial signal intensity. As a result, as... Figure 11A As shown in Chart 500C, XA / XA0 > XB / XB0.

[0178] Furthermore, when the contamination relationship of the solutions is reversed (when the first solution is contaminated), the result is the same as... Figure 11A The result shown is the opposite. In this case, the result obtained is the same as described later. Figure 11B The same results are obtained in Figures 510B and 510C. Therefore, it is preferable to reverse the gradient of the solution, that is, to perform the determination in a gradient pattern of first solution → second solution and a gradient pattern of second solution → first solution.

[0179] exist Figure 11A The test results can be considered as meeting the following conditions W32a and W32b.

[0180] (Condition W32a) The signal intensity reduction of the component with high ionization efficiency is greater than that of the component with low ionization efficiency. Here, the reduction magnitude is the reduction magnitude of each component relative to the signal intensity thresholds TH11A and TH11B. Hereafter, the reduction magnitude will be referred to as the reduction magnitude based on this definition.

[0181] (Condition W32b) The X / X0 of the component with high ionization efficiency becomes a lower value than the X / X0 of the component with low ionization efficiency.

[0182] Thus, if conditions W32a and W32b are met, the determination processing unit 212 determines that the solution has been contaminated.

[0183] The condition that conditions W32a and W32b are true is equivalent to... Figure 9 Condition W32 is met. That is, when it is detected... Figure 11A In this state, it is equivalent to performing Figure 9 Step S412: Processing of W32 → Step S414.

[0184] Thus, by using Figure 10B and Figure 11A The test results shown can be used to determine whether the solution is contaminated.

[0185] Next, refer to Figure 11B .

[0186] exist Figure 11BThe upper section, as Figure 510A, shows the time variation of inclusion concentration. Additionally, the middle section, as Figure 510B, shows the signal intensity of each component. Furthermore, the lower section, as Figure 510C, shows the X / X0 of each component.

[0187] Furthermore, in Figure 510B, signal strength 511A represents the signal strength of the first component, and signal strength 511B represents the signal strength of the second component.

[0188] Additionally, in Figure 510C, signal strength / initial signal strength value 512A is the signal strength / initial signal strength value (X / X0) of the first component, and signal strength / initial signal strength value 512B is the signal strength / initial signal strength value (X / X0) of the second component. Furthermore, in Figure 510C, XA is... Figure 9 The signal intensity of the first component measured in step S401 (the same value as signal intensity 511A). Additionally, XB is... Figure 9 The signal intensity of the second component measured in step S401 (the same value as signal intensity 511B). Furthermore, in Figure 510C, XA0 is... Figure 8 The signal intensity (initial signal intensity value) of the first component measured in step S301. Furthermore, XB0 is... Figure 8 The signal intensity (initial value of signal intensity) of the second component measured in step S301.

[0189] Here, Figure 11B The processing shown can be performed on any one of the first to third flow paths, but... Figure 11B In this context, the focus is on the first-rate path. That is, Figure 11B The diagrams 510A to 510C shown are related to the first flow path.

[0190] in addition, Figure 11B The shape of chart 510B and Figure 10B The shape of chart 410A is different, but this is because although Figure 11B The results shown satisfy the conditions W21a and W21b above, but show a result different from the results shown above. Figure 10B Different examples. Furthermore, the times ta and tb will be discussed later. Additionally, the signal strength thresholds TH11A for the first component and TH11B for the second component are... Figure 10B same.

[0191] In addition, Figure 11B In Figure 510B, signal strength 511A represents the signal strength of the first component measured at time ta. Similarly, signal strength 511B represents the signal strength of the second component measured at time tb.

[0192] In the common section of contamination, contamination exists in the latter part of separation column 105. Therefore, the inclusions are less dependent on retention time. Therefore, as... Figure 11B As shown in Figure 510A, the inclusions dissolve at a substantially constant concentration throughout the holding time. As described above, the common components are the selector valve 106, piping 126, injector 103, and capillary 112 of the mass analysis device 110.

[0193] In this state, since all components uniformly contain inclusions, the lower the ionization efficiency of a component, the stronger the signal intensity is affected by ion suppression. That is, samples with lower ionization efficiency are suppressed more strongly.

[0194] As described above, in this embodiment, the ionization efficiency of the first component is lower than that of the second component. Therefore, in the event of contamination in the common area, such as... Figure 11B As shown in Figure 510B, the decrease in signal strength 511A of the first component is greater than the decrease in signal strength 511B of the second component. That is, the decrease in signal strength of the first component 511A is greater than that of the second component 511B.

[0195] Furthermore, when contamination occurs in the common area, as mentioned above, the first component, with its lower ionization efficiency, exhibits stronger ion suppression compared to the second component, which has a higher ionization efficiency. Therefore, the X / X0 value of the first component, i.e., XA / XA0, is less than the value of the X / X0 value of the second component, i.e., XB / XB0. That is, XB / XB > XA / XA0. XA / XA0 is equivalent to... Figure 11B The signal strength / initial signal strength value 512A, XB / XB0 is equivalent to Figure 11B The signal strength / initial signal strength value is 512B.

[0196] therefore, Figure 11B The measurement results shown are states that satisfy the following conditions W31a and W31b.

[0197] (Condition W31a) The signal intensity of components with low ionization efficiency decreases more than that of components with high ionization efficiency.

[0198] (Condition W31b) The X / X0 of the component with low ionization efficiency is lower than that of the component with high ionization efficiency.

[0199] Thus, if the following conditions W31a and W31b are met, the determination processing unit 212 determines that contamination of a common part has occurred.

[0200] However, even in all solutions (in Figure 11BIn the example, contamination occurs in both the first and second solutions. Figure 11B The conditions W31a and W31b also hold. Therefore, when conditions W31a and W31b are met, the possibility of solution contamination is considered in addition to contamination of the common parts. However, since the probability of all solutions being contaminated simultaneously is low, by performing this contamination determination at a high frequency, it is possible to identify contamination as a common part when conditions W31a and W31b are met.

[0201] Furthermore, the situation where conditions W31a and W31b are true is equivalent to... Figure 9 The condition W31 is met. Therefore, when it is detected... Figure 11B In this state, it is equivalent to Figure 9 Step S412: W31 → Step S413.

[0202] Thus, by using Figure 10B and Figure 11B The test results shown can be used to determine whether contamination is present in common areas.

[0203] Next, regarding Figure 10C The state is described.

[0204] Figure 10C The upper section (Figures 420A-420C) shows the signal strengths of the first and second components in each flow path. Furthermore, in Figure 10C In the diagram, Figure 420A represents the measurement results in the first flow path, Figure 420B represents the measurement results in the second flow path, and Figure 420C represents the measurement results in the third flow path. Furthermore, in Figure 420A, signal strength 421A is the signal strength related to the first component, and signal strength 421B is the signal strength related to the second component. Similarly, in Figure 420B, signal strength 422A is the signal strength related to the first component, and signal strength 422B is the signal strength related to the second component. And in Figure 420C, signal strength 423A is the signal strength related to the first component, and signal strength 423B is the signal strength related to the second component.

[0205] Moreover, regarding Figure 10C In the lower section (Figure 420D), signal strength ratio 424A represents the signal strength ratio in the first flow path, signal strength ratio 424B represents the signal strength ratio in the second flow path, and signal strength ratio 424C represents the signal strength ratio in the third flow path.

[0206] Furthermore, as shown in Figure 420D, an upper limit value TH12U and a lower limit value TH12L for the signal strength ratio threshold TH12 are set. Moreover, a signal strength ratio threshold range TH12R is set as the range between the upper limit value TH12U and the lower limit value TH12L for the signal strength ratio threshold TH12.

[0207] In addition, Figure 10C In Figure 420D, the signal strength ratio R represents the signal strength ratio under uncontaminated conditions. The signal strength ratio R under uncontaminated conditions is predetermined. Figure 8 Step S301). As described above, the upper limit value TH12U and the lower limit value TH12L of the signal strength ratio threshold TH12 are set based on the signal strength ratio R. Additionally, in Figure 8 Step S301 describes what it means to have no contamination.

[0208] In addition, Figure 10C In the above, the upper limit TH12U and lower limit TH12L of the signal strength threshold TH11A for the first component, the signal strength threshold TH11B for the second component, and the signal strength ratio threshold TH12 are related to... Figure 10A as well as Figure 10B Same value.

[0209] exist Figure 10C In the example shown, the following conditions W41 and W11N are satisfied.

[0210] (Condition W41) as follows Figure 10C As shown in Figures 420A-420C, signal strengths 421A-423A and 421B-423B decrease in all flow paths, falling below the signal strength threshold TH11. Specifically, the signal strengths of the first component 421A-423A all become values ​​lower than the signal strength threshold TH11A for the first component. Furthermore, the signal strengths of the second component 421B-423B all become values ​​lower than the signal strength threshold TH11B for the second component. Condition W41 and... Figure 9 The condition W41 is the same ( Figure 9 Step S421: Yes).

[0211] (Condition W11N) In all flow paths, the signal strength ratios 424A to 424C are less than the upper limit TH12U and greater than the lower limit TH12L of the signal strength ratio threshold TH12. In other words, in all flow paths, the signal strength ratios 424A to 424C are within the signal strength ratio threshold range TH12R. Condition W11N is... Figure 9 The condition W11 is not met ( Figure 9 Step S402: No).

[0212] Conditions W41 and W11N both arise from contamination or deterioration of the electrodes of the internal ion source 111 of the mass analyzer 110, which is unaffected by ionization efficiency. Therefore, if both conditions W41 and W11N are met, the determination processing unit 212 determines that the mass analyzer 110 (specifically, the ion source 111) has been contaminated or deteriorated.

[0213] Furthermore, as mentioned above, the fulfillment of condition W41 is equivalent to Figure 9 Condition W41 is true. Furthermore, condition W11N being true is equivalent to... Figure 9 The condition "No" in W11 is true. That is, it is detected that... Figure 10C The state is equivalent to having performed Figure 9 Step S402: "No" → Step S421: "Yes" → Step S422.

[0214] Thus, by using Figure 10C The measurement results shown can be used to determine whether contamination of the mass analysis device 110 (especially the ion source 111) is possible.

[0215] (Summarize)

[0216] exist Figure 12 The pollution determination in the third implementation method is summarized in the text. Furthermore, in... Figure 12 In Chinese, "W11", "W21", "W22", "W31", "W32", and "W41" are equivalent to Figure 9 The conditions are W11, W21, W22, W31, W32, and W41.

[0217] First, sometimes the following conditions are met.

[0218] • The signal strength ratio in any flow path is outside the signal strength ratio threshold range (outside the TH12R signal strength ratio threshold range). Figure 9 Condition W11: Yes).

[0219] • The signal strength is below the signal strength threshold TH11 in all flow paths, and the signal strength ratio is outside the signal strength ratio threshold range (outside the signal strength ratio threshold range TH12R) in all flow paths. Figure 9 (The condition W21 is met).

[0220] • The signal intensity (X) of the component with low ionization efficiency decreases more significantly than that of the component with high ionization efficiency, and the X / X0 ratio of the component with low ionization efficiency is lower than that of the component with high ionization efficiency. Figure 9 (The condition W31 is met). Furthermore, in Figure 12 In the middle, X and X0 and Figure 9 , Figure 11A , Figure 11B X and X0 are the same.

[0221] The condition being met is equivalent to detecting Figure 10B as well as Figure 11B The condition is such that the processing unit 212 determines that contamination has occurred in a common area or as a solution. However, as described above, by increasing the frequency of determining the location of this contamination, the possibility of solution contamination can be reduced. Figure 12 The middle part is set to "△".

[0222] Then, sometimes the following conditions are met.

[0223] • The signal strength ratio in any flow path is outside the signal strength ratio threshold range (outside the TH12R signal strength ratio threshold range). Figure 9 Condition W11: Yes).

[0224] • The signal strength in all flow paths is below the signal strength threshold TH11, and the signal strength ratio in all flow paths is outside the signal strength ratio threshold range (outside the signal strength ratio threshold range TH12R). Figure 9 (The condition W21 is met).

[0225] The signal intensity (X) of the component with high ionization efficiency decreased more significantly than that of the component with low ionization efficiency, and the X / X0 ratio of the component with high ionization efficiency was lower than that of the component with low ionization efficiency. Figure 9 (The condition W32 is true).

[0226] The condition being met is equivalent to detecting Figure 10B as well as Figure 11A The condition of the solution is such that the processing unit 212 determines that the solution has been contaminated.

[0227] Then, sometimes the following conditions are met.

[0228] • The signal strength ratio in any flow path is outside the signal strength ratio threshold range (outside the TH12R signal strength ratio threshold range). Figure 9 Condition W11: Yes).

[0229] • In a specific flow path, the signal strength of that flow path is lower than that of other flow paths, and the signal strength ratio of that flow path is outside the signal strength ratio threshold range (outside the signal strength ratio threshold range TH12R). Figure 9 (The condition W22 is met).

[0230] The condition being met is equivalent to detecting Figure 10A Therefore, the determination and processing unit 212 determines that contamination has occurred in the flow path (specific flow path) that meets the above conditions.

[0231] Then, sometimes the following conditions are met.

[0232] • The signal strength ratio is within the signal strength ratio threshold range (within the TH12R threshold range) in all flow paths. Figure 9 Condition W11: No).

[0233] • The signal strength is below the signal strength threshold TH11 in all flow paths. Figure 9 Condition W41: Yes).

[0234] The condition being met is equivalent to detecting Figure 10C Therefore, the determination and processing unit 212 determines that the mass analysis device 110 (specifically the ion source 111) has been contaminated or deteriorated.

[0235] Furthermore, in the state determined as "the signal strength ratio is within the signal strength ratio threshold range in all flow paths", the state of "the signal strength is lower than the signal strength threshold TH11 in a specific flow path" will not be detected (in...). Figure 12 (The text is incomplete and contains slashes.) Figure 9 In the processing, if the condition that "the signal strength ratio in all flow paths is within the signal strength ratio threshold range" (S402: No) is determined to be "No", the determination processing unit 212 determines that there is no abnormality.

[0236] The signal strength is affected not only by contamination but also by the ionization state in the ion source 111 and the pulsation of the delivery pump 102. Therefore, as in the first embodiment, when determining the contamination site solely by the signal strength value (absolute value), it is necessary to set the threshold TH1 (refer to...) Figure 5A and Figure 5B To prevent false positives, the threshold TH1 is set lower to reduce the sensitivity of the determination. That is, in determining the contamination site based on the value (absolute value) of the signal strength, fluctuations caused by the ionization state in the ion source 111 and the pulsation of the liquid delivery pump 102 need to be considered.

[0237] In the second embodiment, in addition to signal strength, changes in the signal strength ratio are also considered, thereby enabling contamination determination to be performed without being affected by deviations (fluctuations) in signal strength caused by factors other than contamination. Therefore, compared to the first embodiment, even if the threshold (signal strength threshold TH11) is set higher in the contamination determination of the absolute value of signal strength, the probability of false determination can be reduced, and highly sensitive determination can be performed.

[0238] Furthermore, in the second embodiment, it is possible to determine the contamination site in a more detailed manner than in the first embodiment, distinguishing between the contamination state of the solution and the contamination state of the common area. This improves the accuracy of anomaly detection. Moreover, it is sufficient that the mixed sample contains two or more components; even if it contains three or more, the detection can still be performed. In this case, the signal intensity ratio only needs to be calculated for any two specific components used.

[0239] [Third Implementation Method]

[0240] Figure 13A and Figure 13B This is a diagram illustrating the method for determining the cause of pollution in the third embodiment.

[0241] exist Figure 13A and Figure 13B In this process, the time-series data of the signal intensity measured at the contaminated part of the flow path is stored in the storage device 202, and the determination processing unit 212 compares the signal intensity according to the time series. For example, in such a case... Figure 13A As shown in the time series 601 of signal strength, the signal strength gradually (continuously) decreases, considering the accumulation of contaminants in pipes 121a, 121b, 122a, 122b, 123, and 125, and the deterioration of consumable components such as capillary 112. On the other hand, as... Figure 13B As shown in the time series 602 of the signal strength, when the signal strength decreases discontinuously, it is suspected that the solution or standard sample may contain dust or other foreign matter, or that contamination may occur during replacement operations. Figure 13A and Figure 13B The combination of information such as the determination of the separation column 105, capillary tube 112, and cleaning history of solution replacement can further improve the accuracy of identifying the contaminated site.

[0242] According to the third embodiment, the location of contamination can be determined with higher accuracy compared to the case where a single measurement is used for judgment.

[0243] If the contaminated area is determined using the methods shown in the first to third embodiments, the contamination can be removed through restoration actions such as cleaning the determined contaminated area and replacing parts. Then, the restoration action is performed again. Figure 4 The contamination site is identified and treated as shown. Then, in all flow paths, if the signal strength is above the threshold TH1, the user determines that the contamination has been removed. If this state is achieved, normal measurements can be performed. However, normal measurements are not as... Figure 3 , Figure 4 , Figure 8 , Figure 9 Instead of using measurements to pinpoint the location of contamination, measurements are taken on arbitrary samples.

[0244] Furthermore, when the contaminated areas are specific to a particular flow path, the capillary 112 of the ion source 111, or the separation column 105, cleaning is performed by delivering a cleaning solution to the contaminated areas. The suitable cleaning solution varies depending on the type of contaminant; pure water is suitable for removing inorganic substances such as salts. Organic solutions such as isopropanol are suitable for removing high-molecular-weight substances. If the signal strength does not recover after cleaning, consumables such as the separation column 105 and the capillary 112 of the ion source 111 are replaced.

[0245] In the first to third embodiments, the location of the contaminated area can be identified through alarms or other means. Furthermore, the cleaning of the contaminated area can be performed automatically.

[0246] This invention is not limited to the embodiments described above, but includes various modifications. For example, the embodiments described above are detailed for the purpose of easily understanding and illustrating the invention, and are not limited to having all the structures described. Furthermore, a portion of the structure of one embodiment can be replaced with the structure of another embodiment, and the structure of another embodiment can be added to the structure of one embodiment. Additionally, regarding a portion of the structure of each embodiment, other structures can be added, deleted, or replaced.

[0247] Furthermore, the aforementioned structures, functions, components 211-213, storage devices 202, 202a, etc., can also be implemented in hardware, for example, using integrated circuit design, by means of some or all of them. Additionally, as... Figure 2 , Figure 7 As shown, the aforementioned structures and functions can also be implemented by software through the CPU 201 and other processors interpreting and executing the programs that implement each function. In addition to being stored in the HD, the programs, tables, files, and other information that implement each function can also be stored in the memory 210, SSD, or other recording devices, or in recording media such as IC (Integrated Circuit) cards, SD (Secure Digital) cards, and DVD (Digital Versatile Disc).

[0248] Furthermore, in each embodiment, control lines and information lines refer to the lines deemed necessary for the description, but may not represent all control lines and information lines on the product. In reality, it can be assumed that almost all structures are interconnected.

[0249] Symbol Explanation

[0250] 1LC / MS (Liquid Chromatography-Mass Analyzer)

[0251] 2.2a processing device

[0252] Solution tanks 101, 101a, and 101b (for storing solutions)

[0253] 102 liquid delivery pump (liquid chromatograph)

[0254] 103 ejector (liquid chromatograph)

[0255] 104 injection valve (liquid chromatograph)

[0256] 105, 105a~105c separation columns (liquid chromatograph)

[0257] 106 Selector Valve (for liquid chromatographs and common components in all flow paths)

[0258] 110 Mass Analysis Device

[0259] 111 ion source

[0260] 112 Capillary (the part common to all flow paths)

[0261] 121a and 121b piping (for liquid chromatograph)

[0262] 122a and 122b piping (liquid chromatograph, multiple flow paths, solution flow, components constituting the flow paths)

[0263] 123, 123a~123c piping (liquid chromatograph, multiple flow paths, solution flow, components constituting the flow path)

[0264] 124 Sample loop (liquid chromatograph, predetermined mass flow, mixed sample flow, components constituting the flow path)

[0265] 125, 125a~125c piping (liquid chromatograph, multiple flow paths, flow of solutions and mixed samples, components constituting the flow path)

[0266] 126 Piping (Liquid Chromatograph, flow paths connecting to mass analysis equipment, and common points in all flow paths)

[0267] 205 Output Device (Output Section)

[0268] Signal strength of 301~303, 311~313, 401A~403A, 401B~403B, 411A~413A, 411B~413B, 421A~423A, 421B~423B, 501A, 501B, 511A, 511B

[0269] Signal strength ratio of 404A~404C, 414A~414C, 424A~424C

[0270] Signal strength of 502A, 502B, 512A, 512B / Initial signal strength (ratio of signal strength to pre-measured signal strength)

[0271] Time series 601 and 602

[0272] R signal strength ratio

[0273] S101 and S301 are used to measure standard samples in an uncontaminated state (pre-measurement to obtain the pre-measured signal intensity).

[0274] TH1 threshold

[0275] TH11, TH11A, TH11B signal strength thresholds; TH12 signal strength ratio threshold

[0276] TH12U upper limit

[0277] TH12L lower limit

[0278] TH12R signal strength ratio to threshold range

[0279] Z LC / MS system (quality analysis system).

Claims

1. A quality analysis system, characterized in that, The quality analysis system includes: a liquid chromatograph having multiple flow paths; a quality analysis device; and a processing device that acquires the signal intensity as a determination result of a substance from the quality analysis device. Each of the multiple flow paths has a separation column, and the multiple flow paths are arranged in a parallel manner. The multiple flow paths are selected by a selection valve to connect to the quality analysis device. For each of the plurality of flow paths, a predetermined substance is allowed to flow together with the solution, and the predetermined substance is measured using the mass analysis device. The processing device, for each of the plurality of flow paths, determines anomalies in the liquid chromatograph and the quality analysis device based on the signal intensity obtained from the measurement results of the quality analysis device, and outputs the determination results to the output unit. As the predetermined substance, a mixed sample of multiple components with different ionization efficiencies is used. The processing device calculates a signal intensity ratio for each of the flow paths, which is a ratio of the signal intensity of the mixed sample, and determines the abnormality of the liquid chromatograph and the quality analysis device based on the signal intensity and the signal intensity ratio in each flow path.

2. The quality analysis system according to claim 1, characterized in that, In a state where no contamination occurs in the liquid chromatograph and the mass analysis device, the predetermined substance is allowed to flow in the plurality of flow paths respectively, thereby performing a prior determination based on the mass analysis device. Based on the prior determination signal intensity obtained from the results of the prior determination, a threshold for the signal intensity is preset for each of the flow paths. The processing device determines anomalies in the liquid chromatograph and the quality analysis device by comparing the signal intensity obtained in a measurement performed after the prior measurement with the threshold.

3. The quality analysis system according to claim 2, characterized in that, If the signal strength is lower than the threshold in a predetermined flow path among the plurality of flow paths, and the signal strength is higher than the threshold in other flow paths, the processing device determines that the component constituting the flow path with the signal strength lower than the threshold has been contaminated.

4. The quality analysis system according to claim 2, characterized in that, If the signal strength is lower than the threshold in all of the multiple flow paths, it is determined that contamination has occurred in any of the common parts of the multiple flow paths, the solution, and the ion source provided by the mass analysis device.

5. The quality analysis system according to claim 1, characterized in that, The mixed sample, having known component concentrations, is pre-measured under conditions where none of the components constituting the liquid chromatograph and the mass analysis apparatus are contaminated. Based on the pre-measured signal intensity obtained from the pre-measured results, a signal intensity threshold is set as a threshold for the signal intensity for each component, and... Based on the pre-measured signal strength obtained from the pre-measured results, a threshold range for the signal strength ratio is set as the range within which the threshold for the signal strength ratio can be taken. After the prior determination, the mixed sample was measured. The processing device compares multiple signal intensities obtained from the results of the measurement with the signal intensity threshold, and compares the signal intensity ratio calculated based on the multiple signal intensities obtained from the results of the measurement with the signal intensity ratio threshold range, thereby detecting anomalies in the liquid chromatograph and the quality analysis device.

6. The quality analysis system according to claim 5, characterized in that, When the signal strength associated with all components in a particular flow path is lower than the signal strength threshold and the signal strength ratio is outside the range of the signal strength ratio threshold, the processing device determines that any component among the components constituting the flow path has been contaminated.

7. The quality analysis system according to claim 5, characterized in that, When the signal strength associated with all components in all flow paths is lower than the signal strength threshold, and the signal strength ratio in all flow paths is within the signal strength ratio threshold range, the processing device determines that at least one of contamination and deterioration of the quality analysis device has occurred.

8. The quality analysis system according to claim 5, characterized in that, The processing device determines that contamination of the solution has occurred if: the signal intensity associated with all components is below the signal intensity threshold in all flow paths; the signal intensity ratio is outside the signal intensity ratio threshold range in all flow paths; the decrease in signal intensity relative to the signal intensity threshold is greater for the component with high ionization efficiency among the components with different ionization efficiencies contained in the mixed sample than for the component with low ionization efficiency; and the ratio of the signal intensity associated with the component with high ionization efficiency to the pre-measured signal intensity is lower than the value of the ratio of the signal intensity associated with the component with low ionization efficiency to the pre-measured signal intensity.

9. The quality analysis system according to claim 5, characterized in that, The processing device determines that contamination has occurred at least at a common location in each flow path if the following conditions are met: the signal intensity associated with all components is below the signal intensity threshold in all flow paths, and the signal intensity ratio exists outside the signal intensity ratio threshold range in all flow paths; furthermore, the decrease in signal intensity relative to the signal intensity threshold is greater for the component with low ionization efficiency among the components with different ionization efficiencies included in the mixed sample than for the component with high ionization efficiency; and the ratio of the signal intensity associated with the component with low ionization efficiency to the pre-measured signal intensity is lower than the value of the ratio of the signal intensity associated with the component with high ionization efficiency to the pre-measured signal intensity.

10. The quality analysis system according to claim 1, characterized in that, If the signal intensity decreases discontinuously over time, it is determined that at least one of the following has occurred: foreign matter contamination or contamination accompanying the replacement of the liquid chromatograph and the quality analysis device.

11. The quality analysis system according to claim 1, characterized in that, If the signal strength decreases continuously over time, it is determined that at least one of the following has occurred: accumulation of contaminants in the piping constituting the liquid chromatograph and deterioration of components constituting the mass analysis device.

12. A processing apparatus that acquires the signal intensity as a determination result of a substance from a mass analysis device of a liquid chromatograph, said liquid chromatograph mass analysis device comprising a liquid chromatograph having multiple flow paths and said mass analysis device, characterized in that, Each of the plurality of flow paths has a separation column, and the plurality of flow paths are arranged in a parallel manner. The multiple flow paths are selected by a selection valve to connect to the quality analysis device. For each of the plurality of flow paths, a predetermined substance is allowed to flow together with the solution, and the predetermined substance is measured using the mass analysis device. The processing device, for each of the plurality of flow paths, determines anomalies in the liquid chromatograph and the quality analysis device based on the signal intensity obtained from the measurement results of the quality analysis device, and outputs the determination results to the output unit. As the predetermined substance, a mixed sample of multiple components with different ionization efficiencies is used. The processing device calculates a signal intensity ratio for each of the flow paths, which is a ratio of the signal intensity of the mixed sample, and determines the abnormality of the liquid chromatograph and the quality analysis device based on the signal intensity and the signal intensity ratio in each flow path.

13. An anomaly detection method for a quality analysis system, the quality analysis system comprising: a liquid chromatograph having multiple flow paths; a quality analysis device; and a processing device for acquiring signal intensity as a determination result of a substance from the quality analysis device, characterized in that, Each of the plurality of flow paths has a separation column, and the plurality of flow paths are arranged in a parallel manner. The multiple flow paths are selected by a selection valve to connect to the quality analysis device. For each of the plurality of flow paths, a predetermined substance is allowed to flow together with the solution, and the predetermined substance is measured using the mass analysis device. The processing device, for each of the plurality of flow paths, determines anomalies in the liquid chromatograph and the quality analysis device based on the signal intensity obtained from the measurement results of the quality analysis device, and outputs the determination results to the output unit. As the predetermined substance, a mixed sample of multiple components with different ionization efficiencies is used. The processing device calculates a signal intensity ratio for each of the flow paths, which is a ratio of the signal intensity of the mixed sample, and determines the abnormality of the liquid chromatograph and the quality analysis device based on the signal intensity and the signal intensity ratio in each flow path.

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