In vitro diagnosis system calibration management

Abstract

To manage calibration of an in vitro diagnosis (IVD) system automatically.SOLUTION: A computer packaging method of automatically managing calibration of an in vitro diagnosis system includes, for each calibration cycle,: starting repeating a calibration procedure right away at the start of a buffer period prior to expiration of a calibration valid period; interrupting the calibration procedure when receiving a command of implementing a sample IVD examination; and as long as the repeating of the calibration procedure can be started again or resumed during the buffer period, starting again or resuming the calibration procedure after implementing the sample IVD examination. The interruption of the calibration procedure includes a different step in responce to whether the command for implementing the sample IVD examination is received during a period of using a first calibration solution or a subsequent calibration solution in a set of calibration solutions, and whether the command of implementing the sample IVD examination is received during a first step of transferring the first calibration solution or subsequent calibration solution to a measurement unit, or a second step of measuring the first calibration solution or the subsequent calibration solution.SELECTED DRAWING: Figure 2

Description

Technical Field

[0001] The present disclosure relates to a computer-implemented method for automatically managing the calibration of an in vitro diagnostic system and an in vitro diagnostic system that performs operations related to a method for automatically managing calibration.

Background Art

[0002] In the medical field, a physician's diagnosis and a patient's treatment often rely on the measurement of the concentration or other parameters of an analyte in a patient sample by performing an in vitro diagnostic (IVD) test. These measurements are typically performed by an in vitro diagnostic system that can be configured to analyze a particular type of sample and detect a particular type of analyte using various detection techniques. Since a patient's life may depend on the accuracy and reliability of such measurements, it is important that the system functions correctly.

[0003] To confirm that an in vitro diagnostic system is operating correctly, it is a common requirement of in vitro diagnostic systems to implement a series of quality control (QC) procedures.

[0004] One of these procedures is calibration. Most often, calibration is performed using a standard solution of known concentration. In this way, the measured signal can be related to a quantitative result. Calibration needs to be performed at some frequency, depending on the system and other variables that can affect performance. One of these factors can be the aging of the reagents and / or other solutions used, where the reagents and / or other solutions become ineffective after a given time after being exposed to environmental conditions. In particular, for some types of measurement units, such as biosensors, the signal stability of the measurement unit can be another factor. In particular, some detectors and sensors used to measure analyte concentration can be subject to interference, for example due to the presence and / or high concentration of interferents in a particular test sample, and can experience at least temporary signal instability. In particular, some sensors can experience signal drift that may go unnoticed in some cases. This can lead to measurement errors and thus may require more frequent calibration between successive calibrations, as well as so-called QC measurements. This is done by measuring one or more reference samples, also called QC samples, having known values of the analyte or parameter of interest, in the same way as test samples are measured, to further confirm that the calibrated instrument is actually within specifications or tolerances. Thus, in general, there is a time limit to the effectiveness of calibration.

[0005] Typically, during a calibration procedure, the analyzer or its components may not be available for use, e.g., not available to accept a new sample. Thus, the effective throughput and utility, as well as the cost of running an in vitro diagnostic system, can be affected by the fact that a significant amount of time may have to be spent on performing and repeating the calibration procedure. Further, the operator may be in a situation where they have to wait for the analyzer to become available again, e.g., until the calibration procedure is complete, before they can input a new sample into the analyzer. However, especially in a point-of-care environment, such as an emergency situation, intensive care unit, etc., obtaining highly reliable and rapid results may be of utmost importance, and delays can be life-threatening. Also, in some IVD tests, including determining blood gas parameters such as pO2, it is important that the blood sample is processed immediately after being taken from the patient; otherwise, the reliability of the IVD test is affected as a result of exposure to ambient conditions. Further, the operator's time may be wasted, which could otherwise be used more efficiently. If the operator cannot wait for other urgent tasks, usually a retest will be performed later, during which there is a high likelihood that the analyzer could have become available earlier, unnecessarily delaying sample analysis. SUMMARY OF THE INVENTION

[0006] A computer-implemented method and an IVD system for automatically managing the calibration of an in vitro diagnostic (IVD) system comprises a calibration management system that executes a computer-readable program comprising instructions for performing operations related to a method of managing calibration that ensures the analytical performance of the IVD system, i.e., the reliability of IVD test results, while always ensuring the availability of the IVD system in order to process samples and provide IVD test results as quickly as possible. Another advantage is that efficiency in the laboratory workflow is achieved by preventing the unnecessary waste of the operator's time and / or by preventing further stress in an already very demanding situation, for example, by having to search for another available IVD system or having to wait until an IVD system becomes available.

[0007] In particular, the method includes performing a calibration cycle that includes performing a calibration procedure to determine test-specific calibration parameters used when evaluating sample IVD test results, and repeating the calibration procedure to update the test-specific calibration parameters before the expiration of each calibration validity period. Different calibration procedures / cycles may have different calibration validity periods, and performing different calibration procedures / cycles includes using different sets of calibration solutions, each set including at least two different calibration solutions. Using a calibration solution includes a first step of transferring the calibration solution to a measurement unit and a second step of measuring the calibration solution by the measurement unit. For each calibration cycle, the method further includes starting the repetition of the calibration procedure as early as possible at the start of a buffer period before the expiration of each calibration validity period, interrupting the calibration procedure when a command to perform a sample IVD test is received, and restarting or resuming the calibration procedure after performing the sample IVD test as long as the repetition of the calibration procedure can be restarted or resumed within the buffer period. In particular, interrupting the calibration procedure comprises different steps depending on whether a command to perform a sample IVD test is received while using the first calibration solution or a subsequent calibration solution in the set of calibration solutions, and whether a command to perform a sample IVD test is received during the first step of transferring the first calibration solution or a subsequent calibration solution to the measurement unit, or during the second step of measuring the first calibration solution or a subsequent calibration solution.

[0008] As used herein, the term "calibration procedure" refers to a process of checking whether an IVD system is operating accurately by comparing known standards with measurement results delivered by the IVD system. This enables determination of a valid relationship between the measured value and the actual concentration of the analyte in the sample under the actual measurement conditions. Depending on the type of signal and, in particular, the linearity or non-linearity of the signal at different concentrations, this may vary according to a specific sample IVD test, e.g., a specific sample, a specific analyte of interest in the sample, a specific workflow, and measurement conditions. The calibration procedure may include measuring one or more levels of reference materials corresponding to different concentration ranges of calibration materials or standards included in the detection range (dynamic range) of the IVD system and / or the typical range of concentrations of analytes that may be found in the sample. If only one reference material level is measured, the calibration procedure is a one-point calibration procedure. If two levels of reference materials are measured, the calibration procedure is a two-point calibration procedure, etc. A "multi-point calibration procedure" comprises measuring a plurality of reference material levels, i.e., at least two, typically three or more, and in particular measuring each reference material level for each of the plurality of calibration points, thereby obtaining a plurality of respective calibration points.

[0009] According to other embodiments, a "calibration procedure" may also be a procedure that enables correlating the measured sample signal with a qualitative result, i.e., the mere presence or absence of an analyte. In such cases, usually, criteria such as a threshold or cut-off, e.g., separating a normal healthy sample from an abnormal pathogenic sample, are defined. For qualitative calibration, two reference materials are often used, one having no analyte present (negative reference material) and one having a detectable amount of analyte (positive reference material).

[0010] Depending on the specific sample IVD test, different calibration procedures may have to be performed, each of which may involve one or more calibration substances, which may be different in some cases, and ultimately different levels of calibration substances and / or different numbers of levels.

[0011] The calibration procedure may include calculating a calibration result or mathematical function, which is a process of constructing a line or curve that best fits the measured calibration points, and calculating the amount of variation or dispersion (standard deviation) of the measured calibration points, taking into account statistical inferences such as how much uncertainty exists in the line or curve constructed due to unknown and / or random errors occurring in the process, through regression analysis. The process may include comparing the constructed line or curve with a reference line or curve or a previously constructed line or curve under the same conditions, and / or comparing individual calibration points with reference values or previously measured values. In particular, the calibration procedure includes determining test-specific calibration parameters used when evaluating sample IVD test results. Test-specific calibration parameters can be, for example, the slope of the calibration line or curve, the degree of linearity, the zero point, the offset, the inflection point, etc.

[0012] A "calibrator" is a calibration solution that contains the known values of one or more calibration substances or standards used for calibration and is measured under the same conditions as the sample. The calibrator can be provided at different levels corresponding to different concentration ranges of the calibration material, including zero concentration, i.e., the blank solution. Typically, one or two levels of the same calibrator are used for one-point or two-point calibration, respectively, in the case of a linear response to the analyte concentration. If the calibration curve is non-linear, three or more calibrator levels, for example up to five, six or more levels may be used.

[0013] A "calibration material" can be the same analyte of interest whose concentration or value is known, or which generates a known concentration or value by reaction or derivatization, e.g., fragmentation, or can be any other equivalent substance or standard that mimics the analyte of interest or correlates with a particular analyte or sample parameter of interest.

[0014] A "calibration validity period" is a time window having a predetermined length of time starting from the time when the calibration procedure has been successfully completed by determining the calibration parameters specific to the required test, within which the determined test-specific calibration parameters are considered valid, i.e., applicable for evaluating sample IVD test results. Thus, the calibration validity period is set to expire after a predetermined time, which can be, for example, as short as 1 or 2 hours, 6 hours, 12 hours, 24 hours or more, or as long as 1 or 2 hours, 6 hours, 12 hours, 24 hours or more, and can be different for each different calibration procedure, although several different calibration procedures may have the same length of calibration validity period.

[0015] In particular, it is important to repeat the calibration procedure before each calibration period expires in order to update the test-specific calibration parameters before they become invalid and to ensure the continuous analytical performance of the IVD system and the reliability of the IVD test results.

[0016] Thus, the term "calibration cycle" as used herein refers to the repetition of the calibration procedure at regular predetermined intervals, i.e., at a predetermined frequency, for the purpose of updating the test-specific calibration parameters before each calibration validity period expires. In particular, the time and any actions or procedures between a successfully completed calibration procedure and the repetition of the same successfully completed calibration procedure subsequently include replacing the previously determined test-specific calibration parameters with newly determined test-specific calibration parameters and are referred to as the calibration cycle.

[0017] In particular, for each calibration cycle, the method includes starting the repetition of the calibration procedure as early as possible at the start of a buffer period before the end of each calibration validity period, interrupting the calibration procedure upon receiving an instruction to perform a sample IVD test, and restarting or resuming the calibration procedure after performing the sample IVD test as long as the repetition of the calibration procedure can be restarted or resumed within the buffer period.

[0018] As used herein, the term "buffer time period" refers to a period within the calibration validity period that is closest to the end or expiration of the calibration validity period, which allows sufficient flexibility in starting and, if necessary, interrupting, restarting or resuming the repetition of the calibration procedure, and has sufficient time to perform at least one sample IVD test during the interruption if an instruction for a sample IVD test is received after starting the repetition of the calibration procedure. Note that the repetition of the calibration procedure does not necessarily have to be completed before the expiration of the calibration validity period as long as it can be restarted or resumed within the buffer period before the expiration of the calibration validity period. Interruptions can occur multiple times as long as sufficient time remains available to complete the sample IVD test and restart or resume the repetition of the calibration procedure. To avoid continuous interruptions, according to one embodiment, the method includes waiting for a predetermined time after performing the sample IVD test before restarting or resuming the calibration procedure as long as the repetition of the calibration procedure can be restarted or resumed within the buffer period. This is because it can happen that an operator approaches an IVD system having multiple samples to perform multiple sample IVD tests in a continuous order.

[0019] The set of calibration solutions used to perform the calibration procedure may comprise two or more calibration solutions that must be transferred to and measured in the measurement unit of the IVD system in a specific order.

[0020] In particular, interrupting the calibration procedure comprises different steps depending on whether an order is received to perform a sample IVD test while using the first calibration solution or a subsequent calibration solution in the set of calibration solutions, and whether an order is received to perform a sample IVD test during the first step of transferring the first calibration solution or a subsequent calibration solution to the measuring unit, or during the second step of measuring the first calibration solution or a subsequent calibration solution.

[0021] According to one embodiment, the set of calibration solutions comprises a single pair or multiple pairs of calibration solutions, each pair comprising a common calibration solution as the first calibration solution and any other different calibration solution as the subsequent calibration solution.

[0022] Thus, the term "first calibration solution" may refer to the first calibration solution in a set of two or more calibration solutions, or, if the set includes multiple pairs of calibration solutions, to the first calibration solution in each pair of calibration solutions.

[0023] The first calibration solution may in particular be a solution having a predetermined level of calibration material, for example having the lowest or zero level of at least some calibration materials, and / or having the most appropriate level of at least some calibration materials related to test-specific calibration parameters that require more frequent updates and are thus measured more frequently than other calibration solutions.

[0024] Similarly, the term "subsequent calibration solution" may refer to the second, third, fourth, etc. calibration solutions in a set of two or more calibration solutions, or, if the set includes multiple pairs of calibration solutions, to the second calibration solution in each pair of calibration solutions.

[0025] According to one embodiment, when an instruction to perform a sample IVD test is received during the first step of transferring the first calibration solution in the set and / or the first calibration solution in the pair to the measurement unit, interrupting the calibration procedure includes completing the first step of transferring the first calibration solution to the measurement unit and performing the measurement step of the first calibration solution with a reduced measurement time, and aborting any subsequent step of the calibration procedure to perform the sample IVD test.

[0026] As used herein, the term "with a reduced measurement time" means a relative term indicating that the time spent measuring the first calibration solution is a predetermined time shorter than the normal time spent measuring the same calibration solution when the calibration procedure is not interrupted, for example, less than about half the time.

[0027] According to one embodiment, when an instruction to perform a sample IVD test is received during the second step of measuring the first calibration solution in the set and / or the first calibration solution in the pair, interrupting the calibration procedure includes completing the second step of measuring the first calibration solution and aborting any subsequent step of the calibration procedure to perform the sample IVD test.

[0028] According to one embodiment, when an instruction to perform a sample IVD test is received during the first step of transferring a subsequent calibration solution in the set and / or a subsequent calibration solution in the pair to the measurement unit, interrupting the calibration procedure includes aborting the first step of transferring the subsequent calibration solution to the measurement unit and any subsequent step of the calibration procedure to perform the sample IVD test.

[0029] According to one embodiment, when a command to perform a sample IVD test is received during the second step of measuring subsequent calibration solutions in a set and / or subsequent calibration solutions in a pair, interrupting the calibration procedure comprises completing the second step of measuring the subsequent calibration solution and aborting any of the steps following the calibration procedure to perform the sample IVD test.

[0030] According to one embodiment, the method includes performing a washing step with a first calibration solution before performing the sample IVD test. By doing so, the same conditions before sample measurement can be guaranteed, and at the same time, an opportunity to measure the first calibration solution again is provided to obtain the latest test-specific calibration parameters that can be determined by measuring the first calibration solution.

[0031] According to one embodiment, the method includes updating at least a portion of the test-specific calibration parameters after measurement of the first calibration solution or after completed measurement of a pair of calibration solutions. By doing so, it is ensured that, although the calibration procedure may not be completed yet and / or may still be interrupted, these can also be updated so that they can already be used when evaluating the next sample IVD test result in case the calibration procedure is interrupted.

[0032] According to one embodiment, after performing the sample IVD test and following an interruption of the calibration procedure, the method includes restarting the calibration procedure of the calibration procedure using a single pair of calibration solutions and, for a calibration procedure using a plurality of pairs of calibration solutions, resuming the interrupted calibration procedure starting from the pair of calibration solutions where the measurement was interrupted or aborted. Thus, if the measurement of one or more pairs of calibration solutions in a set including a plurality of calibration solutions has already been completed, there is no need to repeat the measurement of that or those pairs before interrupting the calibration procedure, and the test-specific calibration parameters can be updated when they are determined.

[0033] According to one embodiment, the method includes combining different calibration procedures into a single calibration cycle by adding respective calibration solutions and / or pairs of calibration solutions to the same set when different calibration procedures share the same or similar calibration expiration periods and / or when each expiration period has the same expiration.

[0034] The term "sample" means a biological substance that may contain one or more analytes of interest, the detection or analysis of which (qualitative and / or quantitative measurements) may be relevant to a clinical condition. The sample can be of any biological origin, such as physiological fluids including blood, saliva, aqueous humor of the eye, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc. The test sample can be pretreated before use, such as preparing plasma or serum from blood, diluting viscous fluids, dissolving them, etc. The methods of treatment can include filtration, centrifugation, distillation, concentration, inactivation of interfering components, addition of reagents. The sample may in some cases be used directly as obtained from the source, or, for example, after pretreatment and / or a sample preparation workflow to change the nature of the sample, such as after adding an internal standard, diluting with another solution, or mixing with reagents, to enable the performance of one or more in vitro diagnostic tests, enrich (extract / separate / concentrate) the analyte of interest, and / or remove matrix components that may interfere with the detection of the analyte of interest.

[0035] According to one aspect, the sample is blood or a blood-derived substance such as plasma or serum.

[0036] According to certain aspects, the analyte of interest is typically a hemoglobin derivative such as hemoglobin, deoxygenated hemoglobin (HHb), oxyhemoglobin (O2Hb), carboxyhemoglobin (COHb), methemoglobin (MetHb), bilirubin, urea, creatinine, etc., which is measured by an optical detection unit. Next, additional sample parameters can be estimated based on previous measured values such as oxygen saturation (SO2 = O2Hb / (O2Hb + HHb)) and total hemoglobin (tHb = total of all hemoglobins). Other analytes of interest are gases such as pO2 and pCO2, blood electrolytes such as sodium (Na + ), potassium (K + ), chloride (Cl - ), calcium (Ca ++ ), protons (H + ) related to pH, metabolites such as glucose and lactate, etc., which are typically measured by a flow-through sensor path. However, this listing is not exhaustive.

[0037] An in vitro diagnostic (IVD) system for performing IVD tests on patient samples is also disclosed herein. The IVD system includes at least one measurement unit, a fluid system for transferring at least one calibration solution and sample to the at least one measurement unit, and a controller that executes a computer-readable program with instructions for performing operations related to a method of managing calibration according to any of the disclosed embodiments.

[0038] As used herein, the term "in-vitro diagnostic system" refers to an automated or semi-automated analyzer configured to analyze a sample outside the body to provide information for screening, diagnostic, or therapeutic monitoring purposes. The IVD system can be designed and configured according to the medical field of application, the parameters to be determined, and the corresponding laboratory workflow. For example, in a point-of-care testing environment, the IVD system can vary from a handheld device with low throughput, short turnaround time, and a limited number of measurable parameters, to a compact benchtop instrument with high throughput and a large number of measurable parameters. Such IVD systems are designed to detect specific types of parameters, such as gases, electrolytes, metabolites, clinical chemistry analytes, immunochemical analytes, coagulation parameters, hematology parameters, and the like. Depending on the parameter of interest, various different sample IVD tests, including different analysis methods and different detection techniques, can be applied. For example, in the field of blood gas and electrolyte testing, electrochemical measurement principles, and / or conductivity measurement principles, and / or optical detection methods are typically used. The IVD system typically comprises a plurality of functional units, each dedicated to a specific task and cooperating with each other to enable automated sample processing and analysis. Such functional units may include, for example, a sample input interface for receiving a sample, a fluid system, at least one measurement unit or detection unit, a fluid supply unit, and the like. One or more functional units may be integrated into larger units or modules to simplify the operation of the IVD system.

[0039] According to one embodiment, at least one measurement unit is an optical detection unit comprising a cuvette disposed between a light source and a photodetector, and is capable of measuring the intensity of a part of the spectrum of light transmitted or emitted by a specific substance such as an analyte or a calibration material present in a sample or a calibration solution disposed therein. The optical detection unit may be embodied as a flow-through optical detection unit comprising a flow-through cuvette or a flow-through optical path that allows fluids such as a sample and a calibration solution, and optionally other fluids including, for example, air, to flow in and out.

[0040] According to one embodiment, the IVD system may alternatively or additionally comprise a "flow-through sensor path" as a measurement unit, which is a fluid conduit that can be contacted by a sample or calibration solution flowing through the sensor path and which comprises one or more sensors, which can be arranged successively along the path, for example sensors for different parameters / analytes to be detected, and which may be embodied in an exchangeable cartridge-like structure, optionally comprising a plurality of sensors distributed across a plurality of sensor paths. Alternatively, the IVD system may comprise a plurality of measurement units each having a sensor path with a sensor dedicated to one parameter / analyte, which may or may not also be exchangeable. Thus, a sample or calibration solution may be passed through one or more sensor paths and different parameters / analytes may be determined by respective sensors. The term "sensor" is generally used herein to denote a detector configured to detect sample parameters by generating a corresponding signal output that can be quantified and digitized. The sensor can be, for example, a biosensor, a chemical sensor or a physical sensor. The sensor can be selective or specific for one sample parameter of interest or can be configured to detect and quantify a plurality of different sample parameters of interest. Depending on the type of sensor, the sensor can comprise a plurality of sensor elements. The term "sensory element" thus refers to a part of a sensor (e.g., a working electrode, a reference electrode, a counter electrode) that, in combination with one or more other sensor elements, forms a fully functional sensor. According to one embodiment, the flow-through sensor path comprises a pO2 sensor, a pCO2 sensor, a pH sensor, Na + , K + , Ca 2+ , and Cl -One or more ion-selective electrode (ISE) sensors for determining electrolyte values such as, etc., and one or more of one or more metabolite sensors for determining parameters such as lactate and glucose. The sensors may be based on the principles of, for example, current measurement, potential difference measurement, or electrical conductivity measurement, respectively.

[0041] The IVD system may further comprise at least one pump, such as a peristaltic pump, syringe pump, membrane pump, or any other suitable pump, for transferring fluids including the sample and calibration solution through the fluid system.

[0042] At least part of the measurement unit and the fluid system is the same as that used for transferring and measuring the calibration solution, which is why a sample IVD test cannot be performed while the calibration procedure is being executed.

[0043] The IVD system may comprise a dedicated sample input interface for introducing the sample into the IVD system. The sample input interface is located at a position conveniently accessible to the operator and may be configured to transfer the sample from a sample container lifted by the operator to the in vitro diagnostic system. This may include, for example, an outer input port side configured to couple, attach, connect, seat, introduce, or plug in a sample container of, for example, a capillary type or syringe type, and an inner input port side for coupling to or for coupling to one end of the sample input conduit, the sample input conduit being fluidly connected or connectable to the measurement unit. The IVD system may comprise a fluid supply unit, such as a module or component of the IVD system, comprising one or more fluid reservoirs containing calibration solution, among other possible fluids such as quality control (QC) samples, and may optionally also comprise one or more waste containers where the fluid circulating through the fluid system can be discarded at the end of the process.

[0044] The term "controller" encompasses any physical or virtual processing device, in particular a programmable logic computer having a processor that executes a computer-readable program for which instructions are provided to perform operations related to the method of managing calibration according to any of the disclosed embodiments. The controller may be integrated into the in vitro diagnostic system or may be a separate logical entity that communicates with the in vitro diagnostic system. In some embodiments, the controller may be integrated with the data management unit, may be constituted by a server computer, and / or may be distributed / shared across / between multiple in vitro diagnostic systems. The controller may also be configured to control the in vitro diagnostic system such that the workflow and workflow steps are executed by the in vitro diagnostic system. In particular, the controller may communicate and / or cooperate with a scheduler and / or a data manager and / or a user input interface and / or a sample input interface in order to take into account the number of scheduled process operations associated with the execution of the sample IVD test order, as well as the incoming sample IVD test order and / or the received sample IVD test order, and to plan when to start, when to interrupt, and when to restart / resume the execution of the calibration procedure. In particular, the controller may be configured to perform any of the method steps according to any of the above-described embodiments.

[0045] Other and further objects, features and advantages will become apparent from the following description of exemplary embodiments that explain the principles in more detail and from the accompanying drawings.

Brief Description of the Drawings

[0046]

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DETAILED DESCRIPTION OF THE INVENTION

[0047] Those skilled in the art will understand that the elements in the figures are shown for simplicity and clarity and are not necessarily drawn to scale. For example, the dimensions of some elements in the figures may be exaggerated relative to other elements, while other elements may be omitted or represented with a reduced number in order to enhance clarity and improve the understanding of the aspects of the present disclosure. FIG. 1 shows a table including any selection of common calibration solutions, with known values of calibration materials or standards corresponding to different levels of analytes of interest that may be present in a sample, generally shown as "high", "mid", "low". This can be used in one or more calibration procedures to determine inspection-specific calibration parameters, and can be used, for example, to evaluate sample IVD test results to determine the presence and amount of each analyte in a sample. In this example, the analytes of interest or sample parameters associated with each sample IVD test are Na + , K + , Cl - , and Ca ++ and other electrolytes, as well as metabolites such as glucose and lactate that can be detected by respective metabolite sensors (MSS). The calibration solution may alternatively or additionally include other calibration materials or standards related to other analytes of interest or sample parameters, and depending on each measurement principle and IVD system, including specific sample IVD tests such as dynamic range, sensitivity, etc., fewer or more calibration solutions may be used. Therefore, specific values are not shown in this example.

[0048] ISE sensors typically function according to the principle of potential difference measurement. Their differences are only in the membrane materials that enable sensitivity to each electrolyte.

[0049] Glucose sensors generally utilize the glucose oxidase enzyme that oxidizes glucose with oxygen from the air to gluconolactone. The H2O2 generated in this process is measured by current measurement using a manganese dioxide / carbon electrode. Since the sensor restores the oxygen required for the oxidation of glucose by the enzyme reaction, the glucose value is measured without depending on the oxygen concentration in the test sample.

[0050] Lactate sensors typically utilize the lactate oxidase enzyme in which lactate is oxidized to pyruvic acid by oxygen from the air. The H2O2 generated in this process is measured by current measurement in the same manner as the glucose sensor.

[0051] Calibration solution A listed in the table is typically used and measured more frequently than other calibration solutions, for example, always as the first calibration solution and / or between different calibration solutions, and may also be used as a cleaning solution, for example, before and / or after the introduction of the sample.

[0052] Figure 2 shows an example of calibration cycles 10, 20, 30, which includes executing calibration procedures 11, 21, 31 respectively to determine test-specific calibration parameters 12, 22, 32 used respectively when evaluating sample IVD test results, and repeating calibration procedures 11, 21, 31 to update test-specific calibration parameters 12, 22, 32 before the expiration of each respective calibration period, i.e., before starting new cycles 10, 20, 30. Different calibration procedures 11, 21, 31 have different calibration periods respectively. Executing different calibration procedures 11, 21, 31 / cycles 10, 20, 30 includes using different sets of calibration solutions, for example, selected from those in Figure 1. The set of calibration solutions includes at least two, for example, 2, 4, and in some cases, for example, 6 (not shown) or more different calibration solutions. In particular, in this example, the set of calibration solutions comprises a single pair A-B of calibration solutions A, B, C, D or multiple pairs A-B-A-C, A-B-A-D. Each pair A-B, A-C, A-D comprises a common calibration solution A as the first calibration solution and any other different calibration solutions B, C, D as the second or subsequent calibration solutions. Other combinations (not shown) such as A-C, A-D, A-B-A-C-A-D are also possible. Generally, depending on the specific sample IVD test and the content of the calibration solutions, any combination of any number of calibration solutions, not necessarily in pairs, is possible.

[0053] Depending on the specific calibration procedures 11, 21, 31 and the respective sets of calibration solutions used in A-B, A-B-A-C, A-B-A-D, the respective test-specific calibration parameters 12, 22, 32 can be determined. Exemplary test-specific calibration parameters 12, 22, 32 can be determined with respect to each calibration line or calibration curve, for example, as shown in Figure 1, with reference to the analyte or sample parameter of interest, and include slope (SL), offset (OS), linearity (LN), zero point (ZP), which are described in more detail by way of example in Figures 3 to 6. Each calibration parameter is shown with a subscript adjacent to it indicating the respective analyte or sample parameter of interest. Electrolyte Na + 、K + 、Cl - 、and Ca ++For simplicity, they are generally denoted by the same group ISE. The metabolites glucose and lactate are generally denoted by the same group MSS, respectively. The abbreviation CK (Check) can refer to either calibration parameter OS or SL if not otherwise specified. It should also be noted that after each calibration solution used, a subset of the calibration parameters 12, 22, 32 specific to the test can be determined.

[0054] In this example, executing cycle 10 includes executing calibration procedure 11 which involves using calibration solutions A - B every 1.5 hours, meaning that the calibration validity period of calibration procedure 11 is 1.5 hours and the repetition of the calibration procedure must be executed before the expiration of this calibration validity period. Executing calibration cycle 20 includes executing calibration procedure 21 which involves using calibration solution C every 12 hours, meaning that the calibration validity period of calibration procedure 21 is 12 hours and the repetition of the calibration procedure must be executed before the expiration of this calibration validity period. In particular, calibration procedure 21 includes using the pair of calibration solutions A - C combined with the pair of calibration solutions A - B of calibration procedure 11 in a single calibration cycle 20. This is an example of two calibration procedures 11, 21 having different calibration validity periods of 1.5 hours and 12 hours respectively, but they expire simultaneously and are thus combined by adding their respective calibration solutions and / or pairs of calibration solutions to the same set. Similarly, executing calibration cycle 30 includes executing calibration procedure 31 which involves using calibration solution D every 12 hours, meaning that the calibration validity period of calibration procedure 31 is 12 hours and the repetition of the calibration procedure must be executed before the expiration of this calibration validity period. In particular, calibration procedure 31 includes using the pair of calibration solutions A - D combined with the pair of calibration solutions A - B of calibration procedure 11 in a single calibration cycle 30. This is another example of two calibration procedures 11, 21 having different calibration validity periods of 1.5 hours and 12 hours respectively, but they expire simultaneously and are thus combined by adding their respective calibration solutions and / or pairs of calibration solutions to the same set. On the other hand, although both calibration procedures 21 and 31 have a calibration validity period of 12 hours, they are arranged alternately with a 6 - hour period in between, so they expire at different times.

[0055] Combining FIGS. 3 and 4 shows a specific example of calculating the result of a calibration procedure, which is a process of constructing a line, curve, or mathematical function that best fits the measured calibration points. In this case, the calibration curve is the calibration curve used for the evaluation of glucose test results that can be determined by performing the calibration procedure 21 of FIG. 2 to measure calibration solutions A, B, and C. This is because the glucose calibration curve is a non-linear curve that requires the use of three levels of calibration solutions. The dashed curves in FIGS. 3 and 4 refer to the calibration procedure completed using all three levels of calibration solutions A old, B old, and C old at the start of cycle 20 of FIG. 2, thereby determining the calibration parameters ZP, SL old, and LN old specific to the glucose test. To determine the new calibration parameters ZP, SL new, and LN new specific to the glucose test and update the old calibration parameters ZP, SL old, and LN old specific to the glucose test, it is necessary to repeat the calibration procedure 21 before the expiration of the calibration validity period. The difference between FIGS. 3 and 4 is that in FIG. 3, the repetition of the calibration procedure 21 (solid curve) is completed, and thus it is possible to determine all three new calibration parameters ZP, SL new, and LN new specific to the glucose test. In contrast, in FIG. 4, the repetition of the calibration procedure 21 (solid curve) is interrupted after measuring A new and B new, and since C new has not been measured yet, it is not possible to determine the linearity (LN new) of the new curve. However, at least temporarily, it is possible to determine ZP and SL new, thereby updating at least a part of the calibration parameters specific to the glucose test until the calibration procedure is restarted or resumed. For some time, LN old continues to be used.

[0056] FIGS. 5 and 6 together show another specific example of calculating the result of the calibration procedure. In this case, the calibration curve is a calibration curve used for the evaluation of Ca ++ test results that can be determined by performing the calibration procedure 31 of FIG. 2 to measure calibration solutions A and D. This is Ca ++This is because, since the calibration curve is a straight line, it is sufficient to use two levels of calibration solution. The dashed lines in FIGS. 5 and 6 refer to the calibration procedure completed using both levels of calibration solutions A old and D old at the start of cycle 30 in FIG. 2, thereby obtaining a new Ca ++ Determine the inspection-specific calibration parameters OS new and SL new, and the old Ca ++ To update the inspection-specific calibration parameters OS old (not shown) and SL old for the previous cycle 30 and SL old, the Ca for ++ The inspection-specific calibration parameter OS old (not shown) is determined and needs to be updated by repeating the calibration procedure 31 before the expiration of the calibration validity period. The difference between FIGS. 5 and 6 is that in FIG. 5, the repetition of the calibration procedure 31 (solid line) is completed, and thus, it is possible to determine both the new Ca ++ Both the inspection-specific calibration parameters OS new and SL new, whereas in FIG. 6, the repetition of the calibration procedure 31 (solid line) is interrupted after measuring A new, and thus, since D new has not yet been measured, it is impossible to determine the new slope (SL new) of the new line. However, until the calibration procedure is restarted or resumed, at least a temporary OS new can be determined, thereby updating Ca ++ At least some of the inspection-specific calibration parameters. For some time, SL old continues to be used.

[0057] FIG. 7 shows a further aspect regarding performing a calibration procedure using a set 40 of calibration solutions, the set 40 comprising at least two different calibration solutions A, X, where X can be any calibration solution, for example B, C, D. Using calibration solutions A, X comprises a first step t:A, t:X of transferring calibration solutions A, X to a measurement unit respectively, and a second step m:A, m:X of measuring calibration solutions A, X by the measurement unit respectively. In particular, each step t:A, t:X, m:A, m:X has the same duration, for example 30 seconds in this example, which means that it takes 60 seconds for the transfer and measurement of the calibration solutions. This is only an example and can be adapted according to the particular IVD system and calibration solutions used.

[0058] Figure 8 schematically shows a more comprehensive computer-implemented method for automatically managing the calibration of an IVD system. The method includes performing calibration cycles 10, 20, 30, which include executing calibration procedures 11, 21, 31 to determine test-specific calibration parameters 12, 22, 32 used when evaluating sample IVD test results (IVD TR), and repeating the calibration procedure to update the test-specific calibration parameters 12, 22, 32 before the expiration 50 of each calibration period. Different calibration procedures 11, 21, 31 / cycles 10, 20, 30 may have different calibration periods, and performing different calibration procedures 11, 21, 31 / cycles 10, 20, 30 includes using a set 40 of different calibration solutions A, X, comprising at least two different calibration solutions A, X. Using the calibration solutions A, X includes a first step t:A, t:X of transferring the calibration solution to the measurement unit and a second step m:A, m:X of measuring the calibration solution by the measurement unit, as also shown in Figure 7. In particular, for each calibration cycle 10, 20, 30, the method includes starting 41 the earliest repetition of the calibration procedure 11, 21, 31 at the start 48 of a buffer period 49 before the expiration 50 of each calibration period, interrupting 42, 42’, 42’’, 42’’’’ the calibration procedure 11, 21, 31 upon receiving a command 60 to perform a sample IVD test (spl), and restarting 43 or resuming 44 the calibration procedure 11, 21, 31 after performing the sample IVD test (spl) as long as the repetition of the calibration procedure 11, 21, 31 can be restarted 43 or resumed 44 within the buffer period 49.Furthermore, interrupting the calibration procedures 11, 21, 31 at 42, 42', 42'', 42''' comprises different steps depending on whether an instruction 60 to perform a sample IVD test (spl) is received during the use of the first calibration solution A or a subsequent calibration solution X in the set 40 of calibration solutions A, X, and whether an instruction 60 to perform a sample IVD test (spl) is received during the first step t:A, t:X of transferring the first or subsequent calibration solutions A, X respectively to the measuring unit, or during the second step m:A, m:X of measuring the first or subsequent calibration solutions A, X respectively.

[0059] According to one embodiment, when an instruction 60 to perform a sample IVD test (spl) is received during the first step t:A of transferring the first calibration solution A in the set 40 and / or the first calibration solution A in the pair A,X to the measuring unit, interrupting the calibration procedures 11, 21, 31 at 42 comprises completing the first step t:A of transferring the first calibration solution A to the measuring unit, performing a step m':A of measuring the first calibration solution A with a shortened measurement time, and aborting any of the steps following the calibration procedures 11, 21, 31 (marked with a dashed cross) for performing the sample IVD test (spl).

[0060] According to one embodiment, when an instruction 60 to perform a sample IVD test (spl) is received during the second step m:A of measuring the first calibration solution A in the set 40 and / or the first calibration solution A in the pair A,X, interrupting the calibration procedure at 42' comprises completing the second step m:A of measuring the first calibration solution A and aborting any of the steps following the calibration procedure (marked with a dashed cross) for performing the sample IVD test (spl).

[0061] According to one embodiment, when an instruction 60 for performing a sample IVD test (spl) is received during a first step t:X of transferring a subsequent calibration solution X in set 40 and / or pair A, X to a measurement unit, interrupting the calibration procedures 11, 21, 31 42’’ includes interrupting the first step t:X of transferring the subsequent calibration solution X to the measurement unit for performing the sample IVD test (spl), and any subsequent step (marked with a dashed cross) of the calibration procedures 11, 21, 31. The method further comprises performing a washing step (wash) before performing the sample IVD test (spl), and the washing step (wash) has a shorter duration than any interrupted step. In particular, the method may include performing the washing step (wash) with a first calibration solution A before performing the sample IVD test (spl). The method may further comprise shortening the measurement time and performing a measurement step m’:A of the first calibration solution A before performing the sample IVD test (spl).

[0062] According to one embodiment, when an instruction 60 for performing a sample IVD test (spl) is received during a second step m:X of measuring a subsequent calibration solution X in set 40 and / or pair A, X, interrupting the calibration procedures 11, 21, 31 42’’’ includes completing the second step m:X of measuring the subsequent calibration solution X, and interrupting any subsequent step (marked with a dashed cross) of the calibration procedures 11, 21, 31 for performing the sample IVD test (spl). This method further comprises performing a washing step (washing) before performing the sample IVD test (spl), and the washing step (washing) has a shorter duration than the interrupted step. In particular, this method may include performing the washing step (washing) with a first calibration solution A before performing the sample IVD test (spl). The method may further comprise shortening the measurement time and performing a measurement step m’:A of the first calibration solution A before performing the sample IVD test (spl).

[0063] Continuing to refer to FIG. 8, the method further comprises updating at least a part of the calibration parameters 12, 22, 32 specific to the test after measurement of the first calibration solution A or after completed measurement of the pair of calibration solutions A, X.

[0064] Also, after performing a sample IVD test (spl), the method comprises restarting calibration procedures 11, 21, 31 for using a single pair of calibration solutions A, X or for the calibration procedures 42, 42', 42'', interrupted while using the first pair of calibration solutions A, X; and resuming the interrupted calibration procedures 11, 21, 31 starting from the calibration solution pairs 42''' where the measurement for the calibration procedures was interrupted or aborted using a plurality of pairs of calibration solutions.

[0065] Furthermore, restarting 43 or resuming 44 the calibration procedures 11, 21, 31 includes waiting for a predetermined time 47 after performing the sample IVD test (spl) as long as the repetition of the calibration procedure can be restarted 43 or resumed 44 within a buffer period 49.

[0066] FIG. 9 schematically shows an IVD system 200 for performing a sample IVD test, comprising at least one measurement unit 210, a fluid system 213 for transferring at least the calibration solutions A, B, C, D and the sample 2 to the at least one measurement unit 210, and a controller 250 that executes a computer-readable program comprising instructions for performing operations related to the method of managing calibration according to any of the above-described embodiments.

[0067] The measurement unit 210 includes a flow-through sensor path 211 having a plurality of sensors 212 such as ISE sensors and metabolite sensors. The IVD system 200 further includes a pump 240 such as a peristaltic pump disposed downstream of the fluid system 213, a fluid supply unit 220 having a plurality of fluids including calibration solutions A, B, C, and D, and a waste container 224 capable of discarding the fluid circulating the fluid system 213 by the operation of the pump 240. The IVD system 200 further includes a fluid selection valve 230 for selecting fluid A, B, C, D, and / or air 232.

[0068] The IVD system 200 further includes a sample input interface 201 having a sample input port 10 including an outer input port side 11 and an inner input port side 12 configured to insert the open end of the sample container 1. The sample input interface 201 further includes a suction needle 30 having an upstream end 31 and a downstream end 32. The downstream end 32 of the suction needle 30 is fluidly connected to the fluid system 213, but the upstream end 31 is configured to alternately couple to the inner input port side 12 for sucking the sample 2 from the sample container 1 inserted into the outer input port side 11 and the fluid supply unit port 40 fluidly connected to the common outlet port 231 of the fluid selection valve 230. However, the fluid system 213 may be directly connected to the outlet port 231 of the fluid selection valve 230, while the sample may be introduced via different fluid lines separately connected to the fluid selection valve 230, for example.

[0069] Modifications and variations of the disclosed embodiments are of course also possible in light of the above description. Thus, within the scope of the appended claims, it is to be understood that the invention may be practiced in a manner different from that specifically devised in the above examples.

[0070] In particular, it is to be understood that at least some of the drawings or components are schematic and provided for illustration only. Also, the relationship of each element may be other than that shown, and components not relevant to the gist of the present disclosure are omitted.

[0071] Also, throughout the above specification, references to "one aspect", "an aspect", "one example" or "an example", "one embodiment" or "an embodiment" mean that the particular features, structures or characteristics described in connection with the aspect or example or embodiment are included in at least one aspect, example or embodiment. Thus, the appearances of the phrases "in one aspect", "in one aspect", "one example" or "an example", "one embodiment" or "an embodiment" in various places throughout this specification are not necessarily all referring to the same aspect or example or embodiment.

[0072] Furthermore, the particular features, structures, or characteristics may be combined in any suitable combination and / or sub-combination in one or more aspects or examples or embodiments.

Claims

1. 1. A computer-implemented method for automatically managing the calibration of an in vitro diagnostic (IVD) system (200), the method comprising: performing a calibration cycle (10, 20, 30), the calibration cycle (10, 20, 30) including performing a calibration procedure (11, 21, 31) to determine test-specific calibration parameters (12, 22, 32) for use in evaluating sample IVD test results, and repeating the calibration procedures (11, 21, 31) to update the test-specific calibration parameters (12, 22, 32) prior to expiration (50) of their respective calibration validity periods; Different calibration procedures (11, 21, 31) / cycles (10, 20, 30) may have different calibration validity periods; performing different calibration procedures (11, 21, 31) / cycles (10, 20, 30) includes using different sets (40) of calibration solutions (A, X), each set including at least two different calibration solutions (A, X); Using the calibration solution (A,X) comprises a first step (t:A, t:X) of transferring the calibration solution (A,X) to a measurement unit (210) and a second step (m:A, m:X) of measuring the calibration solution (A,X) by the measurement unit (210), For each calibration cycle (10, 20, 30), the method comprises: - commencing (41) a repetition of said calibration procedure (11, 21, 31) at the earliest at the beginning (48) of a buffer period (49) before the expiration (50) of said respective calibration validity period; interrupting (42, 42', 42'', 42''') said calibration procedure (11, 21, 31) upon receiving a command (60) to perform a sample IVD test (spl), and restarting (43) or resuming (44) said calibration procedure (11, 21, 31) after performing said sample IVD test (spl), as long as the repetition of said calibration procedure (11, 21, 31) can be restarted (43) or resumed (44) within said buffer period (49). Including, The method of claim 1, wherein interrupting (42, 42', 42'', 42''') the calibration procedure (11, 21, 31) comprises steps which differ depending on whether the command (60) to perform a sample IVD test (spl) is received while using a first calibration solution (A) or a subsequent calibration solution (X) in a set (40) of calibration solutions (A, X) and whether the command (60) to perform a sample IVD test (spl) is received during the first step (t:A, t:X) of transferring the first calibration solution or a subsequent calibration solution (A, X) to the measurement unit (210) or during the second step (m:A, m:X) of measuring the first calibration solution or a subsequent calibration solution (A, X).

2. 2. The method of claim 1, wherein the set (40) of calibration solutions (A, X) comprises a single pair or multiple pairs of calibration solutions (A, X), each pair comprising a common calibration solution (A) as a first calibration solution and any other different calibration solutions (X, B, C, D) as the subsequent calibration solutions.

3. 3. The method according to claim 1 or 2, wherein when the instruction (60) to perform a sample IVD test (spl) is received during the first step (t:A) of transporting the first calibration solution (A) in the set (40) and / or the first calibration solution (A) in the pair to the measurement unit (210), interrupting (42) the calibration procedure (11, 21, 31) comprises completing the first step (t:A) of transporting the first calibration solution (A) to the measurement unit (210), performing a measurement step (m':A) of the first calibration solution (A) with a reduced measurement time, and canceling any of the subsequent steps of the calibration procedure (11, 21, 31) to perform the sample IVD test (spl).

4. 3. The method according to claim 1 or 2, wherein when the instruction (60) to perform a sample IVD test (spl) is received during the second step (m:A) of measuring the first calibration solution (A) in the set (40) and / or the first calibration solution (A) in the pair, interrupting (42') the calibration procedure (11, 21, 31) comprises completing the second step (m:A) of measuring the first calibration solution (A) and aborting any of the subsequent steps of the calibration procedure (11, 21, 31) for performing the sample IVD test (spl).

5. 3. The method according to claim 1 or 2, wherein when the instruction (60) to perform a sample IVD test (spl) is received during the first step (t:X) of transferring a subsequent calibration solution (X) in a set (40) and / or the subsequent calibration solution (X) in a pair to the measurement unit (210), interrupting (42'') the calibration procedure (11, 21, 31) comprises canceling either the first step (t:X) of transferring the subsequent calibration solution (X) to the measurement unit (210) for performing the sample IVD test (spl) and any subsequent steps of the calibration procedure (11, 21, 31).

6. 3. The method according to claim 1 or 2, wherein when the instruction (60) to perform a sample IVD test (spl) is received during the second step (m:X) of measuring a subsequent calibration solution (X) in a set (40) and / or the subsequent calibration solution (X) in a pair, interrupting (42'''') the calibration procedure (11, 21, 31) comprises completing the second step (m:X) of measuring the subsequent calibration solution (X) and aborting any subsequent step of the calibration procedure (11, 21, 31) to perform the sample IVD test (spl).

7. 7. The method according to claim 5 or 6, comprising performing a step of washing with the first calibration solution (A) before performing the sample IVD test (spl).

8. 8. The method of claim 7, further comprising performing a measurement step (m':A) of the first calibration solution (A) with a reduced measurement time before performing the sample IVD test (spl).

9. 9. The method according to claim 3, further comprising updating at least a portion of the test-specific calibration parameters (12, 22, 32) following completion of the measurement of the first calibration solution (A) or of a pair of calibration solutions (A, X).

10. After performing the sample IVD inspection (spl), the method further comprises: restarting (43) a calibration procedure (11) using a single pair of calibration solutions (A, X) or for a calibration procedure (11) that was interrupted (42, 42', 42'') while using a first said pair of calibration solutions (A, X); - for a calibration procedure (21, 31) using a plurality of pairs of calibration solutions (A, X), resuming (44) the calibration procedure (11, 21, 31) that was interrupted (42''') starting from the pair of calibration solutions for which the measurement was interrupted or stopped; The method according to any one of claims 2 to 9, comprising:

11. The method of any one of claims 1 to 10, wherein restarting (43) or resuming (44) the calibration procedure (11, 21, 31) comprises waiting a predetermined time (47) after performing the sample IVD inspection, as long as a repetition of the calibration procedure (11, 21, 31) can be restarted (43) or resumed (44) within the buffer period (49).

12. The method according to any one of claims 1 to 11, comprising combining different calibration procedures (11, 21, 31) into a single calibration cycle (20, 30) by adding the respective calibration solutions and / or paired calibration solutions to the same set (40) if the different calibration procedures (11, 21, 31) share the same or similar calibration validity periods and / or if the respective validity periods have the same expiration.

13. At least one measuring unit (210); a fluidic system (213) for transporting at least the calibration solutions (A, B, C, D) and the sample (2) to said at least one measuring unit (210); A controller (250) executing a computer readable program with instructions for performing operations related to the method of managing calibration according to any one of claims 1 to 12; An in vitro diagnostic (IVD) system (200) for performing a sample IVD test (spl), comprising:

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