Method for establishing metrological traceability of at least one in vitro diagnostic medical device - Patents.com

Abstract

A method is proposed for establishing metrological traceability of at least one in-vitro diagnostic medical device (110). The method comprises a series of calibration and adjustment steps, the result of each step being dependent on the result of the previous step. The method comprises providing a preliminary calibration curve. The preliminary calibration curve f p describes 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 being measured using the in vitro diagnostic medical device (110). p where parameter (II) is a set of parameters of the prior calibration curve and [0010] TIFF2025515097000361.tif511 is a parameterized function (I). In each adjustment step, a signal or density adjustment function is determined and at least one target density value is assigned.

Description

[Technical field]

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

[0002] In general, the objective of a calibration procedure for mass spectrometry devices is to transfer accuracy from a higher standard, e.g. a reference measurement procedure or reference material, to the analytical application, also called an assay, by assignment of target values ​​for calibrators. Typically, such an approach establishes a traceability chain to the higher standard for each measurement of a patient sample, making analytical applications and their results comparable worldwide. The general process is well described, for example in ISO17511:2020.

[0003] To transfer the accuracy from one method to another, dedicated samples, e.g. patient samples, or calibrators, are often used. These samples are in principle values ​​assigned by the higher order method and are used to calibrate the lower order method. The resulting calibration function usually depends on various factors such as the individual instrument, e.g. hardware parts in case of hardware multiplexing, the reagent lot, e.g. individual reagents within the lot, the new set of calibration samples, the calibration event itself, and time effects. As a result, all individual calibration functions may generally differ in their function parameters. The methods described in the prior art usually include multiple individual independent calibration steps. This means that the variability of each step may generally contribute completely to the overall variability of the entire method. Higher variability usually reduces the robustness of the calibration procedure and increases the uncertainty.

[0004] WO 2021 / 239692 describes a computer-implemented method for calibrating a customer mass spectrometry instrument for a quantifier-confirmator ratio check, the method comprising the following steps: a) at least one manufacturer site standardization step, in which a set of subject samples and a set of calibrator samples are measured in multiple replicates on multiple mass spectrometry instruments, each measurement comprising multiple reaction monitoring with quantifier and confirmator transitions for an analyte and an internal standard, and at least three adjustment factors are determined from the measurements of the set of subject samples and the set of calibrator samples, a first adjustment factor depending on the difference between the analyte and the internal standard, a second adjustment factor depending on the difference between the subject samples and the calibrator samples for the analyte quantifier-confirmator ratio, and a third adjustment factor depending on the difference between the internal standard quantifier-confirmator ratio. a) at least one manufacturer site standardization step, which is dependent on differences between the subject's sample and the calibrator samples for q = 0; b) at least one transfer step, in which the adjustment factor is electronically transferred to a customer mass spectrometry instrument; and c) at least one customer site calibration step, in which the customer site calibration includes at least one calibration measurement, a set of calibrator samples are measured on the customer mass spectrometry instrument from which a quantifier-verifier ratio is determined, and target values ​​for the quantifier-verifier ratios of the analyte and the internal standard are set by applying the adjustment factor to the determined quantifier-verifier ratios.

[0005] EP 3472624 describes a method for providing a calibration curve for an optical D-dimer assay. Summary of the Invention

[0006] Therefore, the object of the present invention is to provide a method, a processing device, a kit comprising a set of in-vitro diagnostic medical devices and IVD MD calibrators and their target concentration values, a computer program and a computer program product for establishing metrological traceability of at least one in-vitro diagnostic medical device, which avoids the above-mentioned drawbacks of known methods, devices, computer programs and computer program products. In particular, the method and device shall minimize or reduce the overall variability of the calibration process. In particular, the calibration process shall be optimized, in particular by increasing the robustness of the calibration process and / or by reducing the uncertainty of the calibration process.

[0007] This problem is addressed by the present invention by a method for establishing metrological traceability of 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 calibrators and their target concentration values, a computer program and a computer program product, having the features of the independent claims. Advantageous embodiments, which may be realized alone or in any combination, are listed in the dependent claims and in the entire specification.

[0008] When used below, the terms "have", "comprise" or "include" or any grammatical variants thereof are used in a non-exclusive manner. Thus, these terms can refer both to the situation where no further features are present in the entity described in this context, in addition to the features introduced by these terms, and to the situation where one or more further features are present. As an example, the expressions "A has B", "A includes B" and "A contains B" can refer both to the situation where no other elements are present in A besides B (i.e., the situation where A consists only of B), and to the situation where one or more further elements are present in entity A besides B, such as element C, element C and D or further elements.

[0009] Furthermore, it should be noted that the terms "at least one" or "one or more" or similar expressions indicating that a feature or element may be present more than once are typically used only once when introducing each feature or element. In the following, in most cases, when referring to each feature or element, the expressions "at least one" or "one or more" will not be repeated, despite the fact that each feature or element may be present more than once.

[0010] Furthermore, when used hereinafter, the terms "preferably", "more preferably", "particularly", "more particularly", "particularly", "more particularly" or similar terms are used with optional features without limiting the possibilities of alternatives. Features introduced by these terms are therefore optional features and are not intended to limit the scope of the claims in any way. The invention may be implemented using alternative features, as recognized by those skilled in the art. Similarly, features introduced by "in an embodiment of the invention" or similar expressions are intended to be optional features without any limitations with respect to alternative embodiments of the invention, without any limitations with respect to the scope of the invention, and without any limitations with respect to the possibilities of combining the features introduced in such a manner with other optional or non-optional features of the invention.

[0011] In a first aspect of the present invention, a method for establishing metrological traceability of at least one in-vitro diagnostic medical device is disclosed.

[0012] The method may be computer-implemented. The term "computer-implemented" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to a method involving at least one computer and / or at least one computer network. The computer and / or computer network may comprise at least one processor configured to perform at least one of the method steps of the method according to the invention. Preferably, each of the method steps is performed by the computer and / or computer network. The method may be performed fully automatically, such as without user interaction. The term "automatically" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to a process that is fully performed by at least one computer and / or computer network and / or machine, in particular without manual action and / or user interaction.

[0013] The term "metrological traceability" as used herein 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, but is not limited to, refer to the property of a measurement result whereby the result can be related to a standard through a documented, sequential series of calibration and adjustment steps.

[0014] The term "in vitro diagnostic medical device" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled 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 medical device configured for in vitro testing of at least one sample derived from the human body and / or configured to provide information for diagnostic, monitoring or compatibility purposes, whether used alone or in combination. The IVD MD may comprise one or more of at least one reagent, at least one calibrator, at least one control substance, at least one specimen container, software, associated equipment or apparatus or other items.

[0015] The in-vitro diagnostic medical device may be a mass spectrometry device. The term "mass spectrometry" as used herein is a broad term and should be given its normal and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but not limited to, refer to an analytical technique for determining the mass-to-charge ratio of ions. Mass spectrometry may be performed using at least one mass spectrometry device. As used herein, the term "mass spectrometry device", also referred to as "mass analyzer", is a broad term and should be given its normal and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but not limited to, refer to an analyzer configured to detect at least one analyte based on the mass-to-charge ratio.

[0016] The mass analyzer may be or may comprise at least one quadrupole mass analyzer. As used herein, the term "quadrupole mass analyzer" is a broad term and should be given its normal and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to a mass analyzer that comprises at least one quadrupole as a mass filter. The quadrupole mass analyzer may comprise multiple quadrupoles. For example, the quadrupole mass analyzer may be a triple quadrupole mass analyzer. As used herein, the term "mass filter" is a broad term and should be given its normal and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to a device configured to select ions to be injected into the mass filter according to their mass-to-charge ratio m / z. The mass filter may comprise two pairs of electrodes. The electrodes may be rod-shaped, for example cylindrical. In the ideal case, the electrodes may be hyperbolic. The electrodes may be designed to be identical. The electrodes may be arranged to extend parallel along a common axis, for example the z-axis. The quadrupole mass analyzer may comprise 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 two pairs of electrodes of the mass filter. The power supply circuit may be configured to hold each opposing electrode pair at the same potential. The power supply circuit may be configured to periodically change the sign of the charge of the electrode pairs such that stable trajectories are possible only for ions within a certain mass-to-charge ratio m / z. The trajectories of the ions in the mass filter may be described by the Mathieu differential equation. To measure ions of different m / z values, the DC and AC voltages may be changed over time to allow ions having different m / z values ​​to be transmitted to the detector of the mass analysis device.

[0017] The mass spectrometry device may further comprise at least one ionization source. As used herein, the term "ionization source", also referred to as "ion source", is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. This term may specifically refer to, but is not limited to, a device configured to generate ions from, for example, neutral gas molecules. The ionization source may be or may comprise 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 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 thermospray (TSP) source, at least one atmospheric pressure chemical ionization (APCI) source, at least one electrospray (ESI) source, and at least one atmospheric pressure ionization (API) source.

[0018] The mass spectrometry device may comprise at least one detector. As used herein, the term "detector" is a broad term and should be given its normal and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to an apparatus configured to detect incoming ions. The detector may be configured to detect charged particles. The detector may be or comprise at least one electron multiplier. The mass spectrometry device, e.g., the detector and / or at least one processing unit of the mass spectrometry device, may be configured to determine at least one mass spectrum of the detected ions. As used herein, the term "mass spectrum" is a broad term and should be given its normal and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to a two-dimensional representation of signal intensity versus charge-to-mass ratio m / z, where the signal intensity corresponds to the abundance of the respective ion. The mass spectrum may be a pixelated image. The signals detected by the detector within a particular m / z range may be integrated to determine the resulting intensity of a pixel of the mass spectrum. Analytes in a sample may be identified by a processing unit, which may be configured to correlate known masses to the identified masses or via characteristic fragmentation patterns.

[0019] The mass spectrometry device may be or comprise a liquid chromatography mass spectrometry device. The mass spectrometry device may be connected to and / or comprise at least one liquid chromatograph. The liquid chromatograph may be used as sample preparation for the mass spectrometry device. Other embodiments of sample preparation may be possible, such as at least one gas chromatograph. As used herein, the term "liquid chromatography mass spectrometry device" is a broad term and should be given its ordinary and customary meaning to those skilled 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 combination of liquid chromatography and mass spectrometry. The mass spectrometry device may comprise at least one liquid chromatograph. The liquid chromatography mass spectrometry device may be or comprise at least one high performance liquid chromatography (HPLC) device or at least one micro liquid chromatography (μLC) device. The liquid chromatography mass spectrometry device may comprise a liquid chromatography (LC) device and a mass spectrometry (MS) device, in this case a mass filter, where 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 comprise an ionization source configured to generate molecular ions and transfer the molecular ions to a gas phase. The interface may further comprise 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.

[0020] As used herein, the term "liquid chromatography (LC) device" is a broad term and should be given its ordinary and customary meaning to those skilled 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, an analytical module configured to separate one or more analytes of interest of a sample from other components of the sample for detection of the one or more analytes using a mass spectrometry device. The LC device may comprise at least one LC column. For example, the LC device may be a single-column LC device or a multi-column LC device having multiple LC columns. The LC column may have a stationary phase through which a mobile phase is pumped to separate and / or elute and / or transfer the analytes of interest. The liquid chromatography mass spectrometry device may further comprise a sample preparation station for automated pre-treatment and preparation of samples, each of which includes at least one analyte of interest.

[0021] As used herein, the term "analyte" relates to any compound or group of compounds to be determined in a sample. The analyte detected by the mass spectrometry device may be part of a sample, e.g., a solid, liquid, or gas sample, to be tested, e.g., measured, using the mass spectrometry device. As a result of the measurement process, the mass spectrometry device may detect the presence and / or abundance and / or concentration of one or more analytes, e.g., multiple analytes, in the sample. The analyte may itself 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 of the sample components may be fragmented during the measurement process, e.g., during an ionization procedure, such that a single sample component may generate multiple different fragments, e.g., charged fragments, that may be at least partially detected as an analyte by the mass spectrometry device.

[0022] For example, the test substance may be a macromolecule, i.e., a compound having a molecular weight of more than 1000u (i.e., more than 1kDa). For example, the test substance may be a biological macromolecule, e.g., a polypeptide, a polynucleotide, a polysaccharide, or a fragment of any of the above. For example, the test substance may be a small molecule compound, i.e., a compound having a molecular weight of up to 1000u (1kDa). For example, the test substance may be a compound that is metabolized by the body of a subject, e.g., a human subject, or a compound that is administered to a subject to induce a change in the subject's metabolism. Thus, for example, the test substance may be a drug of abuse or a metabolite thereof, such as amphetamine, cocaine, methadone, ethyl glucuronide, ethyl sulfate, an opiate, 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.

[0023] For example, the test substance may be a therapeutic agent, 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 meperidine, normeperidine, tramadol, and / or O-desmethyl-tramadol, antibiotics, and / or linezolid; antiepileptic drugs such as phenytoin, valproic acid, free phenytoin, free valproic acid, levetiracetam, carbamazepine, carbamazepine-10,11-epoxide, phenobarbital, primidone, gabapentin, zonisamide, lamotrigine, and / or topiramate. For example, the test substance 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 test substance can be cortisol, DHEA-S, estradiol, progesterone, testosterone, 17-hydroxyprogesterone, aldosterone, dehydroepiandrosterone sulfate (DHEA-S), dihydrotestosterone, and / or cortisone. The test substance may be estradiol, progesterone, testosterone, 17-hydroxyprogesterone, androstenedione, and / or cortisone, e.g., the sample may be a saliva sample and the test substance may be cortisol, estradiol, progesterone, testosterone, 17-hydroxyprogesterone, androstenedione, and / or cortisone, e.g., the sample may be a urine sample and the test substance may be cortisol, aldosterone, and / or cortisone.For example, the test substance may be a vitamin, such as vitamin D, e.g., ergocalciferol (vitamin D2) and / or cholecalciferol (vitamin D3), or derivatives 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 test substance may be a metabolic product of the subject.

[0024] The in vitro diagnostic medical device may comprise at least one hardware part. The in vitro diagnostic medical device may comprise multiple hardware parts. The term "hardware part" is a broad term and should be given its ordinary and customary meaning to those skilled 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 physical and / or tangible part of an in vitro diagnostic medical device. A hardware part may be configured to interact with another component, for example, to perform at least one common function of the in vitro diagnostic medical device. The hardware parts may be processed independently or may be coupled, connectable, or integrable with each other. For example, the hardware part may be or include an instrument or component that forms part of an in vitro diagnostic medical device, such as a mass spectrometry device, for example, one or more of a sample preparation unit of a mass spectrometry device, an ionization unit of a mass spectrometry device, a mass analysis unit of a mass spectrometry device, and a detection unit of a mass spectrometry device. The hardware part may have a particular configuration or setting that may be 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 potential variability in hardware components, calibration of the hardware components may be required.

[0025] As used herein, the term "sample", also referred to as "test sample", relates to any type of composition of matter, and thus the term may refer to any sample, such as, but not limited to, a biological sample and / or an internal standard sample. For example, the sample may be a liquid sample, such as an aqueous sample. For example, the test sample may be selected from the group consisting of physiological fluids, including whole blood, serum, plasma, saliva, ocular lens fluid, tears, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, and amniotic fluid, lavage fluids, tissues, cells, and the like. However, the sample may also be a natural or industrial liquid, such as surface or ground water, sewage, industrial wastewater, process fluids, soil leachates, and the like. For example, the sample may contain or be suspected to contain at least one compound of interest, i.e., the chemical to be determined, referred to as the "analyte". The sample may contain one or more additional compounds that are not the compound to be determined, which are generally referred to as matrices as described herein above. The samples may be used directly as obtained from their respective origin or may be subjected to one or more pretreatment and / or sample preparation steps. Thus, the samples may be pretreated by physical and / or chemical methods, such as centrifugation, filtration, mixing, homogenization, chromatography, precipitation, dilution, concentration, contact with binding agents and / or detection reagents, and / or any other method deemed appropriate by the skilled artisan.

[0026] One or more internal standards may be added to the sample during the sample preparation step, i.e. before, during, and / or after the sample preparation step. The sample may be spiked with an internal standard. For example, an internal standard may be added to the sample at a predetermined concentration. The internal standard may be selected to be easily identifiable under normal operating conditions of a selected detector, such as a photometric cell in a mass spectrometry device, such as a UV-Vis spectroscopy device, an evaporative light scattering refractometer, a conductivity meter, or any device that a person skilled in the art considers appropriate. The concentration of the internal standard may be predetermined and may be significantly higher than the concentration of the analyte. For example, the analyte of interest may generally be vitamin D, drugs of abuse, therapeutic agents, hormones, and metabolites. The internal standard sample may be a sample that includes at least one internal standard with a known concentration. For further details regarding the sample, see, for example, EP 3425369 A1, the entire disclosure of which is incorporated herein by reference. Other analytes of interest are also possible.

[0027] The method comprises a series of calibration and adjustment steps, the result of each of which depends on the result of the previous step, which may make it possible to establish metrological traceability of an in-vitro diagnostic medical device.

[0028] The method includes providing a preliminary calibration curve. p describes 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 being measured using the in vitro diagnostic medical device. p is a parameter

number

number

number

[0029] At each adjustment step, a signal adjustment function g is determined that describes the relationship between the measured signal values ​​and the theoretical signal values. r (

number

[0030] Each adjustment step includes assigning at least one target concentration value from the measured signal values ​​of at least one second calibrator sample, the assigning comprising applying a signal adjustment function determined in a previous adjustment step or an inverse of the signal adjustment function determined in a previous adjustment step to the measured signal values ​​of the second calibrator sample to generate an inverse prior calibration curve.

number

[0031] The method steps and / or sub-steps of the method steps, e.g., the above-mentioned operations included in each of the method steps, may be performed, for example, in a given order. However, different orders are possible. The method may further include additional method steps not listed. Moreover, one or more or even all of the method steps and / or sub-steps may be performed only once or repeatedly.

[0032] As outlined above, the method according to the invention uses a sequence of calibration and adjustment steps such that a stabilization of the metrological traceability of an in-vitro diagnostic medical device is possible. In particular, the method according to the invention solves the problem of transferring trueness from a higher order standard, e.g. a reference measurement procedure or a reference substance, to the analytical application. Known processes are described in ISO17511:2020, in which in each step a specific measurement procedure and a specific substance are used, the target values ​​of which were assigned in the previous step. However, in the known processes of ISO17511:2020, multiple separate and independent calibration steps are used. This means that the variability of each step contributes entirely to the overall variability of the entire process. The invention proposes a different approach for establishing a traceability chain, i.e. using a sequence 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 as follows: A leading calibration curve is used (leading calibration curve f p describes the relationship between the concentration c of the analyte in the sample and the signal s of the sample measured with the IVD device), said prior calibration curves being kept unchanged during the entire chain of the process. Instead of having a different calibration (and therefore a different calibration curve) for each step of the chain, an adjustment step is proposed in which a signal adjustment function is determined that describes the relationship between the measured signal values ​​and the theoretical signal values. Each adjustment step may comprise the following two steps, e.g. sub-steps: - determining a signal adjustment function using the measured signal values ​​of the first calibrator sample and using theoretical signal values ​​of the first calibrator sample derived from a prior calibration curve, the theoretical signal values ​​being determined by applying the prior calibration curve using pre-assigned target concentration values ​​ci of the first calibrator sample. - assigning a target concentration value from the measured signal values ​​of the second calibrator sample, which can be used in a subsequent step. This can be done using the determined signal adjustment function (or inverse function), which is applied to the measured signal values ​​of the second calibrator sample to determine the theoretical signal values ​​of the second calibrator sample. An inverse prior calibration curve can then be applied to the determined theoretical signal values ​​of the second calibrator sample to determine the target concentration value.

[0033] These two adjustment (sub)steps, i.e., determination of the signal adjustment function and assignment of target values ​​of calibrators to be used as "preassigned target concentration values" in the subsequent adjustment steps, can be performed for each process in the chain, thus achieving traceability.

[0034] The term "calibration step" is a broad term and should be given its ordinary and customary meaning to those skilled 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, any process of determining a relationship between a measurement signal generated by an in-vitro diagnostic medical device, for example, upon sample testing, and a corresponding analyte concentration value of the sample. The method may include multiple calibration steps. Each of the calibration steps may include one or several steps that may be performed repeatedly, for example, or may be supplemented by further steps, such as to enhance or improve the calibration. For example, the calibration step may include providing a preliminary calibration curve, for example, a relationship between a measurement signal generated by an in-vitro diagnostic medical device and a corresponding analyte concentration value of the sample.

[0035] The term "adjustment step" is a broad term and should be given its ordinary and customary meaning to those skilled 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 process of determining a signal adjustment function. The method may include multiple adjustment steps. Each of the adjustment steps may include one or several steps that may be performed repeatedly or may be supplemented by further steps, such as to enhance or improve the adjustment. For example, an 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.

[0036] The sequence of calibration and adjustment steps may include at least one calibration step, in which, for example, a preliminary calibration curve is provided, and at least one adjustment step, in which, for example, a signal adjustment function is determined and a target concentration value is assigned to the calibrator sample. The adjustment step in this sequence may follow the calibration step, since it uses a theoretical signal value of the first calibrator sample derived from the preliminary calibration curve. The sequence may include additional calibration and / or adjustment steps. For example, a second adjustment step, a third adjustment step, and a fourth adjustment step may be subsequently performed.

[0037] The sequence 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 (singular or plural) is used to indicate a step of the standardization procedure. The method may include a hierarchy of calibration and adjustment steps. The sequence of calibration and adjustment steps may include performing method steps from a reference to a final measurement system, the result of each step depending on the result of the previous step. The method may include establishing metrological traceability by ensuring traceability to higher reference system components as required by ISO17511:2020. Metrological traceability may refer to a hierarchy of calibration and adjustment steps and a sequence of value assignments, which may allow an unbroken link between the measurement results of a sample up to the highest available reference system component in the hierarchy.

[0038] Each of the calibration and adjustment steps may include using at least one measurement procedure. The term "measurement procedure" is a broad term and should be given its normal and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically refer to a given measurement method, including, but not limited to, a detailed description of the measurement according to one or more measurement principles and any calculations to obtain a measurement result based on a measurement model. The measurement procedure may be performed on at least one substance, which is specified according to the respective measurement procedure. The measurement procedure used in each calibration step and each adjustment step may be performed as described in ISO17511:2020.

[0039] For example, the sequence of calibration and adjustment steps includes a first calibration and adjustment step using a purpose-built measurement procedure for purity assessment, e.g., quantitative NMR, mass balance, etc. A different measurement procedure, e.g., a measurement procedure based on gas chromatography-mass spectrometry (GC / MS) or liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS), can serve as the primary reference measurement procedure. Other methods are feasible.

[0040] The series of calibration and adjustment steps may further include a second calibration and adjustment step using a primary reference measurement procedure for calibrator preparation, e.g., gravimetric preparation, on at least one certified primary standard material. The primary reference measurement procedure may be or may include a reference measurement procedure used to obtain a measurement result regardless of the measurement standard of the same type of quantity. As used herein, the term "certified reference material (CRM)" is a broad term and should be given its ordinary and customary meaning to those skilled 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 reference material with documentation issued by a trusted institution and providing one or more specified property values ​​with associated uncertainties and traceability using a valid procedure. The primary reference measurement procedure for calibrator preparation and CRM may meet the requirements described in ISO17511:2020 and ISO15194. The target concentration value of the CRM may be assigned by the first calibration and adjustment step.

[0041] The series of calibration and adjustment steps may further include a third calibration and adjustment step using a primary reference measurement procedure for the measurand for at least one primary calibrator. The term "measurand" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, a quantity that is intended to be measured. The term "calibrator" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, a substance 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 CRM in a suitable solvent. The primary reference measurement procedure for the measurand and primary calibrator may meet the requirements described in ISO17511:2020. A target concentration value for the primary calibrator may be assigned by the second calibration and adjustment step.

[0042] The series of calibration and adjustment steps may further include a fourth calibration and adjustment step using a manufacturer-selected measurement procedure for at least one secondary calibrator. The secondary calibrator may be a measurement standard established by calibration against a primary measurement standard of the same type of quantity. The manufacturer-selected measurement procedure and secondary calibrator may meet the requirements described in ISO17511:2020. The secondary calibrator may be at least one of a human sample, a pool of human samples, a sample with a matrix, and a sample corresponding to a human sample. The target concentration value of the secondary calibrator may be assigned by the third calibration and adjustment step. The term "manufacturer" is a broad term and should be given its ordinary and customary meaning to those skilled 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, an entity that has responsibility for the design, manufacture, fabrication, assembly, packaging or labeling of an IVD MD, assembly of a measurement system, or pre-marketing and / or pre-operational conformity of an IVD MD, regardless of whether these operations are performed by the entity or by a third party on its behalf. The manufacturer's selected measurement procedure may include one or more of homogeneous or heterogeneous immunoassays or liquid chromatography combined with tandem mass spectrometry (LC-MS / MS). Other measurement procedures are feasible. The manufacturer's selected measurement procedure may be at least partially automated. The manufacturer's selected measurement procedure may, for example, correspond to or be adapted to the customer's measurement procedure.

[0043] As outlined above, the method includes providing a prior calibration curve. The term "prior calibration curve" as used herein is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to any mathematical function that 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 using a mass spectrometry device. The prior calibration curve may include at least one mathematical operation, such as, for example, multiplication by at least one coefficient or another type of mathematical operation. The prior calibration curve is a parameterized function. The term "parameterized function" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or customized meaning. The term may specifically, but is not limited to, refer to any mathematical function having at least one parameter, a plurality of parameters, such as, for example, a set of at least two parameters. The prior calibration curve f p is a parameter

number

number

number

number

number

number

number

number

number

number

number

number

number

[0044] The term "providing a preliminary calibration curve" is a broad term and should be given its ordinary and customary meaning to those skilled 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, one or more of determining a preliminary calibration curve by at least one of setting and selecting a preliminary calibration curve. For example, the process of setting a preliminary calibration curve may include determining at least one of its forms and / or parameter values, such as by selecting at least one model function and / or by fitting at least one of the parameter values.

number

[0045] A leading calibration curve, in particular an inverse leading calibration curve, can assign a concentration c to the sample tested by the in vitro diagnostic medical device based on at least one theoretical signal value derived from the measured signal value. Additionally or alternatively, a leading calibration curve, for example an inverse leading calibration curve, can assign a concentration c to the sample tested by the 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 leading calibration curve can contribute to assign a concentration c to the sample by assigning a theoretical concentration value to the sample based on the measured signal value of the sample, and the concentration c is assigned to the sample based on the theoretical concentration value in a further step.

[0046] The preliminary calibration curve may be an assay- and / or application-specific function. For example, multiple conditions, such as one or more different instruments, different reagent lots, and different measurement conditions that may be used in the assay or application, may be used for its determination. For example, the preliminary calibration curve may be determined by using multiple conditions, such as one or more of multiple instruments, and / or hardware parts, and / or reagent lots, etc. The provision of the preliminary calibration curve may be part of at least one of the calibration and adjustment steps. The provision of the preliminary calibration curve may be performed in a higher step of the hierarchy, such as one of the first steps of the hierarchy.

[0047] For example, the preliminary calibration curve may be determined by using at least one primary calibrator. At least one target concentration value of the primary calibrator may be established based on a primary reference measurement procedure for calibrator preparation. For example, the preliminary calibration curve is provided by using at least one secondary calibrator. At least one target concentration value of the secondary calibrator may be established based on a primary reference measurement procedure for the measurand. Other examples for providing the preliminary calibration curve at other steps of the hierarchy are also feasible. Additionally or alternatively, the preliminary calibration curve may be provided by retrieving the preliminary calibration curve from at least one database, such as a cloud. Providing the preliminary calibration curve may be performed once or repeatedly.

[0048] As used herein, the term "target concentration value" is a broad term and should be given its common and ordinary meaning to one of ordinary skill in the art and should not be limited to a specific or special meaning. The term may specifically refer to, but is not limited to, assigned concentration values, e.g., concentration values ​​pre-assigned in higher order calibration and adjustment steps.

[0049] As used herein, the term "signal" is a broad term and should be given its common and ordinary meaning to those skilled in the art and should not be limited to a special or special meaning. The term may specifically 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 in response to detection of at least one analyte. The signal may be a measurement signal of the in vitro diagnostic medical device. The signal may be a measurement signal on an in vitro diagnostic medical device and / or hardware component j by iteration l, j

number

[0050] As used herein, the term "concentration" is a broad term and should be given its common and ordinary meaning to those skilled in the art and should not be limited to a special or special meaning. The term may refer to, but is not limited to, a value in which the abundance of a component or constituent in a given volume, such as a sample volume, is set relative to said volume, e.g., divided by the volume. The placeholder "c" may represent concentration. Concentration may be described by different types of quantities, such as mass concentration, molar concentration, or volume concentration. It should be noted that the term concentration may quantify components or constituents present in a volume of a liquid sample as well as in a volume of a solid or gas sample. The concentration of an analyte may be identified and / or quantified by a concentration value.

[0051] The relationship between the measured signal values ​​of a calibrator sample and the target concentration value of said calibrator sample may be insufficiently described, such as not precisely or accurately, by the prior calibration curve. As an example, the concentration value as determined using the prior calibration curve based on the measured signal values ​​of said calibrator sample may differ from the target concentration value of said calibrator sample by more than a predefined threshold. For example, this may result from the fact that the prior calibration curve was determined based on a sample other than said calibrator sample. In the standardization process, the prior calibration curve may nevertheless be kept unchanged, and instead, as a further function, a signal adjustment function may be determined and / or adjusted. Although the standardization process includes several calibration and adjustment steps, the prior calibration curve may be established initially, such as at a higher step in the hierarchy, and may be kept unchanged over two or more subsequent adjustment steps. As an example, possible subsequent adjustments and / or fine-tuning may be taken into account by the signal adjustment function described in more detail below.

[0052] At each adjustment step, the signal adjustment function g r was decided,

number

number

number

number

number

[0053] The functional form of the signal conditioning function may be, for example, one or more of a Rodbart model function, a Pade model function, a quadratic model function, or any other nonlinear or linear function. For example, the Pade model function may be given by:

[0054]

number

number

number

number

[0055]

number

number

number

number

number

[0056] As described above, the signal conditioning function describes the relationship between the measured signal values ​​and the theoretical signal values. The relationship shown can be described only by a function that maps the measured signal values ​​to the theoretical signal values, as well as by a function that maps the theoretical signal values ​​to the measured signal values. Either of these functions can be considered as a signal conditioning function. Depending on the selection when determining the signal conditioning function, either the signal conditioning function or its inverse can be applied to determine the theoretical signal values ​​from the measured signal values. The signal conditioning function or the inverse of the signal conditioning function can be applied to the measured signal values ​​of the second calibrator sample to determine at least one theoretical signal value of the second calibrator sample.

[0057] As used herein, the term "first calibrator sample" is a broad term and should be given its common and ordinary meaning to those skilled in the art and should not be limited to a special or special meaning. The term may specifically refer to, but is not limited to, a calibrator having a pre-assigned target concentration value. The first calibrator sample may include at least one set of calibrator samples including a plurality of calibrator samples. The target concentration value of the first calibrator sample may be assigned by a higher step in the hierarchy. For example, the target concentration value may be pre-assigned in a previous adjustment step. Different subsequent adjustment steps may use different first calibrator samples.

[0058] The first calibrator sample may be measured using an in vitro diagnostic medical device, such as a mass spectrometry device, to determine a measured signal value of the first calibrator sample. The signal adjustment function may be based on a theoretical signal of a prior calibration curve.

number

number

number

number

number

number

[0059] As used herein, the term "theoretical signal value" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a specific or special meaning. The term may specifically refer to, but is not limited to, a signal value calculated from a given center value. The theoretical signal value of the first calibrator sample is calculated by multiplying the preassigned target concentration value c of the first calibrator sample by the preassigned target concentration value c of the first calibrator sample. i can be determined by applying a priori calibration curves to

[0060] Upon measuring the signal value of the first calibrator sample and determining the theoretical signal value of the first calibrator sample, a signal conditioning function may be determined.

[0061] Each adjustment step includes assigning at least one target concentration value from the measured signal values ​​of at least one second calibrator sample. The method may include assigning a target concentration value of the second calibrator sample for use in subsequent calibration and adjustment steps. As used herein, the term "second calibrator sample" is a broad term and should be given its common and ordinary meaning to one of ordinary skill in the art and should not be limited to a special or special 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 a signal value of at least one second calibrator sample. The second calibrator may have an unknown target concentration value. The signal value of the second calibrator sample may be measured with each individual hardware component. A theoretical signal value may be assigned by applying an inverse signal adjustment function to the measured signal values. The theoretical signal value is inversely related to the theoretical signal value of the second calibrator sample.

number

number

number

number

number

number

number

number

[0062] The target concentration value of the second calibrator sample may be assigned as at least one average value from the plurality of target concentration values, the average value being one or more of an arithmetic mean, a median, or a weighted arithmetic mean value of the plurality of target concentration values. The plurality of target concentration values ​​may result, for example, from at least one iteration of the adjustment steps. The weights of the weighted arithmetic mean value may be given, for example, by the inverse of the variation of the iterations performed on a particular instrument and / or hardware part.

[0063] The signal conditioning function may connect the measured signal value of the first calibrator sample with a theoretical signal of the first calibrator sample derived from the preassigned target concentration and the prior calibration function. The assignment of the target concentration value of the second calibrator sample may be determined by applying the signal conditioning function.

[0064] The measured signal values ​​of the second calibrator sample can be used to assign a target concentration value to the second calibrator sample. Such an assignment may be performed using a signal adjustment function (or its inverse) and a prior calibration function, as described in detail above. In other words, the method according to the invention proposes to adjust the measured signal values ​​to theoretical signal values, which can be converted to target concentration values ​​using a prior calibration curve.

[0065] The standardization process may include multiple adjustment steps, such that more than one signal conditioning function, e.g., two or even more signal conditioning functions, may be determined during the standardization step, and / or previously determined signal conditioning functions may be adjusted during the standardization step. During the standardization process, the signal conditioning functions may be fine-tuned or adjusted for specific conditions. As an example, a first signal conditioning function may be supplemented and / or replaced by a second signal conditioning function, etc.

[0066] The method includes multiple calibration and adjustment steps 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, assigning target values ​​to a pilot calibrator, adjusting the pilot calibration curve with the pilot calibrator, and assigning target values ​​to a product calibrator. These steps may be performed at the manufacturer's site.

[0067] As outlined above, the step of providing a preliminary calibration curve may be embodied as including the establishment of a preliminary calibration curve, for example, this step may be performed as one of the initial steps of the standardization process.

[0068] The step of setting the preliminary calibration curve may include determining a functional form of the preliminary calibration curve.

number

number

[0069] For example, the method may include at least one step of establishing a preliminary calibration curve, which includes measuring signal values ​​of a set of primary calibrators using an in vitro diagnostic medical device.

number

number

number

number

number

number

number

[0070] For example, the method may include at least one step of establishing a preliminary calibration curve, which includes measuring signal values ​​of a set of secondary calibrators using an in vitro diagnostic medical device.

number

number

number

number

number

number

number

[0071] Following providing a leading calibration curve, for example by setting a leading calibration curve using a primary or secondary calibrator or by deriving a leading calibration curve, the method may further include at least one step of adjusting the leading calibration curve, including determining a first signal conditioning function. For example, as outlined above, providing a leading calibration curve may include using a primary calibrator. The method may further include determining a leading calibration curve for each of secondary calibrators i=1,...,I(I

number

number

number

number

number

number

number

[0072] The step of adjusting the prior calibration curve may include, for example, determining a first signal conditioning function while keeping the prior calibration curve unchanged.

[0073] The pre-assigned target concentration values ​​of the secondary calibrators may be determined in a higher order calibration and / or adjustment step, for example involving a primary reference measurement procedure for the measurand.

[0074] In a subsequent calibration and adjustment step, the two functions, the prior calibration function and the first signal adjustment function, can be used together to assign at least one target concentration value to a sample, such as a prior calibrator. The target concentration value can be assigned to the sample based on the prior calibration curve and the 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 theoretical signal values ​​and the inverse of the prior calibration curve for the theoretical signal values.

[0075] The method may include at least one step of target value assignment of the preliminary calibrator. As used herein, the term "preliminary calibrator" is a broad term and should be given its common and ordinary meaning to those skilled in the art and should not be limited to a special or special meaning. The term may specifically refer to, but is not limited to, a measurement standard used to calibrate or verify a measurement instrument or measurement system. The preliminary calibrator may be a sample, which does not necessarily have to be as close to the human sample matrix as the primary and secondary calibrators. The preliminary calibrator may correspond to the sample indicated as the manufacturer's working calibrator in the standard ISO17511:2020.

[0076] As an example, the step of target value assignment of the leading calibrator may be performed for the first time, immediately after the step of setting the leading calibration curve. In this case, the signal adjustment function may not yet be determined and therefore may not be available. The target concentration value may be assigned to the leading calibrator using only the leading calibration curve, for example by applying the inverse function of the leading calibration curve to the measured signal value of the leading calibrator. Alternatively, the step of target value assignment of the leading calibrator may be performed in multiple step iterations, so that the step of adjustment of the leading calibration curve, which follows the step of target value assignment of the leading calibrator in the hierarchy of calibration and adjustment steps, has already been performed. For the iteration of the step of target value assignment of the leading calibrator, the signal adjustment function may be available. In this case, the step of target value assignment of the leading calibrator may be performed using both the leading calibration curve and the signal adjustment function.

[0077] For example, the step of assigning a target value of the lead calibrator may include assigning at least one target concentration value of the at least one lead calibrator.

number

number

number

number

number

number

number

number

number

number

number

[0078] The target concentration value of the leading calibrator may be assigned, for example, as at least one average value from a plurality of target concentration values, the average value being one or more of an arithmetic mean, a median, or a weighted arithmetic mean value of the plurality of target concentration values.

[0079] The method may further include checking whether the assignment of the target concentration value of the leading calibrator is successful. The method may further include measuring a signal value of the independent control sample using an in vitro diagnostic medical device, such as a mass spectrometry device. To check whether the assignment of the target concentration value of the leading calibrator is successful, the method may include converting the measured signal value of the independent control sample to a concentration value by applying a signal adjustment function g1 and a leading calibration curve, and comparing the concentration value to a predetermined target concentration value of the independent control sample. The independent control sample may be adjusted to a target value established by a higher order method.

number

number

[0080] The method may include at least one step of adjusting the prior calibration curve using at least one prior calibrator k. The step of adjusting the prior calibration curve may include adjusting a second signal adjustment function k by:

number

number

number

number

number

number

number

number

number

[0081] The manufacturer's in-house standard measurement procedure may, for example, include at least one of homogeneous immunoassay, heterogeneous immunoassay and liquid chromatography combined with tandem mass spectrometry (LC-MS / MS). Other measurement procedures are feasible. The manufacturer's in-house standard measurement procedure may be at least partially automated. The manufacturer's in-house standard measurement procedure may, for example, correspond to or be adapted to the customer's measurement procedure.

[0082] The step of adjusting the prior calibration curve by the prior calibrator may, for example, comprise determining a signal adjustment function g2 using the measured signal values ​​of the prior calibrator while keeping the prior calibration curve itself unchanged. In the following, as will be explained in more detail below, the two functions, namely the prior calibration function and the second signal adjustment function, may be used together to assign at least one target concentration value of at least one further second calibrator sample, e.g. a product calibrator.

[0083] The method may further comprise at least one step of target value assignment of a product calibrator. The product calibrator may correspond to a sample indicated in the standard ISO17511:2020 as an end-user in-vitro diagnostic medical device calibrator. The step of target value assignment of the product calibrator comprises assigning at least one target concentration value of the at least one product calibrator.

number

number

number

number

number

number

number

number

number

[0036] Further comprising converting the

number

number

[0084] The target concentration value of the product calibrator may be assigned, for example, as at least one average value from a plurality of target concentration values, the average value being one or more of an arithmetic mean, a median, or a weighted arithmetic mean of the plurality of target concentration values.

[0085] The method may further include checking whether the target concentration value of the product calibrator was successfully assigned. The method may further include measuring a signal value of the independent control sample using an in vitro diagnostic medical device, such as a mass spectrometry device, and converting the measured signal value of the independent control sample into a concentration value by applying a signal adjustment function g2 and a priori calibration curve. The method may further include comparing the concentration value with a preassigned target concentration value of the independent control sample. The target concentration value

number

[0086] The method may further include performing at least one customer calibration step. For example, the method may include determining the accepted target concentration values.

number

[0087] In a further aspect of the invention, a method for establishing metrological traceability of at least one in-vitro diagnostic medical device is disclosed. The method comprises a series of calibration and adjustment steps, the result of each step being dependent on the result of the previous step. The method comprises providing a preliminary calibration curve, f p describes 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 using an in vitro diagnostic medical device, and a priori calibration curve f p is a parameter

number

number

number

number

number

number

number

number

[0088] With regard to the definitions and embodiments of the methods described in the further aspects, reference is made to the definitions and embodiments of the methods described in the first aspect of the invention.

[0089] As used herein, the term "concentration adjustment function" is a broad term and should be given its ordinary and customary meaning to those skilled in the art and should not be limited to a special or special meaning. The term may specifically 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 a 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 Rodbart model function, a Pade model function, a quadratic model function, or any other nonlinear or linear function. For example, the Pade model function may be given by:

number

number

number

number

number

number

number

number

number

[0090] The concentration adjustment function connects a pre-assigned target concentration of the first calibrator sample with a theoretical concentration of the measurement signal of the first calibrator sample, and the assignment of the target concentration value of the second calibrator sample can be determined by applying the concentration adjustment function.

[0091] In a further aspect of the present invention, a processing device is disclosed, the processing device comprising: p The processing device is configured to retrieve and / or store the preliminary calibration curve f p Parameters

number

number

[0092] The preliminary calibration curve is predetermined at the manufacturer's side by using one or both of the methods according to the invention, for example according to any one of the embodiments described above and / or according to any one of the embodiments described in more detail below. For possible details and options of the method, as well as terms and definitions, reference may therefore be made to the description of the method for establishing metrological traceability of at least one in-vitro diagnostic medical device, as given above or further below.

[0093] As used herein, the term "processing device" is a broad term and should be given its normal and customary meaning to those skilled in the art, and should not be limited to a special or customized meaning. This term may specifically refer to a device or combination of devices configured to control at least one function of at least one other device, such as, but not limited to, at least one other component of an in vitro diagnostic medical device, for example, a mass spectrometry device. The processing device may, for example, comprise at least one processor and / or at least one data storage device. Thus, by way of example, the at least one processing device may comprise at least one data processing device on which software code including some computer commands is stored. The processing device may be an element of the in vitro diagnostic medical device or a further device, for example, a remote device.

[0094] The processing device may be further configured to perform at least one customer-side calibration step for the IVD medical device using at least one set of product calibrators to adjust the signal conditioning function. The customer-side calibration step may include: - the signal value of at least one product calibrator k using a customer-side measurement procedure for an IVD medical device;

number

number

number

number

number

number

[0095] The processing device performs at least one customer-side calibration step for the IVD medical device using at least one set of product calibrators to obtain a concentration adjustment function h s The customer side calibration step may further include: - the signal value of at least one product calibrator k using a customer-side measurement procedure for an IVD medical device;

number

number

number

number

number

number

number

[0096] In a further aspect of the present invention, a kit is disclosed comprising an in vitro diagnostic medical device, such as a mass spectrometry device, and a set of product calibrators. The target concentration values ​​of the product calibrators are determined using one or both of the methods according to the present invention. For possible details regarding the kit as well as terms and definitions, reference may be made to the description of the method further provided above or below.

[0097] For example, the following information may be provided in the kit: -Function form and parameters of the preliminary calibration curve f

number

number

[0098] This information may allow for calibration of the in vitro diagnostic medical device at the customer site, with which the individual instrument can be recalibrated and a sample read can be performed, for example as described in WO 2021 / 122739.

[0099] In a further aspect of the present invention, a computer program is disclosed, the computer program being adapted to perform the method according to any one of the above embodiments and / or any one of the embodiments described in more detail below while the program is running 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 a computer readable storage medium.

[0100] As used herein, the terms "computer-readable data carrier" and "computer-readable storage medium" may specifically refer to non-transitory data storage means such as a hardware storage medium having computer-executable instructions stored thereon. A computer-readable data carrier or storage medium may specifically be or include a storage medium such as a random access memory (RAM) and / or a read-only memory (ROM).

[0101] Thus, in particular one, more than one or even all of the method steps as described above, in particular the calibration and / or preparation steps, may be carried out using a computer or a computer network, preferably using a computer program.

[0102] In a further aspect of the present invention, a computer program product is disclosed having program code means which may be stored on or are stored on a storage medium for performing a method according to any one of the above embodiments and / or any one of the embodiments described in more detail below when the program code means is executed on a computer or a computer network. In particular, the program code means may be stored on a computer readable data carrier and / or a computer readable storage medium.

[0103] As used herein, a computer program product refers to a program as a tradeable product. The product may generally exist in any format, such as a paper format, or may exist 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.

[0104] Further disclosed and proposed herein is a data carrier storing a data structure which, after being loaded into a computer or computer network, such as a working memory or main memory of a computer or computer network, is capable of performing the methods according to one or more of the embodiments disclosed herein.

[0105] Further disclosed and suggested herein is a non-transitory computer-readable medium having instructions that, 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.

[0106] Finally, a modulated data signal containing instructions readable by a computer system or computer network for carrying out a method according to one or more of the embodiments disclosed herein is disclosed and proposed herein.

[0107] With respect to computer-implemented aspects of the present invention, one or more or all of the method steps of the method according to one or more of the embodiments disclosed herein may be implemented by using a computer or a computer network. Thus, in general, any of the method steps including providing and / or manipulating data may be implemented by using a computer or a computer network. In general, these method steps may include any method steps, except for those that typically require manual work, such as providing a sample and / or performing a specific aspect of the actual measurement. In particular, the steps of providing a preliminary calibration curve, determining a signal conditioning function, and / or assigning at least one target concentration value may be implemented using a computer or a computer network.

[0108] In summary, without excluding further embodiments, the following embodiments can be envisaged:

[0109] Embodiment 1: A method for establishing metrological traceability of at least one in-vitro diagnostic medical device (110), the method comprising a series of calibration and adjustment steps, the result of each step being dependent on the result of the previous step, The method includes providing a preliminary calibration curve, p describes 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 in an in vitro diagnostic medical device, and a priori calibration curve f p is a parameter

number

number

number

number

number

[0110] Embodiment 2: The method of embodiment 1, wherein the series of calibration and adjustment steps includes a first calibration and adjustment step using a fit-for-purpose measurement procedure for purity assessment, the series of calibration and adjustment steps further includes a second calibration and adjustment step using a primary reference measurement procedure for calibrator preparation for at least one certified primary reference material, the series of calibration and adjustment steps further includes a third calibration and adjustment step using a primary reference measurement procedure for the measurand for the at least one primary calibrator, and a fourth calibration and adjustment step using a manufacturer selected measurement procedure for the at least one secondary calibrator.

[0111] Embodiment 3: The method of embodiment 2, wherein the preliminary calibration curve is determined by using at least one primary calibrator, and at least one target concentration value of the primary calibrator is established based on a primary standard measurement procedure for calibrator preparation.

[0112] Embodiment 4: The method of embodiment 2 or 3, wherein the preliminary calibration curve is determined by using at least one secondary calibrator, and at least one target concentration value of the secondary calibrator is established based on a primary reference measurement procedure for the measurand.

[0113] Embodiment 5: The method of any one of embodiments 1 to 4, wherein the preliminary calibration curve is determined by using multiple conditions, such as one or more of multiple instruments, and / or hardware parts, and / or reagent lots, etc.

[0114] Embodiment 6: The method of any one of claims 1 to 5, wherein the preliminary calibration curve does not change over two or more adjustment steps.

[0115] Embodiment 7: The functional form of the preliminary calibration curve is the fitted parameter value

number

[0116] Embodiment 8: The signal conditioning function is the function

number

number

number

number

number

number

number

number

number

number

[0117] Embodiment 9: The assignment of target concentration values ​​is performed by measuring a second calibrator sample k (

number

number

number

number

number

number

[0118] Embodiment 10: The signal conditioning function is a function

number

number

number

number

[0119] Embodiment 11: The functional form of the signal conditioning function is the fitted parameter value

number

[0120] Embodiment 12: The method according to any one of embodiments 1 to 11, wherein the pre-assigned target concentration value is pre-assigned in a previous adjustment step.

[0121] Embodiment 13: The method of any one of embodiments 1 to 12, wherein the target concentration value of the second calibrator sample is assigned as an average value from at least one of a plurality of target concentration values, and the average value is one or more of an arithmetic mean, a median, or a weighted arithmetic mean value of the plurality of target concentration values.

[0122] Embodiment 14: The method according to any one of embodiments 1 to 13, wherein the in vitro diagnostic medical device is a mass spectrometry device (111).

[0123] Embodiment 15: The method of any one of claims 1 to 14, wherein the method includes one or more of the following steps: setting an advance calibration curve, adjusting the advance calibration curve, assigning a target value to the advance calibrator, adjusting the advance calibration curve by the advance calibrator, and assigning a target value to the product calibrator, and the above steps are performed at the manufacturer's side.

[0124] Embodiment 16: The method comprises at least one step of establishing a preliminary calibration curve, the step comprising: A primary reference measurement procedure is used to measure signal values ​​of a reference sample using an in vitro diagnostic medical device, such as a mass spectrometry device.

number

number

number

number

number

number

number

[0125] Embodiment 17: The method includes:

number

number

number

number

number

number

number

[0126] Embodiment 18: The method includes at least one step of assigning a target value for a preliminary calibrator, the step comprising: at least one target concentration value for at least one leading calibrator;

number

number

number

number

number

number

number

number

number

number

number

[0127] Embodiment 19: A method includes measuring a signal value of an independent control sample using an in vitro diagnostic medical device such as a mass spectrometry device, converting the measured signal value of the independent control sample to a concentration value by applying a signal adjustment function g1 and a priori calibration curve, and comparing the concentration value with a pre-assigned target concentration value of the independent control sample,

number

[0128]

[0046] Embodiment 20: The method includes at least one step of adjusting an advance calibration curve using at least one advance calibrator k, the step of adjusting the advance calibration curve being based on a second signal adjustment function

number

number

number

number

number

number

number

number

number

[0129] Embodiment 21: A method includes at least one step of assigning a target value for a product calibrator, the step comprising: At least one target concentration value for at least one product calibrator k

number

number

number

number

number

number

number

number

number

number

number

[0130] Embodiment 22: A method includes measuring a signal value of an independent control sample using an in vitro diagnostic medical device such as a mass spectrometry device, converting the measured signal value of the independent control sample to a concentration value by applying a signal conditioning function g2 and a priori calibration curve, and comparing the concentration value with a pre-assigned target concentration value of the independent control sample,

number

[0131] Embodiment 23: The method of any one of embodiments 1 to 22, further comprising performing at least one customer-side calibration step.

[0132] Embodiment 24: A method for establishing metrological traceability of at least one in-vitro diagnostic medical device (110), the method comprising a series of calibration and adjustment steps, the result of each step being dependent on the result of the previous step, The method includes providing a preliminary calibration curve, p describes 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 in the in vitro diagnostic medical device (110), and a priori calibration curve f p is a parameter

number

number

number

number

number

number

number

number

[0133] Embodiment 25: The method of embodiment 24, wherein a concentration adjustment function connects a pre-assigned target concentration value of the first calibrator sample with a theoretical concentration value of the measurement signal of the first calibrator sample, and the assignment of the target concentration value of the second calibrator sample is determined by applying the concentration adjustment function.

[0134] Embodiment 26: A processing device (112), comprising: a processing device (112) for determining at least one predetermined preliminary calibration curve f p and the processing device is configured to retrieve and / or store a preliminary calibration curve f p Parameters

number

number

[0135] Embodiment 27: The processing device (112) according to embodiment 26, wherein the processing device (112) is an element of an in vitro diagnostic medical device (110) or a further device.

[0136] Embodiment 28: A kit comprising an in-vitro diagnostic medical device (110), a set of product calibrators and their target concentration values, wherein the target concentration values ​​of the product calibrators are assigned by using the method according to any one of embodiments 1 to 23 or 24 to 25.

[0137] Embodiment 29: A computer program adapted to carry out the method according to any one of embodiments 1 to 23 or 24 to 25, when said computer program is run on a computer.

[0138] Embodiment 30: A computer program product having program code means, which may be stored in or is stored in a storage medium for performing a method according to any one of embodiments 1 to 23 or 24 to 25 when the program code means is executed on a computer or a computer network. [Brief description of the drawings]

[0139] Further optional features and embodiments are disclosed in more detail in the following description of the embodiments, preferably in conjunction with the dependent claims. Therein, each optional feature may be realized in an independent manner as well as in any possible combination, as understood by a person skilled in the art. The scope of the present invention is not limited by the preferred embodiments. The embodiments are illustrated diagrammatically in the figures, where the same reference signs in these figures refer to the same or functionally equivalent elements. [Figure 1] Schematic representation of a processing device as an element of an in vitro diagnostic medical device. [Diagram 2] 1 is a flow chart of an exemplary embodiment of a method for establishing metrological traceability of at least one in-vitro diagnostic medical device. [Figure 3A] Illustrative preliminary calibration curves for each test substance (3A) and adjustment of the preliminary calibration curves (3B). [Figure 3B] Illustrative preliminary calibration curves for each test substance (3A) and adjustment of the preliminary calibration curves (3B). [Figure 4] 1 is a flow chart outlining two methods for establishing metrological traceability of at least one in vitro diagnostic medical device. [Diagram 5] 3 shows an exemplary embodiment of the method according to the invention; [Figure 6A] 3 shows an exemplary embodiment of the method according to the invention; [Figure 6B] 3 shows an exemplary embodiment of the method according to the invention; [Figure 6C] 3 shows an exemplary embodiment of the method according to the invention; [Figure 6D] 3 shows an exemplary embodiment of the method according to the invention; [Figure 7] 3 shows an exemplary embodiment of the method according to the invention; [Figure 8A] 3 shows an exemplary embodiment of the method according to the invention; [Figure 8B] 3 shows an exemplary embodiment of the method according to the invention; [Figure 8C] 3 shows an exemplary embodiment of the method according to the invention; [Figure 8D] 3 shows an exemplary embodiment of the method according to the invention; [Figure 9A] 3 shows an exemplary embodiment of the method according to the invention; [Figure 9B] 3 shows an exemplary embodiment of the method according to the invention; [Figure 9C] 3 shows an exemplary embodiment of the method according to the invention; [Figure 9D] 3 shows an exemplary embodiment of the method according to the invention; [Figure 10A] 3 shows an exemplary embodiment of the method according to the invention; [Figure 10B] 3 shows an exemplary embodiment of the method according to the invention; [Figure 10C] 3 shows an exemplary embodiment of the method according to the invention; [Figure 10D] 3 shows an exemplary embodiment of the method according to the invention; DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0140] FIG. 1 shows a schematic diagram of a processing device 112 forming part of an in-vitro diagnostic medical device 110. The in-vitro diagnostic medical device 110 may be a medical device configured for in-vitro testing of at least one sample derived from a human body. Additionally or alternatively, the in-vitro diagnostic medical device 110 may be a medical device configured to provide information for diagnostic, monitoring or compatibility purposes. The in-vitro diagnostic medical device 110 may be used alone or in combination with further devices. The in-vitro diagnostic medical device 110 may comprise one or more of at least one reagent, at least one calibrator, at least one control substance, at least one specimen container, software, associated equipment or apparatus or other items. The in-vitro diagnostic medical device 110 shown in FIG. 1 is embodied as a mass spectrometry device 111. Further possibilities are feasible.

[0141] The processing device 112 may be a device or 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, for example one other component of the mass spectrometry device 111, as shown in FIG. 1. The processing device 112 may, for example, comprise at least one processor 118 and / or at least one data storage device 120. The processing device 112 may comprise multiple processors 118 and / or multiple data storage devices 120. The in-vitro diagnostic medical device 110 may comprise a further processor 118 as shown in FIG. 1. The at least one processing device 112 may comprise at least one data processing device in which software code including several computer commands is stored. As shown in FIG. 1, the processing device 112 may be an element of the in-vitro diagnostic medical device 110. Additionally or alternatively, the processing device 112 may be an element of a further device, for example a remote device.

[0142] The processing device 112 calculates at least one predetermined preliminary calibration curve f p , and the preliminary calibration curve f p A set of parameters

number

number

number

number

number

number

number

number

number

number

number

number

number

number

[0143] The preliminary calibration curve can be an assay and / or application specific function.For example, multiple conditions, such as one or more different instruments, different reagent lots and different measurement conditions that can be used in the assay or application, can be used for the determination.The preliminary calibration curve can be provided by using multiple conditions, such as one or more of multiple instruments, reagent lots, etc.

[0144] The processing device 112 is further configured to perform one or both of the methods for establishing metrological traceability of at least one in-vitro diagnostic medical device 110 according to any one of the embodiments disclosed herein. Examples and / or details of the methods for establishing metrological traceability of at least one in-vitro diagnostic medical device 110 are further discussed below, for example with respect to Figures 2, 3A, 3B and 4. The predetermined prior calibration curves that may be stored by the processing device 112 are those previously determined at the manufacturer's side by using one or both of the methods according to the present invention.

[0145] The mass analysis device 111 may be a mass analyzer configured to detect at least one analyte in at least one sample based on the mass-to-charge ratio. The mass spectrometer device 111 may be or may include at least one quadrupole mass analyzer 113 with at least one quadrupole as a mass filter configured to select ions to be injected into the mass filter according to their mass-to-charge ratio m / z. The mass filter may comprise two pairs of electrodes. The electrodes may be rod-shaped, for example cylindrical. In the ideal case, the electrodes may be hyperbolic. The electrodes may be designed identically. The electrodes may be arranged to extend in parallel along a common axis, for example the z-axis. The quadrupole mass analyzer 113 may comprise multiple quadrupoles. For example, the quadrupole mass analyzer 113 may be a triple quadrupole mass analyzer. The quadrupole mass analyzer 113 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 two pairs of electrodes of the mass filter. The power supply circuit may be configured to hold each opposing electrode pair at the same potential. The power supply circuit may be configured to periodically change the sign of the charge of the electrode pairs such that stable trajectories are possible only for ions within a particular mass-to-charge ratio m / z. The trajectories of the ions in the mass filter may be described by the Mathieu differential equation. To measure ions of different m / z values, the DC and AC voltages may be changed over time to allow ions having different m / z values ​​to be transmitted to the detector 114 of the mass analysis device 111, as shown in FIG. 1.

[0146] 1, the mass spectrometry device 111 may further comprise at least one ionization source 115 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 thermospray (TSP) source, at least one atmospheric pressure chemical ionization (APCI) source, at least one electrospray (ESI) source, and at least one atmospheric pressure ionization (API) source.

[0147] The detector 114 of the mass analysing device 111 may be configured to detect incoming ions, such as charged particles. The detector 114 may be or may comprise at least one electron multiplier. The mass analysing device 111, e.g., the detector 114 of the mass analysing device 111, which may also be referred to as a processor 118, and / or at least one processing unit 118, may be configured to determine at least one mass spectrum of the detected ions, e.g., a two-dimensional representation of signal intensity versus charge-to-mass ratio m / z, where the signal intensity corresponds to the abundance of the respective ion. The mass spectrum may be a pixelated image. The signals detected by the detector 114 within a particular m / z range may be integrated to determine the resulting intensity of the pixels of the mass spectrum. The analytes in the sample may be identified by the processing unit 118. The processing unit 118 may be configured to correlate known masses to the identified masses or to correlate via characteristic fragmentation patterns.

[0148] The mass spectrometry device 111 may be or may comprise a liquid chromatography mass spectrometry device. The mass spectrometry device 111 may be connected to and / or comprise at least one liquid chromatograph (not shown) that may be used for sample preparation for the mass spectrometry device 111. Other embodiments of sample preparation may be possible, such as at least one gas chromatograph.

[0149] The sample may be, for example, a solid, liquid, or gas sample. As an example, the sample may be a biological sample, for example a human sample or a pool of human samples. For example, the sample may be a liquid sample, for example an aqueous sample. For example, the test sample may be selected from the group consisting of physiological fluids, including whole blood, serum, plasma, saliva, ocular lens fluid, tears, cerebrospinal fluid, sweat, urine, milk, peritoneal fluid, mucus, synovial fluid, peritoneal fluid, and amniotic fluid, lavage fluids, tissues, cells, etc. However, the sample may also be a natural or industrial liquid, for example surface or ground water, sewage, industrial wastewater, process fluids, soil leachates, etc. The sample may contain one or more additional chemical compounds, which are not determined and are generally referred to as matrices. The sample may be used directly as obtained from the respective source or may be subjected to one or more pretreatment and / or sample preparation steps. Thus, the sample may be pretreated by physical and / or chemical methods, such as centrifugation, filtration, mixing, homogenization, chromatography, precipitation, dilution, concentration, contact with binding agents and / or detection reagents, and / or any other method that the skilled artisan considers appropriate. One or more internal standards may be added to the sample in the sample preparation step, i.e. before, during, and / or after the sample preparation step. The sample may be spiked with an internal standard. For example, the internal standard may be added to the sample at a predetermined concentration. The internal standard may be selected to be easily identifiable under the normal operating conditions of the selected detector, such as, for example, a photometric cell in a mass spectrometry device, such as a UV-Vis spectroscopy device, an evaporative light scattering refractometer, a conductivity meter, or any device that the skilled artisan considers appropriate. The concentration of the internal standard may be predetermined and may be significantly higher than the concentration of the analyte.

[0150] The sample may include one or more analytes of interest. The analytes may be, for example, chemical, biochemical or biological compounds, e.g., molecules or fragments thereof, that are detected by the mass spectrometry device 111 during the measurement of the sample. As a result of the measurement process, the mass spectrometry device can detect the presence and / or abundance and / or concentration of one or more analytes, e.g., multiple analytes, in the sample. The analytes may themselves be sample components. Additionally or alternatively, the analytes may be fragments of components present in the sample. As an example, one or more of the sample components may be fragmented during the measurement process, e.g., during an ionization procedure, such that a single sample component can generate multiple different fragments, e.g., charged fragments, that can be at least partially detected as an analyte by the mass spectrometry device.

[0151] The concentration c of the analyte may be determined as the amount of the analyte present in a given volume set relative to said volume, such as, for example, the sample volume. The concentration may be described, for example, by at least one of mass concentration, molar concentration, and volume concentration. The concentration of the analyte may be specified and / or quantified by a concentration value.

[0152] The in-vitro diagnostic medical device 110, such as the mass spectrometry device 111, may comprise a number of hardware parts 116. The hardware parts 116 may be physical and / or tangible parts of the in-vitro diagnostic medical device 110. The hardware parts 116 may include, for example, an instrument or an instrument component forming a part of the in-vitro diagnostic medical device 110, such as the mass spectrometry device 111. For example, the hardware parts 116 may be part of one or more of the sample preparation unit of the mass spectrometry device 111, the ionization unit of the mass spectrometry device 111, the mass analysis unit of the mass spectrometry device 111, and the detection unit of the mass spectrometry device 111. For example, the hardware parts 116 may be part of at least one of the quadrupole mass analyzer 113, the detector 114, the ionization source 115. Further possibilities are feasible. The hardware parts 116 may have a particular configuration or setting that may be variable or adjustable, for example in an application-specific manner. Additionally or alternatively, the configuration or setting may vary due to manufacturing tolerances. As an example, potential variability in the hardware components 116 may require calibration of the hardware components 116, e.g., calibration including one or more calibration steps, such as forming part of one or both series of calibration and adjustment steps of a method for establishing metrological traceability of at least one in-vitro diagnostic medical device 110.

[0153] In Fig. 2, an exemplary embodiment of a method for establishing metrological traceability of at least one in-vitro diagnostic medical device 110 is shown in a schematic flow chart. The method includes a series of calibration and adjustment steps, the result of each step being dependent on the result of the previous step. The method may further include additional method steps not listed. Furthermore, one or more or even all of the method steps and / or sub-steps may be performed only once or repeatedly, for example to generate at least one average value. As an example, a target concentration value assigned as part of the method may be assigned as at least one average value.

[0154] In the following, a method for establishing metrological traceability of at least one in-vitro diagnostic medical device 110 is described by a specific embodiment shown in Fig. 2. In the described specific embodiment, the in-vitro diagnostic medical device 110 is a mass spectrometry device 111. In general, it is easily understood by those skilled in the art that the method can also be implemented using other in-vitro diagnostic medical devices 110.

[0155] Figure 2 shows the substances, e.g. samples, used in the method in the left hand box. The measurement procedure, e.g. for measuring the sample, is shown in the right hand box.

[0156] FIG. 2 shows an exemplary sequence of calibration and adjustment steps including 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. The method may include a hierarchy of calibration and adjustment steps. The sequence of calibration and adjustment steps may include performing method steps from a reference to a final measurement system, with the result of each step depending on the result of the previous step. The method may include establishing metrological traceability by ensuring traceability to higher reference system components as required by ISO17511:2020. Metrological traceability may refer to a hierarchy of calibration and adjustment steps and a sequence of value assignments, which may allow an unbroken link between the measurement results of a sample up to the highest available reference system component in the hierarchy.

[0157] 2, the series of calibration and adjustment steps may include a first calibration and adjustment step, indicated by reference numeral 122, using a fit-for-purpose measurement procedure for purity assessment, e.g., quantitative NMR, mass balance, etc. ("p.1. Fit-for-purpose measurement procedure for purity assessment"). A target concentration value of at least one certified primary reference material, indicated by reference numeral 126 ("m.1. Certified Primary Reference Material (CRM)") may be assigned by the first calibration and adjustment step, indicated by reference numeral 128.

[0158] The series of calibration and adjustment steps may further include a second calibration and adjustment step using a primary reference measurement procedure for calibrator preparation ("p.2. Primary reference measurement procedure for calibrator preparation"), such as, for example, gravimetric preparation, indicated with reference number 130, for at least one certified primary reference material 126. The primary reference measurement procedure 130 may be or may include a reference measurement procedure used to obtain a measurement result regardless of the measurement standard of the same type of quantity. The CRM 126 may be a reference material with a document issued by a trusted institution and providing one or more specified characteristic values ​​with associated uncertainties and traceability using a valid procedure. The primary reference measurement procedure for calibrator preparation 130 and the CRM 126 may meet the requirements described in ISO17511:2020 and ISO15194.

[0159] The series of calibration and adjustment steps may further include a third calibration and adjustment step using a primary reference measurement procedure for a measurand ("p.3 Primary reference measurement procedure for measurand"), indicated by reference 132, for at least one primary calibrator ("m.2. Primary calibrator prepared as a solution of m.1 in a suitable solvent"), indicated by reference 134. The measurand may be a quantity intended to be measured. The calibrator may be a substance used as a measurement standard. The primary calibrator 132 may be a measurement standard created as an artifact established using a primary reference measurement procedure or selected by convention. The primary calibrator 132 may be prepared as a solution of CRM 126 in a suitable solvent. The primary reference measurement procedure for the measurand and the primary calibrator 132 may meet the requirements described in ISO17511:2020. A target concentration value for the primary calibrator 132 may be assigned by the second calibration and adjustment step 130.

[0160] The series of calibration and adjustment steps may further include a fourth calibration and adjustment step using a manufacturer-selected measurement procedure, indicated by reference number 142 ("p4. manufacturer-selected measurement procedure") on at least one secondary calibrator, indicated by reference number 136 ("m.3 secondary calibrator (reference sample or pool or human sample)"). The secondary calibrator 136 may be a measurement standard established by calibration against a primary measurement standard of the same type and amount. The manufacturer-selected measurement procedure 142 and the secondary calibrator 136 may meet the requirements described in ISO17511:2020. The secondary calibrator 136 may be at least one of a human sample, a pool of human samples, a sample with a matrix, and a sample corresponding to a human sample. The manufacturer-selected measurement procedure 142 may include one or more of a homogeneous or heterogeneous immunoassay or liquid chromatography coupled with tandem mass spectrometry (LC-MS / MS). Other measurement procedures are feasible. The manufacturer-selected measurement procedure 142 may be at least partially automated. The manufacturer's selected measurement procedure 142 may, for example, correspond to or be adapted to a customer's measurement procedure. The target concentration values ​​of the secondary calibrators 136 may be assigned by the third calibration and adjustment step 134.

[0161] The series of calibration and adjustment steps may further include a fifth calibration and adjustment step using a manufacturer's internal standard measurement procedure ("p5. Manufacturer's internal standard measurement procedure"), indicated at 150, on at least one preliminary calibrator ("m.4. Manufacturer's working calibrator (preliminary calibrator)"), indicated at 146 in FIG. 2. The preliminary calibrator may correspond to a sample indicated as a manufacturer's working calibrator in the standard ISO17511:2020. The target concentration value of the preliminary calibrator 146 may be assigned by the fourth calibration and adjustment step 142.

[0162] The series of calibration and adjustment steps may further include a sixth calibration and adjustment step using a measurement procedure on the end user's IVD medical device 110 ("p.6. End User IVD MD"), indicated by reference numeral 156, for at least one product calibrator ("m.5. End User IVD MD Calibrator (Product Calibrator)"), indicated by reference numeral 154 in FIG. 2. A target concentration value for the product calibrator 154 may be assigned by the fifth calibration and adjustment step 150. The sixth calibration and adjustment step 156 may further include assigning a target concentration value to a human sample ("m.6. Human sample with result"), indicated by reference numeral 160 in FIG. 2.

[0163] The method includes providing a prior calibration curve. The prior calibration curve may be any mathematical function that describes 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 using a mass spectrometry device. The prior calibration curve, in particular the inverse prior calibration curve, can assign a concentration c to the sample tested by the in vitro diagnostic medical device based on at least one of the measured signal values ​​and a theoretical signal value derived from the measured signal values. Additionally or alternatively, the prior calibration curve can contribute to assigning a concentration c to the sample by assigning a theoretical concentration value to the sample based on the measured signal values ​​of the sample, and the concentration c is assigned to the sample based on the theoretical concentration value in a further step, for example by applying a concentration adjustment function or its inverse function.

[0164] The prior calibration curve may include at least one mathematical operation, such as, for example, multiplication by at least one coefficient or another type of mathematical operation. The prior calibration curve is a parameterized function. p is a parameter

number

number

number

number

[0165]

number

number

number

number

number

number

number

number

number

[0166] Providing a leading calibration curve may include one or more of determining the leading calibration curve by at least one of setting and selecting a leading calibration curve. For example, the process of setting a leading calibration curve may include determining at least one of its form and / or parameter values, such as by selecting at least one model function and / or by fitting at least one of the parameter values.

number

[0167] The preliminary calibration curve can be an assay- and / or application-specific function.For example, multiple conditions, such as one or more different instruments, different reagent lots, and different measurement conditions that can be used in the assay or application, can be used for its determination.For example, the preliminary calibration curve can be determined by using multiple conditions, such as one or more of multiple instruments, and / or hardware parts, and / or reagent lots, etc.

[0168] The provision of the preliminary calibration curve may be part of at least one of the calibration and adjustment steps. The provision of the preliminary calibration curve may be performed in a higher step of the hierarchy, for example, in one of the first steps of the hierarchy. For example, the preliminary calibration curve may be determined by using at least one primary calibrator 132. At least one target concentration value of the primary calibrator 132 may be established based on a primary reference measurement procedure 130 for calibrator preparation. For example, the preliminary calibration curve is provided by using at least one secondary calibrator 136. At least one target concentration value of the secondary calibrator 136 may be established based on a primary reference measurement procedure 134 for the measurand. Other examples for providing the preliminary calibration curve in other steps of the hierarchy are also feasible. Additionally or alternatively, the preliminary calibration curve may be provided by retrieving the preliminary calibration curve from at least one database, for example, a cloud. The provision of the preliminary calibration curve may be performed once or repeatedly.

[0169] For example, the step of providing a preliminary calibration curve may be embodied as including setting a preliminary calibration curve. For example, this step may be performed as one of the initial steps of the standardization process. The step of setting a preliminary calibration curve may include determining a functional form of the preliminary calibration curve. The step of setting a preliminary calibration curve may include determining a functional form of the preliminary calibration curve.

number

number

[0170] As shown in Fig. 2, the method may include at least one step of establishing a preliminary calibration curve. The step of "establishing a preliminary calibration curve" is labeled 138 in Fig. 2. In the embodiment of Fig. 2, the step of establishing a preliminary calibration curve includes measuring a set of signal values ​​of a secondary calibrator 136 using the in-vitro diagnostic medical device 110.

number

number

number

number

number

number

number

[0171] The relationship between the measured signal values ​​of a calibrator sample and the target concentration value of the calibrator sample may be insufficiently described, such as not precisely or accurately, by the prior calibration curve. As an example, the concentration value as determined using the prior 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 predefined threshold. For example, this may result from the fact that the prior calibration curve was determined based on a sample other than the calibrator sample. In the standardization process shown in FIG. 2, the prior calibration curve may nevertheless be kept unchanged, and instead, as a further function, a signal adjustment function may be determined and / or adjusted. Although the standardization process includes several calibration and adjustment steps, the prior calibration curve may be established initially, such as at a higher step in the hierarchy, and may be kept unchanged over two or more subsequent adjustment steps.

[0172] At each adjustment step, a signal adjustment function g is determined that describes the relationship between the measured signal values ​​and the theoretical signal values. r (

number

number

[0173] The method includes multiple calibration and adjustment steps performed successively, as outlined above. For example, as shown in FIG. 2, the method may include one or more of: setting a pilot calibration curve 138, adjusting the pilot calibration curve 140, assigning target values ​​to the pilot calibrator 144, adjusting the pilot calibration curve with the pilot calibrator 148, and assigning target values ​​to the product calibrator 152. These steps may be performed at the manufacturer site.

[0174] As shown in FIG. 2, following the establishment 138 of a preliminary calibration curve, the method continues by calculating the secondary calibrators i=1,...,I(I

number

number

[0175] - the signal value of the secondary calibrator 136 using the manufacturer's selected measurement procedure 142

number

number

number

number

number

[0176] Adjusting the prior calibration curve 140 may, for example, include determining a first signal adjustment function while keeping the prior calibration curve unchanged. The pre-assigned target concentration values ​​of the secondary calibrator 136 may be determined in a higher order calibration and / or adjustment step, including, for example, a primary reference measurement procedure 134 for the measurand.

[0177] In the subsequent calibration and adjustment step, the two functions, the leading calibration function and the first signal adjustment function, may be used together to assign at least one target concentration value to a sample, such as the leading calibrator 146 in the leading calibrator target value assignment step 144. Additionally or alternatively, the target concentration value may be assigned to the sample based only on the leading calibration curve, for example, by applying the inverse of the leading calibration curve to the measured signal values ​​of the sample measured using the in-vitro diagnostic medical device 110. For example, if the target concentration value assignment is performed before the first signal adjustment function is determined, the target concentration value may be assigned to the sample based only on the leading calibration curve. As an example, the leading calibrator target value assignment step 144 may be initially performed immediately after the leading calibration curve setting step 138. In this case, the signal adjustment function may not yet be determined and therefore may not be available. The target concentration value may be assigned to the leading calibrator using only the leading calibration curve, for example, by applying the inverse of the leading calibration curve to the measured signal values ​​of the leading calibrator. Alternatively, the step 144 of assigning the target values ​​of the leading calibrators may be performed in multiple step iterations, so that the step 140 of adjusting the leading calibration curve, which follows the step 144 of assigning the target values ​​of the leading calibrators in the hierarchy of calibration and adjustment steps, has already been performed. Thus, a signal adjustment function may be available for the iteration of step 144. In this case, the step of assigning the target values ​​of the leading calibrators may be performed using both the leading calibration curve and the signal adjustment function.

[0178] For example, the step of assigning target values ​​of the lead calibrators 144 may include assigning at least one target concentration value of at least one lead calibrator 146.

number

number

number

number

number

number

number

number

number

number

number

[0179] The target concentration value of the leading calibrator 146 may be assigned, for example, as at least one average value from a plurality of target concentration values, the average value being one or more of an arithmetic mean, a median, or a weighted arithmetic mean value of the plurality of target concentration values.

[0180] 2, the step 140 of "adjusting the advanced calibration curve" may be embodied as a step 148 of "adjusting the advanced calibration curve with an advanced calibrator" using, for example, at least one forward calibrator k. The step of adjusting the advanced calibration curve with an advanced calibrator 146 may be embodied as a step 148 of "adjusting the advanced calibration curve with an advanced calibrator" using, for example, at least one forward calibrator k.

number

number

number

number

number

number

number

number

number

[0181] In-house manufacturer standard measurement procedures 150 that may be used to measure the signal values ​​of the preliminary calibrators 146 may include, for example, at least one of homogeneous immunoassays, heterogeneous immunoassays, and liquid chromatography combined with tandem mass spectrometry (LC-MS / MS). Other measurement procedures are feasible.

[0182] The step 148 of adjusting the leading calibration curve by the leading calibrator may for example comprise determining a signal adjustment function g2 using the measured signal values ​​of the leading calibrator 146, while keeping the leading calibration curve itself unchanged. In the following, the two functions, the leading calibration function and the second signal adjustment function, may be used together to assign at least one target concentration value of at least one further second calibrator sample, for example the product calibrator 154.

[0183] The method may further include at least one step 152 of "Assign Target Values ​​for Product Calibrators" of Figure 2. The step 152 of assigning target values ​​for product calibrators includes assigning at least one target concentration value for at least one product calibrator.

number

number

number

number

number

number

number

number

number

[0036] Further comprising converting the

number

number

[0184] The target concentration value of the product calibrator may be assigned, for example, as at least one average value from a plurality of target concentration values, the average value being one or more of an arithmetic mean, a median, or a weighted arithmetic mean of the plurality of target concentration values.

[0185] The method may further include measuring a signal value of the independent control sample using an in vitro diagnostic medical device 110, such as a mass spectrometry device 111, and converting the measured signal value of the independent control sample to a concentration value by applying a signal conditioning function g2 and a priori calibration curve. The method may further include comparing the concentration value to a predetermined target concentration value of the independent control sample. The target concentration value

number

[0186] The step 152 of assigning target values ​​of the product calibrators may be the last step of the method for establishing metrological traceability performed at the manufacturer's side. The method may further include performing at least one customer-side calibration step. For example, the step of assigning the accepted target concentration values.

number

number

number

number

number

number

number

[0187] The target concentration values ​​may be pre-assigned by the manufacturer, for example in step 158 of assigning target values ​​for human samples, by using a method for establishing metrological traceability as described in any one of the above embodiments.

[0188] FIG. 3A shows a diagram of the preliminary calibration curves 157 per analyte. Thus, FIG. 3A shows three preliminary calibration curves 157 for three different analytes. In FIG. 3A, the following curves are shown: one preliminary calibration curve marked as 157a for analyte A, one preliminary calibration curve marked as 157b for analyte B, and one preliminary calibration curve marked as 157c for analyte C. The x-axis of the diagram shows the analyte concentration in arbitrary units 161. The y-axis of the diagram shows the signal in arbitrary units 162, for example counts. FIG. 3B shows the preliminary calibration curve 157a of FIG. 3A as a continuous line and two further curves 159 as dotted lines, which show in an exemplary manner the effect of two different signal adjustment functions on the relationship between the signal and the concentration of a particular analyte in a given exemplary analyte A. The use and / or application of a signal conditioning function may correspond to the effect of tilting and / or shifting the prior calibration curve, as shown in FIG. 3B.

[0189] FIG. 4 shows a flow chart outlining two methods for establishing metrological traceability of at least one in vitro diagnostic medical device 110. Reference number 162 in the top box indicates both methods as "Methods for establishing metrological traceability for at least one in vitro diagnostic medical device". Reference number 164 in the following box indicates what may be available at this point in both methods. Available may be a prior calibration curve, a preassigned target concentration value of the first calibrator sample, and a measurement signal value of the first calibrator sample. The prior calibration curve may be specifically abbreviated as "LCC", the term "preassigned" may be specifically abbreviated as "preassigned", and the term "first calibrator sample" may be specifically abbreviated as "first calibrator sample" in FIG. 4 and in its context. st In the adjustment step, a first calibrator sample may be used, as shown in the horizontal box marked 166. Thereafter, a second calibrator sample may be used, as shown in the adjacent horizontal box marked 168. In the adjustment step, first, a leading calibration curve or its inverse may be applied, as shown in the box marked 170. As shown in the respective boxes on the left, a leading calibration curve may be applied to a pre-assigned target concentration value of the first calibrator sample to determine a theoretical signal value of the first calibrator sample. Alternatively, as shown in parallel in the boxes on the right, an inverse of the leading calibration curve may be applied to the measurement signal of the first calibrator sample to determine the theoretical concentration of the first calibrator sample.

[0190] An adjustment function may then be determined, as shown in the box marked with reference number 172. As shown on the left, a signal adjustment function may be determined that describes the relationship between the measured signal values ​​and the theoretical signal values. In particular, the signal adjustment function may be fitted to map the theoretical signal values ​​of the first calibrator sample to the pre-assigned target concentration values ​​of the first calibrator sample (this option is shown in FIG. 4), or vice versa (not shown). Alternatively, as shown in the right-hand flow, a concentration adjustment function may be determined that describes the relationship between the theoretical concentration of the first calibrator sample and the pre-assigned target concentration values ​​of the first calibrator sample. In particular, the concentration adjustment function may be fitted to map the pre-assigned target concentration values ​​of the first calibrator sample to the theoretical concentration values ​​of the first calibrator sample (this option is shown in FIG. 4), or vice versa (not shown).

[0191] A target concentration value may then be assigned to the second calibrator sample, as shown in the box marked with reference number 174. In particular, this may be done by successively applying the inverse of the adjustment function (or adjustment function) and the inverse of the prior calibration curve, or vice versa, as shown by the horizontal box marked 176. Thus, as shown in the left-hand flow, an inverse signal adjustment function may be applied to the measured signal values ​​of the second calibrator sample to determine the theoretical signal values ​​of the second calibrator sample, and then an inverse of the prior calibration curve may be applied to the theoretical signal values ​​of the second calibrator sample to assign a target concentration value to the second calibrator sample. It should be noted that if the above option was used in which the signal adjustment function was fitted to map the pre-assigned target concentration values ​​of the first calibrator sample to the theoretical signal values ​​of the first calibrator sample (and not the inverse), the concentration adjustment function may be used, but not the inverse. For better overview, this option is again not shown in FIG. 4. The right hand flow shows the corresponding steps, in particular the application of the inverse of the prior calibration curve to the measurement signal values ​​of the second calibrator sample to assign theoretical concentration values ​​to the second calibrator sample. Following this, the inverse of the concentration adjustment function can be applied to the theoretical concentration values ​​of the second calibrator sample to assign target concentration values ​​to the second calibrator sample. Again, it should be noted that the concentration adjustment function can be used, but not the inverse, if the above option was used in which the concentration adjustment function was fitted to map the theoretical concentration values ​​of the first calibrator sample to the pre-assigned concentration values ​​of the first calibrator sample. For better overview and comparison of the method for establishing metrological traceability of at least one in-vitro diagnostic medical device 110, this option is not shown in FIG. 4.

[0192] 5-10 provide an overview of exemplary embodiments of methods for establishing metrological traceability of at least one in-vitro diagnostic medical device 110. FIG.

[0193] FIG. 5 shows a flow chart of this exemplary embodiment.

[0194] In a first step, a reference measurement procedure ("RMP") 134 of the measurand is performed for a primary calibrator ("PRIMARY CAL") 132. Then, in a calibration step 128, a target value for a secondary calibrator ("SECONDARY CAL") 136 is determined using the RMP 134 for the secondary calibrator 136.

[0195] In this exemplary embodiment, a preliminary calibration curve is established 138 by using a secondary calibrator 136. A manufacturer selected measurement procedure ("MMP") 142 is performed on the secondary calibrator 136. This preliminary calibration curve is used in all subsequent steps and is indicated in parentheses.

[0196] Next, in this embodiment, further at step 138, a preliminary calibration curve adjustment may be performed using the secondary calibrator 136, the manufacturer's selected measurement procedure ("MMP") 142, and the assigned target concentration values.

[0197] Next, in step 144, a manufacturer selected measurement procedure ("MMP") 142 is used to assign target concentration values ​​for a working calibrator ("WORKING CAL") 146, also referred to as a leading calibrator.

[0198] Next, in step 148, a preliminary calibration curve adjustment may be performed using the working calibrators 146, the Manufacturer's Standard Measurement Procedures ("MSMPs") 150, and the assigned target concentration values.

[0199] Next, in step 152, a target value for the product calibrator ("Product CAL") 154 is assigned using a Manufacturer's Internal Standard Measurement Procedure ("MSMP") 150.

[0200] Next, in step 140, a preliminary calibration curve adjustment is performed using the product calibrator ("Product CAL") 154, the measurement procedure ("Assay") 156 for the end user's IVD medical device 110, and the assigned target concentration values.

[0201] Next, in step 158, a measurement of the human sample is generated using a measurement procedure ("assay") 156 of the end user's IVD medical device 110.

[0202] Figures 6A, 6B, 6C, 6D and 7 show the experimental results of setting up a preliminary calibration curve 138. In particular, the signal vs. target value is shown in [μg / ml]. As substances i=31 secondary calibrators 136 (in this case samples containing carbamazepine) were used. These i=31 secondary calibrators 136 were measured on three LC / MS instruments, with three repetitions on each instrument (i.e. i=31, j=3, l=3), resulting in a total of nine measurements (nine results (signals) per sample): sijl ) were obtained, which are shown in Figures 6A, 6B, 6C, and 6D.

[0203] Figure 6A shows a comparison of three replicates of measured signal values ​​for each secondary calibrator 136 for three instruments, with circles representing instrument 1, triangles representing instrument 2, and crosses representing instrument 3. Figures 6B-6D show the experimental results for each individual instrument, with circles, crosses, and triangles representing the respective replicates. Additionally, the resulting preliminary calibration curves 138 are shown in Figures 6A-6D.

[0204] The target value of the secondary calibrator 136 has been pre-assigned by using a reference measurement procedure, such as, for example, reference measurement procedure for the measurand ("RMP" in FIG. 5) 134.

[0205] The table below gives an overview of the experimental results of the signal values ​​(secondary calibrator (SPC), target value [μg / ml] (target), minimum signal value (min), arithmetic mean signal value (arithmetic mean), median signal value (median), maximum signal value (max), standard deviation (SD) and coefficient of variation (CV) of the signal values). [Table 1]

[0206] The preliminary calibration curve can be determined by applying a regression fit, for example, in this case a weighted least squares fit is used. This is shown in Figure 7. The median signal of the nine results per sample is shown on the Y-axis of Figure 7, and the target value of the sample is shown on the X-axis of Figure 7. The Pade model function was used as the functional form of the preliminary calibration curve in this example.

number

number

number

number

[0207] Following establishment 138 of the preliminary calibration curve, the method may include step 144 in which target concentration values ​​of the preliminary calibrators 146 are assigned.

[0208] In this experiment, eight preliminary calibrators (LCal) 146 were measured using three LC / MS instruments with three replicates on each instrument (i.e., k = 8, j = 3, l = 3), resulting in a total of nine measurements and nine signals per calibrator: kjl lead,measThe table below gives an overview of the experimental results: signal values ​​(preliminary calibrator (LCal), minimum value (Min), arithmetic mean value (ArithmeticMean), median value (Median), maximum value (Max), standard deviation (SD) and coefficient of variation (CV)). [Table 3]

[0209] The measurement signal of the prior calibrator 146 was then converted to a concentration value using the prior calibration curve and, if necessary, a signal adjustment function.

[0210] In this experiment, the adjustment of the preliminary calibration curve was performed using the secondary calibrator 136. Figures 8A-8D show the determination of the signal adjustment function for the recalibration of the preliminary calibration curve using the sample curve panel (secondary calibrator) measurements. In particular, the samples used to determine the preliminary calibration curve were used, with reference to the description of Figure 6. The measured signal ("Signal") is shown on the Y-axis of Figures 8A-8D, and the theoretical signal ("Theoretic Signal") is shown on the X-axis. Figure 8A shows a comparison of the arithmetic mean values ​​of three replicates of three instruments, with circles representing instrument 1, triangles representing instrument 2, and crosses representing instrument 3. Figures 8B-8D show the experimental results for each individual instrument, with the circles, crosses, and triangles representing the respective replicates. The fit results are shown in each figure. In Figures 8B-8D, the following intercepts and slopes were determined: [Table 4]

[0211] The results are used to determine concentration values ​​for each of the preliminary calibrators, and the median of these concentrations is used as the target value for the preliminary calibrator 146. In particular, the median concentration in [μg / ml] of the nine readings (from nine signals per calibrator) was used as the target concentration value for the preliminary calibrator 146. The following table gives an overview of the experimental concentration results in [μg / mL]. [Table 5]

[0212] Next, the method may include a step 152 in which a target concentration value for the product calibrator 154 is assigned.

[0213] In this experiment, two product calibrators 154 were measured using three LC / MS instruments with three replicates on each instrument (i.e., k=2, j=3, l=3), resulting in a total of nine measurements and nine signals per calibrator. The table below gives an overview of the experimental results for signal values ​​(product calibrator (PCal), minimum (Min), arithmetic mean (Arithmetic Mean), median (Median), maximum (Max), standard deviation (SD) and coefficient of variation (CV)). [Table 6]

[0214] The measurement signal of the product calibrator 154 was then converted to a concentration value using a priori calibration curve and a signal conditioning function.

[0215] 9A-9D show the determination of a signal adjustment function for the recalibration of the preliminary calibration curve using the preliminary calibrator 146 and the determined target values ​​of the preliminary calibrator 146. The measured signal ("Signal") is shown on the Y-axis of FIG. 9A-9D, and the theoretical signal ("Theoretic Signal") is shown on the X-axis. FIG. 9A shows a comparison of the arithmetic mean values ​​of three replicates for each preliminary calibrator 146 for three instruments, with circles representing instrument 1, triangles representing instrument 2, and crosses representing instrument 3. In FIG. 9B-9D, the experimental results for each individual instrument are shown, with circles, crosses, and triangles representing the respective replicates. The fit results are shown in each figure. In FIG. 9B-9D, the following intercepts and slopes were determined: [Table 7]

[0216] The results are used to determine the respective concentration values, and the median of these concentrations is used as the target value for the product calibrator 154. In particular, the median concentration in [μg / ml] of the nine readings (from nine signals per 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]. [Table 8]

[0217] Next, the method may include a step 158 in which final measured concentration values ​​for the human samples and controls (particularly the QC samples and / or marker samples “m.6. Human samples with results”) are assigned.

[0218] In this experiment, three human samples were measured using three LC / MS instruments with three replicates on each instrument (i.e., k=2, j=3, l=3), resulting in a total of nine measurements and nine signals per sample. The table below gives an overview of the experimental results of the signal values ​​(control sample (QC), minimum value (Min), arithmetic mean value (Arithmetic Mean), median value (Median), maximum value (Max), standard deviation (SD) and coefficient of variation (CV)) and their pre-assigned target values ​​in [μg / mL]. [Table 9]

[0219] The measurement signals of the human samples were then converted to concentration values ​​using a priori calibration curves and a signal fitting function.

[0220] 10A-10D show the determination of a signal adjustment function for the recalibration of the advanced calibration curve using the determined target values ​​of the product calibrator 146 and the advanced calibrator 154. The measured signal ("Signal") is shown on the Y-axis of FIGS. 10A-10D, and the theoretical signal ("Theoretic Signal") is shown on the X-axis. FIG. 10A shows a comparison of the arithmetic mean values ​​of three replicates for each product calibrator 154 for three instruments, with circles representing instrument 1, triangles representing instrument 2, and crosses representing instrument 3. In FIGS. 10B-10D, the experimental results for each individual instrument are shown, with the circles, crosses, and triangles representing the respective replicates. The fit results are shown in each figure. In FIGS. 10B-10D, the following intercepts and slopes were determined: [Table 10]

[0221] The results are used to determine the respective concentration values, and the arithmetic mean of these concentrations is used to calculate the relative recovery to its pre-assigned target value. The table below gives an overview of the experimental results in [μg / mL]. [Table 11] [Explanation of symbols]

[0222] 110 In-vitro diagnostic medical devices 111 Mass spectrometry devices 112 Processing Device 113 Quadrupole Mass Spectrometer 114 Detector 115 Ionization Source 116 Hardware Parts 118 processors 120 Data storage device 122 "p.1. Fit-for-purpose measurement procedures for purity assessment (e.g., qNMR, mass balance)" 124 Target Allocation 126 “m.1.Certified Primary Reference Material (CRM)” 128 calibration steps 130 "p.2. Primary standard measurement procedures for calibrator preparation (e.g., weight preparation)" 132 "m.2. A primary calibrator prepared as a solution of m.1 in a suitable solvent." 134 "p.3. Primary reference measurement procedure for measurand" 136 "m.3. Secondary calibrator (reference sample or pool or human sample)" 138 Setting the preliminary calibration curve 140 Adjustment of preliminary calibration curve 142 "p.4. Manufacturer's selected measurement procedure" 144 Advanced Calibrator Target Value Allocation 146 "m.4. Manufacturer's working calibrator (preliminary calibrator)" 148 Adjustment of preliminary calibration curves using preliminary calibrators 150 "p.5. Manufacturer's internal standard measurement procedure" 152 "Product Calibrator Target Value Allocation" 154 "m.5. End-user IVD MD calibrator (product calibrator)" 156 "p.6. End User IVD MD" 157 Preliminary Calibration Curve 157a Preliminary calibration curve for test substance A 157b Preliminary calibration curve for test substance B 157c Preliminary calibration curve for test substance C 158 Target value allocation for human samples 159 Curves showing the effect of signal conditioning functions 160 "m.6. Human samples with results" 161 Concentration in arbitrary units 162 Method for establishing metrological traceability of at least one in vitro diagnostic medical device 163 Arbitrary Unit Signals 164 Available: a preliminary calibration curve (LCC), a preassigned target concentration value of the first calibrator sample, and a measurement signal value of the first calibrator sample. 166 First Calibrator Sample 168 Second Calibrator Sample 170 Application of a priori calibration curve or its inverse 172 Determination of Adjustment Function 174 Assigning a target concentration value to the second calibrator sample 176 Inverse of the adjustment function (or the adjustment function) and successive application of the inverse of the preceding calibration curve, or vice versa

Claims

1. A method for establishing metrological traceability of at least one in-vitro diagnostic medical device (110), said method comprising a series of calibration and adjustment steps, the result of each step being dependent on the result of the previous step, The method includes providing a preliminary calibration curve, the preliminary calibration curve f ｐ describes the relationship between at least one concentration c of at least one analyte in at least one sample and the signal s of said sample measured with said in vitro diagnostic medical device (110), and said preliminary calibration curve f ｐ is a parameter [0010] is the set of parameters of the preliminary calibration curve, [0025] A parameterized function [0030] and At each adjustment step, a signal adjustment function g is provided that describes the relationship between the measured signal values ​​and the theoretical signal values. ｒ ( [0045] is a set of parameters of the signal conditioning 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 prior calibration curve, the theoretical signal value being a pre-assigned target concentration value c of the first calibrator sample. ｉ and determining by applying said prior calibration curve using Each adjustment step includes assigning at least one target concentration value from the measured signal values ​​of at least one second calibrator sample, the assigning comprising applying the signal adjustment function determined in the previous adjustment step or an inverse of the signal adjustment function determined in the previous adjustment step to the measured signal values ​​of the second calibrator sample, and forming the inverse prior calibration curve. [0050] determining at least one theoretical signal value for the second calibrator sample by applying to the theoretical signal value of the second calibrator sample.

2. 2. The method of claim 1, wherein the series of calibration and adjustment steps includes a first calibration and adjustment step using a fit-for-purpose measurement procedure for purity assessment, the series of calibration and adjustment steps further includes a second calibration and adjustment step using a primary reference measurement procedure for calibrator preparation for at least one certified primary reference material, the series of calibration and adjustment steps further includes 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 manufacturer selected measurement procedure for at least one secondary calibrator.

3. 3. The method of claim 1 or 2, wherein the preliminary calibration curve is determined by using at least one primary calibrator, and at least one target concentration value of the primary calibrator is established based on the primary reference measurement procedure for calibrator preparation.

4. 4. The method according to claim 2 or 3, wherein the preliminary calibration curve is determined by using at least one secondary calibrator, and at least one target concentration value of the secondary calibrator is established based on the primary reference measurement procedure for the measurand.

5. 5. The method of claim 1, wherein the assigned target concentration value of the second calibrator sample is usable in a subsequent adjustment step to determine the signal adjustment function.

6. 6. The method of claim 1, wherein the preliminary calibration curve does not change over two or more adjustment steps.

7. The signal conditioning function is a function [006] and [0070] is the set of parameters of the signal conditioning function, R [0080] and i is the first calibrator sample i=1,....I(I [0090] ) and the signal conditioning function is a theoretical signal of the prior calibration curve [0010] is the preassigned target concentration value of the first calibrator sample) as the measured signal value of the first calibrator sample ##EQU00011## , j represents the instruments and / or hardware parts (116) j=1, . . . , J of said in-vitro diagnostic medical device (110), J≧1, and l is the iteration ##EQU00012## , the determination of the signal conditioning function is based on the signal value of the first calibrator sample. ##EQU00013## and measuring the theoretical signal ##EQU14## and adapting the signal conditioning function, thereby calculating the adapted parameter ##EQU00015## The method of claim 1 , further comprising determining:

8. The assignment of the target concentration value is performed by measuring the second calibrator sample k ( ##EQU00016## and K≧1) ##EQU00017## and successively applying the inverse function [0018] The target concentration value [0019] and converting the resulting signal into [0020] and ##EQU00021##

9. The signal conditioning function is a function [0022] and [0023] is the set of parameters of the signal conditioning function, R [0024] where i is the first calibrator sample i=1,....I(I [0025] 9. The method of claim 1, wherein the signal conditioning function connects the measured signal value of the first calibrator sample with the preassigned target concentration value and the theoretical signal of the first calibrator sample derived from the prior calibration curve, and the assignment of the target concentration value of the second calibrator sample is determined by applying the signal conditioning function.

10. The method according to any one of claims 1 to 9, wherein the in-vitro diagnostic medical device (110) is a mass spectrometry device (111).

11. A method for establishing metrological traceability of at least one in-vitro diagnostic medical device (110), said method comprising a series of calibration and adjustment steps, the result of each step being dependent on the result of the previous step, The method includes providing a preliminary calibration curve, the preliminary calibration curve f ｐ describes the relationship between at least one concentration c of at least one analyte in at least one sample and the signal s of said sample measured with said in vitro diagnostic medical device (110), and said preliminary calibration curve f ｐ is a parameter [0026] is the set of parameters of the preliminary calibration curve, [0027] A parameterized function [0028] and In each adjustment step, a concentration adjustment function h is calculated that describes the relationship between the theoretical concentration value of the measurement signal value of the first calibrator sample and the preassigned target concentration value of the first calibrator sample. ｓ ( [0029] is a parameter of the concentration adjustment function) is determined, and the theoretical concentration value of the first calibrator sample is calculated by the inverse function of the prior calibration curve using the measured signal value of the first calibrator sample. [0030] is determined by applying The assignment of the target concentration value is performed by calculating the inverse function of the preliminary calibration curve using the measured signal value of the second calibrator sample. [0031] to obtain a theoretical density value; and applying the density adjustment function [0032] Or the inverse function of the density adjustment function [Equation 33] to obtain the target concentration value for the second calibrator sample.

12. 12. The method of claim 11, wherein the concentration adjustment function connects a pre-assigned target concentration value of the first calibrator sample with the theoretical concentration value of the measurement signal of the first calibrator sample, and the assignment of the target concentration value of the second calibrator sample is determined by applying the concentration adjustment function.

13. A processing device (112), said processing device (112) being adapted to generate at least one predetermined preliminary calibration curve f ｐ and the processing device (112) is configured to retrieve and / or store the preliminary calibration curve f ｐ Parameters [0034] where P is a positive integer, and the prior calibration curve f ｐ describes the relationship between at least one concentration c of at least one analyte in at least one sample and a signal s of said sample being measured using an in vitro diagnostic medical device (110), and said preliminary calibration curve f ｐ is a parameterized function [Equation 35] and wherein 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 one of claims 1 to 12 referring to a method.

14. 13. A kit comprising an in-vitro diagnostic medical device (110), a set of product calibrators and their target concentration values, the target concentration values ​​of the product calibrators being assigned by using a method according to any one of claims 1 to 10 or 11 to 12.

15. A computer program adapted to carry out the method according to any one of claims 1 to 10 or 11 to 12 when said computer program is run on a computer.

16. A computer program product having program code means, said program code means being capable of being stored on a storage medium or being stored on a storage medium for performing the method of any one of claims 1 to 10 or 11 to 12 when said program code means is executed on a computer or a computer network.

Images