Method for establishing metrological traceability for at least one in vitro diagnostic medical device

Abstract

The invention proposes a method for establishing a metrological traceability for at least one in vitro diagnostic medical device (110). The method includes a series of calibration steps and adjustment steps. The result of each step depends on the result of the previous step. The method includes providing a pilot calibration curve. The lead calibration curve fp describes a relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of the sample measured with the in vitro diagnostic medical device (110). The pilot calibration curve fp is a parameterized function (I), wherein parameters (II) are a set of parameters of the pilot calibration curve and P > = 1. In each adjustment step, a signal adjustment function or a concentration adjustment function is determined and at least one target concentration value is specified. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a method, a processing device, a kit comprising an in vitro diagnostic medical device and a set of IVD MD calibrators and their target concentration values, a computer program and a computer program product for establishing metrological traceability for at least one in vitro diagnostic medical device (IVD MD). Background Art

[0002] In general, the goal of a mass spectrometry device calibration procedure is to transfer authenticity from a higher-order reference (e.g., a reference measurement procedure or reference material) to an analytical application, also called an assay, by specifying target values ​​for the calibrant. Typically, such methods establish a traceability chain for each measurement of a patient sample to a higher-order reference and make the analytical application and its results comparable around the world. The general process has been well described, for example, in ISO 17511:2020.

[0003] In order to transfer authenticity from one method to another method, special samples, such as patient samples, or calibrators are often used. Usually, these samples are the values ​​specified in the high-order method and are used for the calibration of low-order methods. The calibration function obtained usually depends on various factors, such as: independent instruments, hardware components (for example, in the case of hardware multiplexing), reagent batches, independent reagents (for example, in a batch), a new group of calibration samples, calibration events themselves and time effects. Therefore, the function parameters of each independent calibration function may be different usually. The method described in the prior art usually includes a plurality of independent and independent calibration steps. This means that the variance of each step may usually contribute completely to the overall variance of the whole method. Higher variance will usually make the calibration method less robust and increase uncertainty.

[0004] WO 2021 / 239692 A1 describes a computer-implemented method for calibrating a customer mass spectrometer for a quantifier-qualifier ratio calibration. The method comprises the following steps: a) at least one manufacturer on-site standardization, wherein a set of subject samples and a set of calibrator samples are measured in multiple replicates on multiple mass spectrometer instruments, wherein each measurement comprises multiple reaction monitoring by quantifier and qualifier transitions for an analyte and an internal standard, wherein at least three adjustment factors are determined from the measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor depends on the difference between the analyte and the internal standard, wherein a second adjustment factor depends on the difference between the subject sample and the calibrator sample for the analyte quantifier-qualifier ratio, wherein a third adjustment factor depends on the difference between the subject sample and the calibrator sample for the internal standard quantifier-qualifier ratio; b) at least one transmission step, wherein the adjustment factors are electronically transmitted to a customer mass spectrometer instrument; c) at least one customer on-site calibration, wherein the customer on-site calibration comprises at least one calibration measurement, wherein a set of calibrator samples are measured on the customer mass spectrometer instrument and the quantifier-qualifier ratios are determined from the set of calibrator samples, wherein target values ​​for the quantifier-qualifier ratios for the analyte and for the internal standard are set by applying the adjustment factors to the determined quantifier-qualifier ratios.

[0005] EP 3 472 624 B1 describes a method for providing a calibration curve for an optical D-dimer determination.

[0006] Issues to be resolved

[0007] Therefore, it is an object of the present invention to provide a method, a processing device, a kit comprising an in vitro diagnostic medical device and a set of IVD MD calibrants and target concentration values ​​thereof, a computer program and a computer program product for establishing metrological traceability for at least one in vitro diagnostic medical device, which avoids the above-mentioned disadvantages of known methods, devices, computer programs and computer program products. In particular, the method and device should minimize or reduce the overall variance of the calibration process. In particular, the calibration process should be optimized, in particular by increasing the robustness of the calibration process and / or by reducing the uncertainty of the calibration process. Summary of the invention

[0008] This problem is solved by a method for establishing metrological traceability for at least one in vitro diagnostic medical device, a processing device, a kit comprising an in vitro diagnostic medical device and a set of IVD MD calibrants and target concentration values ​​thereof, a computer program and a computer program product having the features of the independent claims. In the dependent claims and throughout the description, advantageous embodiments are listed which can be realized individually or in any combination.

[0009] As used below, the terms "having", "comprising" or "including" or any grammatical variations thereof are used in a non-exclusive manner. Thus, these terms may refer to the absence of other features in the entity described in this context in addition to the features introduced by these terms, or the presence of one or more other features. As an example, the expressions "A has B", "A includes B" and "A contains B" may refer to the absence of other elements in A in addition to B (i.e., the presence of A solely and exclusively consisting of B); or to the presence of one or more other elements in entity A in addition to B (such as element C, element C and element D, or even other elements).

[0010] Further, it should be noted that the terms "at least one", "one or more" or similar expressions indicating that a feature or element may be present once or more than once are usually used only once when introducing the corresponding feature or element. In the following, in most cases, when referring to the corresponding feature or element, the expression "at least one" or "one or more" is not repeated even though the corresponding feature or element may be present only once or more than once.

[0011] Further, as used hereinafter, the terms "preferably", "more preferably", "particularly", "more particularly", "specifically", "more specifically" or similar terms are used in conjunction with optional features without limiting the possibilities of alternatives. Therefore, the features introduced by these terms are optional features and are not intended to limit the scope of the claims in any way. As the skilled person will recognize, the present invention can be implemented by using alternative features. Similarly, the features introduced by "in one embodiment of the present invention" or similar expressions are intended to be optional features without any limitation on alternative embodiments of the present invention, without any limitation on the scope of the present invention, and without any limitation on the possibility of combining the features introduced in this manner with other optional or non-optional features of the present invention.

[0012] In a first aspect of the present invention, a method for establishing metrological traceability for at least one in vitro diagnostic medical device is disclosed.

[0013] The method can be computer-implemented. As used herein, the term "computer-implemented" is a broad term and should be given its ordinary and customary meaning for a person of ordinary skill in the art, and should not be limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a method involving at least one computer and / or at least one computer network. The computer and / or computer network may include at least one processor, which is configured to perform at least one of the method steps of the method according to the present invention. Preferably, each method step is performed by a computer and / or a computer network. The method may be performed completely automatically (such as, without user interaction). As used herein, the term "automatically" is a broad term and is given its ordinary and customary meaning for a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a process performed entirely by means of at least one computer and / or at least one computer network and / or at least one machine, in particular, without the need for manual operation and / or interaction with a user.

[0014] As used herein, the term "metrological traceability" is a broad term and should be given its ordinary and customary meaning to persons of ordinary skill in the art and should not be limited to a special or customary meaning. The term may specifically refer to, but is not limited to, the property of a measurement result whereby the result can be related to a reference through a documented, complete chain of calibration and adjustment steps.

[0015] As used herein, the term "in vitro diagnostic medical device" (IVD MD) is a broad term and is given the common and customary meaning to those of ordinary skill in the art, and is not limited to a special or customized meaning. Whether used alone or in combination, the term may specifically refer to, but is not limited to, a medical device that is configured to perform in vitro examination of at least one sample derived from the human body, and / or is configured to provide information for diagnosis, monitoring or compatibility purposes. An IVDMD may include one or more of at least one reagent, at least one calibrator, at least one control material, at least one sample container, software, related instruments or equipment, or other items.

[0016] The in vitro diagnostic medical device can be a mass spectrometer. As used herein, the term "mass spectrometer" is a broad term and will be given its common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or customary meaning. The term may specifically refer to, but is not limited to, an analytical technique for determining the mass-to-charge ratio of an ion. Mass spectrometry may be performed using at least one mass spectrometer. As used herein, the term "mass spectrometer", also referred to as "mass analyzer", is a broad term and is given its common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or customary meaning. The term may specifically refer to, but is not limited to, an analyzer configured to detect at least one analyte based on a mass-to-charge ratio.

[0017] The mass analyzer may be or may include at least one quadrupole mass analyzer. As used herein, the term "quadrupole mass analyzer" is a broad term and is given its ordinary and customary meaning to ordinary technicians in the field, and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a mass analyzer including at least one quadrupole as a mass filter. A quadrupole mass analyzer may include multiple quadrupoles. For example, a quadrupole mass analyzer may be a triple quadrupole mass spectrometer. As used herein, the term "mass filter" is a broad term and is given its ordinary and customary meaning to ordinary technicians in the field, and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a device configured to select ions injected into the mass filter according to the mass-to-charge ratio m / z of the ions. The mass filter may include two pairs of electrodes. The electrodes may be rod-shaped, such as cylindrical. Ideally, the electrodes may be hyperbolic. The electrodes may be designed to be identical. The electrodes may be arranged to extend in parallel along a common axis, such as the z-axis. The quadrupole mass analyzer may include at least one power supply circuit configured to apply at least one direct current (DC) voltage and at least one alternating current (AC) voltage between the two pairs of electrodes of the mass filter. The power supply circuit may be configured to maintain each relative electrode pair at the same potential. The power supply circuit may be configured to periodically change the charge sign of the electrode pair so that only ions within a certain mass-to-charge ratio m / z range may have a stable trajectory. The trajectory of the ions in the mass filter can be described by the Mathieu differential equation. In order to measure ions with different m / z values, the DC voltage and the AC voltage can be adjusted in time so that ions with different m / z values ​​can be transmitted to the detector of the mass spectrometer.

[0018] The mass spectrometer may further include at least one ionization source. As used herein, the term "ionization source", also referred to as "ion source", is a broad term and is given its ordinary and customary meaning to those of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a device configured to generate ions, for example, from neutral gas molecules. The ionization source may be or may include at least one source selected from the group consisting of: at least one gas phase ionization source, such as at least one electron impact (EI) source or at least one chemical ionization (CI) source; at least one desorption ionization source, such as at least one plasma desorption (PDMS) source, at least one fast atom bombardment (FAB) source, at least one secondary ion mass spectrometry (SIMS) source, at least one laser desorption (LDMS) source, and at least one matrix-assisted laser desorption (MALDI) source; at least one spray ionization source, such as at least one thermal spray (TSP) source, at least one atmospheric pressure chemical ionization (APCI) source, at least one electrospray (ESI) and at least one atmospheric pressure ionization (API) source.

[0019] The mass spectrometer may include at least one detector. As used herein, the term "detector" is a broad term and is given its common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a device configured to detect input ions. The detector may be configured to detect charged particles. The detector may be or may include at least one electron multiplier. A mass spectrometer, for example, a detector and / or at least one processing unit of a mass spectrometer, may be configured to determine at least one mass spectrogram of the detected ions. As used herein, the term "mass spectrogram" is a broad term and is given its common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a two-dimensional representation of signal intensity compared to mass-to-charge ratio m / z, wherein the signal intensity corresponds to the abundance of the corresponding ions. A mass spectrogram may be a pixelated image. In order to determine the resulting intensity of a mass spectrogram pixel, the signal detected by the detector within a certain m / z range may be integrated. The analyte in the sample may be identified by the processing unit. The processing unit may be configured to associate a known mass with an identified mass or by a characteristic fragmentation pattern.

[0020] The mass spectrometer may be or may include a liquid chromatography mass spectrometer. The mass spectrometer may be connected to and / or may include at least one liquid chromatograph. The liquid chromatograph may be used as a sample preparation for the mass spectrometer. Other embodiments of sample preparation are also feasible, such as at least one gas chromatograph. As used herein, the term "liquid chromatography mass spectrometer" is a broad term and is given a common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a combination of liquid chromatography and mass spectrometry. The mass spectrometer may include at least one liquid chromatograph. The liquid chromatography mass spectrometer may be or may include at least one high performance liquid chromatography (HPLC) device or at least one microfluidic liquid chromatography (μLC) device. The liquid chromatography mass spectrometer may include a liquid chromatography (LC) device and a mass spectrometer (MS) device, in the present case a mass filter, wherein the LC device and the mass filter are coupled via at least one interface. The interface coupling the LC device and the MS device may include an ionization source configured to generate molecular ions and transfer molecular ions to the gas phase. The interface may further include at least one ion mobility module disposed between the ionization source and the mass filter. For example, the ion mobility module may be a high-field asymmetric waveform ion mobility spectrometry (FAIMS) module.

[0021] As used herein, the term "liquid chromatography (LC) device" is a broad term and is given its ordinary and customary meaning to those of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, an analytical module configured to separate one or more target analytes of a sample from other components of the sample for use in detecting the one or more analytes using a mass spectrometer. The LC device may include at least one LC column. For example, the LC device may be a single-column LC device or a multi-column LC device having a plurality of LC columns. The LC column may have a stationary phase through which a mobile phase is pumped to separate and / or elute and / or transmit the target analyte. The liquid chromatography-mass spectrometer device may further include a sample preparation station for automated pretreatment and preparation of samples, each sample including at least one target analyte.

[0022] The term "analyte" as used herein refers to any chemical compound or group of compounds that should be determined in a sample. The analyte detected by a mass spectrometer can be a part of a sample, for example, a solid, liquid or gas sample that is examined (e.g., measured with a mass spectrometer). As a result of the measurement process, the mass spectrometer can detect the presence and / or abundance and / or concentration of one or more analytes (e.g., multiple analytes in a sample). The analyte itself can be a sample component. Additionally or alternatively, the analyte can be a fragment of a component present in the sample. As an example, one or more sample components may be cracked during the measurement process, such as during an ionization procedure, so that a single sample component can produce a plurality of different fragments, such as charged fragments, which can be at least partially detected as analytes by a mass spectrometer.

[0023] For example, the analyte may be a macromolecule, i.e., a compound having a molecular mass greater than 1000u (i.e., greater than 1kDa). For example, the analyte may be a biomacromolecule, e.g., a polypeptide, a polynucleotide, a polysaccharide, or a fragment of any of the above. For example, the analyte may be a small molecule chemical compound, i.e., a compound having a molecular mass of at most 1000u (1kDa). For example, the analyte may be a compound metabolized by the body of a subject (e.g., a human subject), or may be a compound administered to a subject to induce metabolic changes in the subject. Thus, for example, the analyte may be an illicit drug or a metabolite thereof, such as amphetamine; cocaine; methadone; ethyl glucuronide; ethyl sulfate; an opium, such as buprenorphine, 6-monoacylmorphine, codeine, dihydrocodeine, morphine, morphine-3-glucuronide, and / or tramadol; and / or an opioid, such as acetylfentanyl, carfentanyl, fentanyl, hydrocodone, norfentanyl, oxycodone, and / or oxymorphone.

[0024] For example, the analyte can be a therapeutic drug, such as valproic acid; clonazepam; methotrexate; voriconazole; mycophenolic acid (total); mycophenolic acid-glucuronide; acetaminophen; salicylic acid; theophylline; digoxin; immunosuppressants, such as cyclosporine, everolimus, sirolimus and / or tacrolimus; analgesics, such as pethidine, norpethidine, tramadol and / or O-desmethyltramadol; antibiotics, such as gentamicin, tobramycin, amikacin, vancomycin-resistant, piperacillin (tazobactam), meropenem and / or linezolid; antiepileptic drugs, such as phenytoin sodium, valproic acid, free phenytoin sodium, free valproic acid, levetiracetam, carbamazepine, carbamazepine-10,11-epoxide, phenobarbital, primidone, gabapentin, zonisamide, lamotrigine and / or topiramate. For example, the analyte can be a hormone such as Cortisol, estradiol, progesterone, testosterone, 17-hydroxyprogesterone, aldosterone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), dihydrotestosterone and / or cortisone; for example, the sample can be a serum or plasma sample and the analyte can be Cortisol, DHEA-S, estradiol, progesterone, testosterone, 17-hydroxyprogesterone, aldosterone, DHEA, dihydrotestosterone and / or cortisone; for example, the sample can be a saliva sample and the analyte can be Cortisol, estradiol, progesterone, testosterone, 17-hydroxyprogesterone, androstenedione and / or cortisone; for example, the sample can be a urine sample and the analyte can be Cortisol, aldosterone and / or cortisone. For example, the analyte may be a vitamin, such as vitamin D, in particular ergocalciferol (vitamin D2) and / or cholecalciferol (vitamin D3) or a derivative thereof, such as 25-hydroxy-vitamin-D2, 25-hydroxy-vitamin-D3, 24,25-dihydroxy-vitamin-D2, 24,25-dihydroxy-vitamin-D3, 1,25-dihydroxy-vitamin-D2 and / or 1,25-dihydroxy-vitamin-D3. For example, the analyte may be a metabolite of the subject.

[0025] The in vitro diagnostic medical device may include at least one hardware component. The in vitro diagnostic medical device may include multiple hardware components. The term "hardware component" is a broad term and is given a common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a physical and / or tangible component of an in vitro diagnostic medical device. A hardware component may be configured to interact with another component, for example, to achieve at least one common function for an in vitro medical device. Hardware components may be processed independently, or may be coupled, connected or integrated with each other. For example, a hardware component may be or may include an instrument or component that forms a part of an in vitro diagnostic medical device (such as a mass spectrometer), for example, one or more of the following items: a sample preparation unit of a mass spectrometer, an ionization unit of a mass spectrometer, a mass analyzer unit of a mass spectrometer, and a detection unit of a mass spectrometer. The hardware component may have a specific configuration or setting that is variable or adjustable (for example, in an application-specific manner). Additionally or alternatively, the configuration or setting may vary due to manufacturing tolerances. For example, due to the potential variability of the hardware component, the hardware component may need to be calibrated.

[0026] As used herein, the term "sample", also referred to as "test sample", may refer to any type of material composition; therefore, the term may refer to, but is not limited to, any arbitrary sample, such as a biological sample and / or an internal standard sample. For example, the sample may be a liquid sample, such as a water sample. For example, the test sample may be selected from the group consisting of: physiological fluids, including whole blood, serum, plasma, saliva, lens fluid, tears, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid and amniotic fluid; lavage fluid; tissue, cells, etc. However, the sample may also be a natural or industrial liquid, such as surface water or groundwater, sewage, industrial wastewater, processing fluid, soil eluate, etc. For example, the sample may include or may be suspected of including at least one target chemical compound, i.e., a chemical substance that should be determined, which is referred to as an "analyte". The sample may include one or more additional chemical compounds that are not determined and are generally referred to as "matrix", as specified above. The sample may be used directly when obtained from the corresponding source, or may be subjected to one or more pretreatment and / or sample preparation steps. Thus, the sample may be pre-treated by physical and / or chemical methods, for example by centrifugation, filtration, mixing, homogenization, chromatography, precipitation, dilution, concentration, contact with binding and / or detection reagents and / or any other method deemed suitable by a person skilled in the art.

[0027] In the sample preparation step, i.e. before, during and / or after the sample preparation step, one or more internal standards may be added to the sample. The sample may be doped with an internal standard. For example, the internal standard may be added to the sample at a predefined concentration. The internal standard may be selected to be easy to identify under normal operating conditions of a selected detector (e.g., a mass spectrometer, a photometric cell (e.g., in a UV-visible spectroscopy device), an evaporative light scattering refractometer, a conductivity meter, or any device deemed appropriate by the technician). The concentration of the internal standard may be predetermined and significantly higher than the concentration of the analyte. For example, in general, the target analyte may be vitamin D, drugs of abuse, therapeutic drugs, hormones, and metabolites. The internal standard sample may be a sample comprising at least one internal standard substance with a known concentration. For further details on the corresponding samples, reference is made to, for example, EP 3 425 369 A1, the entire disclosure of which is included herein by reference. Other target analytes are also possible.

[0028] The method consists of a series of calibration and adjustment steps. The result of each step depends on the result of the previous step. This can allow the establishment of metrological traceability for in vitro diagnostic medical devices.

[0029] The method includes providing a pilot calibration curve. The pilot calibration curve f p The reference calibration curve f describes the relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of the sample measured with an in vitro diagnostic medical device. p For parameterized functions The parameters is a set of parameters of the pilot calibration curve and P ≥ 1.

[0030] In each adjustment step, the signal adjustment function g describing the relationship between the measured signal value and the theoretical signal value r The signal adjustment function is determined by determining the relationship between the measured signal value of the first calibrator sample and the theoretical signal value of the first calibrator sample derived from the pilot calibration curve, where r is a set of parameters of the signal adjustment function. The theoretical signal value is obtained by applying the pilot calibration curve using the pre-specified target concentration value c of the first calibrator sample. i To be determined.

[0031] Each adjustment step includes assigning at least one target concentration value based on the measured signal value of at least one second calibrator sample. The assigning includes determining at least one theoretical signal value for the second calibrator sample by applying a signal adjustment function determined in a previous adjustment step or an inverse of a signal adjustment function determined in a previous adjustment step to the measured signal value of the second calibrator sample, and applying an inverse pilot calibration curve to the measured signal value of the second calibrator sample. Theoretical signal value applied to the second calibrant sample.

[0032] The method steps and / or sub-steps of the method steps, such as the above-mentioned actions included in each method step, can be performed, for example, in a given order. However, different orders are also feasible. The method may further include other method steps that are not listed. In addition, one or more or even all of the method steps and / or sub-steps can be performed only once or repeatedly.

[0033] As described above, the method according to the present invention uses a series of calibration and adjustment steps so that metrological traceability for in vitro diagnostic medical devices can be established. In particular, the method according to the present invention solves the problem of transferring authenticity from a higher-order reference (e.g., a reference measurement procedure or a reference material) to an analytical application. A known process is described in ISO 17511:2020, in which a specific measurement procedure and a specific material are used in each step, whose target value is specified in the previous step. However, in the known process of ISO 17511:2020, multiple separate and independent calibration steps are used. This means that the variance of each step completely affects the overall variance of the entire process. The present invention proposes a different method for establishing a traceability chain, namely using a series of calibration and adjustment steps, in which the result of each step depends on the result of the previous step. The traceability chain can be achieved in the following way. Using a pilot calibration curve (pilot calibration curve f p The calibration curve is described as the relationship between the concentration c of the analyte in the sample and the signal s of the sample measured with the IVD device) and the pilot calibration curve remains unchanged during the whole process chain. Instead of having a different calibration (and thus a different calibration curve) for each step of the chain, an adjustment step is proposed, wherein a signal adjustment function is determined, which describes the relationship between the measured signal value and the theoretical signal value. Each adjustment step may comprise two steps, e.g. sub-steps:

[0034] - determining a signal adjustment function by using a measured signal value of the first calibrator sample and using a theoretical signal value of the first calibrator sample derived from a pilot calibration curve; the theoretical signal value is determined by applying the pilot calibration curve using a pre-specified target concentration value ci of the first calibrator sample;

[0035] - Assigning a target concentration value (which can be used in subsequent steps) based on the measured signal value of the second calibrator sample. This can be done by using a determined signal adjustment function (or inverse) that is applied to the measured signal value of the second calibrator sample, thereby determining a theoretical signal value for the second calibrator sample. The inverse pilot calibration curve can then be applied to the determined theoretical signal value of the second calibrator sample, thereby determining a target concentration value.

[0036] These two adjustment (sub)steps, ie determination of the signal adjustment function for the calibrant and target value assignment, which is used as "pre-assigned target concentration value" in the subsequent adjustment step, can be performed for each process of the chain, thereby achieving traceability.

[0037] The term "calibration step" is a broad term and is given a common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, any process for determining the relationship between a measured signal generated by an in vitro diagnostic medical device (e.g., during a sample examination) and a corresponding analyte concentration value of a sample. The method may include multiple calibration steps. Each calibration step may include one or more steps, which, for example, may be repeated or may be supplemented by further steps, such as to enhance or improve the calibration. For example, a calibration step may include providing a pilot calibration curve, such as a relationship between a measured signal generated by an in vitro diagnostic medical device and a corresponding analyte concentration value of a sample.

[0038] The term "adjustment step" is a broad term and is to be given the ordinary and customary meaning to one of ordinary skill in the art and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, the process of determining a signal adjustment function. The method may include a plurality of adjustment steps. Each adjustment step may include one or more steps, which may, for example, be repeated or may be supplemented by further steps, such as to enhance or improve the adjustment. For example, the adjustment step may include determining a signal adjustment function using a first calibrator sample, and assigning a target concentration value to a second calibrator sample.

[0039] A series of calibration and adjustment steps may include at least one calibration step, e.g., in which a pilot calibration curve is provided, and at least one adjustment step, e.g., in which a signal adjustment function is determined and a target concentration value is assigned to the calibrator sample. The adjustment step in the series may follow the calibration step, since it uses the theoretical signal value of the first calibrator sample derived from the pilot calibration curve. The series of steps may include additional calibration steps and / or adjustment steps. For example, a second, third, and fourth adjustment step may be performed subsequently.

[0040] A series of calibration and adjustment steps may include multiple calibration and / or adjustment steps. The method may include an entire standardization procedure. The result of each step depends on the result of the previous step. In the following, the expression "calibration and adjustment steps" (in the singular or plural) is used to represent the steps of the standardization procedure. The method may include layered calibration and adjustment steps. A series of calibration and adjustment steps may include method steps from reference to final measurement system, wherein the result of each step depends on the result of the previous step. The method may include establishing metrological traceability by ensuring the traceability of higher-order reference system components required by ISO 17511:2020. Metrological traceability may refer to layered calibration and adjustment steps and a series of value assignments, which may allow an uninterrupted link between the measurement results for a sample up to the highest available reference system component in the layer.

[0041] Each of the calibration and adjustment steps may include the use of at least one measurement procedure. The term "measurement procedure" is a broad term and is given its ordinary and customary meaning to a person of ordinary skill in the art and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a detailed description of a measurement according to one or more measurement principles and a given measurement method based on a measurement model and including any calculations used to obtain a measurement result. A measurement procedure may be performed on at least one material, wherein the material is specified according to a corresponding measurement procedure. The measurement procedures used in the corresponding calibration step and the corresponding adjustment step may be performed as described in ISO 17511:2020.

[0042] For example, a series of calibration and adjustment steps includes a first calibration and adjustment step using a measurement procedure for purity assessment suitable for the intended use, such as quantitative NMR, mass balance, etc. A different measurement procedure can serve as a primary reference measurement procedure, such as a measurement procedure based on gas chromatography-mass spectrometry (GC / MS) or liquid chromatography-tandem mass spectrometry (LC-MS / MS). Other methods are also feasible.

[0043] The series of calibration and adjustment steps may further include a second calibration and adjustment step using a primary reference measurement procedure for calibrant preparation, for example, a weight preparation, for at least one certified primary reference material. The primary reference measurement procedure may be or may include a reference measurement procedure for obtaining measurement results that are independent of a certain amount of a similar measurement standard. The term "certified reference material (CRM)" is a broad term and is given its ordinary and customary meaning to a person of ordinary skill in the art, and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a reference material that is accompanied by a document issued by an authoritative body and uses a valid procedure to provide one or more specified property values ​​with associated uncertainties and traceability. The primary reference measurement procedure and CRM used for calibrant preparation may meet the requirements described in ISO17511:2020 and ISO 15194. The target concentration value for the CRM may be specified by a first calibration and adjustment step.

[0044] A series of calibration and adjustment steps may further include a third calibration and adjustment step using a primary reference measurement procedure for a measured person for at least one primary calibrator. The term "measured person" is a broad term and is given a common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, the amount intended to be measured. The term "calibrator" is a broad term and is given a common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a material used as a measurement standard. A primary calibrator may be a measurement standard established using a primary reference measurement procedure, or created as an artifact, selected by convention. A primary calibrator may be prepared as a solution of a CRM in a suitable solvent. The primary reference measurement procedure and primary calibrator for the measured person may meet the requirements described in ISO 17511:2020. The target concentration value for the primary calibrator may be specified by a second calibration and adjustment step.

[0045] A series of calibration and adjustment steps may further include a fourth calibration and adjustment step using a measurement procedure selected by the manufacturer for at least one secondary calibrator. The secondary calibrator may be a measurement standard established by calibration relative to a primary measurement standard of the same type for an equivalent. The measurement procedure and secondary calibrator selected by the manufacturer may meet the requirements described in ISO 17511:2020. The second calibrator may be at least one of the following items: a human sample, a human sample pool, a sample with a matrix, and a sample comparable to a human sample. The target concentration value for the secondary calibrator may be specified by a third calibration and adjustment step. The term "manufacturer" is a broad term and is given a common and customary meaning to a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, an entity responsible for the design, manufacture, production, assembly, packaging or labeling of IVD MD, an entity responsible for assembling a measurement system or adjusting it before IVD MD is put on the market and / or put into use, whether these operations are performed by the entity or by a third party on its behalf. The measurement procedure selected by the manufacturer may include one or more of a homogeneous or heterogeneous immunoassay or liquid chromatography-tandem mass spectrometry (LC-MS / MS). Other measurement procedures are also feasible. The measurement procedure selected by the manufacturer may be at least partially automated. For example, the measurement procedure selected by the manufacturer may be comparable or coordinated with the measurement procedure of the customer.

[0046] As described above, the method includes providing a pilot calibration curve. As used herein, the term "pilot calibration curve" is a broad term and should be given its common and customary meaning for a person of ordinary skill in the art, and should not be limited to a special or custom meaning. The term specifically may refer to, but is not limited to, any mathematical function describing the relationship between at least one concentration c of at least one analyte in at least one sample and the signal s of the sample measured with a mass spectrometer. The pilot calibration curve may include at least one mathematical operation (e.g., multiplication with at least one factor) or any other type of mathematical operation. The pilot calibration curve is a parameterized function. The term "parameterized function" is a broad term and is given its common and customary meaning for a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term specifically may refer to, but is not limited to, any mathematical function having at least one parameter, for example, multiple parameters, such as a set of at least two parameters. The pilot calibration curve f p For parameterized functions The parameters is a set of parameters of a pilot calibration curve and P ≥ 1. The term "parameter" is a broad term and is given the ordinary and customary meaning to ordinary technicians in the field and is not limited to a special or customized meaning. The term can specifically refer to, but is not limited to, any quantity that affects the output or behavior of a mathematical function and is considered to be constant. Parameters can be configured to determine the behavior of a mathematical function. In contrast, the variables of a mathematical function can be considered to be varied. In general, the term "parameter set" can refer to multiple parameters of a single mathematical function. The pilot calibration curve can be a function form of the pilot calibration curve and the fitted parameter values. Together, for example, determine. The functional form can be, for example, one or more of a Roddart model function, a Padé model function, a quadratic model function, or any other nonlinear or linear function. For example, the Padé model function can be given by:

[0047]

[0048] Where y is the signal value, x is the concentration or target value, and p1, p2, and p3 are the parameters of the function. For example, the Rodbard model function is given by:

[0049]

[0050] Where y is the signal value, x is the concentration or target value, and p1, p2, p3, and p4 are the parameters of the function. Other functional forms are also possible.

[0051] The term "providing a pilot calibration curve" is a broad term and is given the ordinary and customary meaning to a person of ordinary skill in the art and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, determining one or more of the pilot calibration curves by setting and selecting at least one of the pilot calibration curves. For example, the process of setting the pilot calibration curve may include establishing the pilot calibration curve, such as by determining at least one of its form and / or parameter values. The setting of the pilot calibration curve may be established by at least one of the modeling and / or fitting procedures, such as by selecting at least one model function and / or by determining at least one of the fitting parameter values. For example, the setting of the pilot calibration curve may include generating at least one specific parameter value in a modeling and / or fitting procedure.

[0052] A pilot calibration curve, in particular an inverse pilot calibration curve, can assign a concentration c to a sample examined by an in vitro diagnostic medical device based on at least one theoretical signal value derived from the measured signal values. Additionally or alternatively, a pilot calibration curve, such as an inverse pilot calibration curve, can assign a concentration c to a sample examined by an in vitro diagnostic medical device based on at least one measured signal value measured by the in vitro diagnostic medical device. Additionally or alternatively, a pilot calibration curve can help assign a concentration c to a sample by assigning a theoretical concentration value to the sample based on the measured signal values ​​of the sample, wherein in a next step, the concentration c is assigned to the sample based on the theoretical concentration value.

[0053] The leading calibration curve can be a function specific to determination and / or application. For example, multiple conditions can be used to determine it, such as one or more of the different instruments, different reagent batches and different measurement conditions that can be used in determination or application. For example, the leading calibration curve can be determined by using multiple conditions, such as one or more of multiple instruments and / or hardware components and / or reagent batches, etc. The provision of the leading calibration curve can be a part of at least one of the calibration and adjustment steps. The provision of the leading calibration curve can be carried out with a hierarchical high-order step, such as one of the first steps in the hierarchical.

[0054] For example, a pilot calibration curve can be determined by using at least one primary calibrator. At least one target concentration value of a primary calibrator can be established based on a primary reference measurement procedure for calibrator preparation. For example, a pilot calibration curve is provided by using at least one secondary calibrator. At least one target concentration value of a secondary calibrator can be established based on a primary reference measurement procedure for a measured person. Other examples for providing a pilot calibration function in other steps of stratification are also feasible. Additionally or alternatively, a pilot calibration curve can be provided by retrieving a pilot calibration curve, such as from at least one database (e.g., cloud). The provision of a pilot calibration curve can be performed once or repeatedly.

[0055] The term "target concentration value" is a broad term and is given its ordinary and customary meaning to those of ordinary skill in the art and is not limited to a special or customary meaning. The term may specifically refer to, but is not limited to, a specified concentration value, such as a concentration value pre-specified in a high-level calibration and adjustment step.

[0056] As used herein, the term "signal" is a broad term and should be given its common and customary meaning for those of ordinary skill in the art, and should not be limited to a special or custom meaning. The term specifically may refer to, but is not limited to, any electronic signal generated by an in vitro diagnostic medical device and / or at least one hardware component when detecting at least one analyte. The signal may be a measurement signal of an in vitro diagnostic medical device. The signal may be a measured signal on an in vitro diagnostic medical device and / or hardware component j, where l is repeated, where j≥1 and l≥0. The generation of a signal may be part of a measurement process. For example, in the case of a mass spectrometer, a signal or a set of signals may be interpreted to determine (e.g., identify) an analyte and / or its concentration detected. The signal may be plotted in a mass spectrum as a function of the mass-to-charge ratio of the analyte.

[0057] As used herein, the term "concentration" is a broad term and is given a common and customary meaning for those of ordinary skill in the art, and is not limited to a special or custom meaning. The term may refer to, but is not limited to, the abundance of a component or ingredient in a given volume (such as a sample volume), relative to the volume setting (e.g., divided by the volume). The placeholder "c" may represent concentration. Concentration may be described in terms of different types of amounts, such as mass concentration, molar concentration, or volume concentration. It should be noted that the term concentration may quantify the components or ingredients present in the volume of a liquid sample and the volume of a solid or gas sample. The concentration of an analyte may be specified and / or quantified by a concentration value.

[0058] The relationship between the measured signal value of the calibrator sample and the target concentration value of the calibrator sample may be insufficiently described by the pilot calibration curve alone, such as not being precise or accurate enough. As an example, the concentration value determined using the pilot calibration curve based on the measured signal value of the calibrator sample may differ from the target concentration value of the calibrator sample by more than a predetermined threshold value. For example, this may be due to the fact that the pilot calibration curve is determined based on a sample other than the calibrator sample. However, in the standardization process, the pilot calibration curve can remain unchanged, and alternatively, another function, i.e., the signal adjustment function, can be determined and / or adjusted. Although the standardization process includes several calibration and adjustment steps, the pilot calibration curve can be initially established, such as in a hierarchical high-order step, and can remain unchanged in two or more subsequent adjustment steps. As an example, the possible subsequent adjustment and / or refinement that the signal adjustment function described in more detail below can take into account.

[0059] In each adjustment step, the signal adjustment function g is determined r, where r is a set of parameters of the signal adjustment function. As used herein, the term "signal adjustment function" is a broad term and should be given its ordinary and customary meaning to ordinary technicians in the field, and should not be limited to a special or customized meaning. The term can specifically refer to, but is not limited to, any mathematical function that describes the relationship between the measured signal value of a sample and the theoretical signal value of the sample. The signal adjustment function can be a linear or nonlinear function. The signal adjustment function can be a parameterized function. The signal adjustment function can be written as where r1,..,r R is a set of parameters of the signal adjustment function, R≥1 and i is the first calibrant sample, i=1,...,I, I≥1.

[0060] The functional form of the signal adjustment function can be, for example, one or more of a Roddart model function, a Padé model function, a quadratic model function, or any other nonlinear or linear function. For example, the Padé model function can be given by:

[0061]

[0062] Where y is the signal value, x is the concentration or target value, and p1, p2, and p3 are the parameters of the function. For example, the Rodbard model function is given by:

[0063]

[0064] Where y is the signal value, x is the concentration or target value, and p1, p2, p3, and p4 are the parameters of the function. Other functional forms are also possible.

[0065] As described above, the signal adjustment function describes the relationship between the measured signal values ​​and the theoretical signal values. The indicated relationship can be described by a function that maps only the measured signal values ​​to the theoretical signal values ​​and by a function that maps the theoretical signal values ​​to the measured signal values. Both functions can be considered as signal adjustment functions. Depending on the selection when determining the signal adjustment function, the signal adjustment function or its inverse can be applied to determine the theoretical signal value from the measured signal value. The signal adjustment function or the inverse of the signal adjustment function can be applied to the measured signal value of the second calibrator sample to determine at least one theoretical signal value of the second calibrator sample.

[0066] As used herein, the term "first calibrator sample" is a broad term and should be given its ordinary and customary meaning to those of ordinary skill in the art, and should not be limited to a special or customized meaning. The term specifically may refer to, but is not limited to, a calibrator having a pre-specified target concentration value. The first calibrator sample may include at least one set of calibrator samples, which includes a plurality of calibrator samples. The target concentration value of the first calibrator sample may be specified by a hierarchical high-order step. For example, the target concentration value may be pre-specified in a previous adjustment step. Different first calibrator samples may be used for different subsequent adjustment steps.

[0067] The first calibrator sample can be measured using an in vitro diagnostic medical device (e.g., a mass spectrometer) to determine a measured signal value for the first calibrator sample. The signal adjustment function can relate the following two: the theoretical signal of the pilot calibration curve, where where i ≥ 1 and c i is a pre-specified target concentration value for the first calibrant sample and a measured signal value for the first calibrant sample Where j represents an instrument and / or hardware component of an in vitro diagnostic medical device, j=1, .., J and J≥1, and l is a repeat l=1, .., L and L≥1. Determination of the signal adjustment function may include measuring the signal value of the first calibrator sample Calculation of theoretical signal and fitting the signal conditioning function, thereby determining the fitted parameters The lead calibration curve and the signal adjustment function may complement each other in relating measured signal values ​​of a sample to a target concentration value of at least one analyte in the sample.

[0068] As used herein, the term "theoretical signal value" is a broad term and should be given its ordinary and customary meaning to one of ordinary skill in the art and should not be limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a calculated signal value from a given center value. The theoretical signal value of a first calibrator sample may be obtained by applying a pilot calibration curve to a pre-specified target concentration value c of the first calibrator sample. i to be sure.

[0069] After measuring the signal value of the first calibrator sample and determining the theoretical signal value of the first calibrator sample, a signal adjustment function can be determined.

[0070] Each adjustment step includes specifying at least one target concentration value based on the measured signal value of at least one second calibrator sample. The method may include specifying the target concentration value of the second calibrator sample for subsequent calibration and adjustment steps. As used herein, the term "second calibrator sample" is a broad term and should be given its ordinary and customary meaning to a person of ordinary skill in the art, and should not be limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a calibrator that is different from the first calibrator sample. The method may include measuring the signal value of at least one second calibrator sample. The second calibrator may have an unknown target concentration value. The signal value for the second calibrator sample may be measured with each individual hardware component. The theoretical signal value may be specified by applying the inverse signal adjustment function to the measured signal value. The inverse pilot calibration curve may be applied to the target concentration value of the second calibrator sample. The theoretical signal value of the second calibrator sample is applied to the theoretical signal value of the second calibrator sample to convert the theoretical signal value into a target concentration value. For example, the designation of the target concentration value may include measuring the signal value of the second calibrator sample k using an in vitro diagnostic medical device where k = 1, .. , K and K ≥ 1, where j represents an instrument and / or hardware component, j = 1, .. , J and J ≥ 1, and l is a repetition l = 1, .. , L and L ≥ 1, and the measured signal value is converted by successively applying the following inverse function Convert to target concentration value c kjl :

[0071] and

[0072]

[0073] The target concentration value of the second calibrant sample can be assigned as at least one average value from a plurality of target concentration values, wherein the average value is one or more of an average value, a median value, or a weighted average value of the plurality of target concentration values. For example, the plurality of target concentration values ​​can be generated by repeating at least one adjustment step. The weight for the weighted average value can be given, for example, by the inverse of the variability of the repeats performed on a particular instrument and / or hardware component.

[0074] The signal adjustment function can relate the measured signal value of the first calibrator sample to the theoretical signal of the first calibrator sample derived from the pre-specified target concentration and the pilot calibration function. The designation of the target concentration value for the second calibrator sample can be determined by applying the signal adjustment function.

[0075] The measured signal value of the second calibrator sample can be used to assign a target concentration value to the second calibrator sample. Such assignment can be performed using a signal adjustment function (or its inverse) and a pilot calibration function as described in detail above. In other words, the method according to the present invention proposes adjusting the measured signal value to a theoretical signal value, which can be converted to a target concentration value using a pilot calibration curve.

[0076] The normalization process may include multiple adjustment steps, so that more than one signal adjustment function may be determined during the normalization step, for example, two or even more signal adjustment functions, and / or a previously determined signal adjustment function may be adjusted during the normalization step. During the normalization process, the signal adjustment function may be refined or adjusted according to specific conditions. As an example, a first signal adjustment function may be supplemented and / or replaced by a second signal adjustment function, etc.

[0077] The method includes a plurality of calibration and adjustment steps that are performed in succession. For example, the method may include one or more of the following steps: setting a pilot calibration curve; adjusting the pilot calibration curve; specifying a target value for a pilot calibrator; adjusting the pilot calibration curve by the pilot calibrator; specifying a target value for a product calibrator. This step may be performed at the manufacturer's site.

[0078] As described above, the step of providing a pilot calibration curve may be embodied as comprising the setting of a pilot calibration curve. For example, this step may be performed as one of the initial steps of a standardization process.

[0079] The step of setting a pilot calibration curve may include determining a functional form of the pilot calibration curve. The step of setting a pilot calibration curve may include determining a functional form of the pilot calibration curve. Parameters Parameter value.

[0080] For example, the method may include at least one step of setting a pilot calibration curve. This step may include measuring a set of signal values ​​of a primary calibrator with an in vitro diagnostic medical device. where i represents a primary calibrant i=1,..,I and I≥1, j represents an instrument and / or hardware component j=1,..,J and J≥1, and l represents a replicate l=1,..,L and L≥1, and a pre-specified target concentration value c using the set of primary calibrants i and the measured signal value Determine the pilot calibration curve Parameters The set of primary calibrators may include at least one primary calibrator, such as at least three primary calibrators, for example 20 to 30 primary calibrators. However, the set of primary calibrators may also include a different number of primary calibrators, for example more than 30 primary calibrators. The target concentration value c of the primary calibrator i It can be pre-specified in a high-order calibration and / or adjustment step, which for example includes a primary reference measurement procedure for calibrant preparation. For example, the primary reference measurement procedure can be based on gas chromatography-mass spectrometry (GC / MS) or liquid chromatography-tandem mass spectrometry (LC-MS / MS). Other techniques are also possible.

[0081] For example, the method may include at least one step of setting a pilot calibration curve. This step may include measuring a set of signal values ​​of a secondary calibrator with an in vitro diagnostic medical device. where i represents a secondary calibrant i=1,..,I and I≥1, j represents an instrument and / or hardware component j=1,..,J and J≥1, and l represents a replicate l=1,..,L and L≥1, and a pre-specified target concentration value c using the set of secondary calibrants i and the measured signal value Determine the pilot calibration curve Parameters The set of secondary calibrators may include at least one secondary calibrator, such as at least three secondary calibrators, for example 20 to 30 secondary calibrators. However, the set of secondary calibrators may also include a different number of secondary calibrators, for example more than 30 secondary calibrators. The target concentration value c of the secondary calibrator i It may be pre-specified in a high-order calibration and / or adjustment step, which for example comprises a primary reference measurement procedure for the person being measured.

[0082] Subsequently providing a pilot calibration curve, for example by setting the pilot calibration curve using a primary or secondary calibrator or retrieving the pilot calibration curve, the method may further include at least one step of adjusting the pilot calibration curve, the step comprising determining a first signal adjustment function. For example, as described above, providing the pilot calibration curve may include using a primary calibrator. The method may include at least one step of adjusting the pilot calibration curve, the step comprising using a set of secondary calibrators i=1,...,I, I≥1 to determine the first signal adjustment function The determination of the first signal adjustment function includes:

[0083] - Measure the signal value of the secondary calibrant using the measurement procedure selected by the manufacturer

[0084] - The theoretical signal is calculated by

[0085]

[0086] where c i a predetermined target concentration value for the secondary calibrant, and

[0087] - Fitting the signal conditioning function g1, thereby determining the fitted parameters

[0088] The step of adjusting the pilot calibration curve may, for example, comprise determining a first signal adjustment function while keeping the pilot calibration curve unchanged.

[0089] The pre-specified target concentration value of the secondary calibrant may be determined in a higher-order calibration and / or adjustment step, which for example comprises a primary reference measurement procedure for the measured person.

[0090] In a subsequent calibration and adjustment step, two functions, a lead calibration function and a first signal adjustment function, can be used in combination to assign at least one target concentration value to a sample, such as a lead calibrant. The target concentration value can be assigned to the sample based on the lead calibration curve and at least one signal adjustment function, for example by successively applying the inverse of the signal adjustment function to the measured signal values ​​to determine a theoretical signal value and applying the inverse of the lead calibration curve to the theoretical signal value.

[0091] The method may include at least one step of target value designation of a lead calibrator. As used herein, "lead calibrator" is a broad term and should be given its ordinary and customary meaning to a person of ordinary skill in the art, and should not be limited to a special or customary meaning. The term may specifically refer to, but is not limited to, a measurement standard for calibrating or verifying a measuring instrument or measuring system. The lead calibrator may be a sample that does not need to be as close to a human sample matrix as the primary and secondary calibrators. The lead calibrator may correspond to a sample represented as a manufacturer's working calibrator in standard ISO 17511:2020.

[0092] As an example, the target value assignment step for the lead calibrator may initially be performed directly after the step of setting the lead calibration curve. In this case, the signal adjustment function may not have been determined yet, and therefore, no signal adjustment function is available. A target concentration value may be assigned to the lead calibrator using a separate lead calibration curve, for example by applying the inverse of the lead calibration curve to the measured signal value of the lead calibrator. Alternatively, the target value assignment step for the lead calibrator may be performed in a repeated step, so that an adjustment step of the lead calibration curve has been performed, which step is in the layered calibration and adjustment steps, after the target value assignment step for the lead calibrator. For the repetition of the target value assignment step for the lead calibrator, the signal adjustment function may be available. In this case, the target value assignment step for the lead calibrator may be performed using both the lead calibration curve and the signal adjustment function.

[0093] For example, the step of specifying target values ​​for the lead calibrants may include specifying at least one target concentration value for at least one lead calibrant Target concentration values ​​for lead calibrants The designation may include measuring a signal value of a lead calibrant k where k=1, .., K and K≥1 using an in vitro diagnostic medical device Where j represents the instrument and / or hardware component j = 1, .., J and J ≥ 1, and l represents the replicate l = 1, .., L and L ≥ 1. Target concentration value of the lead calibrant The specification may further include converting the measured signal value into Convert to target concentration value

[0094] and

[0095]

[0096] The target concentration value for the lead calibrant can, for example, be specified as at least one average value from a plurality of target concentration values, where the average value is one or more of a mean, a median, or a weighted average of the plurality of target concentration values.

[0097] The method may further include checking whether the specification of the target concentration value of the lead calibrator was successful. The method may further include measuring the signal value of the independent control sample using an in vitro diagnostic medical device (e.g., a mass spectrometry device). In order to check whether the specification of the target concentration value of the lead calibrator was successful, the method may include converting the measured signal value of the independent control sample into a concentration value by applying the signal adjustment function g1 and the lead calibration curve, and comparing the concentration value with a predefined target concentration value of the independent control sample. The independent control sample may have a target value established by the high-order method. m=1, .., M1, M1≥1. If the absolute or relative deviation of the read concentration from the target value of the independent control sample remains within a predefined limit, the target value of the new calibrator can be accepted. The method can further include comparing the concentration value with a predefined target concentration value of the independent control sample, wherein if the deviation between the concentration value of the independent control sample and the predefined target concentration value of the independent control sample is within a predefined tolerance range, the target concentration value is accepted. is received.

[0098] The method may include at least one step of adjusting a pilot calibration curve using at least one pilot calibrant k. The step of adjusting the pilot calibration curve may include determining a second signal adjustment function by the following steps: where q1,..,q Q is a set of parameters of the second signal adjustment function, and Q ≥ 1,

[0099] - The signal value of at least one lead calibrant k is measured on the in vitro diagnostic medical device using the manufacturer's established measurement procedure Where j represents an instrument and / or hardware component j=1,..,J and

[0100] J≥1, and l means repetition l=1,..,L and L≥1,

[0101] - The theoretical signal is calculated by

[0102] and - fitting the signal conditioning function g2, thereby determining the fitted parameters

[0103] The manufacturer's standing measurement procedure may include, for example, at least one of a homogeneous immunoassay, a heterogeneous immunoassay, and a liquid chromatography-tandem mass spectrometry (LC-MS / MS). Other measurement procedures are also feasible. The manufacturer's standing measurement procedure may be at least partially automated. For example, the manufacturer's standing measurement procedure may be comparable or coordinated with the customer's measurement procedure.

[0104] The step of adjusting the lead calibration curve by the lead calibrator may, for example, include determining a signal adjustment function g2 using the measured signal value of the lead calibrator, while keeping the lead calibration curve itself unchanged. In the following, two functions, the lead calibration function and the second signal adjustment function, may be used in combination to specify at least one target concentration value for at least one additional second calibrator sample (e.g., a product calibrator as described in further detail below).

[0105] The method may further comprise at least one step of target value specification for a product calibrator. The product calibrator may correspond to a sample indicated as an end-user in vitro diagnostic medical device calibrator in standard ISO 17511:2020. The step of target value specification for a product calibrator may comprise specifying at least one target concentration value for at least one product calibrator k Target concentration values ​​for product calibrants The designation includes the use of an in vitro diagnostic medical device to measure the signal value of a product calibrant k where k = 1, .., K and K ≥ 1 Where j represents an instrument and / or hardware component j = 1, .., J and J ≥ 1, and l represents a replicate l = 1, .., L and L ≥ 1, where the target concentration value of the product calibrant is determined Further comprising converting the measured signal value into Convert to target concentration value

[0106] and

[0107]

[0108] The target concentration value for a product calibrant can be specified, for example, as at least one average from a plurality of target concentration values, where the average is one or more of a mean, a median, or a weighted average of the plurality of target concentration values.

[0109] The method may further include checking whether the designation of the target concentration value of the product calibrant is successful. The method may further include measuring the signal value of the independent control sample using an in vitro diagnostic medical device (e.g., a mass spectrometer), and converting the measured signal value of the independent control sample into a concentration value by applying the signal adjustment function g2 and the pilot calibration curve. The method may further include comparing the concentration value with a pre-specified target concentration value of the independent control sample. If the deviation between the concentration value of the independent control sample and the pre-specified target concentration value of the independent control sample is within a pre-defined tolerance range, the target concentration value is can be accepted.

[0110] The method may further include performing at least one client calibration step. For example, having an accepted target concentration value The product calibrants can be used for the client calibration procedure.

[0111] In a further aspect of the present invention, a method for establishing metrological traceability for at least one in vitro diagnostic medical device is disclosed. The method comprises a series of calibration steps and adjustment steps. The result of each step depends on the result of the previous step. The method comprises providing a pilot calibration curve, wherein the pilot calibration curve fp describes the relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of the sample measured with an in vitro diagnostic medical device, wherein the pilot calibration curve f p For parameterized functions The parameters is a set of parameters of the pilot calibration curve and P ≥ 1. In each adjustment step, a concentration adjustment function h is determined that describes the relationship between the theoretical concentration of the measured signal value of the first calibrator sample and the pre-specified target concentration value of the first calibrator sample. s , where s is a set of parameters for the concentration adjustment function, where the theoretical concentration of the first calibrant sample is obtained by applying the inverse of the pilot calibration curve The target concentration value is determined using the measured signal value of the first calibrator sample. The designation of the target concentration value includes applying the inverse of the pilot calibration curve using the measured signal value of the second calibrator sample. The theoretical concentration value is thus obtained, and the concentration adjustment function is applied to the theoretical concentration value or the inverse of the concentration adjustment function The target concentration value for the second calibrant sample is thereby obtained.

[0112] With regard to the definitions and embodiments of the method described in the further aspects, reference is made to the definitions and embodiments of the method described in the first aspect of the present invention.

[0113] As used herein, the term "concentration adjustment function" is a broad term and is given a common and customary meaning to those of ordinary skill in the art, and is not limited to a special or custom meaning. The term specifically may refer to, but is not limited to, any mathematical function that describes the relationship between a target concentration value of a sample and a theoretical concentration value of the sample. The concentration adjustment function may be a linear or nonlinear function. The concentration adjustment function may be a parameterized function. The functional form of the concentration adjustment function may be, for example, one or more of a Roddart model function, a Padé model function, a quadratic model function, or any other nonlinear or linear function. For example, the Padé model function may be given by:

[0114]

[0115] Where y is the signal value, x is the concentration or target value, and p1, p2, and p3 are the parameters of the function. For example, the Rodbard model function is given by:

[0116]

[0117] Where y is the signal value, x is the concentration or target value, and p1, p2, p3, and p4 are the parameters of the function. Other functional forms are also possible.

[0118] The concentration adjustment function may relate a pre-specified target concentration for a first calibrator sample to a theoretical concentration of a measured signal for the first calibrator sample, and the assignment of a target concentration value for a second calibrator sample may be determined by applying the concentration adjustment function.

[0119] In a further aspect of the present invention, a processing device is disclosed. The processing device is configured to retrieve and / or store at least one predetermined pilot calibration curve f p The processing device is further configured to store a pilot calibration curve f p A set of parameters Where P is a positive integer. The pilot calibration curve f p The reference calibration curve f describes the relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of the sample measured with an in vitro diagnostic medical device. p is a parameterized function The processing device is further configured for carrying out one or both of the methods according to the invention for establishing metrological traceability for at least one in vitro diagnostic medical device.

[0120] The pilot calibration curve is predetermined at the manufacturer's end by using one or both of the methods according to the invention, for example, according to any of the above-described embodiments and / or according to any of the embodiments described in further detail below. Therefore, for possible details and options of the method and for terms and definitions, reference may be made to the description of the method for establishing metrological traceability for at least one in vitro diagnostic medical device as given above or as further given below.

[0121] As used herein, the term "processing device" is a broad term and is given a common and customary meaning for a person of ordinary skill in the art, and is not limited to a special or custom meaning. The term may specifically refer to, but is not limited to, a device or combination of devices configured to control at least one function of at least one other device, such as at least one function of at least one other component of an in vitro diagnostic medical device (e.g., a mass spectrometer). The processing device may, for example, include at least one processor and / or at least one data storage device. Therefore, as an example, at least one processing device may include at least one data processing device having a software code stored thereon, the software code including a plurality of computer commands. The processing device may be an element of an in vitro diagnostic medical device or other device (e.g., a remote device).

[0122] The processing device may be further configured to perform at least one client calibration step for the IVD medical device on at least one set of product calibrants, thereby adjusting the signal adjustment function. The client calibration step may include

[0123] - Using a client measurement program on an IVD medical device to measure the signal value of at least one product calibrant k Where j represents an instrument and / or hardware component j=1,..,J and J≥1, and l

[0124] It means repeating l=1,..,L and L≥1,

[0125] - The theoretical signal is calculated by

[0126]

[0127] in a pre-specified target concentration value for the set of product calibrants, wherein the target concentration value is pre-specified at the manufacturer's end by using one or both of the methods according to any one of the above embodiments and / or according to any one of the embodiments described in further detail below,

[0128] - fitting the signal conditioning function, thereby determining fitted parameters of the signal conditioning function.

[0129] The processing device may be further configured to perform at least one client calibration step for the IVD medical device on at least one set of product calibrants, thereby adjusting the concentration adjustment function h s The client calibration steps may include

[0130] - Using a client measurement program on an IVD medical device to measure the signal value of at least one product calibrant k Where j represents an instrument and / or hardware component j=1,..,J and J≥1, and l

[0131] It means repeating l=1,..,L and L≥1,

[0132] -Calculate the theoretical concentration value signal from

[0133]

[0134] - Use calculated theoretical concentrations and pre-specified target concentrations Fitting a concentration adjustment function, thereby determining fitted parameters of the concentration adjustment function, wherein a pre-specified target concentration value is pre-specified at the manufacturer's end by using one or both methods according to any of the above-mentioned embodiments and / or according to any of the embodiments described in further detail below.

[0135] In a further aspect of the invention, a kit is disclosed, comprising an in vitro diagnostic medical device (e.g., a mass spectrometry device) and a set of product calibrants. The target concentration values ​​of the product calibrants are determined by using one or both of the methods according to the invention. For possible details about the kit as well as terms and definitions, reference may be made to the description of the methods given above or further below.

[0136] For example, the kit can provide the following information:

[0137] - Functional form f and parameters of the pilot calibration curve P ≥ 1. These parameters may be specific to the assay but independent of other components of the measurement system, such as the instrument, reagent batch, or calibrator batch. Therefore, they do not require adjustment once transferred to the in vitro diagnostic medical device and when other system components change.

[0138] - Functional form of the signal conditioning function on an in vitro diagnostic medical device. The function may have another functional form as a signal conditioning function within the standardization.

[0139] - A set of K2 product calibrants, where K2 ≥ 1, where the assigned target values ​​come from step "Assignment of target values ​​for product calibrants".

[0140] This information can allow calibration of in vitro diagnostic medical devices at the client end. With this information, individual instruments can be recalibrated and sample readings can be performed, for example as described in WO 2021 / 122739.

[0141] In a further aspect of the present invention, a computer program is disclosed, wherein the computer program is suitable for performing a method according to any one of the above embodiments and / or according to any one of the embodiments described in further detail below, while the program is being executed on a computer. In particular, the computer program may include computer executable instructions for performing the method when the instructions are executed on a computer or a computer network. In particular, the computer program may be stored on a computer-readable data carrier and / or on a computer-readable storage medium.

[0142] As used herein, the terms "computer-readable data carrier" and "computer-readable storage medium" may specifically refer to a non-transitory data storage device, such as a hardware storage medium having computer-executable instructions stored thereon. A computer-readable data carrier or storage medium may specifically be or may include a storage medium such as a random access memory (RAM) and / or a read-only memory (ROM).

[0143] Thus, in particular one, more than one or even all method steps as indicated above, in particular the calibration and / or adjustment steps, may be performed by using a computer or a computer network, preferably by using a computer program.

[0144] In a further aspect of the present invention, a computer program product is disclosed, which has program code means, wherein the program code means can be stored on a storage medium or is stored on a storage medium, and when the program code means is executed on a computer or on a computer network, the computer program product is used to perform a method according to any of the above embodiments and / or according to any of the embodiments described in further detail below. Specifically, the program code means can be stored on a computer-readable data carrier and / or on a computer-readable storage medium.

[0145] As used herein, a computer program product refers to a program that is a tradable product. The product may generally exist in any format (such as in paper format) or on a computer-readable data carrier and / or a computer-readable storage medium. In particular, the computer program product may be distributed over a data network.

[0146] The present invention further discloses and proposes a data carrier having a data structure stored thereon, which, after being loaded into a computer or a computer network, such as after being loaded into a working memory or a main memory of the computer or the computer network, can execute a method according to one or more embodiments disclosed herein.

[0147] Further disclosed and proposed herein is a non-transitory computer-readable medium comprising instructions, which, when executed by one or more processors, cause the one or more processors to perform a method according to one or more of the embodiments disclosed herein.

[0148] Further disclosed and proposed herein is a modulated data signal containing instructions readable by a computer system or a computer network for performing a method according to one or more embodiments disclosed herein.

[0149] With reference to the computer-implemented aspects of the present invention, one or more method steps or even all method steps of the method according to one or more embodiments disclosed herein can be performed using a computer or a computer network. Therefore, generally speaking, any method step including providing and / or manipulating data can be performed using a computer or a computer network. Generally speaking, these method steps can include any method step other than the method step that usually requires manual operation (such as providing a sample and / or performing some aspects of the actual measurement). Specifically, the steps of providing a pilot calibration curve, determining a signal adjustment function and / or specifying at least one target concentration value can be performed using a computer or a computer network.

[0150] To summarize and without excluding other possible embodiments, the following embodiments may be envisaged:

[0151] Embodiment 1: A method for establishing metrological traceability for at least one in vitro diagnostic medical device, wherein the method comprises a series of calibration and adjustment steps, wherein the result of each step depends on the result of the previous step, wherein the method comprises providing a pilot calibration curve, wherein the pilot calibration curve f p describes a relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of the sample measured with the in vitro diagnostic medical device, wherein the pilot calibration curve f p For parameterized functions The parameters is a set of parameters of the pilot calibration curve and P ≥ 1, where in each adjustment step, the signal adjustment function g describing the relationship between the measured signal value and the theoretical signal value r The signal adjustment function is determined by determining a relationship between a measured signal value of a first calibrator sample and a theoretical signal value of the first calibrator sample derived from the pilot calibration curve, wherein r is a set of parameters of the signal adjustment function, wherein the theoretical signal value is obtained by applying the pilot calibration curve using a pre-specified target concentration value c of the first calibrator sample. i To be sure,

[0152] wherein each adjustment step comprises assigning at least one target concentration value based on the measured signal value of at least one second calibrator sample, wherein the assigning comprises determining at least one theoretical signal value for the second calibrator sample by applying the signal adjustment function determined in the previous adjustment step or the inverse of the signal adjustment function determined in the previous adjustment step to the measured signal value of the second calibrator sample, and inverting the pilot calibration curve The theoretical signal value applied to the second calibrant sample.

[0153] Embodiment 2: The method according to the preceding embodiment, wherein the series of calibration and adjustment steps comprises a first calibration and adjustment step using a measurement procedure for purity assessment suitable for the intended use, wherein the series of calibration and adjustment steps further comprises a second calibration and adjustment step using a primary reference measurement procedure for calibrator preparation for at least one certified primary reference material, wherein the series of calibration and adjustment steps further comprises a third calibration and adjustment step using a primary reference measurement procedure for a measured person for at least one primary calibrator, and a fourth calibration and adjustment step using a measurement procedure selected by the manufacturer for at least one secondary calibrator.

[0154] Embodiment 3: The method according to the preceding embodiment, wherein the pilot calibration curve is determined by using at least one primary calibrator, wherein at least one target concentration value of the primary calibrator is established based on the primary reference measurement procedure used for calibrator preparation.

[0155] Embodiment 4: The method according to any one of the two preceding embodiments, wherein the pilot calibration curve is determined by using at least one secondary calibrator, wherein at least one target concentration value of the secondary calibrator is established based on the primary reference measurement procedure for the measured subject.

[0156] Embodiment 5: The method according to any one of the preceding embodiments, wherein the lead calibration curve is determined by using one or more of multiple conditions such as multiple instruments and / or hardware components and / or reagent batches.

[0157] Embodiment 6: The method according to any one of the preceding embodiments, wherein the pilot calibration curve does not change in two or more adjustment steps.

[0158] Embodiment 7: The method according to any one of the preceding embodiments, wherein the functional form of the pilot calibration curve is the same as the fitted parameter value. The pilot calibration curve is formed together, wherein the functional form of the pilot calibration curve is one or more of a Rodbart model function, a Padé model function, a quadratic model function, or any other nonlinear or linear function.

[0159] Embodiment 8: The method according to any one of the preceding embodiments, wherein the signal adjustment function is a function where r1,..,r R is a set of parameters of the signal adjustment function, R≥1 and i is the first calibrant sample, i=1,...,I,I≥1, wherein the signal adjustment function relates the following two: the theoretical signal of the pilot calibration curve where i ≥ 1 and ci is a pre-specified target concentration value of the first calibrant sample; and a measured signal value of the first calibrant sample wherein j represents an instrument and / or hardware component, j=1, .., J and J≥1, and l is a repetition l=1, .., L and L≥1, wherein the determination of the signal adjustment function comprises measuring the signal value of the first calibrant sample Calculate the theoretical signal and fitting the signal conditioning function, thereby determining the fitted parameters

[0160] Embodiment 9: The method according to any one of the preceding embodiments, wherein the specifying of the target concentration value comprises measuring the signal value of the second calibrator sample k using the in vitro diagnostic medical device where k = 1, .., K and K ≥ 1, and the measured signal values ​​are converted to Convert to target concentration value c kjl :

[0161] and

[0162]

[0163] Embodiment 10: The method according to any one of the preceding embodiments, wherein the signal adjustment function is a function where r1,..,r R is a set of parameters of the signal adjustment function, R ≥ 1 and i is the first calibrator sample, i = 1, ..., I, I ≥ 1, wherein the signal adjustment function relates the measured signal value of the first calibrator sample to the theoretical signal of the first calibrator sample derived from the pre-specified target concentration and the pilot calibration function, wherein the assignment of the target concentration value for the second calibrator sample is determined by applying the signal adjustment function.

[0164] Embodiment 11: The method according to any one of the preceding embodiments, wherein the functional form of the signal adjustment function is the same as the fitted parameter value. Together, the signal adjustment function is formed, wherein the functional form of the signal adjustment function is one or more of a Rodbart model function, a Padé model function, a quadratic model function, or any other nonlinear or linear function.

[0165] Embodiment 12: The method according to any one of the preceding embodiments, wherein the pre-specified target concentration value is pre-specified in a previous adjusting step.

[0166] Embodiment 13: The method according to any of the preceding embodiments, wherein the target concentration value of the second calibrant sample is specified as at least one average from a plurality of target concentration values, wherein the average is one or more of a mean, a median, or a weighted average of the plurality of target concentration values.

[0167] Embodiment 14: The method according to any one of the preceding embodiments, wherein the in vitro diagnostic medical device is a mass spectrometry device.

[0168] Embodiment 15: A method according to any one of the preceding embodiments, wherein the method comprises one or more of the following steps: setting the pilot calibration curve; adjusting the pilot calibration curve; specifying a target value for a pilot calibrator; adjusting the pilot calibration curve by a pilot calibrator; specifying a target value for a product calibrator, wherein the steps are performed at the manufacturer end.

[0169] Embodiment 16: The method according to the preceding embodiment, wherein the method comprises at least one step of setting the pilot calibration curve, the step comprising:

[0170] The in vitro diagnostic medical device, such as a mass spectrometer, is used to measure the signal values ​​of a set of reference samples using a primary reference measurement procedure Where i represents a reference sample i=1, .., I and I≥1, j represents an instrument and / or hardware component j=1, .., J and J≥1, and l represents a repeat l=1, .., L and L≥1, and a pre-specified target concentration value c of the reference sample set is used. i and the measured signal value Determine the pilot calibration curve Parameters Parameter value.

[0171] Embodiment 17: The method according to the preceding embodiment, wherein the method comprises at least one step of adjusting the pilot calibration curve, the step comprising determining a first signal adjustment function using a set of secondary calibrants i=1, ..., I, I≥1 The determining of the first signal adjustment function comprises:

[0172] - measuring the signal value of the secondary calibrant on the in vitro diagnostic medical device, such as a mass spectrometer, using a measurement procedure selected by the manufacturer

[0173] - The theoretical signal is calculated by

[0174]

[0175] where c ithe pre-specified target concentration value for the secondary calibrant, and

[0176] - Fitting the signal conditioning function g1, thereby determining the fitted parameters

[0177] Embodiment 18: The method according to the preceding embodiment, wherein the method comprises at least one step of target value specification of a pilot calibrant, the step comprising:

[0178] Specify at least one target concentration value for at least one lead calibrant wherein the target concentration value of the lead calibrant The designation includes measuring the signal value of the lead calibrant k where k=1, .., K and K≥1 using the in vitro diagnostic medical device such as a mass spectrometer Wherein j represents the instrument and / or hardware component j=1, .., J and J≥1, and l represents the repetition l=1, .., L and L≥1, wherein the target concentration value of the lead calibrant The designation further comprises converting the measured signal value into Convert to target concentration value

[0179] and

[0180]

[0181] Embodiment 19: A method according to the above embodiment, wherein the method includes measuring the signal value of an independent control sample using the in vitro diagnostic medical device such as a mass spectrometer, converting the measured signal value of the independent control sample into a concentration value by applying the signal adjustment function g1 and the pilot calibration curve, and comparing the concentration value with a pre-specified target concentration value of the independent control sample, wherein if the deviation between the concentration value of the independent control sample and the pre-specified target concentration value of the independent control sample is within a predefined tolerance range, then accepting the target concentration value.

[0182] Embodiment 20: The method according to any of the two preceding embodiments, wherein the method comprises at least one step of adjusting the pilot calibration curve using the at least one pilot calibrant k, wherein the step of adjusting the pilot calibration curve comprises determining a second signal adjustment function by the following steps where q1,..,q Q is a set of parameters of the second signal adjustment function and Q ≥ 1,

[0183] - measuring the signal value of at least one lead calibrant k on said in vitro diagnostic medical device, such as a mass spectrometry device, using the manufacturer's customary measurement procedure Wherein j represents the instrument and / or hardware component j=1, .., J and J≥1, and l represents repetition l=1, .., L and L≥1,

[0184] - The theoretical signal is calculated by

[0185] as well as

[0186] - Fitting the signal conditioning function g2, thereby determining the fitted parameters

[0187] Embodiment 21: The method according to the preceding embodiment, wherein the method comprises at least one step of target value specification for a product calibrant, the step comprising:

[0188] Specify at least one target concentration value for at least one product calibrant k wherein the target concentration value of the product calibrant The designation includes measuring the signal value of the product calibrant k where k=1, .., K and K≥1 using the in vitro diagnostic medical device such as a mass spectrometer Wherein j represents the instrument and / or hardware component j=1, .., J and J≥1, and l represents the repetition l=1, .., L and L≥1, wherein the target concentration value of the product calibrant The designation further comprises converting the measured signal value into Convert to target concentration value

[0189] and

[0190]

[0191] Embodiment 22: A method according to the above embodiment, wherein the method includes measuring the signal value of an independent control sample using the in vitro diagnostic medical device such as a mass spectrometer, converting the measured signal value of the independent control sample into a concentration value by applying the signal adjustment function g2 and the pilot calibration curve, and comparing the concentration value with a pre-specified target concentration value of the independent control sample, wherein if the deviation between the concentration value of the independent control sample and the pre-specified target concentration value of the independent control sample is within a predefined tolerance range, then accepting the target concentration value.

[0192] Embodiment 23: A method according to any one of the preceding embodiments, wherein the method further comprises performing at least one client calibration step.

[0193] Embodiment 24: A method for establishing metrological traceability for at least one in vitro diagnostic medical device (110), wherein the method comprises a series of calibration steps and adjustment steps, wherein the result of each step depends on the result of the previous step,

[0194] The method comprises providing a pilot calibration curve, wherein the pilot calibration curve f p describes a relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of said sample measured by said in vitro diagnostic medical device (110), wherein said pilot calibration curve f p For parameterized functions The parameters is a set of parameters of the pilot calibration curve and P ≥ 1, wherein in each adjustment step, a concentration adjustment function h describing the relationship between the theoretical concentration value of the measured signal value of the first calibrator sample and the pre-specified target concentration value of the first calibrator sample is determined s , wherein s is a set of parameters of the concentration adjustment function, wherein the theoretical concentration value of the first calibrant sample is obtained by applying the inverse of the pilot calibration curve determined using the measured signal value of the first calibrant sample,

[0195] wherein the specifying of the target concentration value comprises applying the inverse of the pilot calibration curve using the measured signal value of the second calibrant sample Thus, a theoretical concentration value is obtained, and the concentration adjustment function is applied to the theoretical concentration value. or the inverse of the concentration adjustment function The target concentration value of the second calibrant sample is thereby obtained.

[0196] Embodiment 25: A method according to the previous embodiment, wherein the concentration adjustment function relates the following two: the pre-specified target concentration value of the first calibrator sample to the theoretical concentration value of the measured signal of the first calibrator sample, and the designation of the target concentration value of the second calibrator sample is determined by applying the concentration adjustment function.

[0197] Embodiment 26: A processing device (112), wherein the processing device is configured to retrieve and / or store at least one predetermined pilot calibration curve f p , wherein the processing device is further configured to store the pilot calibration curve f p A set of parameters Where P is a positive integer, wherein the pilot calibration curve f p describes a relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of said sample measured with an in vitro diagnostic medical device (110), wherein said pilot calibration curve f p For parameterized functions The processing device (112) is further configured to perform a method for establishing metrological traceability for at least one in vitro diagnostic medical device (110) according to any of the aforementioned embodiments relating to methods.

[0198] Embodiment 27: The processing device (112) according to the previous embodiment, wherein the processing device (112) is a component of an in vitro diagnostic medical device (110) or another device.

[0199] Embodiment 28: A kit comprising an in vitro diagnostic medical device (110) and a set of product calibrators and target concentration values ​​thereof, wherein the target concentration values ​​of the product calibrators are specified by using a method according to any one of the preceding embodiments 1 to 23 or 24 to 25.

[0200] Embodiment 29: A computer program, wherein the computer program is adapted to perform the method according to any one of the preceding embodiments 1 to 23 or 24 to 25 when the program is executed on a computer.

[0201] Embodiment 30: A computer program product having a program code tool, wherein the program code tool can be stored or is stored on a storage medium for performing a method according to any one of the aforementioned embodiments 1 to 23 or 24 to 25 when the program code tool is executed on a computer or a computer network. BRIEF DESCRIPTION OF THE DRAWINGS

[0202] Other optional features and embodiments will be disclosed in more detail in the subsequent description of embodiments, preferably in conjunction with the dependent claims. Wherein, as will be appreciated by those skilled in the art, each optional feature can be implemented in a separate manner and in any arbitrarily feasible combination. The scope of the present invention is not limited by the preferred embodiments. Embodiments are schematically depicted in the accompanying drawings. Wherein, the same reference numerals in these drawings refer to the same or functionally equivalent elements.

[0203] In the attached picture:

[0204] Figure 1 A schematic diagram showing a processing device as a component of an in vitro diagnostic medical device;

[0205] Figure 2A flow chart showing an exemplary embodiment of a method for establishing metrological traceability for at least one in vitro diagnostic medical device;

[0206] Figure 3A and Figure 3B A graph showing the pilot calibration curve for each analyte (3A) and the adjustment of the pilot calibration curve (3B);

[0207] Figure 4 showing a flow chart giving an overview of two methods for establishing metrological traceability for at least one in vitro diagnostic medical device; and

[0208] Figures 5 to 10D An illustrative example of the method according to the invention is shown. DETAILED DESCRIPTION

[0209] Figure 1 1 shows a schematic diagram of a processing device 112, which forms a part of an in vitro diagnostic medical device 110. The in vitro diagnostic medical device 110 can be a medical device that is configured to perform an in vitro examination of at least one sample derived from a human body. Additionally or alternatively, the in vitro diagnostic medical device 110 can be a medical device configured to provide information for diagnostic, monitoring or compatibility purposes. The in vitro diagnostic medical device 110 can be used alone or in combination with other devices. The in vitro diagnostic medical device 110 may include one or more of at least one reagent, at least one calibrator, at least one control material, at least one sample container, software, related instruments or equipment, or other items. Figure 1 The in vitro diagnostic medical device 110 shown is embodied as a mass spectrometry device 111. Further possibilities are possible.

[0210] The processing device 112 can be a device or a combination of devices configured to control at least one function of at least one other device, such as at least one other component of the in vitro diagnostic medical device 110 (e.g., at least one other component of the mass spectrometry device 111), such as Figure 1 The processing device 112 may include, for example, at least one processor 118 and / or at least one data storage device 120. The processing device 112 may include multiple processors 118 and / or multiple storage devices 120. The in vitro diagnostic medical device 110 may include, for example, Figure 1 The at least one processing device 112 may include at least one data processing device having software code stored thereon, the software code including a plurality of computer commands. Figure 1 As depicted, processing device 112 may be an element of in vitro diagnostic medical device 110. Additionally or alternatively, processing device 112 may be an element of another device (eg, a remote device).

[0211] The processing device 112 is configured to retrieve and / or store at least one predetermined pilot calibration curve f p And the pilot calibration curve f p A set of parameters Where P is a positive integer. The pilot calibration curve f p The pilot calibration curve f describes the relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of the sample measured with an in vitro diagnostic medical device 110 (such as a mass spectrometer 111). p is a parameterized function A pilot calibration curve may be a set of parameters A parameter can be a mathematical quantity that affects the output or behavior of a mathematical function and is considered constant. Therefore, the pilot calibration curve f p The set of parameters The behavior of the pilot calibration curve may be configured to determine the behavior of the pilot calibration curve. The pilot calibration curve may include at least one mathematical operation (e.g., multiplication with at least one factor) or any other type of mathematical operation. The pilot calibration curve may be a function of the pilot calibration curve and the fitted parameter value. As an example, the functional form can be one or more of a Roddart model function, a Padé model function, a quadratic model function, or any other nonlinear or linear function. For example, the Padé model function can be given by:

[0212]

[0213] Where y is the signal value, x is the concentration or target value, and p1, p2, and p3 are the parameters of the function. For example, the Rodbard model function is given by:

[0214]

[0215] Where y is the signal value, x is the concentration or target value, and p1, p2, p3, and p4 are the parameters of the function. Other functional forms are also possible.

[0216] The leading calibration curve can be a function specific to the determination and / or application. For example, a variety of conditions can be used to determine it, such as one or more of different instruments, different reagent batches, and different measurement conditions that can be used in the determination or application. For example, a leading calibration curve can be provided by using a variety of conditions (such as one or more of multiple instruments, reagent batches).

[0217] The processing device 112 is further configured to perform one or both of the methods for establishing metrological traceability for at least one in vitro diagnostic medical device 110 according to any of the embodiments disclosed herein. Examples and / or details of the methods for establishing metrological traceability for at least one in vitro diagnostic medical device 110 are further discussed below, for example, Figure 2 , 3A , 3B and 4. The predetermined pilot calibration curve that may be stored by the processing device 112 is predetermined at the manufacturer's end by using one or both of the methods according to the present invention.

[0218] The mass spectrometer device 111 can be a mass analyzer configured to detect at least one analyte in at least one sample based on a mass-to-charge ratio. The mass spectrometer device 111 can be or can include at least one quadrupole mass analyzer 113, which includes at least one quadrupole as a mass filter, and the mass filter is configured to select ions injected into the mass filter according to the mass-to-charge ratio m / z of the ions. The mass filter may include two pairs of electrodes. The electrodes may be rod-shaped, such as cylindrical. Ideally, the electrodes may be hyperbolic. The electrodes may be designed to be identical. The electrodes may be arranged to extend in parallel along a common axis, such as a z-axis. The quadrupole mass analyzer 113 may include a plurality of quadrupoles. For example, the quadrupole mass analyzer 113 may be a triple quadrupole mass spectrometer. The quadrupole mass analyzer 113 may include at least one power supply circuit, which is configured to apply at least one direct current (DC) voltage and at least one alternating current (AC) voltage between the two pairs of electrodes of the mass filter. The power supply circuit may be configured to keep each relative electrode pair at the same potential. The power supply circuit can be configured to periodically change the charge sign of the electrode pair so that only ions within a certain mass-to-charge ratio m / z range can have a stable trajectory. The trajectory of the ions in the mass filter can be described by the Mathieu differential equation. In order to measure ions with different m / z values, the DC voltage and the AC voltage can be adjusted in time so that ions with different m / z values ​​are transmitted to the detector 114 of the mass spectrometer 111, such as Figure 1 shown.

[0219] like Figure 1As shown, the mass spectrometer 111 may further include at least one ionization source 115, which is configured to generate ions, for example, from neutral gas molecules. The ionization source 115 may be or may include at least one source selected from the group consisting of: at least one gas phase ionization source, such as at least one electron impact (EI) source or at least one chemical ionization (CI) source; at least one desorption ionization source, such as at least one plasma desorption (PDMS) source, at least one fast atom bombardment (FAB) source, at least one secondary ion mass spectrometry (SIMS) source, at least one laser desorption (LDMS) source, and at least one matrix-assisted laser desorption (MALDI) source; at least one spray ionization source, such as at least one thermal spray (TSP) source, at least one atmospheric pressure chemical ionization (APCI) source, at least one electrospray (ESI) and at least one atmospheric pressure ionization (API) source.

[0220] The detector 114 of the mass spectrometer 111 can be configured to detect incoming ions, such as charged particles. The detector 114 can be or can include at least one electron multiplier. The mass spectrometer 111 (e.g., the detector 114 of the mass spectrometer 111 and / or at least one processing unit 118 (also referred to as a processor 118)) can be configured to determine at least one mass spectrum of the detected ions, for example, a two-dimensional representation of signal intensity and mass-to-charge ratio m / z, wherein the signal intensity corresponds to the abundance of the corresponding ions. The mass spectrometer can be a pixelated image. In order to determine the resulting intensity of the mass spectrometer pixel, the signal detected by the detector 114 within a certain m / z range can be integrated. The analyte in the sample can be identified by the processing unit 118. The processing unit 118 can be configured to associate a known mass with an identified mass or to be configured by a characteristic fragmentation pattern.

[0221] The mass spectrometer 111 may be specifically or may include a liquid chromatography mass spectrometer. The mass spectrometer 111 may be connected to and / or may include at least one liquid chromatograph (not shown), which may be used for sample preparation of the mass spectrometer 111. Other embodiments of sample preparation are also feasible, such as at least one gas chromatograph.

[0222] The sample can be, for example, a solid, liquid or gas sample. As an example, the sample can be a biological sample, such as a human sample or a human sample pool. For example, the sample can be a liquid sample, such as a water sample. For example, the test sample can be selected from the group consisting of the following items: physiological body fluids, including whole blood, serum, plasma, saliva, lens fluid, tears, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid and amniotic fluid; lavage fluid; tissue, cells, etc. However, the sample can also be a natural or industrial liquid, such as surface water or groundwater, sewage, industrial waste water, processing fluid, soil eluate, etc. The sample can include one or more additional chemical compounds, which are not determined and are generally referred to as matrix. The sample can be used directly when obtained from the corresponding source, or can be subjected to one or more pretreatment and / or sample preparation steps. Therefore, the sample can be pretreated by physical and / or chemical methods, such as by centrifugation, filtration, mixing, homogenization, chromatography, precipitation, dilution, concentration, contact with binding and / or detection reagents and / or any other method considered suitable by those skilled in the art. During the sample preparation step, i.e., before, during and / or after the sample preparation step, one or more internal standards may be added to the sample. The sample may be spiked with an internal standard. For example, the internal standard may be added to the sample at a predefined concentration. The internal standard may be selected so that it is easily identified under normal operating conditions of a selected detector, such as a mass spectrometer, a photometric cell (e.g., in a UV-visible spectrometer), an evaporative light scattering refractometer, a conductivity meter, or any device deemed appropriate by the skilled person. The concentration of the internal standard may be predetermined and significantly higher than the concentration of the analyte.

[0223] The sample may include one or more analytes of interest. The analyte may be, for example, a chemical, biochemical or biological compound, such as a molecule or a fragment thereof, detected by the mass spectrometer 111 during the measurement of the sample. As a result of the measurement process, the mass spectrometer may detect the presence and / or abundance and / or concentration of one or more analytes (e.g., multiple analytes in the sample). The analyte itself may be a sample component. Additionally or alternatively, the analyte may be a fragment of a component present in the sample. As an example, one or more sample components may be cracked during the measurement process, such as during an ionization procedure, so that a single sample component may produce a plurality of different fragments, such as charged fragments, which may be detected as analytes at least in part by the mass spectrometer.

[0224] The concentration c of the analyte can be determined, for example, as the abundance of the analyte in a given volume set relative to the volume (such as the sample volume). The concentration can be described, for example, by at least one of mass concentration, molar concentration, and volume concentration. The concentration of the analyte can be specified and / or quantified by a concentration value.

[0225] In vitro diagnostic medical device 110, such as mass spectrometer 111, may include multiple hardware components 116. Hardware components 116 may be physical and / or tangible components of in vitro diagnostic medical device 110. Hardware components 116 may, for example, include an instrument or component of an instrument that forms a part of in vitro diagnostic medical device 110 (such as mass spectrometer 111). For example, hardware components 116 may be part of one or more of the following items: a sample preparation unit of mass spectrometer 111, an ionization unit of mass spectrometer 111, a mass analyzer unit of mass spectrometer 111, and a detection unit of mass spectrometer 111. For example, hardware components 116 may be part of at least one of quadrupole mass analyzer 113, detector 114, ionization source 115. Further possibilities are feasible. Hardware components 116 may have a specific configuration or setting that is variable or adjustable (e.g., in an application-specific manner). Additionally or alternatively, the configuration or setting may vary due to manufacturing tolerances. As an example, due to potential variability of hardware component 116, calibration of hardware component 116 may be required, for example, calibration including one or more calibration steps, such as calibration that forms part of a series of calibration and adjustment steps of one or both of the methods for establishing metrological traceability for at least one in vitro diagnostic medical device 110.

[0226] exist Figure 2 In the schematic flow chart, an exemplary embodiment of a method for establishing metrological traceability for at least one in vitro diagnostic medical device 110 is shown. The method comprises a series of calibration and adjustment steps, wherein the result of each step depends on the result of the previous step. The method may further comprise other method steps not listed. Furthermore, one or more or even all of the method steps may be performed only once or repeatedly, for example to generate at least one average value. As an example, a target concentration value specified as part of the method may be specified as at least one average value.

[0227] The following will be Figure 2 The specific embodiment shown is used to describe a method for establishing metrological traceability for at least one in vitro diagnostic medical device 110. In the specific embodiment described, the in vitro diagnostic medical device 110 is a mass spectrometry device 111. It is easy for a person skilled in the art to understand that, in general, the method can also be performed using other in vitro diagnostic medical devices 110.

[0228] Figure 2 The materials used during the method, for example samples, are shown in the boxes on the left. The measurement procedures, for example for sample measurements, are shown in the boxes on the right.

[0229] Figure 2A series of exemplary calibration and adjustment steps including multiple calibration and / or adjustment steps is shown. The method may include an entire standardization procedure. The result of each step depends on the result of the previous step. The method may include a hierarchical calibration and adjustment step. A series of calibration and adjustment steps may include method steps that proceed from a reference to a final measurement system, wherein the result of each step depends on the result of the previous step. The method may include establishing metrological traceability by ensuring traceability of higher-order reference system components as required by ISO 17511:2020. Metrological traceability may refer to a hierarchical calibration and adjustment step and a series of value assignments, which may allow an uninterrupted link between measurement results for a sample up to the highest available reference system component in the hierarchy.

[0230] like Figure 2 As depicted, a series of calibration and adjustment steps may include a first calibration and adjustment step using a measurement procedure for purity assessment suitable for the intended use, such as quantitative NMR, mass balance, etc. ("p. 1. measurement procedure for purity assessment suitable for the intended use"), which is indicated by reference numeral 122. A target concentration value for at least one certified primary reference material ("m. 1. certified primary reference material (CRM)") indicated by reference numeral 126 may be specified by the first calibration and adjustment step indicated by reference numeral 128.

[0231] The sequence of calibration and adjustment steps may further include a second calibration and adjustment step using a primary reference measurement procedure for calibrant preparation (e.g., gravimetric preparation) indicated by reference numeral 130 ("p. 2. Primary reference measurement procedure for calibrant preparation") on at least one certified primary reference material 126. The primary reference measurement procedure 130 may be or may include a reference measurement procedure for obtaining measurement results that are independent of a measurement standard of the same kind for a certain amount. The CRM 126 may be a reference material that is accompanied by documentation published by an authoritative organization and uses a valid procedure to provide one or more specified property values ​​with associated uncertainties and traceability. The primary reference measurement procedure 130 and the CRM 126 for calibrant preparation may meet the requirements described in ISO 17511:2020 and ISO 15194.

[0232] The sequence of calibration and adjustment steps of the sequence may further include a third calibration and adjustment step of at least one primary calibrator ("m.2. Primary calibrator prepared as a solution of m.1 in a suitable solvent") represented by reference numeral 132 using a primary reference measurement procedure for a measured object ("p.3 Primary reference measurement procedure for a measured object") represented by reference numeral 134. The measured object may be the quantity intended to be measured. The calibrator may be a material used as a measurement standard. The primary calibrator 132 may be a measurement standard established using the primary reference measurement procedure, or created as an artifact, selected by convention. The primary calibrator 132 may be prepared as a solution of the CRM 126 in a suitable solvent. The primary reference measurement procedure for the measured object and the primary calibrator 132 may meet the requirements described in ISO 17511:2020. The target concentration value for the primary calibrator 132 may be specified by the second calibration and adjustment step 130.

[0233] The sequence of the series of calibration and adjustment steps may further include a fourth calibration and adjustment step using a manufacturer-selected measurement procedure ("p4. Manufacturer-selected measurement procedure") represented by reference numeral 142 for at least one secondary calibrator ("m.3 Secondary calibrator (reference sample or pool or human sample)") represented by reference numeral 136. The secondary calibrator 136 may be a measurement standard established by calibration relative to a primary measurement standard of the same type for one equivalent. The manufacturer-selected measurement procedure 142 and the secondary calibrator 136 may meet the requirements described in ISO 17511:2020. The second calibrator 136 may be at least one of the following: a human sample, a pool of human samples, a sample with a matrix, and a sample comparable to a human sample. The manufacturer-selected measurement procedure 142 may include one or more of a homogeneous or heterogeneous immunoassay or liquid chromatography-tandem mass spectrometry (LC-MS / MS). Other measurement procedures are also feasible. The manufacturer-selected measurement procedure 142 may be at least partially automated. For example, the manufacturer's selected measurement procedure 142 may be comparable or coordinated with a customer's measurement procedure. A target concentration value for the secondary calibrant 136 may be specified by the third calibration and adjustment step 134 .

[0234] The series of calibration and adjustment steps may further include Figure 2 At least one lead calibrator ("m.4. Manufacturer's working calibrator (lead calibrator)") indicated by reference numeral 146 in the fifth calibration and adjustment step using the manufacturer's established measurement procedure ("p5. Manufacturer's established measurement procedure") indicated by reference numeral 150. The lead calibrator may correspond to a sample indicated as a manufacturer's working calibrator in standard ISO 17511:2020. The target concentration value for the lead calibrator 146 may be specified by the fourth calibration and adjustment step 142.

[0235] The series of calibration and adjustment steps may further include Figure 2 The at least one product calibrator ("m.5. End User IVD MD Calibrator (Product Calibrator)") indicated by reference numeral 154 in the sixth calibration and adjustment step of the measurement procedure on the end user's IVD medical device 110 ("p.6. End User IVD MD") indicated by reference numeral 156. The target concentration value for the product calibrator 154 may be specified by the fifth calibration and adjustment step 150. The sixth calibration and adjustment step 156 may further include specifying the target concentration value to Figure 2 Human samples are indicated by reference numeral 160 in the figure ("m.6. Human Samples and Results").

[0236] The method includes providing a pilot calibration curve. The pilot calibration curve can be any mathematical function describing the relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of the sample measured by a mass spectrometer. The pilot calibration curve, in particular the inverse pilot calibration curve, can assign the concentration c to a sample examined by an in vitro diagnostic medical device based on at least one of a measured signal value and a theoretical signal value derived from the measured signal value. Additionally or alternatively, the pilot calibration curve can help assign the concentration c to the sample by assigning the theoretical concentration value to the sample based on the measured signal value of the sample, wherein in a next step, the concentration c is assigned to the sample based on the theoretical concentration value, for example by applying a concentration adjustment function or its inverse.

[0237] The pilot calibration curve may include at least one mathematical operation (e.g., multiplication with at least one factor) or any other type of mathematical operation. The pilot calibration curve is a parameterized function. The pilot calibration curve f p For parameterized functions The parameters is a set of parameters of the pilot calibration curve and p≥1. The pilot calibration curve can be obtained by combining the function form of the pilot calibration curve with the fitted parameter values. Together, for example, determine. The functional form can be, for example, one or more of a Roddart model function, a Padé model function, a quadratic model function, or any other nonlinear or linear function. For example, the Padé model function can be given by:

[0238]

[0239] Where y is the signal value, x is the concentration or target value, and p1, p2, and p3 are the parameters of the function. For example, the Rodbard model function is given by:

[0240]

[0241] Where y is the signal value, x is the concentration or target value, and p1, p2, p3, and p4 are the parameters of the function. Other functional forms are also possible.

[0242] The provision of the pilot calibration curve may include determining one or more of the pilot calibration curves by setting and selecting at least one of the pilot calibration curves. For example, the process of setting the pilot calibration curve may include establishing the pilot calibration curve, such as by determining at least one of its form and / or parameter values. The setting of the pilot calibration curve may be established by at least one of the modeling and / or fitting procedures, such as by selecting at least one model function and / or by determining at least one of the fitting parameter values. For example, the setting of the pilot calibration curve may include generating at least one specific parameter value in a modeling and / or fitting procedure.

[0243] The leading calibration curve can be a function specific to an assay and / or application. For example, a variety of conditions can be used to determine it, such as one or more of different instruments, different reagent batches, and different measurement conditions that can be used in an assay or application. For example, the leading calibration curve can be determined using a variety of conditions, such as one or more of a variety of instruments and / or hardware components and / or reagent batches, etc.

[0244] The provision of a pilot calibration curve can be part of at least one of the calibration and adjustment steps. The provision of a pilot calibration curve can be performed in a hierarchical high-order step, for example, one of the first steps in the hierarchical. For example, a pilot calibration curve can be determined by using at least one primary calibrator 132. At least one target concentration value of a primary calibrator 132 can be established based on a primary reference measurement procedure 130 for calibrator preparation. For example, a pilot calibration curve is provided by using at least one secondary calibrator 136. At least one target concentration value of a secondary calibrator 136 can be established based on a primary reference measurement procedure 134 for a measured person. Other examples for providing a pilot calibration function in other steps of the hierarchical are also feasible. Additionally or alternatively, a pilot calibration curve can be provided by retrieving a pilot calibration curve, such as from at least one database (e.g., cloud). The provision of a pilot calibration curve can be performed once or repeatedly.

[0245] For example, the step of providing a pilot calibration curve can be embodied as including the setting of a pilot calibration curve. For example, this step can be performed as one of the initial steps of a standardization process. The step of setting a pilot calibration curve can include determining the functional form of the pilot calibration curve. The step of setting a pilot calibration curve can include determining the functional form of the pilot calibration curve. Parameters Parameter value.

[0246] like Figure 2As shown, the method may include at least one step of setting a pilot calibration curve. The step of "setting a pilot calibration curve" is Figure 2 In the figure, it is marked with reference numeral 138. Figure 2 In an embodiment of the present invention, the step of setting the pilot calibration curve may include measuring the signal values ​​of a set of secondary calibrants 136 using the in vitro diagnostic medical device 110. where i represents a secondary calibrant i=1,..,I and I≥1, j represents an instrument and / or hardware component j=1,..,J and J≥1, and l represents a replicate l=1,..,L and L≥1, and a pre-specified target concentration value c using the set of secondary calibrants i and the measured signal value Determine the pilot calibration curve Parameters The set of secondary calibrators 136 may include at least one secondary calibrator 136, such as at least three secondary calibrators 136, for example 20 to 30 secondary calibrators 136. However, the set of secondary calibrators 136 may also include a different number of secondary calibrators 136, for example more than 30 secondary calibrators 136. The target concentration value c of the secondary calibrator 136 i It may be pre-specified in a high-level calibration and / or adjustment step, which for example comprises a primary reference measurement procedure 134 for the person being measured.

[0247] The relationship between the measured signal values ​​of a calibrator sample and the target concentration value of the calibrator sample may be insufficiently described by the pilot calibration curve alone, such as not being precise or accurate enough. As an example, the concentration value determined using the pilot calibration curve based on the measured signal values ​​of the calibrator sample may differ from the target concentration value of the calibrator sample, such as by more than a predetermined threshold. This may be due, for example, to the fact that the pilot calibration curve was determined based on a sample other than the calibrator sample. However, in Figure 2 In the illustrated normalization process, a pilot calibration curve may remain unchanged, and alternatively, another function, i.e., a signal adjustment function, may be determined and / or adjusted. Although the normalization process includes several calibration and adjustment steps, a pilot calibration curve may be initially established, such as in a hierarchical high-order step, and may remain unchanged during two or more subsequent adjustment steps.

[0248] In each adjustment step, the signal adjustment function g describing the relationship between the measured signal value and the theoretical signal value r The signal adjustment function is determined by determining the relationship between the measured signal value of the first calibrator sample and the theoretical signal value of the first calibrator sample derived from the pilot calibration curve, where r is a set of parameters of the signal adjustment function. The theoretical signal value is obtained by applying the pilot calibration curve using the pre-specified target concentration value c of the first calibrator sample.i Each adjustment step includes assigning at least one target concentration value based on the measured signal value of at least one second calibrator sample. The assigning includes determining at least one theoretical signal value for the second calibrator sample by applying the signal adjustment function determined in the previous adjustment step or the inverse of the signal adjustment function determined in the previous adjustment step to the measured signal value of the second calibrator sample, and inverting the pilot calibration curve. Theoretical signal value applied to the second calibrant sample.

[0249] The method comprises a plurality of calibration and adjustment steps as described above which are performed in succession. Figure 2 As shown, the method may include setting a pilot calibration curve 138; adjusting the pilot calibration curve 140; specifying a target value for a pilot calibrant 144; adjusting the pilot calibration curve by the pilot calibrant 148; and specifying a target value for a product calibrant 152. This step may be performed at the manufacturer's site.

[0250] After setting the pilot calibration curve 138, as Figure 2 As shown, the method may further include at least one step of adjusting the pilot calibration curve 140, the step comprising using a set of secondary calibrants i=1, ..., I, I≥1 to determine the first signal adjustment function The determination of the first signal adjustment function includes:

[0251] - Measure the signal value of the secondary calibrant 136 using the measurement procedure 142 selected by the manufacturer - The theoretical signal is calculated by

[0252]

[0253] where c i is a predetermined target concentration value for the secondary calibrant 136, and

[0254] - Fitting the signal conditioning function g1, thereby determining the fitted parameters

[0255] The step of adjusting the pilot calibration curve 140 may, for example, include determining a first signal adjustment function while keeping the pilot calibration curve unchanged. The pre-specified target concentration value of the secondary calibrant 136 may be determined in a high-order calibration and / or adjustment step, which may, for example, include a primary reference measurement procedure 134 for a measured subject.

[0256] In subsequent calibration and adjustment steps, two functions, namely the lead calibration function and the first signal adjustment function, can be used in combination to assign at least one target concentration value to the sample, for example, the lead calibrator 146 in the step of target value assignment 144 of the lead calibrator. In addition or alternatively, the target concentration value can be assigned to the sample based on a separate lead calibration curve, for example, by applying the inverse of the lead calibration curve to the measured signal value of the sample measured using the in vitro diagnostic medical device 110. For example, in the case where the assignment of the target concentration value is performed before determining the first signal adjustment function, the target concentration value can be assigned to the sample based on the separate lead calibration curve. As an example, the step of target value assignment 144 of the lead calibrator can initially be performed directly after the step of setting the lead calibration curve 138. In this case, the signal adjustment function may not have been determined, and therefore, no signal adjustment function is available. The target concentration value can be assigned to the lead calibrator using a separate lead calibration curve, for example, by applying the inverse of the lead calibration curve to the measured signal value of the lead calibrator. Alternatively, the step of target value assignment 144 for the lead calibrant may be performed in a repeated step such that the step of adjusting the lead calibration curve 140 has been performed, in the layered calibration and adjustment steps, after the step of target value assignment 144 for the lead calibrant. Thus, the signal adjustment function may be available for the repeated step 144. In this case, the step of target value assignment for the lead calibrant may be performed using both the lead calibration curve and the signal adjustment function.

[0257] For example, the step of specifying target values ​​for the lead calibrants 144 may include specifying at least one target concentration value for at least one lead calibrant 146. Target concentration value of lead calibrant 146 The designation may include measuring a signal value of a lead calibrant k, where k=1, .., K and K≥1, using the in vitro diagnostic medical device 110 Where j represents an instrument and / or hardware component j=1, .., J and J≥1, and l represents a replicate l=1, .., L and L≥1. Target concentration value of the lead calibrant 146 The specification may further include converting the measured signal value into Convert to target concentration value

[0258] and

[0259]

[0260] The target concentration value for lead calibrant 146 may be specified, for example, as at least one average value from a plurality of target concentration values, where the average value is one or more of a mean, a median, or a weighted average of the plurality of target concentration values.

[0261] like Figure 2 As shown, the step of “adjusting the pilot calibration curve” 140 may be embodied, for example, as a step of “adjusting the pilot calibration curve by the pilot calibrant” 148 using at least one pilot calibrant k. The step of adjusting the pilot calibration curve by the pilot calibrant 146 may include determining the second signal adjustment function by the following steps: where q1,..,q Q is a set of parameters of the second signal adjustment function, and Q ≥ 1,

[0262] - measuring the signal value of at least one lead calibrant k 146 on the in vitro diagnostic medical device 110 using the manufacturer's customary measurement procedure 150 Where j represents an instrument and / or hardware component

[0263] j=1,..,J and J≥1, and l indicates repetition l=1,..,J and L≥1,

[0264] - The theoretical signal is calculated by

[0265] as well as

[0266] - Fitting the signal conditioning function g2, thereby determining the fitted parameters

[0267] The manufacturer's custom measurement procedure 150 that can be used to measure the signal value of the lead calibrant 146 can include, for example, at least one of a homogeneous immunoassay, a heterogeneous immunoassay, and liquid chromatography-tandem mass spectrometry (LC-MS / MS). Other measurement procedures are also possible.

[0268] The step of adjusting the lead calibration curve 148 by the lead calibrator may, for example, include determining a signal adjustment function g2 using the measured signal value of the lead calibrator 146, while keeping the lead calibration curve itself unchanged. Hereinafter, two functions, the lead calibration function and the second signal adjustment function, may be used in combination to specify at least one target concentration value for at least one additional second calibrator sample (e.g., product calibrator 154).

[0269] The method may further include Figure 2 The step of "target value assignment for product calibrants" 152 may include assigning at least one target concentration value for at least one product calibrant k. Target concentration values ​​for product calibrants The designation includes the use of an in vitro diagnostic medical device to measure the signal value of a product calibrant k where k = 1, .., K and K ≥ 1 Where j represents an instrument and / or hardware component j=1, .., J and J≥1, and l represents a replicate l=1, .., L and L≥1, wherein the target concentration value of the product calibrant 154 is determined Further comprising converting the measured signal value into Convert to target concentration value

[0270] and

[0271]

[0272] The target concentration value for a product calibrant can be specified, for example, as at least one average from a plurality of target concentration values, where the average is one or more of a mean, a median, or a weighted average of the plurality of target concentration values.

[0273] The method may further include measuring the signal value of the independent control sample using the in vitro diagnostic medical device 110 (e.g., the mass spectrometer 111), and converting the measured signal value of the independent control sample into a concentration value by applying the signal adjustment function g2 and the pilot calibration curve. The method may further include comparing the concentration value with a predefined target concentration value of the independent control sample. If the deviation between the concentration value of the independent control sample and the predefined target concentration value of the independent control sample is within a predefined tolerance range, the target concentration value is can be accepted.

[0274] The step of specifying 152 the target value of the product calibrant may be the last step of the method for establishing metrological traceability performed at the manufacturer end. The method may further include performing at least one client calibration step. For example, having an accepted target concentration value The product calibrants may be used in the client calibration step. As an example, a further step of adjusting the pilot calibration curve may be performed using product calibrants having a specified target concentration value. The processing device 112 may be further configured to perform at least one client calibration step for the IVD medical device 110 on at least one set of product calibrants 154. The signal adjustment function may thereby be calibrated. The client calibration step may include

[0275] - Using a client measurement program on the in vitro diagnostic medical device 110 (eg, the mass spectrometer device 111) to measure the signal value of at least one product calibrant k Where j represents an instrument and / or hardware component 116 j=1, .., J and J≥1, and l represents a repetition l=1, .., L and L≥1,

[0276] - The theoretical signal is calculated by

[0277]

[0278] in A predefined target concentration value for a set of product calibrants 154

[0279] - fitting the signal conditioning function, thereby determining fitted parameters of the signal conditioning function.

[0280] The target concentration value may have been pre-specified at the manufacturer's end by using the method for establishing metrological traceability described in any of the above embodiments, for example, in the step of target value assignment 158 ​​for human samples.

[0281] Figure 3A A graph of the lead calibration curve 157 for each analyte is shown. Thus, Figure 3A Three pilot calibration curves associated with three different analytes are shown 157. Figure 3A , the following curves are shown, a pilot calibration curve labeled 157a for analyte A, a pilot calibration curve 157b for analyte B, and a pilot calibration curve 157c for analyte C. The x-axis of the graph shows the analyte concentration 161 in arbitrary units. The y-axis of the graph shows the signal 162 in arbitrary units, such as in a number of counts. Figure 3B Will Figure 3A The lead calibration curve 157a is shown as a solid line, and the other two curves 159 are shown as dashed lines, which illustrate in an exemplary manner the effect of two different signal adjustment functions on the relationship between the signal and concentration of a particular analyte in a given exemplary analyte A. Using and / or applying a signal adjustment function may correspond to the effect of tilting and / or shifting the lead calibration curve, such as Figure 3B as shown in .

[0282] Figure 4 A flow chart is shown giving an overview of two methods for establishing metrological traceability for at least one in vitro diagnostic medical device 110. Reference numeral 162 in the top box indicates the two methods as "Methods for establishing metrological traceability for at least one in vitro diagnostic medical device". Reference numeral 164 in the lower box indicates what is available at this point for the two methods. Available may be a pilot calibration curve, a pre-specified target concentration value for a first calibrator sample, and a measured signal value for the first calibrator sample. In Figure 4In the context thereof, in particular, the pilot calibration curve may be particularly abbreviated as “LCC”, the term “pre-specified” may be particularly abbreviated as “pre-ass.”, and the term “first calibrant sample” may be abbreviated as “1 st cal". In the adjustment step, a first calibrator sample may be used, as shown in the side box labeled 166. Subsequently, a second calibrator sample may be used, as shown in the adjacent side box labeled 168. In the adjustment step, a pilot calibration curve or its inverse may first be applied, as shown in the box labeled 170. As shown in the corresponding box on the left, the pilot calibration curve may be applied to the pre-specified target concentration value of the first calibrator sample to determine the theoretical signal value of the first calibrator sample. Alternatively, and as shown in parallel in the right-hand box, the inverse of the pilot calibration curve may be applied to the measured signal of the first calibrator sample to determine the theoretical concentration of the first calibrator sample.

[0283] Next, an adjustment function may be determined, as shown in the box labeled with reference numeral 172. A signal adjustment function that describes the relationship between the measured signal value and the theoretical signal value may be determined, as shown on the left. In particular, the signal adjustment function may be fitted such that it maps the theoretical signal value of the first calibrant sample to a pre-specified target concentration value of the first calibrant sample (this option is in Figure 4 Alternatively and as shown in the flow on the right, a concentration adjustment function describing the relationship between the theoretical concentration of the first calibrator sample and the pre-specified target concentration value of the first calibrator sample can be determined. In particular, the concentration adjustment function can be fitted so that it maps the pre-specified target concentration value of the first calibrator sample to the theoretical concentration value of the first calibrator sample (this option is in Figure 4 ), or vice versa (not shown).

[0284] Next, a target concentration value can be assigned to the second calibrator sample, as shown in the box marked with reference numeral 174. In particular, this can be accomplished by successively applying the inverse of the adjustment function (or adjustment functions) and the inverse of the lead calibration curve, or vice versa, as shown in the side box marked 176. Thus, as shown in the flow on the left, the inverse signal adjustment function can be applied to the measured signal values ​​of the second calibrator sample to determine the theoretical signal value of the second calibrator sample, and then the inverse of the lead calibration curve can be applied to the theoretical signal value of the second calibrator sample to assign a target concentration value to the second calibrator sample. It is worth noting that in the case of using the above-mentioned option (wherein the signal adjustment function is fitted so that it maps the pre-specified target concentration value of the first calibrator sample to the theoretical signal value of the first calibrator sample (and vice versa)), a concentration adjustment function can be used instead of its inverse. For better overview, Figure 4Again this option is not shown in . The process on the right shows the corresponding steps, in particular, applying the inverse of the pilot calibration curve to the measured signal values ​​of the second calibrator sample to assign a theoretical concentration value to the second calibrator sample. The inverse of the concentration adjustment function can then be applied to the theoretical concentration values ​​of the second calibrator sample to assign a target concentration value to the second calibrator sample. It is again worth noting that in case the above-mentioned option is used (wherein the concentration adjustment function is fitted so that it maps the theoretical concentration values ​​of the first calibrator sample to the pre-specified concentration values ​​of the first calibrator sample), the concentration adjustment function can be used instead of its inverse. In order to better outline and compare the methods for establishing metrological traceability for at least one in vitro diagnostic medical device 110, this option is not shown in . Figure 4 Shown in.

[0285] Figure 5 to 1 0 gives an overview of an exemplary embodiment of a method for establishing metrological traceability for at least one in vitro diagnostic medical device 110.

[0286] Figure 5 A flow chart of this exemplary embodiment is shown.

[0287] In a first step, a reference measurement procedure ("RMP") 134 for a measured person is performed on a primary calibrator ("Primary CAL") 132. Next, in a calibration step 128, a target value for a secondary calibrator ("Secondary CAL") 136 is determined using the RMP 134.

[0288] In the exemplary embodiment, a pilot calibration curve 138 is set by using a secondary calibrant 136. A manufacturer selected measurement procedure ("MMP") 142 is performed on the secondary calibrant 136. The pilot calibration curve is used in all subsequent steps and is indicated by curved brackets.

[0289] Next, in this embodiment, still in step 138, an adjustment of the pilot calibration curve may be performed using the secondary calibrant 136, the manufacturer selected measurement procedure ("MMP") 142, and the specified target concentration value.

[0290] Next, in step 144, a manufacturer-selected measurement procedure ("MMP") 142 is used to specify a target concentration value for a working calibrant ("working CAL") 146 (also denoted lead calibrant).

[0291] Next, in step 148, an adjustment of the pilot calibration curve is performed using the working calibrant 146, the manufacturer's scheduled measurement procedure ("MSMP") 150, and the specified target concentration value.

[0292] Next, in step 152 , a target value for a product calibrant (“Product CAL”) 154 is specified using the manufacturer's established measurement procedure (“MSMP”) 150 .

[0293] Next, in step 140, an adjustment of the pilot calibration curve is performed using the product calibrant ("Product CAL") 154, the measurement procedure ("Assay") 156 on the end user's IVD medical device 110, and the specified target concentration value.

[0294] Next, in step 158, a measured value for the human sample is generated using a measurement procedure ("assay") 156 on the end user's IVD medical device 110.

[0295] Fig. 6A , 6B , 6C, 6D and Figure 7 The results of an experiment to set up a lead calibration curve 138 are shown. In particular, the signal is shown in relation to the target value (in [μg / ml]). i=31 secondary calibrators 136 (in this case samples containing carbazine) were used as material. These i=31 secondary calibrators 136 were measured on three LC / MS instruments, with three replicates per instrument (i.e. i=31, j=3, l=3), resulting in a total of nine measurements (9 results (signals) per sample): s ijl ),like Fig. 6A , 6B , 6C and 6D.

[0296] Fig. 6A A comparison of the measured signal values ​​for three replicates on each secondary calibrant 136 for the three instruments is shown, with circles representing Instrument 1, triangles representing Instrument 2, and crosses representing Instrument 3. Figures 6B to 6D , the experimental results for each individual instrument are shown, where circles, crosses, and triangles represent respective replicates. In addition, the resulting pilot calibration curve 138 is Figures 6A to 6D is shown in each of the .

[0297] The target value for the secondary calibrant 136 is pre-specified, for example, by using a reference measurement procedure, such as in a reference measurement procedure for a person being measured ( Figure 5 “RMP” in (134).

[0298] The following table provides an overview of the experimental results for the signal values ​​(secondary calibrator (SPC), target value [μg / ml] (Target), minimum signal value (Min), mean signal value (Mean), median signal value (Median), maximum signal value (Max), standard deviation (SD) of the signal values, and coefficient of variation (CV)).

[0299] i j*l type Target Minimum average value median Maximum SD CV [%] 0 9 SCP 0 0.000013 0.000102 0.000105 0.000219 0.000077 76.2 1 9 SCP 0.904 0.192 0.199 0.196 0.207 0.00579 2.9 2 9 SCP 1.08 0.219 0.236 0.242 0.248 0.012 5.1 3 9 SCP 1.42 0.273 0.294 0.293 0.313 0.0114 3.9 4 9 SCP 1.61 0.341 0.352 0.349 0.377 0.0105 3 5 9 SCP 2.18 0.437 0.459 0.461 0.473 0.0115 2.5 6 9 SCP 2.67 0.569 0.58 0.583 0.591 0.00761 1.3 7 9 SCP 3.24 0.637 0.678 0.691 0.699 0.0236 3.5 8 9 SCP 3.81 0.783 0.82 0.813 0.856 0.0272 3.3 9 9 SCP 4.52 0.874 0.91 0.919 0.939 0.0227 2.5 10 9 SCP 4.71 1.01 1.02 1.02 1.04 0.0115 1.1 11 9 SCP 6.33 1.29 1.34 1.35 1.38 0.0348 2.6 12 9 SCP 6.85 1.41 1.44 1.42 1.51 0.0379 2.6 13 9 SCP 7.29 1.49 1.55 1.56 1.57 0.0269 1.7 14 9 SCP 7.87 1.64 1.69 1.7 1.72 0.0333 2 15 9 SCP 9.1 1.7 1.79 1.78 1.9 0.0588 3.3 16 9 SCP 10.2 1.88 1.99 1.98 2.12 0.088 4.4 17 9 SCP 10.6 1.94 2.1 2.14 2.25 0.121 5.8 18 9 SCP 11.5 2.14 2.22 2.2 2.3 0.0685 3.1 19 9 SCP 10.6 2.18 2.29 2.31 2.42 0.087 3.8 20 9 SCP 11.7 2.29 2.4 2.35 2.6 0.121 5 21 9 SCP 13.2 2.47 2.67 2.63 2.93 0.152 5.7 22 9 SCP 12.9 2.72 2.86 2.86 2.98 0.0898 3.1 23 9 SCP 13.8 2.74 2.85 2.86 2.97 0.0923 3.2 24 9 SCP 15.1 2.8 2.99 3.03 3.12 0.105 3.5 25 9 SCP 14.7 2.91 3.11 3.18 3.2 0.116 3.7 26 9 SCP 16.4 3.14 3.24 3.25 3.37 0.0652 2 27 9 SCP 17.7 3.16 3.29 3.26 3.45 0.086 2.6 28 9 SCP 15.9 3.32 3.44 3.43 3.56 0.0804 2.3 29 9 SCP 16.5 3.16 3.42 3.49 3.59 0.163 4.8 30 9 SCP 16.4 3.23 3.47 3.37 3.81 0.199 5.7

[0300] The lead calibration curve can be determined by applying a regression fit, for example in this case using a weighted least squares fit. Figure 7 The median signal of the 9 results for each sample is shown in Figure 7 The target value of the sample is shown on the Y-axis. Figure 7 The Padé model function is used as the functional form of the pilot calibration curve in this example.

[0301]

[0302] Where y is the signal value, x is the concentration or target value, and p1, p2, and p3 are the parameters of the function. The following are found:

[0303] P1 P2 P3 Pade[μg / mL] 0.0001048 0.21432 0.003476

[0304] After setting the pilot calibration curve 138 , the method may include step 144 , where a target concentration value for the pilot calibrant 146 is specified.

[0305] In this experiment, eight lead calibrants (LCal) 146 were measured on three LC / MS instruments with three replicates per instrument (i.e., k=8, j=3, l=3), resulting in a total of nine measurements and nine signals per calibrant: s kjl lead,meas The following table gives an overview of the experimental results of the signal values ​​(lead calibrant (LCal), minimum value (Min), mean (Mean), median (Median), maximum value (Max), standard deviation (SD) and coefficient of variation (CV)):

[0306] k j*l type Minimum average value median Maximum SD CV [%] 1 9 LCal 0.168 0.18 0.184 0.186 0.00771 4.3 2 9 LCal 0.21 0.218 0.218 0.226 0.00622 2.9 3 9 LCal 0.299 0.307 0.304 0.315 0.00587 1.9 4 9 LCal 0.772 0.804 0.805 0.829 0.0164 2 5 9 LCal 1.46 1.48 1.48 1.52 0.0175 1.2 6 9 LCal 2.06 2.13 2.14 2.19 0.0533 2.5 7 9 LCal 2.64 2.7 2.71 2.75 0.0421 1.6 8 9 LCal 3.19 3.34 3.36 3.51 0.107 3.2

[0307] The measured signal of the lead calibrant 146 is then converted to a concentration value using the lead calibration curve and, if necessary, a signal adjustment function.

[0308] In this experiment, adjustment of the pilot calibration curve was performed using secondary calibrant 136 . Figures 8A to 8D The use of a sample curve set (secondary calibrant) measurement to determine a signal adjustment function for recalibrating a pilot calibration curve is shown. In particular, the sample used to determine the pilot calibration curve is used, see the description of Figure 6. FIG. 8A to FIG. 8D In FIG. 1 , the measured signal (“Signal”) is shown on the Y-axis and the theoretical signal (“Theoretical Signal”) is shown on the X-axis. Fig. 8AA comparison of the mean values ​​of three replicates for three instruments is shown, with circles representing instrument 1, triangles representing instrument 2, and crosses representing instrument 3. Figures 8B to 8D In the , experimental results for each individual instrument are shown, where circles, crosses, and triangles represent respective replicates. Fit results are shown in each figure. Figures 8B to 8D , the following intercepts and slopes were determined:

[0309] Sample ID intercept Slope 1 -0.0000323 0.98713 2 -0.0001081 1.02579 3 -0.0001104 1.03035 4 -0.0000013 1.01675 5 0.0000112 0.98578 6 0.0000554 0.98932 7 0.0000732 0.99335 8 0.0000778 0.98383 9 0.0000918 0.99455

[0310] The results were used to determine the corresponding concentration values ​​for the lead calibrator, and the median of these concentrations was used as the target value for the lead calibrator 146. In particular, the median concentration in [μg / ml] of the 9 read concentrations (9 signals from each calibrator) was used as the target concentration value for the lead calibrator 146. The following table gives an overview of the experimental concentration results (in [μg / mL]):

[0311] Sample ID N Minimum average value Median / Target Maximum SD CV [%] 1 9 0.797 0.84 0.848 0.867 0.0246 2.9 2 9 0.997 1.02 1.02 1.05 0.0183 1.8 3 9 1.38 1.44 1.45 1.49 0.0361 2.5 4 9 3.71 3.8 3.81 3.87 0.0597 1.6 5 9 6.85 7.09 7.04 7.39 0.167 2.4 6 9 10.1 10.3 10.3 10.5 0.115 1.1 7 9 12.7 13.2 13.2 13.4 0.228 1.7 8 9 16.1 16.5 16.5 17.1 0.302 1.8

[0312] Next, the method may include step 152 , in which a target concentration value for a product calibrant 154 is specified.

[0313] In this experiment, two product calibrants 154 were measured on three LC / MS instruments, with three replicates per instrument (i.e., k=2, j=3, l=3), resulting in a total of nine measurements and nine signals per calibrant. The following table gives an overview of the experimental results (product calibrant (PCal), minimum value (Min), mean (Mean), median (Median), maximum value (Max), standard deviation (SD) and coefficient of variation (CV)) of the signal values:

[0314] Sample ID N Minimum average value median Maximum SD CV [%] PCal1 9 0.321 0.343 0.344 0.367 0.0152 4.4 PCal2 9 2.47 2.61 2.61 2.74 0.0913 3.5

[0315] The measured signal of the product calibrant 154 is then converted to a concentration value using the pilot calibration curve and the signal adjustment function.

[0316] Figures 9A to 9D Determining a signal adjustment function for recalibrating the pilot calibration curve using the pilot calibrator 146 and the determined target value of the pilot calibrator 146 is shown. Figures 9A to 9D In FIG. 1 , the measured signal (“Signal”) is shown on the Y-axis and the theoretical signal (“Theoretical Signal”) is shown on the X-axis. Fig.9A A comparison of the averages of the three replicates on each lead calibrator 146 for the three instruments is shown, with circles representing instrument 1, triangles representing instrument 2, and crosses representing instrument 3. Figures 9B to 9DIn the , experimental results for each individual instrument are shown, where circles, crosses, and triangles represent respective replicates. Fit results are shown in each figure. Figures 9B to 9D , the following intercepts and slopes were determined:

[0317]

[0318] The results were used to determine the corresponding concentration values, and the median of these concentrations was used as the target value for the product calibrator 154. In particular, the median concentration in [μg / ml] of the 9 read concentrations (9 signals from each calibrator) was used as the target concentration value for the product calibrator 154. The following table gives an overview of the experimental concentration results (in [μg / mL]):

[0319] Sample ID N type Minimum average value Median / Target Maximum SD CV [%] PCal1 9 PCal 1.56 1.61 1.59 1.71 0.0572 3.6 PCal2 9 PCal 12.2 12.7 12.7 13.1 0.287 2.3

[0320] Next, the method may include step 158, wherein final measured concentration values ​​for human samples and controls (particularly QC samples and / or marker samples "m.6. Human Samples and Results") are assigned.

[0321] In this experiment, three human samples were measured on three LC / MS instruments with three replicates per instrument (i.e., k=3, j=3, l=3), resulting in a total of nine measurements and nine signals per sample. The following table gives an overview of the experimental results for the signal values ​​(control sample (QC), minimum value (Min), mean (Mean), median (Median), maximum value (Max), standard deviation (SD) and coefficient of variation (CV)) and their pre-specified target values ​​(in [μg / mL]):

[0322] Sample ID N type Target Minimum average value median Maximum SD CV [%] QC1 9 QC 2.03 0.404 0.425 0.425 0.441 0.0123 2.9 QC2 9 QC 7.51 1.57 1.61 1.6 1.68 0.0356 2.22 QC3 9 QC 14.1 2.75 2.85 2.82 3.06 0.0994 3.5

[0323] The measured signals of the human samples were then converted to concentration values ​​using the pilot calibration curve and the signal adjustment function.

[0324] Figures 10A to 10D Determining a signal adjustment function for recalibrating the lead calibration curve using the product calibrant 146 and the determined target value of the lead calibrant 154 is shown. Figures 10A to 10D In FIG. 1 , the measured signal (“Signal”) is shown on the Y-axis and the theoretical signal (“Theoretical Signal”) is shown on the X-axis. Fig. 10A A comparison of the averages of the three replicates on each product calibrator 154 for the three instruments is shown, with circles representing Instrument 1, triangles representing Instrument 2, and crosses representing Instrument 3. Figures 10B to 10D In the , experimental results for each individual instrument are shown, where circles, crosses, and triangles represent respective replicates. Fit results are shown in each figure. Figures 10B to 10D, the following intercepts and slopes were determined:

[0325] system flow intercept Slope Instruments, 1 1 -0.01152 0.95558 Instruments, 1 2 -0.00697 0.97205 Instruments, 1 3 -0.00473 0.96256 Instruments, 2 1 0.003305 1.01117 Instruments, 2 2 -0.002 1.04354 Instruments, 2 3 0.001018 1.05473 Instruments, 3 1 -0.0039 0.99773 Instruments, 3 2 0.000107 1.00411 Instruments, 3 3 -0.00401 0.99803

[0326] The results were used to determine the corresponding concentration values, and the average of these concentrations was used to calculate the relative recovery for its pre-specified target value. The following table gives an overview of the experimental results (in [μg / mL]):

[0327]

[0328] Reference numerals list

[0329] 110 In vitro diagnostic medical devices

[0330] 111 Mass Spectrometry Device

[0331] 112 Processing device

[0332] 113 Quadrupole Mass Analyzer

[0333] 114 Detector

[0334] 115 Ionization Source

[0335] 116 Hardware Components

[0336] 118 Processor

[0337] 120 Data storage device

[0338] 122 “p.1. Measurement procedures for purity assessment appropriate for the intended use (e.g.

[0339] qNMR, mass balance)”

[0340] 124 Target value specification

[0341] 126 “m.1. Certified primary reference materials (CRMs)”

[0342] 128 Calibration Procedure 130 “p.2. Primary reference measurement procedure for calibrant preparation (e.g., gravimetric preparation)”

[0343] 132 "m.2. A primary calibrant prepared as a solution of m.1 in a suitable solvent"

[0344] 134 "p.3. Primary Reference Measurement Procedure for Measured Persons"

[0345] 136 “m.3. Secondary calibrants (reference samples or pools or human samples)”

[0346] 138 Setting of the pilot calibration curve

[0347] 140 Adjustment of the pilot calibration curve

[0348] 142 "p.4. Measurement procedure selected by the manufacturer"

[0349] 144 Target value specification for lead calibrant

[0350] 146 “m.4. Manufacturer’s working calibration material (pilot calibration material)”

[0351] 148 Adjustment of the pilot calibration curve by the pilot calibrant

[0352] 150 "p.5. Manufacturer's standing measurement procedures"

[0353] 152 “Specification of target values ​​for product calibrants”

[0354] 154 “m.5. End-user IVD MD calibrators (product calibrators)”

[0355] 156 “p.6. End User IVD MD”

[0356] 157 Pilot calibration curve

[0357] 157a Pilot calibration curve for analyte A

[0358] 157b Pilot calibration curve for analyte B

[0359] 157c Pilot calibration curve for analyte C

[0360] 158 Target value assignment for human samples

[0361] 159 Curve showing the effect of the signal conditioning function

[0362] 160 "m.6. Human samples and results"

[0363] 161 Concentration in arbitrary units

[0364] 162 Method for establishing metrological traceability for at least one in vitro diagnostic medical device

[0365] 163 Signals of arbitrary units

[0366] 164 Available: Lead Calibration Curve (LCC), pre-specified target concentration value of the first calibrator sample, and measured signal value of the first calibrator sample

[0367] 166 First Calibrator Sample

[0368] 168 Second Calibrator Sample

[0369] 170 Apply the pilot calibration curve or its inverse

[0370] 172 Determination of adjustment function

[0371] 174 assigning a target concentration value to a second calibrant sample 176 successively applying the inverse of the adjustment function (or adjustment functions) and the inverse of the pilot calibration curve,

[0372] Or vice versa

Claims

1. A method for establishing metrological traceability for at least one in vitro diagnostic medical device (110), wherein the method comprises a series of calibration and adjustment steps, wherein the result of each step depends on the result of the previous step, The method comprises providing a pilot calibration curve, wherein the pilot calibration curve f p describes a relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of said sample measured by said in vitro diagnostic medical device (110), wherein said pilot calibration curve f p For parameterized functions The parameters is a set of parameters of the pilot calibration curve and P ≥ 1, wherein in each adjustment step, the signal adjustment function g describing the relationship between the measured signal value and the theoretical signal value r is determined by determining a relationship between a measured signal value of a first calibrator sample and a theoretical signal value of the first calibrator sample derived from the pilot calibration curve, wherein r is a set of parameters of the signal adjustment function, wherein the theoretical signal value is obtained by applying the pilot calibration curve using a pre-specified target concentration value c of the first calibrator sample. i wherein each adjustment step comprises assigning at least one target concentration value according to the measured signal value of at least one second calibrator sample, wherein the assigning comprises determining at least one theoretical signal value of the second calibrator sample by applying the signal adjustment function determined in a previous adjustment step or the inverse of the signal adjustment function determined in a previous adjustment step to the measured signal value of the second calibrator sample, and inverting the pilot calibration curve The theoretical signal value applied to the second calibrant sample.

2. The method according to the preceding claim, wherein the series of calibration and adjustment steps comprises a first calibration and adjustment step using a measurement procedure for purity assessment suitable for the intended use, wherein the series of calibration and adjustment steps further comprises a second calibration and adjustment step using a primary reference measurement procedure for calibrator preparation for at least one certified primary reference material, wherein the series of calibration and adjustment steps further comprises a third calibration and adjustment step using a primary reference measurement procedure for a measurand for at least one primary calibrator, and a fourth calibration and adjustment step using a measurement procedure selected by the manufacturer for at least one secondary calibrator.

3. The method according to the preceding claim, wherein the pilot calibration curve is determined by using at least one primary calibrator, wherein at least one target concentration value of the primary calibrator is established based on the primary reference measurement procedure used for calibrator preparation.

4. The method according to any of the two preceding claims, wherein the pilot calibration curve is determined by using at least one secondary calibrator, wherein at least one target concentration value of the secondary calibrator is established based on the primary reference measurement procedure for the measured person.

5. The method according to any of the preceding claims, wherein the specified target concentration value of the second calibrant sample can be used in a subsequent adjustment step for determining the signal adjustment function.

6. The method according to any one of the preceding claims, wherein the pilot calibration curve does not change over two or more adjustment steps.

7. A method according to any one of the preceding claims, wherein the signal adjustment function is a function where r1,..,r R is a set of parameters of the signal adjustment function, R≥1 and i is the first calibrant sample, i=1,...,I, I≥1, wherein the signal adjustment function relates the following two: the theoretical signal of the pilot calibration curve where i ≥ 1 and c i is a pre-specified target concentration value of the first calibrant sample; and a measured signal value of the first calibrant sample wherein j represents an instrument and / or hardware part (116) of the in vitro diagnostic medical device (110), j=1, .., J and J≥1, and l is a repetition l=1, .., L and L≥1, wherein the determination of the signal adjustment function comprises measuring the signal value of the first calibrator sample Calculate the theoretical signal and fitting the signal conditioning function, thereby determining the fitted parameters 8. The method according to any one of the preceding claims, wherein the specifying of the target concentration value comprises measuring a signal value of the second calibrant sample k using the in vitro diagnostic medical device (110). where k=1, .., K and K≥1, and the measured signal value is converted into the value by successively applying the following inverse function Convert to target concentration value c kjl : and 9. A method according to any one of the preceding claims, wherein the signal adjustment function is a function where r1,..,r R is a set of parameters of the signal adjustment function, R ≥ 1 and i is the first calibrator sample, i = 1, ..., I, I ≥ 1, wherein the signal adjustment function relates the measured signal value of the first calibrator sample to the theoretical signal of the first calibrator sample derived from the pre-specified target concentration value and the pilot calibration function, wherein the designation of the target concentration value of the second calibrator sample is determined by applying the signal adjustment function.

10. The method according to any of the preceding claims, wherein the in vitro diagnostic medical device (110) is a mass spectrometry device (111).

11. A method for establishing metrological traceability for at least one in vitro diagnostic medical device (110), wherein the method comprises a series of calibration steps and adjustment steps, wherein the result of each step depends on the result of the previous step, The method comprises providing a pilot calibration curve, wherein the pilot calibration curve f p describes a relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of said sample measured by said in vitro diagnostic medical device (110), wherein said pilot calibration curve f p For parameterized functions The parameters is a set of parameters of the pilot calibration curve and P ≥ 1, wherein in each adjustment step, a concentration adjustment function h describing the relationship between the theoretical concentration value of the measured signal value of the first calibrator sample and the pre-specified target concentration value of the first calibrator sample is determined s , wherein s is a set of parameters of the concentration adjustment function, wherein the theoretical concentration value of the first calibrant sample is obtained by applying the inverse of the pilot calibration curve determined using the measured signal value of the first calibrant sample, wherein the specifying of the target concentration value comprises applying the inverse of the pilot calibration curve using the measured signal value of the second calibrant sample Thus, a theoretical concentration value is obtained, and the concentration adjustment function h is applied to the theoretical concentration value. s or the inverse of the concentration adjustment function The target concentration value of the second calibrant sample is thereby obtained.

12. The method of the preceding claim, wherein the concentration adjustment function relates a pre-specified target concentration value for the first calibrator sample to the theoretical concentration value of the measured signal of the first calibrator sample, and the assignment of the target concentration value for a second calibrator sample is determined by applying the concentration adjustment function.

13. A processing device (112), wherein the processing device (112) is configured to retrieve and / or store at least one predetermined pilot calibration curve f p , wherein the processing device (112) is further configured to store the pilot calibration curve f p A set of parameters Wherein P is a positive integer, wherein the leading calibration curve f p describes a relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of said sample measured with an in vitro diagnostic medical device (110), wherein said pilot calibration curve f p For parameterized functions The processing device (112) is further configured to carry out a method for establishing metrological traceability for at least one in vitro diagnostic medical device (110) according to any of the preceding claims relating to a method.

14. A kit comprising an in vitro diagnostic medical device (110), a set of product calibrators and target concentration values ​​thereof, wherein the target concentration values ​​of the product calibrators are specified by using a method according to any one of the preceding claims 1 to 10 or 11 to 12.

15. A computer program, wherein the computer program is adapted to perform the method according to any of the preceding claims 1 to 10 or 11 to 12 when the program is executed on a computer.

16. A computer program product having program code means, wherein the program code means can be stored or are stored on a storage medium for carrying out the method according to any of the preceding claims 1 to 10 or 11 to 12 when the program code means are executed on a computer or on a computer network.

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