Chromatograph having operation controller that causes automatic purging in a case of detection failure

To make it easy to address the case in which a chromatograph does not appropriately operate. A chromatograph (liquid chromatograph 100) for analyzing a sample by supplying an eluent and the sample and separating a component contained in the sample to detect the component, the chromatograph including: a detection portion (controller 170) configured to detect a fault in the analysis; and an operation controller (controller 170) configured to cause a constituent element related to the analysis to perform at least one of an operation for identifying a factor of the fault and an operation for avoiding the fault.

This application claims the benefit of Japanese Patent Application No. 2018-185298 filed Sep. 28, 2018, which is hereby incorporated by reference in its entirety into this application.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a chromatograph, and more particularly, to a technology capable of facilitating an appropriate operation and the like of the chromatograph.

2. Description of the Related Art

As a technology capable of facilitating an appropriate operation of a chromatograph, there has been known a technology involving displaying a guidance on check items when a known sample is analyzed and an analysis error occurs (see, for example, Patent Literature 1).

SUMMARY OF THE INVENTION

However, when the chromatograph does not appropriately operate, the cause thereof cannot always be identified based on an analysis result. In addition, even when the guidance on the check items is displayed, skill and experience of a user may be required in some cases in order to address an error. Thus, it is not always easy to enable the chromatograph to appropriately operate.

The present invention has been made in view of the forgoing, and an object of the present invention is to make it easier to address the case in which a chromatograph does not appropriately operate.

In order to achieve the above-mentioned object, according to a first aspect of the present invention, there is provided a chromatograph for analyzing a sample by supplying an eluent and the sample and separating a component contained in the sample to detect the component, the chromatograph including: a detection portion configured to detect a fault in the analysis; and an operation controller configured to cause a constituent element related to the analysis to perform at least one of an operation for identifying a factor of the fault and an operation for avoiding the fault.

With this, when various faults in the analysis of the sample are detected, the operation for identifying the factors of the faults and the operation for avoiding the faults are performed. Thus, the case in which the chromatograph does not appropriately operate can easily be addressed.

According to the present invention, the case in which the chromatograph does not appropriately operate can easily be addressed.

DESCRIPTION OF THE EMBODIMENTS

Now, an embodiment of the invention is described in detail with reference to the drawings.

A schematic configuration of a liquid chromatograph100is illustrated inFIG.1. The liquid chromatograph100includes a pump110(gradient pump), an auto-sampler120, guard columns132and133(or pre-columns), a separation column142, a temperature sensor143and a column thermostat144, a reactor152, a detector160, and a controller170(detection portion, operation controller). The pump110is configured to feed an eluent supplied from an eluent tank112through a valve111. The auto-sampler120is configured to inject a sample (not shown) and has an automatic purging function. The guard columns132and133are provided so as to be switchable with a six-way valve131. The separation column142is provided so as to be separable with a six-way valve141. The temperature sensor143and the column thermostat144are configured to detect and control the temperature of the separation column142. The reactor152is provided so as to be separable with a six-way valve151. The detector160is configured to detect a separated component in a sample. The controller170is configured to control the operation of each constituent element of the liquid chromatograph100. One or a plurality of (in) line filters may be provided separably or switchably together with or in place of the guard columns132,133, and the like, and may be similarly controlled. In addition, the type of the reactor152is not particularly limited, and for example, a cartridge type reactor, a reaction column, or a reaction coil can be applied.

Specifically, the controller170is configured to detect an abnormal increase in pump pressure and a fault such as a detection failure of each component, for example, based on the pump pressure detected by a pressure sensor113, the temperature of the separation column142detected by the temperature sensor143, and the detection result of each component in the sample detected by the detector160, and to cause each portion to perform an operation for identifying a factor of the fault and an operation for avoiding the fault. More specifically, the controller170includes an inference engine170aas illustrated inFIG.2, and is configured to adjust the operations of the six-way valves131to151, the column thermostat144, and the pump110based on the knowledge data obtained from a knowledge data storage170band a communication portion170c, and the like in accordance with the input signals input from the pressure sensor113, the temperature sensor143, and the detector160. Now, a specific example is described below.

(Identification of Factor of Pump Pressure Abnormality and Avoidance of Abnormality)

When the pump pressure detected by the pressure sensor113is abnormally increased, the controller170identifies a factor of an increase in pump pressure by sequentially switching to control the six-way valves131to151, for example, as shown in Table 1.

TABLE 1Operation for identifyingSensingfactor or operation forPhenomenondatacountermeasures, and resultsPresumed factorOther operation examplesIncrease inPumpPressure is decreased throughFailure of reactor 152Guidance on replacement of reactor 152pressurePressureseparation of reactor 152Pressure is decreased throughFailure of separation columnGuidance on replacement of separationseparation of separation142column 142column 142Pressure is decreased throughFailure of guard column 132switching from guard column132 to guard column 133Pressure is decreased throughFailure of guard column 133switching from guard column133 to guard column 132UnclearGuidance on service callSeparationChromatogramSwitching of eluent is delayedSwitching of eluent isfailure(Separationexcessively earlydegree)Switching of eluent is hastenedSwitching of eluent isexcessively lateColumn temperature is changedColumn temperature isinappropriateSwitching timing of columnSwitching timing of columntemperature is changedtemperature is inappropriateComposition of eluent isComposition of eluent ischangedinappropriateLow peakChromatogramPeak height is increased byPurging is insufficient(Peak height)performing AS automaticpurging when AS automaticpurging has not been performedNinhydrin reagent is degradedIn case in which peak height is low even afteror reference sample is degradedAS automatic purging is performed, when twoor more weeks have elapsed after replacement ofninhydrin reagent, replacement of ninhydrinreagent is presented, and when two or moreweeks have not elapsed after replacement ofninhydrin reagent and one or more months haveelapsed after preparation of reference sample,preparation of reference sample is presented.

For example, first, the guard columns132and133are switched from one to another with the six-way valve131. When the pump pressure is decreased to an appropriate pressure with this, the guard columns132and133are identified as the factor of the fault, and the fault is avoided, with the result that the subsequent detection can be appropriately performed.

In addition, when the pump pressure is not decreased even through switching of the guard columns132and133, the reactor152is then separated from a liquid feeding flow passage with the six-way valve151. When the pump pressure is decreased to an appropriate pressure with this, the reactor152is identified (presumed) as the factor of the fault. In this case, a message for prompting a user to replace the reactor152is displayed on a display portion (not shown). When the reactor152is replaced by the user, the subsequent detection can be appropriately performed.

Further, when the pump pressure is not decreased even through separation of the reactor152, the separation column142is then separated from the liquid feeding flow passage with the six-way valve141. When the pump pressure is decreased to an appropriate pressure with this, the separation column142is identified as the factor of the fault, and a message for prompting the user to replace the separation column142is displayed in the same manner as in the case of the reactor152. When the separation column142is replaced by the user, the subsequent detection can be appropriately performed. The guard columns132and133may be switched after an attempt to separate the reactor152is made, that is, so that confirmation is performed sequentially from a downstream side.

When the factor of the fault is automatically identified, and the fault is avoided, inspection can be smoothly continued. In addition, it is not required for an analysis operator to pay attention to an appropriate pump pressure.

The number of the guard columns132and133to be provided is not limited to two. Only one guard column may be provided so as to be replaced by the user in the case of a fault in the same manner as in the separation column142and the reactor152. Meanwhile, three or more guard columns may be provided so as to be sequentially switched to be used. In addition, each number of the separation column142and the reactor152to be provided is not always limited to one. A plurality of separation columns142and a plurality of reactors152may be provided, respectively, so as to be automatically switched.

In addition, when the six-way valves131to151are switched, for example, the flow rate of the pump may be controlled so that an abrupt increase in pump pressure is prevented.

In addition, when the factor of the fault cannot be identified even though the above-mentioned operations are performed, for example, an inquiry to an expert may be automatically made through communication means such as the Internet or a message for prompting the user to make an inquiry through service call through use of a telephone, sending of mail, or the like.

(Detection and Avoidance of Fault Through Analysis of Chromatogram)

The detection of a fault through analysis is not limited to the detection using a sensor such as the pressure sensor113as described above. For example, the fault may be detected by obtaining a chromatographic performance indicator through analysis of a chromatogram obtained after measurement is performed once or more. In addition, the operation for identifying a factor of the fault or the operation for avoiding the fault may be the operation of setting various apparatus setting parameters set in an apparatus for measurement. As the chromatographic performance indicator, for example, a Resolution, a separation factor, theoretical plate number, a peak area, a peak height, a peak width, a retention time, a holdup time, a retention factor, a height equivalent to a theoretical plate, a column pressure loss, a symmetry factor, a peak-valley ratio, an SN ratio, a baseline noise, a baseline drift, a limit of detection, a limit of quantitation, accuracy, and trueness can be applied. In particular, for example, a degree of a separation performance including at least one of the Resolution, the separation factor, the theoretical plate number, the height equivalent to a theoretical plate, and the peak width of the component can be applied. In addition, the apparatus setting parameters refer to setting of hardware, and for example, a gradient elution time program, an eluent switching timing, an eluent composition, a flow rate, an injection volume, a sample dilution magnification ratio, a column temperature, a column temperature switching timing, column selection, a reaction temperature, a reaction reagent composition, a detection wavelength, a detection wavelength switching timing, and a response time constant can be applied. In particular, for example, an elution condition including at least one of the eluent switching timing, the gradient elution time program, the column temperature switching timing, and the flow rate can be applied.

With this, the measurement operation can also be changed on the apparatus side so as to satisfy an optimum condition. Further, for example, in the case in which samples each having the same composition are mounted on a plurality of auto-samplers in order to perform repeating measurement or the like, when a fault is detected as described above through analysis of an initial measurement result, the setting may be changed to perform subsequent measurement. In this case, the change in setting in the apparatus may be announced to repeat measurement. In addition, the change in condition may be instructed to a measurer.

In addition, it may be determined whether or not the set condition has a flaw or whether or not the apparatus side is not operated in accordance with the set condition for some reason although the set condition is appropriate, and the operation in accordance with the determination may be performed. That is, for example, when the Resolution is less than a threshold value (specifically, for example, when the separation degree between Ala and Cys is less than 1.2), this fault is generally caused by a flaw of the set condition. However, there is also a possibility that the theoretical plate number of the separation column that is the constituent element of the apparatus may be decreased although the set condition is appropriate. In such case, the number of theoretical stages of the separation column as well as the separation degree are added to a determination indicator, and it can be determined whether the fault is caused by the condition flaw or the apparatus. In the case of the condition flaw, the set condition is changed. In this case, for example, when the theoretical plate number of an isolated peak of Gly or the like is less than 3,000, it is determined that the fault is caused by the apparatus. Then, this determination may be displayed as a presumed factor caused by the apparatus or an operation of avoiding the fault, such as a switching operation of a (separation) column, may be caused to be performed.

(Avoidance of Separation Degree Failure 1)

When it is detected that the separation degree of a predetermined component is not appropriate through analysis of the chromatogram obtained as the detection result of the detector160, the separation failure can be automatically avoided by controlling the eluent switching timing also as shown in Table 1.

Specifically, for example, in the case in which analysis of an amino acid is performed through use of a gradient method, when there is detected an early peak state, which is at least one of a state in which a Resolution between alanine (Ala) and cysteine (Cys) is 1.0 or less and a state in which a peak time difference t1between alanine (Ala) and cysteine (Cys) is a predetermined time or less, as shown inFIG.3A, the eluent switching timing is delayed through control of the valve111. Meanwhile, when there is detected a late peak state, which is at least one of a state in which a Resolution between cysteine (Cys) and valine (Val) is 1.0 or less and a state in which a peak time difference t2between alanine (Ala) and cysteine (Cys) is a predetermined time or more, as shown inFIG.3B, the eluent switching timing is hastened through control of the valve111. When such control is performed, a peak time difference t3between alanine (Ala) and cysteine (Cys) can be set to be appropriate as shown inFIG.3C.

(Avoidance of Separation Degree Failure 2)

The influence of the column temperature on the retention time of each component contained in the sample varies depending on the sample. For example, as shown inFIG.4, in Glu, a degree of increase in retention time in the case of a low column temperature is large as compared to those of AspNH2 and GluNH2. In view of the foregoing, in the same manner as in the above-mentioned (Avoidance of Separation Degree Failure 1), when it is detected that the Resolution of a predetermined component is not appropriate through analysis of the chromatogram obtained as the detection result of the detector160, a factor of the separation degree failure may be identified or the separation degree failure may be automatically avoided through control of the set temperature of the column thermostat144.

(Avoidance of Separation Degree Failure 3)

In addition, for example, as shown inFIG.5, the separation degree failure can be avoided by switching the timing, at which the set temperature of the column thermostat144is switched from 40° C. to 70° C., from 63 minutes to 48 minutes after a predetermined reference time to mainly shorten only the retention time of Trp.

(Avoidance of Separation Degree Failure 4)

In addition, for example, as shown inFIG.6, the separation failure of NH3 and Hylys (and an isomer thereof) can be avoided by changing the composition of an eluent from B4=100% to B1/B4=60/40% during a period from 66 minutes to 72 minutes after a predetermined reference time.

(Avoidance of Separation Degree Failure 5)

In addition, for example, as shown inFIG.7, the separation failure of 3Mehis, Ans, and Car can be avoided by changing the composition of an eluent from B4=100% to B2/B4=20/80% during a period from 85 minutes to 98 minutes after a predetermined reference time.

(Avoidance of Peak Height Failure)

Description is given of an exemplary case in which, for example, it is detected that the peak height of aspartic acid (Asp) is not appropriate through analysis of the chromatogram obtained as the detection result of the detector160with reference to a flowchart ofFIG.8and the above-mentioned Table 1.

First, prior to analysis, a reference value R of a peak height at a time when aspartic acid (Asp) that is a reference sample is detected is read from a database or the like (not shown).

When the analysis of the sample is performed, a peak height H is measured based on a chromatogram of an analysis result.

It is determined whether or not the measured peak height H is, for example, less than 0.7 time the reference value R. When the measured peak height H is not less than 0.7 time the reference value R, the flow proceeds to (Step S112), and for example, a measurement completion display or the like is performed. Thus, a measurement operation is completed.

Meanwhile, when the measured peak height H is, for example, less than 0.7 time the reference value R, it is determined whether or not automatic purging of the auto-sampler (AS)120has been performed.

When it is determined that the automatic purging has not been performed in (Step S104) as described above, the automatic purging is performed. After that, the flow is returned to (Step S102), and the analysis is performed again. Thus, the steps subsequent to the measurement of the peak height H are repeated. Specifically, an attempt to avoid the peak height failure is made. When the peak height failure has been avoided, the flow proceeds to (Step S112) as described above, and the measurement operation is completed.

Meanwhile, when the automatic purging has been performed, for example, in order to present another avoidance measures to a user, a replacement date of a ninhydrin reagent is first read.

It is determined whether or not two or more weeks have elapsed after the replacement date of the ninhydrin reagent.

When two or more weeks have elapsed after the replacement date of the ninhydrin reagent, a message for prompting the user to replace the ninhydrin reagent is displayed, and the measurement operation is completed.

In addition, when two or more weeks have not elapsed after the replacement date of the ninhydrin reagent, it is determined whether or not one or more months have elapsed after the preparation of the reference sample.

When one or more months have elapsed after the preparation of the reference sample, a message for prompting the user to prepare a new reference sample is displayed, and the measurement operation is completed.

Meanwhile, when one or more months have not elapsed after the preparation of the reference sample, another factor is presumed. Therefore, for example, display for showing an abnormal state of the apparatus is performed, and the measurement operation is completed. When such unclear factor is presumed, an inquiry to an expert may be automatically made through communication means such as the Internet or a message for prompting the user to make an inquiry through service call through use of a telephone, sending of mail, or the like.

When it is determined in (Step S103) that the peak height H is, for example, less than 0.7 time the reference value R, the automatic purging of the auto-sampler120is always performed. After that, confirmation of other factors and the like are performed after (Step S106) without performing automatic analysis again, and the measurement operation may be completed.

As described above, when various faults in the analysis of the sample are detected, the operation for identifying the factors of the faults and the operation for avoiding the faults are performed. Thus, the case in which the chromatograph does not appropriately operate can be easily addressed.