JP6507883B2 - Reagent preparation apparatus and sample analyzer - Google Patents

Description

  The present invention relates to a reagent preparing apparatus for automatically preparing a reagent and discharging it to a supply destination.

  Among the reagents used in the analyzer, it is possible to provide the user with a common liquid that consumes a large amount, for example, a buffer solution or dilution solution to be mixed with the sample, a washing solution containing a surfactant, salts, etc. Burden on the transportation cost, storage location, etc. for transportation operators, carriers and users. Therefore, these reagents are provided to the user in the form of a concentrated solution or concentrated solution as a compact reagent stock solution, and the reagent stock solution is diluted by a reagent preparation apparatus provided side by side with or incorporated in an analysis apparatus in the field, It has been practiced to automatically supply the analyzer (see, for example, Patent Document 1).

  In an apparatus for automatically preparing a reagent used for such sample analysis, although control is performed so that a fixed amount of reagent is supplied to the analyzer every one preparation operation, the characteristics of the prepared reagent are controlled. It can happen often that it does not enter the control range. Reagents that do not fall within the control range are usually discarded, and the operation of the device will be stopped to cope with problems. Patent Document 2 suppresses the decrease in the operating efficiency of the apparatus by continuing the reagent preparation operation until the number of times the characteristics of the prepared reagent do not meet the predetermined conditions reach the predetermined number, and the amount of the discarded reagent is Discloses a reagent preparing apparatus for reducing This document describes reagent preparation due to transient failure that may be recovered by repeating reagent preparation and hardware failure in a situation where the quality of the prepared reagent does not meet predetermined conditions. It is pointed out that there is a defect (continuity) that does not improve even if it is repeated.

WO 2009/031461 pamphlet JP 2012-189552 A

  In the invention of Patent Document 2, if the number of times that the prepared reagent quality does not meet the predetermined conditions is set to a large number of times, even if the preparation is repeated, the possibility of recovery is low (continuity). There is a risk that necessary reagents will be prepared. In addition, if the number of times that does not meet the predetermined conditions is set to a small number, the number of repetitive preparation steps required to recover from the transient failure is insufficient, which may result in a large number of operation stoppages of the apparatus and a decrease in operation efficiency. .

  The present invention provides a reagent preparation device considering an operation efficiency which is free from unnecessary reagent disposal and suppresses an increase in running cost when a defect occurs in the reagent preparation device and suppresses a running cost increase. The purpose is

  The present inventors have found that when a failure with low recovery possibility (continuous) occurs, the characteristics of the repeatedly prepared reagent remain at the same level and no improvement is observed. The present invention determines the possibility of recovery from the transition of reagent characteristics upon repeated preparation when a failure occurs in the reagent preparing device, and performs repeated preparation or preparation termination.

  That is, a reagent preparing device according to a first aspect of the present invention for solving the above problems comprises: reagent preparing means for repeating preparing operation of preparing a predetermined amount of reagent by diluting and mixing reagent stock solution with a solvent; Evaluation means for measuring the quality characteristics of a predetermined amount of reagent prepared by the method and outputting an evaluation value, wherein it can be determined whether the evaluation value is within a control range including the target value of the quality characteristics The control means for controlling the operation of the reagent preparation means based on the evaluation means and the evaluation value of the evaluation means, wherein both the current value of the evaluation value and the previous value fall within a predetermined management range And the control means is controlled to stop the preparation operation when it is not indicated that the current value exceeds the predetermined threshold value and is closer to the target value than the previous value. It is characterized by

  Here, it is preferable that the value of the previous time is the value of the time immediately before the current value, in other words, it is preferable that these are the values of consecutive times. The quality characteristics are not particularly limited, and examples thereof include conductivity, pH, ion concentration and the like. Furthermore, if the evaluation value of the evaluation means for evaluating the quality characteristics of the predetermined amount of reagent prepared by the reagent preparation means does not fall within the predetermined control range, it is preferable to control to discard the prepared reagent.

  The sample analyzer according to the second aspect of the present invention comprises: reagent preparation means for repeating a preparation operation of preparing a predetermined amount of reagent by diluting and mixing a stock solution of reagent with a solvent; An evaluation unit that measures a quality characteristic of a reagent and outputs an evaluation value, wherein the evaluation unit is capable of determining whether the evaluation value is within a control range including a target value of the quality characteristic; Control means for controlling the operation of the reagent preparation means based on the evaluation value of the means, wherein the current value of the evaluation value and the previous value do not fall within a predetermined management range, and the current value is When it is not shown that the target value is approached by exceeding the predetermined threshold value compared to the previous cycle value, the control means is controlled to stop the preparation operation, and the reagent prepared by the reagent preparation means is used. Analyzer for measuring the composition of samples A sample dispensing unit that dispenses a sample to be measured into a reaction container, a reaction processing unit of a sample using a reagent, a detection unit that detects a signal derived from a target component subjected to reaction processing, and an analysis state or And the analyzer comprising at least display means for displaying an analysis result.

  In this sample analyzer, it is preferable that the value of the previous cycle is the value of the cycle immediately before the current value, in other words, it is preferable that these are the values of the continuous cycle. The quality characteristics are not particularly limited, and examples thereof include conductivity, pH, ion concentration and the like. Furthermore, when the evaluation value is out of the predetermined management range, the control means preferably controls to display an error message to that effect on the display means and to stop the operation of the sample dispensing unit. Further, when stopping the preparation operation, it is preferable to display an error message to that effect on the display means.

  The various error messages may be output to the display means provided in the reagent preparation device, or may be output to the display means provided in the computer that controls the analyzer. The reagent preparation device may be incorporated inside the casing of the analyzer, or may be provided separately from the analyzer. In addition, the control means which is a component of the present invention may be a dedicated processor provided in the reagent preparation apparatus, or may be a processor which is also used as a control means of the analysis apparatus, or uses an external computer You can also

  In the present invention, “the present value has exceeded the predetermined threshold compared to the previous value and approaches the target value” means, for example, from the absolute value of the difference between the previous value and the target value. And the target value minus the absolute value of the difference, which means that the value is greater than a predetermined threshold. Here, the predetermined threshold can be appropriately set according to which value is used as the previous value used to compare the present value. Note that setting a larger threshold means setting a higher improvement hurdle, that is, requiring the target value to be closer to the target value, conversely setting a smaller threshold results in a hurdle of improvement. It means setting lower, that is, it may be as close as possible to the target value.

  In the present invention, when the evaluation result of the reagent deviates from the control range due to some defect in the reagent preparing apparatus, the reagent preparing operation is not immediately stopped, so that a transient defect can be tolerated. In addition, since the present invention judges the possibility of recovery from the transition of the reagent characteristics re-prepared when the result of the reagent preparation goes out of control range, it tolerates transient failure and accelerates the failure not to recover. Can be detected. Although there is a trade-off relationship between tolerating transient defects and detecting defects that do not recover early, in the present invention, by setting the threshold appropriately, the trade-off is optimized at a high level. Can be

FIG. 1 is a block diagram showing an example of the configuration of the sample analyzer of the present invention. FIG. 2 is a schematic view for explaining an example of the contents of control of the control means of the present invention. FIG. 3 is a flowchart showing an example of the control operation of the present invention. FIG. 4 is a diagram showing an example of an error display when the evaluation value during preparation of a reagent deviates from the control range in the present invention. FIG. 5 is a diagram showing an example of an error display when stopping the reagent preparation operation in the present invention.

  DESCRIPTION OF THE PREFERRED EMBODIMENTS Embodiments of the reagent preparation device according to the present invention and the sample analysis system provided with the same will be described with reference to the drawings.

[Configuration and preparation method of automatic preparation apparatus]
FIG. 1 shows an example of the apparatus configuration of the present invention. The reagent preparation device 26 includes a reagent preparation means 19, an evaluation means 16 and a control means 20. In FIG. 1, the evaluation means 16 is depicted as a configuration included in the reagent preparation means 19.

  The reagent preparing means 19 includes two reagent concentrated solution bottles 11, a syringe pump 14 for sending a fixed amount of reagent concentrated solution to the mixing container 12, a reservoir 10 of pure water for dilution, and dilution thereof Diaphragm pump 15 for sending pure water for mixing toward the mixing vessel 12, liquid level sensor 17 for defining the liquid level in the mixing vessel 12 for defining the amount of pure water for dilution, dilution, and dilution Conductivity meter as evaluation means 16 installed on the flow path to monitor the concentration of the reagent, supply tank 13 for storing the prepared reagent and supplying it to the analyzer 25, provided in the supply tank 13 A liquid level sensor 18 and solenoid valves 1 to 6 for appropriately controlling the direction of liquid feeding are provided.

  The analyzer 25 for measuring the components of the sample using the reagent prepared by the reagent preparation means 19 includes a sample dispensing unit 22 for dispensing the sample to be measured into a reaction container, and a reaction processing unit 23 for the sample using the reagent. The detection unit 24 detects a signal derived from the target component subjected to the reaction processing, and the display unit 21 displays the analysis state and the analysis result. The control means 20 controls the operation of the reagent preparation means 19 and the operation of the display means 21 and / or the analyzer 25 based on the evaluation value of the conductivity meter. Details of the control method will be described later with reference to the drawings.

  Next, the apparatus configuration and the method of reagent preparation will be described in more detail. For example, a bottle 11 of a concentrated cleaning solution (reagent stock solution) to be diluted 36 times with water is placed at the installation position of FIG. In FIG. 1, two reagent concentrated solution bottles 11 can be installed, and a mechanism (not shown) that automatically switches to the other bottle when an optical sensor (not shown) detects that one bottle is empty. (Shown). Each pure water tank is equipped with an empty sensor and a full water sensor (not shown), and is controlled so as to always maintain a certain range of liquid level.

  As an example, the operation | movement in the case of adding pure water to 5.55 mL of concentrated solutions and diluting 36 times is demonstrated. In order to promote dilution and mixing, for example, a fixed volume of 6 divided aliquots and a fixed amount of pure water (about 20 mL) are alternately sent 6 times to the mixing container side, and finally the total volume of the mixture is 200 mL. Add pure water as you like. The liquid level sensor 17 installed at a total position of 200 mL is monitored at 0.2 second intervals, and when the liquid level reaches 200 mL, the operation of the diaphragm pump 15 is stopped.

  After the liquid concentrate and pure water have been fed, the conductivity is measured. First, the solenoid valves 4, 5 and 6 are switched to configure a loop flow path including the mixing container 12, the conductivity meter (the evaluation means 16), and the diaphragm pump 15. The diaphragm pump 15 is activated for a predetermined time (tens of seconds) to circulate and stir the liquid in the loop flow path. During stirring, the value of the conductivity sensor (evaluation means 16) is monitored at intervals of about 1 second, and the average of the conductivity signals at three points immediately before the end of the stirring is regarded as the conductivity of the diluted solution. Further, since the conductivity sensor is affected by the temperature, the conductivity is corrected to a 25 ° C. reference value using the temperature of a thermistor (not shown) installed in the mixing vessel 12. The corrected conductivity is compared with a reference value stored in advance in the device. The concentration comparison value (%) of the diluted solution is calculated with the reference value as 100%. The reference value is a conductivity signal obtained by measuring the liquid (in this case, the washing solution) prepared to the target concentration to be referred to by the conductivity sensor of the apparatus. If the concentration comparison value is within the control range (for example, within 100 ± 10%), the prepared diluted solution is sent to the prepared reagent supply tank 13. That is, the flow path on the mixing container 12 side of the solenoid valve 6 is switched to the supply tank 13 side, the diaphragm pump 15 is activated, and the diluted solution (prepared reagent) in the mixing container 12 is a conductivity sensor (evaluation means 16) -Solenoid valve 4-diaphragm pump 15-Solenoid valve 5- Sends liquid to the supply tank 13 through the flow path of the solenoid valve 6. When the conductivity sensor (evaluation means 16) detects the mixing of air, it can be seen that the delivery of the dilution liquid is almost completed. On the other hand, if the concentration comparison value is out of the control range, the solenoid valve 5 is switched and the diaphragm pump 15 sends the diluted solution to the waste liquid tank. After discarding, re-prepare the reagents. After readjustment, control of the previous value comparison is performed in addition to whether the concentration comparison value is within the control range. Details will be described later.

  At least the liquid level sensor 18 is provided in the supply tank 13 of the prepared reagent, and is constantly operated at intervals of 5 seconds. The reagent preparation means is in a standby state when the reagent remains in the supply tank 13 sufficiently, but when the reagent in the supply tank 13 is consumed and the liquid level falls to a certain level as the analyzer operates, the preparation of the reagent is performed. Start again. The position of the liquid level sensor 18 takes into consideration the time required for the next reagent preparation and the time required for re-preparation due to preparation failure, and even in the situation where the operation of the reagent preparation has to be stopped, the analyzer It is preferable to set the position where the necessary reagent remains in the supply tank 13 until the sample remaining on the top and waiting for the reaction process outputs the analysis result.

  In addition, although the structure for preparing one type of reagent as an automatic preparation means was shown in FIG. 1, it is also possible to prepare two or more series of different reagents simultaneously by the same structure.

[Control processing at the time of preparation failure]
The details of the control process including the case where the evaluation result of the reagent preparation is out of the management range will be described with reference to a flow chart (FIG. 3) and a schematic view (FIG. 2) for explaining control contents.

  Following the reagent preparation operation S1 of mixing the concentrated solution and pure water to prepare the reagent, the concentration measurement of the reagent is performed by the conductivity sensor (S2). The concentration of the reagent can be expressed as a concentration comparison value (%) with a reference value corresponding to the target concentration. For example, with the control range set to 100 ± 10%, it is determined whether the concentration comparison value is within the control range (S3). If it is within the control range (YES), the prepared reagent is transferred to the supply tank (S13). If sample dispensing has not been stopped (S14 NO), the process proceeds to step 16 and the reagent in the supply tank is consumed as the analyzer operates and waits until the liquid level drops to a certain extent (S16 NO), indicating that the liquid level has dropped. When it is detected (YES in S16), preparation of the reagent is started again (S1).

  On the other hand, if it is not within the management range in step S3 (NO), the operation (sampling) of the sample dispensing unit which dispenses a new sample into the reaction container in the analyzer is stopped (S4). Then, for example, an error display regarding out of the density range as shown in FIG. 4 is performed (S5). The prepared reagent having a concentration outside the control range is discarded (S6), and repreparation of the reagent and concentration measurement are performed (S7). Step S7 is an operation combining steps S1 and S2. The re-prepared reagent is subjected to concentration evaluation / determination in step S8. If it is in the control range (S8 YES), the process proceeds to step S13, and the prepared reagent is transferred to the supply tank. If the sample dispensing stop is in progress in step S14 (S14 YES), the sample dispensing stop is canceled in step S15, and the process proceeds to step 16 to wait until the liquid level in the supply tank is lowered.

  If the control range is out of control in step S8 again (NO), the concentration measured in step S7 is compared with the concentration measured in step S2 last time (S9). That is, the absolute value of the difference between the current value and the target value is subtracted from the absolute value of the difference between the previous value and the target value, and the magnitude of the value is compared with the predetermined threshold.

  The circumstances around this will be described in detail using one example with reference to FIG. Assuming that the concentration comparison value (corresponding to the previous value) measured in step S2 is represented by plot 1a (10%) in FIG. 2, the concentration comparison value (corresponding to the current value) in step S7 re-prepared is, for example, 45%) or 2b (25%). Using the concentration comparison values of plots 1a and 2b, the absolute value of the difference between the current value (2b or 2c) and the target value was subtracted from the absolute value of the difference between the previous value (1a) and the target value (100%) The value is 15% for the current value 2b and 35% for the current value 2c. When the threshold value is set to 30%, the improvement of the current value 2b is not higher than the threshold value 30% but is insufficient (S9 NO), the prepared reagent is discarded (S10), and the liquid preparation operation as shown in FIG. Error display (S11) is performed. On the other hand, in the case of the current value 2c, it shows an improvement of 35% over the threshold value 30% compared to the previous value 1a (step S9 YES), so return to step S6 and discard the previously prepared reagent. Re-preparation (S7). Assuming that the evaluation value (concentration comparison value) obtained in step S7 is plot 3b (55%) or 3c (76%) in FIG. 2, both are out of the control range (S8 NO), and the evaluation judgment of step S9 is performed again. Do. This time, the current value is plot 3b or 3c, and the previous value is plot 2c. Comparing the absolute values of the difference between the density comparison values 3b and 2c with the target value is an improvement of 10%, and it does not exceed the threshold of 30% and becomes step S9NO. On the other hand, the concentration comparison value 3c is improved by 31%, resulting in S9 YES, and the process returns to step S6. After discarding the previously prepared reagent, the reagent is re-reprepared again (S7). Assuming that the evaluation values (concentration comparison values) obtained in step S7 are the plots 4a (95%) and 4b (78%) in FIG. 2, the plot 4a is within the management range and step S8 YES is obtained, and step S13 is performed. Proceed to transfer the prepared reagent to the supply tank. If the sample dispensing stop is in progress in step S14 (S14 YES), the sample dispensing stop is canceled in step S15, and the process proceeds to step 16 to wait until the liquid level in the supply tank is lowered. On the other hand, since the plot 4b is improved by about 2% in step S9 and does not exceed the threshold 30%, step S9 becomes NO and the reagent is discarded (S10), an error is displayed (S11), and the liquid preparation operation is stopped (S12) Go to

  After stopping the preparation operation of step 12, the monitoring of the liquid level sensor 18 provided in the supply tank 13 of the prepared reagent is stopped, and the liquid preparation operation is not started even if the liquid disappears. Then, when the measurement of the sample currently being processed is finished, the analyzer is also stopped. Further, the control is such that the next measurement can not be started unless the reagent preparation device returns, and when the measurement start button is pressed, an error (not shown) indicating that the automatic preparation is stopped is output.

1 to 7 Solenoid valve 10 Storage tank for pure water for dilution 11 Concentrated liquid bottle 12 Mixing container 13 Supply tank for prepared reagent 14 Syringe pump 15 Diaphragm pump 16 Evaluation means 17 and 18 Liquid level sensor 19 Reagent preparation means 20 Control means 21 Display Means 22 Sample Dispensing Unit 23 Reaction Processing Unit 24 Detection Unit 25 Analyzer 26 Reagent Preparation Device 27 Sample Analyzer

Claims (7)

Reagent preparation means for repeating a preparation operation of diluting a reagent stock solution with a solvent to prepare a predetermined amount of reagent;
An evaluation unit that measures the quality characteristics of a predetermined amount of reagent prepared by the reagent preparation unit and outputs an evaluation value, wherein the evaluation value is within a control range including a target value of the quality characteristic. The evaluation means capable of judging;
Control means for controlling the operation of the reagent preparation means based on the evaluation value of the evaluation means, wherein the current value of the evaluation value and the previous value do not fall within a predetermined management range, and the current value The control means for controlling to stop the preparation operation if it is not indicated that the target value has been approached by exceeding a predetermined threshold value with respect to the value of the previous cycle;
Reagent preparation device equipped with The reagent preparation device according to claim 1, wherein the previous cycle value is the previous cycle value of the current value. The reagent preparation according to claim 1 or 2, wherein the control means controls the reagent preparation means to discard the prepared reagent when the evaluation value of the evaluation means does not fall within a predetermined control range. apparatus. Reagent preparation means for repeating a preparation operation of diluting a reagent stock solution with a solvent to prepare a predetermined amount of reagent;
An evaluation unit that measures the quality characteristics of a predetermined amount of reagent prepared by the reagent preparation unit and outputs an evaluation value, wherein the evaluation value is within a control range including a target value of the quality characteristic. The evaluation means capable of judging;
Control means for controlling the operation of the reagent preparation means based on the evaluation value of the evaluation means, wherein the current value of the evaluation value and the previous value do not fall within a predetermined management range, and the current value The control means for controlling to stop the preparation operation if it is not indicated that the target value has been approached by exceeding a predetermined threshold value with respect to the value of the previous cycle;
A sample dispensing unit for measuring a component of a sample using the reagent prepared by the reagent preparing means, which dispenses a sample to be measured into a reaction container; a reaction processing unit for a sample using a reagent; A detection unit for detecting a signal derived from the target component subjected to the reaction processing, and the analysis device having at least a display means for displaying an analysis state or an analysis result;
Sample analyzer equipped with The sample analyzer according to claim 4, wherein the previous cycle value is the previous cycle value of the current value. When the evaluation value of the evaluation means does not fall within a predetermined management range, the control means causes an error message to that effect to be displayed on the display means, and controls the operation of the sample dispensing unit to be stopped. The sample analyzer according to claim 4 or 5, characterized in that The sample analyzer according to any one of claims 4 to 6, wherein the control means causes an error message to that effect to be displayed on the display means when stopping the preparation operation.

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