Automatic analysis device

Abstract

The following configuration is employed in order to provide an automatic analysis device that has a plurality of chromatographic separation units, and makes it possible to quickly determine whether or not a malfunction has occurred in the device and an abnormality has occurred in the results of mass spectrometry.　This automatic analysis device comprises: separation columns for executing an equilibration step, a chromatographic separation step, and a column washing step in the stated order; a mass spectrometry unit to which the plurality of separation columns are connected via a switching valve; and a control unit for controlling the switching valve such that a solution from a second separation column undergoing the equilibration step is sent to the mass spectrometry unit via the switching valve before a solution from a first separation column undergoing the chromatographic separation step is sent to the mass spectrometry unit via the switching valve, and a solution from a third separation column undergoing the equilibration step is sent to the mass spectrometry unit via the switching valve after the solution from the first separation column undergoing the chromatograph separation step is sent to the mass spectrometry unit via the switching valve.

Description

Automatic analyzer

[0001] The present invention relates to an automatic analyzer.

[0002] A liquid chromatograph is a device that identifies components by utilizing the property that each component in a solution containing a measurement target component reaches a detector at different times due to differences in the interaction between the component and a separation column. To improve the throughput of this liquid chromatograph, there is a multi-stream liquid chromatography system (multi-column chromatograph device). This is a device that shares a detector among a plurality of liquid chromatographs provided in parallel, and each liquid chromatograph processes by shifting the equilibration, elution, and washing processes, and continuously elutes the measurement target component to the detector (see Patent Document 1).

[0003] International Publication No. 2020 / 105661

[0004] In Patent Document 1, for the purpose of improving the analysis throughput, an analysis sequence was implemented in which, after performing mass spectrometry on the eluate from one separation column, mass spectrometry on the eluate from the next separation column was performed. In such an analysis, even if some malfunction occurs in the device and abnormal measurement results are obtained by mass spectrometry, there was a concern that the operator would not notice it and report incorrect analysis results or that it would be necessary to re-measure precious specimens.

[0005] An object of the present invention is to provide an automatic analyzer having a plurality of chromatographic separation units that can quickly determine whether a malfunction has occurred in the device and an abnormality has occurred in the result of mass spectrometry.

[0006] The configuration of the present invention for achieving the above object is as follows. A separation column that executes each process in the order of an equilibration process, a liquid chromatograph separation process, and a column washing process, a mass spectrometry unit to which a plurality of separation columns are connected via a switching valve, and before sending the solution from the first separation column in the liquid chromatograph separation process to the mass spectrometry unit via the switching valve, the solution from the second separation column in the equilibration process is sent to the mass spectrometry unit via the switching valve, and a control unit that controls the switching valve.

[0007] According to the present invention, it is possible to provide an automated analyzer having multiple chromatographic separation units that can quickly determine whether a malfunction has occurred in the device and whether an abnormality has occurred in the mass spectrometry results.

[0008] Schematic diagram of a multistream liquid chromatograph-mass spectrometer. Diagram showing the analysis sequence when performing continuous analysis with gradient elution. Diagram showing an example of a gradient program for eluting a sample. Diagram showing an example of a gradient program for eluting a sample. Diagram explaining the analysis sequence when there are multiple LC columns. Diagram explaining the position of the switching valve when performing the measurement shown in Figure 4. Diagram showing the connection diagram of the switching valve. Diagram showing the analysis sequence when the equilibration, LC separation, and washing processes are performed in series on each column. Diagram showing the sequence of the analysis processing schedule. Diagram showing another example of the sequence of the analysis processing schedule. Diagram showing the results of mass spectrometry of the LC separation solution from the first LC column and the solution in the final state of the equilibration process of the second LC column. Flowchart showing the analysis flow.

[0009] Embodiments of the present invention will be described below with reference to the accompanying drawings. It should be noted that the present invention is not limited to these embodiments and can be applied within the scope of the technical concept. For example, in this embodiment, there is one separation column per stream, but the number of separation columns can be any number of one or more.

[0010] Figure 1 shows a multi-stream liquid chromatograph system. The liquid chromatograph analysis unit 101 (also referred to as the "LC analysis unit") comprises multiple separation columns (also referred to as "LC columns" or the "liquid chromatograph separation unit"), namely the first LC column 103, the second LC column 104, the third LC column 105, and the fourth LC column 106. The first LC column is referred to as Stream 1, the second LC column as Stream 2, the third LC column as Stream 3, and the fourth LC column as Stream 4.

[0011] The first LC column 103 includes two liquid delivery pumps (also called liquid delivery units or discharge units) 150a and 150b that deliver different solvents from reagent bottle A and reagent bottle B at varying concentrations, a mixer for mixing the solvents, a sample injection valve (also called a sample injection unit or injection port) 121 for introducing the sample into the flow path 107, and a column thermostat (not shown) for stabilizing the performance of the LC column.

[0012] Although Figure 1 shows the second LC column 104, the third LC column 105, and the fourth LC column 106 configured for use in isocratic mode, where a single solvent is dispensed from a single reagent bottle, they may also be used in gradient mode, using different solvents, similar to the first LC column 103.

[0013] The first LC column 103, the second LC column 104, the third LC column 105, and the fourth LC column 106 are connected in parallel to each other and are connected to a single mass spectrometry unit 102 (also referred to as the "MS analysis unit" or "mass spectrometer") via a flow path 112 by a flow path switching valve (also referred to as the "flow path switching unit") 118.

[0014] Furthermore, a reagent bottle 120 is also connected to the flow path switching valve 118. The reagent contained in the reagent bottle 120 flows directly to the mass spectrometry unit 102 without passing through the LC column. Therefore, it contains reagents for directly confirming the detection status in the mass spectrometry unit 102 (for example, standard samples with known concentrations to quantitatively determine the analysis results in the mass spectrometry unit), and analysis is performed in the mass spectrometry unit 102 as needed.

[0015] The device control unit 122 controls the operation of each liquid chromatograph separation unit 103, 104, 105, and 106, the flow path switching valve 118, and the mass spectrometry unit 102. The device control unit 122 is also connected to a device operation unit 123 equipped with a device display unit capable of displaying analysis results and other information.

[0016] The liquid delivery pump performs gradient elution by delivering multiple different solvents to the separation column while varying their mixing ratios. In gradient elution, the liquid delivery pump initially delivers solvents to the separation column in a composition with low sample dissolving power, so that almost all of the components in the mixed sample solution injected into the separation column are adsorbed onto the separation column.

[0017] Next, the liquid delivery pump gradually changes the solvent mixture ratio to a composition with high elution power, so that the components in the sample adsorbed on the separation column are desorbed from the separation column one by one and eluted to the detector in sequence. After the target component is detected, the liquid delivery pump changes the solvent mixture ratio to a composition with the highest elution power in order to wash away any components that are difficult to desorb from the separation column.

[0018] Thus, in gradient elution, the solvent composition in the separation column changes with a single analysis of a single sample. For example, the conditions for gradient elution are: Solvent A is ultra-high-purity water for LC / MS analysis (LC / MS grade water), and Solvent B is a solvent prepared by mixing 0.04 mM ammonium fluoride with ultra-high-purity methanol for LC / MS analysis (0.04 mM Ammonium fluoride in LC / MS grade methanol). When these are delivered at a flow rate of 440 μL / min, for a certain period from the start of delivery, the solvents are delivered in a mixture of 54% Solvent A and 46% Solvent B. After that, the mixture is changed to 39% Solvent A and 61% Solvent B, and then to 2% Solvent A and 98% Solvent B, and so on, while changing the mixing ratio of the solvents.

[0019] When performing continuous analysis using gradient elution, equilibration (sometimes abbreviated as equi.) is required after each analysis to return the solvent in the separation column to its initial concentration in order to start the next analysis. In other words, gradient elution in liquid chromatography requires the processes of equilibration (equil.), elution (also called "LC separation"), and washing (also called "column washing") for each measurement, as shown in Figure 2. Of these processes, the time the detector takes to acquire analytical results is limited to the elution process, and even more specifically, the time during which the target component is eluted. Generally, the detector is in a standby state for analysis during the equilibration and washing processes.

[0020] The equilibration process, LC separation process, and washing process described above will be explained in detail. Figure 3 shows two examples of gradient programs for eluting the sample (Example of Program A in Figure 3A and Example of Program B in Figure 3B).

[0021] In Figures 3A and 3B, gradient programs A and B are used for the analysis of different target components. Both gradient programs consist of three main processes: "column equilibration" 201, "elution of target component (LC separation)" 202, and "column washing" 203. In Figures 3A and 3B, the vertical axis represents the solvent composition of the pump, and the horizontal axis represents time.

[0022] Taking the first LC column 103 as an example, the liquid delivery pumps 150a and 150b equilibrate the inside of the column to its initial state with a solvent mixture ratio that has a weak sample dissolving power (column equilibration 201). After sufficient time (t1) for column equilibration 201, the sample injection valve (injection port) 121 injects the sample solution into the flow path in the first LC column 103.

[0023] Once the sample solution is injected, the liquid delivery pumps 150a and 150b deliver the solution while gradually changing the composition of the mixed solution so that the component to be measured is separated from other components in the sample. The component to be measured is eluted and detected by the mass spectrometer 102, which is the detector.

[0024] Once the elution of the target component 202 is complete (t2), the liquid delivery pumps 150a and 150b change the solvent composition of the mixed solution to a mixing ratio that provides strong elution, and wash away any other contaminants adsorbed on the first LC column 103 (column washing 203).

[0025] The analysis is completed after a sufficient time (t3) for cleaning the inside of the first LC column 103. If continuous analysis is required, this process is repeated.

[0026] As shown in gradient programs A and B, the solvent mixing ratio for each process differs depending on the component being measured. However, in continuous analysis, column equilibration 201 prevents the conditions of the previous analysis from affecting the next analysis. Furthermore, column washing 203 prevents contaminating components in the previous sample solution from affecting the next analysis.

[0027] Here, in the processes of gradient programs A and B, the part in which the detector of the mass spectrometry unit 102 operates to detect the measurement component is the elution of the measurement target component 202.

[0028] In the multi-stream liquid chromatograph system shown in Figure 1, the instrument control unit 122 adjusts the timing of sample injection into the injection port so that the elution of the target component (elution process) 202, in which the detector of the mass spectrometry unit 102 operates, does not overlap between streams 1 to 4 of the first LC column 103, the second LC column 104, the third LC column 105, and the fourth LC column 106.

[0029] Figure 4 illustrates the analysis sequence when there are multiple LC columns. In Figure 4, the LC separation cycle (612) using the first LC column is denoted as cycle No. n, the preceding cycle as n-1, and the subsequent cycle as n+1. In liquid chromatography-mass spectrometry (LC / MS analysis) using a multistream, the solution eluted by LC separation using the separation column (612, 622, 632) is continuously supplied to the mass spectrometry unit 102 for mass spectrometry (MS analysis) (641, 642, 643). This allows the mass spectrometry unit 102 to analyze without being paused in the middle of a cycle, thus shortening the measurement time (improving throughput).

[0030] Figure 5 illustrates the position of the switching valve when performing the measurement shown in Figure 4. When mass spectrometry (641) is performed on the eluate obtained from LC separation (612) using the first LC column, the first position (201) in Figure 5 is selected. In this case, the solutions from the second LC column, the third LC column, the fourth LC column, and the reagent bottle are connected to the flow path leading to the waste liquid section. Figure 6 shows an actual connection diagram of the switching valve.

[0031] The first position (A) in the upper left of Figure 6 is a valve connection diagram for when the eluted material from LC separation (612) using the first LC column is subjected to mass spectrometry (641). Since valve number 1 of the switching valve is connected to the flow path 107 that leads to the first LC column, the solution from the first LC column flows to the mass spectrometry unit 102 (in the figure, the solution in the dashed flow path is sent to the mass spectrometry unit and subjected to mass spectrometry).

[0032] Since valves 2 and 3 of the switching valve are connected inside the switching valve, the flow path 108 connected to the second LC column is connected to the flow path 114 connected to the waste liquid section. Since valves 4 and 5 of the switching valve are connected inside the switching valve, the flow path 109 connected to the third LC column is connected to the flow path 115 connected to the waste liquid section. Since valves 6 and 7 of the switching valve are connected inside the switching valve, the flow path 110 connected to the fourth LC column is connected to the flow path 116 connected to the waste liquid section. Since valves 8 and 9 of the switching valve are connected inside the switching valve, the flow path 111 connected to the reagent bottle 120 via pump 119 is connected to the flow path 117 connected to the waste liquid section.

[0033] When mass spectrometry (642) is performed on the eluate obtained from LC separation (622) using the second LC column in Figure 4, the second position (202) in Figure 5 is selected. In this case, the flow path connected to the waste liquid section consists of the first LC column, the third LC column, the fourth LC column, and the reagent bottle.

[0034] The second position (B) in the upper right of Figure 6 is a valve connection diagram for when eluted material from LC separation (622) using a second LC column is subjected to mass spectrometry (642). Since valve number 3 of the switching valve is connected to the flow path 108 that leads to the second LC column, the solution from the second LC column flows into the mass spectrometry unit (the solution in the dashed flow path is sent to the mass spectrometry unit and subjected to mass spectrometry).

[0035] Since valves 4 and 5 of the switching valve are connected inside the switching valve, the channel 109 connected to the second LC column is connected to the channel 115 connected to the waste liquid section. Since valves 6 and 7 of the switching valve are connected inside the switching valve, the channel 110 connected to the fourth LC column is connected to the channel 116 connected to the waste liquid section. Since valves 8 and 9 of the switching valve are connected inside the switching valve, the channel 111 connected to the reagent bottle 120 via pump 119 is connected to the channel 117 connected to the waste liquid section. Since valves 10 and 1 of the switching valve are connected inside the switching valve, the channel 107 connected to the first LC column is connected to the channel 113 connected to the waste liquid section.

[0036] The explanation of the third position (203), fourth position (204), and fifth position (205) in Figure 6 is omitted, but each flow path and mass spectrometry unit are connected in the same way as described above. Since the switching valve is rotary (rotary multi-way valve), for example, when changing from the first position to the third position, the switch is made via the second position. Even in this case, the pump connected to the second LC column, which is connected to the mass spectrometry unit in the second position, does not operate while the switching valve is passing through the second position, and the time spent passing through the second position is also short, so the solution remaining in the flow path 108 connected to the second LC column does not flow to the mass spectrometry unit 102.

[0037] Incidentally, in LC / MS analysis using a multi-stream system, measurement time is shortened by performing only the mass spectrometry necessary for measuring the target component. However, as a trade-off for this shortened measurement time, mass spectrometry (MS analysis) of background ions (equilibrium (611, 621, 631) and washing (613, 623, 633)) cannot be performed. Therefore, it is not possible to check the degree of impurity contamination or column stabilization using mass spectrometry. As shown in Figure 7, if the equilibration, LC separation, and washing processes in one column are completed before performing the equilibration, LC separation, and washing processes in the next column, mass spectrometry can be performed at each step. However, this defeats the purpose of using a multi-stream system in order to improve throughput.

[0038] The inventors diligently studied an LC / MS analyzer that shortens the measurement time using the analysis sequence shown in Figure 4, and that allows for mass spectrometry to be performed to the extent that impurities are present and the degree of column stabilization can be confirmed during the equilibration and washing processes carried out before and after the LC separation process, leading to the following embodiment.

[0039] Figure 8 shows the sequence of the analytical processing schedule. After the LC separation step in the first LC column (the first position of the switching valve in Figure 6), in conventional equipment, the switching valve is set to the second position in order to perform mass analysis on the eluent from the LC separation step in the second LC column. In this embodiment, however, an additional switching valve position is added, as shown at the bottom of Figure 8.

[0040] Specifically, before the equilibration process of the second LC column is completed, the switching valve is switched to the second position to send the solution in the final state of the second LC column equilibration process to the mass spectrometer for mass spectrometry. Subsequently, after the equilibration process of the third LC column begins, the switching valve is switched to the third position to perform mass spectrometry on the solution in the initial state of the third LC column equilibration process. By rotating the switching valve counterclockwise, it is moved to the fourth and fifth positions, and in the first position, mass spectrometry is performed on the solution in the initial state of the first LC column washing process.

[0041] By doing so, it becomes possible to perform mass spectrometry of the solution outside the LC separation process in the first to third LC columns. Further, if necessary, mass spectrometry of the reagent in the reagent bottle can also be performed at the fifth position in FIG. 6. The mass spectrometry value at this time is smaller than or equivalent to the background value in the mass spectrometry during equilibration and cleaning related to the column. Therefore, it can be used as a reference for the background value. That is, between switching the switching valve from the first position to the second position, after rotating the switching valve once through the second position, the third position, the fourth position, the fifth position, and the first position, as in the conventional case, returning to the second position is a feature of this embodiment.

[0042] For example, assuming that the mass spectrometry time of the eluate separated by the conventional device is 40 seconds, it is possible to maintain each position of the second position, the third position, and the first position for 3 seconds each, and by reducing the mass spectrometry time of the eluate to 40 seconds - (3 seconds × 3) - (time required for the rotation of the switching valve) ≒ 31 seconds, the same throughput as the conventional device can be ensured (on the premise that the mass spectrometry of the reagent bottle at the fifth position is not performed).

[0043] Note that the time required for the rotation of the switching valve is about 0.2 seconds per position, so the time required for rotating the switching valve once is estimated to be about 0.2 seconds × 5 = 1 second. The mass spectrometry time of the eluate and the holding time at each position of the second position, the third position, and the first position are preferably set appropriately in view of the accuracy of the mass spectrometry of the eluate and the measurement accuracy of the background value measured at each position of the second position, the third position, and the first position.

[0044] Further, although not shown in FIG. 8, the switching of the switching valve position shown below FIG. 8 (switching for rotating the switching valve once) may be provided similarly between positions 2 and 3, 3 and 5, and 5 and 1 of the switching valve, so that each time the separation columns LC1 to LC4 are switched, the mass spectrometry background value in the equilibration process and the cleaning process can be obtained.

[0045] Furthermore, the direction in which the switching valve is rotated one full turn may be the opposite direction to that shown in the example. Alternatively, during the first LC1-LC4 analysis, the switching valve position shown in the lower part of Figure 8 may be used only between switching valve positions 1 and 2, and during the second LC1-LC4 analysis, the switching valve position shown in the lower part of Figure 8 may be used only between switching valve positions 2 and 3. Doing so can reduce the number of switching cycles of the switching valve, which is expected to extend the lifespan of the switching valve.

[0046] Figure 8 illustrates an example of using the first LC column (LC1) to the third LC column (LC3) for analytical processing. Figure 9 shows an example of additional switching valve positions when all separation columns from LC1 to LC4 shown in Figure 1 are used for analysis. Figure 9 shows a method of rotating the switching valve once between switching valve positions 2 and 3. By rotating the switching valve once between switching valve positions 2 and 3, it becomes possible to perform mass spectrometry on the final state of the LC3 equilibration process, the initial state of the LC4 equilibration process, the state of the reagent supplied from the reagent bottle (if necessary), the final state of the LC1 washing process, and the initial state of the LC2 washing process, and to obtain the background values ​​for each state.

[0047] Note that in Figure 1, since four separation columns are used, there are only up to five valve positions. However, if there are five or more separation columns, the same analytical processing as shown in Figure 9 can be performed by increasing the number of valve positions accordingly. Also, even in the setup shown in Figure 9, as mentioned above, it is possible to acquire the mass spectrometry background values ​​for the equilibration and washing processes each time the separation column is switched (i.e., between switching valve positions 1 and 2, between 2 and 3, between 3 and 4, between 4 and 5, and between 5 and 1).

[0048] Figure 10(a) shows the mass spectrometry results (mass spectrum of the measurement target) in the LC separation step using the first LC column (the first position of the switching valve in Fig. 6), and Fig. 10(b) shows the result of performing mass spectrometry by feeding the solution in the final state of the equilibration step of the second LC column to the mass spectrometry section by switching the switching valve to the second position before the equilibration step of the second LC column ends. The vertical axis represents the count value, and the horizontal axis represents m / z (mass-to-charge ratio). The region without peaks indicates the background value.

[0049] The background values in Fig. 10(a) and Fig. 10(b) should originally show almost the same value. However, if the background values of the two are extremely different, there may be some problems with the device, such as dirt remaining on the separation column or the like. If the background values differ by more than a predetermined value, the device control unit 122 controls the display unit attached to the device operation unit 123 to display a message recommending device maintenance, so that correct measurement results can be obtained without wasting precious samples.

[0050] Also, the change of the background value over time may be stored in the storage unit of the device control unit 122, and a threshold value for recommending maintenance may be calculated based on the past background values stored in the storage unit. Further, the time when the extrapolation line of the change over time intersects the threshold value for recommending maintenance may be displayed (notified) on the display unit (notification unit) of the device operation unit 123 as the time when maintenance is required.

[0051] Also, the way the background value changes for each type of problem may be stored in the device control unit 122 in advance, and the type of maintenance recommended (such as the above-mentioned poor column cleaning) may be indicated by the change in the background value.

[0052] Furthermore, when the measurement result is not satisfactory (for example, the IS signal value drifts, is too large, or too small), carryover is observed, or when the QC measurement is out of specification, it is possible to determine whether it is caused by background ions.

[0053] Furthermore, by using the background value obtained from the mass analysis of the solution delivered directly from the reagent bottle 120 to the mass spectrometry unit 102 without passing through the separation column, rather than the value measured by mass during the equilibration and washing process (the mass measurement of the solution that has passed through the separation column), it becomes possible to measure the background value of the mass spectrometry unit alone and detect whether or not there is an abnormality in the mass spectrometry unit alone.

[0054] Furthermore, by using the mass spectrometry background value of the solution from reagent bottle 120 as a reference background value and comparing it with the mass spectrometry background value of the solution that has passed through the separation column, the degree of contamination of the separation column can also be evaluated.

[0055] This embodiment is particularly effective in devices that use multi-streams to perform random access (allowing the flow path to be set regardless of the analysis item) and schedule measurements to minimize the time required.

[0056] Next, we will explain the flowchart showing the analysis flow using Figure 11. First, the analysis items to be analyzed are registered in the device using the device operation unit 123 in Figure 1 (S902). Examples of analysis items include the steroids estradiol and testosterone, the immunosuppressants cyclosporine and tacrolimus, and the antibiotics gentamicin and tobramycin. The requested items vary depending on the patient sample, and the user makes the request from the device operation unit.

[0057] Next, the analysis processing schedule is performed (S903). Using multi-streams, random access is supported (the flow path can be set regardless of the analysis item), and scheduling is performed to determine which analysis flow path (stream) to use, which analysis item to analyze, and in what order, in order to minimize the measurement time.

[0058] Next, in the analysis processing scheduling in S903, a schedule is implemented to perform the analysis of the sample in the LC column channel designated for analysis (S904). In Figure 11, this is indicated as performing the analysis in the nth LC column channel (LC n channel). In the embodiment shown in Figure 1, there are four analysis columns, from the first LC column to the fourth LC column, so there are n=1 to n=4.

[0059] Note that Figure 11 is illustrated assuming that the analysis starts from the LC1 channel, but it is not limited to such an embodiment and merely represents the intention to schedule the analysis process for all available analysis columns. For example, if the first LC column is unavailable for analysis due to column lifespan or other reasons, the analysis will start from the LC2 channel.

[0060] Furthermore, the analysis processing schedule does not necessarily have to be in the order of LC1, LC2, LC3, LC4; it may also be scheduled in the order of LC4, LC3, LC2, LC1. Moreover, for some analysis items, it may be scheduled to be assigned randomly.

[0061] In the analysis processing scheduling in S903, the sample is eluted in the LC column flow path designated for analysis (here referred to as LC1, the first separation column) (S905), and the mass analysis of the sample eluted in S905 is performed in the first position of the switching valve position shown in Figure 6 (S906).

[0062] Next, as explained using Figure 8, the MS valve position switching n→n+1→n+2→n+3→n+4→n involves switching the switching valve through the first position, second position, third position, fourth position, fifth position, and back to the first position, and then performing mass spectrometry (S907).

[0063] Furthermore, in the case shown in Figure 9, the MS valve position switching n→n+1→n+2→n+3→n+4→n involves switching the switching valve to the second position, third position, fourth position, fifth position, first position, and then back to the second position, and performing mass spectrometry (S907). Background values ​​are obtained from the mass spectrum shown in Figure 10, which is obtained in S907, and these are compared (S908).

[0064] Next, it is determined whether the difference between the background value obtained by mass spectrometry of the eluent from LC1 (the background value shown in Figure 10(a)) and the background value obtained by mass spectrometry of solutions from other columns performed before and after the analysis in LC1 (in Figure 8, the background value obtained by mass spectrometry of the final state of the equilibration process of LC2 (the background value shown in Figure 10(b)), the initial state of the equilibration process of LC3, and the initial state of the washing process of LC1), and / or the value stored in the memory unit of the device control unit 122, which is not shown in Figure 8, falls within a predetermined range (S909).

[0065] If the value is within the predetermined range, the LC1 column is determined to be ready for analysis, and the analysis process proceeds to the next separation column, and the scheduled analysis is performed (S904). If the value is not within the predetermined range, a decision is made on whether to mask the analysis processing schedule using the LC1 channel of the LC1 column (S910). "Masking" means that the software of the control unit prevents the LC1 channel of the LC1 column from being designated as a channel to be used for analysis.

[0066] In a multi-stream liquid chromatography system, for example, if a separation column reaches the end of its lifespan, it can be replaced by masking it. Similarly, in this embodiment, masking is performed when the background value is abnormal. If masking is performed, the system proceeds to the analysis processing scheduling (S903), and after rescheduling, the schedule is executed (S994). If masking is not performed, the system notifies the user of a maintenance recommendation for the LCn flow path (S911), and then the schedule is executed (S904).

[0067] The analysis will be terminated once the analysis using the separation column has been completed for all analysis request items requested in S902.

[0068] 101: Liquid chromatography analysis unit, 102: Mass spectrometry unit, 103: First LC column, 104: Second LC column, 105: Third LC column, 106: Fourth LC column, 107-117: Flow channels, 118: Flow channel switching valve, 119: Pump, 120: Reagent bottle, 121: Injection port, 122: Device control unit, 123: Device operation unit, 150a, 150b: Liquid delivery pump.

Claims

1. An automated analyzer comprising: a separation column that performs each step in the order of equilibration step, liquid chromatography separation step, and column washing step; a mass spectrometry unit in which a plurality of the separation columns are connected via a switching valve; and a control unit that controls the switching valve so that, before the solution from the first separation column in the liquid chromatography separation step is sent to the mass spectrometry unit via the switching valve, the solution from the second separation column in the equilibration step is sent to the mass spectrometry unit via the switching valve.

2. An automated analyzer according to claim 1, characterized in that the control unit controls the switching valve so that, after the solution from the first separation column in the liquid chromatography separation step is sent to the mass spectrometry unit via the switching valve, the solution from the third separation column in the equilibration step is sent to the mass spectrometry unit via the switching valve.

3. An automatic analyzer according to claim 2, wherein the switching valve is a rotary multi-way valve and is configured to simultaneously supply the solutions from the second and third separation columns to the waste liquid section when the solution from the first separation column in the liquid chromatography separation step is being supplied to the mass spectrometry section.

4. An automated analyzer according to claim 2, characterized in that the control unit compares the background value obtained when the solution from the first separation column in the liquid chromatography separation step is analyzed by the mass spectrometry unit, the background value obtained when the solution from the second separation column in the equilibration step is analyzed by the mass spectrometry unit, and the background value obtained when the solution from the third separation column in the equilibration step is analyzed by the mass spectrometry unit, and determines whether the first separation column requires maintenance.

5. An automated analyzer according to claim 1, wherein the switching valve has a reagent position for supplying a reagent to the mass spectrometry unit without going through the separation column, and the control unit compares the background value when the reagent supplied to the mass spectrometry unit without going through the separation column is analyzed in the mass spectrometry unit with the background value when the solution from the first separation column in the liquid chromatography separation step is analyzed in the mass spectrometry unit, and determines whether or not maintenance of the first separation column is required.

6. An automated analyzer according to claim 4, characterized in that the control unit determines whether maintenance of the first separation column is required by determining whether the difference between the background value obtained when the solution from the first separation column in the liquid chromatography separation step is analyzed by the mass spectrometry unit, the background value obtained when the solution from the second separation column in the equilibration step is analyzed by the mass spectrometry unit, and the background value obtained when the solution from the third separation column in the equilibration step is analyzed by the mass spectrometry unit exceeds a threshold determined based on past measured values ​​of the background value stored in the control unit.

7. An automatic analyzer according to claim 4, characterized in that the control unit includes a notification unit that notifies the first separation column when it determines that maintenance is required.

8. An automated analyzer according to claim 1, characterized in that there are four or more separation columns connected to the mass spectrometry section via the switching valve.

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