Computer-implemented method for calibrating customer mass spectrometry instruments for quantifier-qualifier ratio calibration

Abstract

The present invention provides a computer-implemented method for calibrating a customer mass spectrometer (118) for a quantifier-qualifier ratio calibration. The method comprises the following steps: a) at least one manufacturer's on-site standardization, wherein a set of subject samples and a set of calibrator samples are measured in multiple replicates on multiple mass spectrometers (114), wherein each measurement comprises multiple reaction monitoring of quantifier and qualifier transitions for an analyte and an internal standard, wherein at least three adjustment factors are determined from the measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α depends on the difference between the analyte and the internal standard, wherein a second adjustment factor β depends on the difference between the subject sample and the calibrator sample for the analyte quantifier-qualifier ratio, and wherein the third adjustment factor β depends on the difference between the subject sample and the calibrator sample for the analyte quantifier-qualifier ratio. a) an adjustment factor γ that depends on the difference in the quantifier-qualifier ratio for the internal standard between the subject sample and the calibrator sample; b) at least one transfer step, wherein the adjustment factor is electronically transferred to a customer mass spectrometer (118); c) at least one customer on-site calibration, wherein the customer on-site calibration includes at least one calibration measurement, wherein a set of calibrator samples are measured on the customer mass spectrometer (118) and the quantifier-qualifier ratio is determined therefrom, wherein the target value of the quantifier-qualifier ratio for the analyte and for the internal standard is set by applying the adjustment factor to the determined quantifier-qualifier ratio.

Description

Technical Field

[0001] The present invention relates to a computer-implemented method for calibrating a customer's mass spectrometer for quantifier-qualifier ratio calibration, a computer-implemented method for quantifier-qualifier ratio calibration, a computer program, and a mass spectrometer system. The method can be used in in vitro diagnostic assays. Background Art

[0002] The known quantitative factor - qualitative factor peak area ratio (expressed as QQ ratio) is an important quality control measure used to verify peak identity and interference within each measured patient sample. The use of the QQ ratio is a well-established method for liquid chromatography mass spectrometry (LC-MS) assays and is considered by many guidelines, such as the "Guide to Quality Control of Forensic Toxicological Analysis" (GTFCh) published by the "Toxicology and Forensic Chemistry Association" from the Clinical and Laboratory Standards Institute (CLSI) C62-A. The target value of the QQ ratio for verifying peak identity and interference can be set during assay development, during validation, or in conjunction with calibration assays. The setting of the target value is done on a specific instrument. The corresponding acceptance criteria can be defined during assay development or can be set based solely on guideline recommendations.

[0003] For example, the use of the QQ ratio as a quality measure to check peak identity and interference is described in US 2017 / 0108478 A1, WO 2018 / 207228 A1, WO 2018 / 136825 A1, and US20120318970 A1.

[0004] Although this ratio is analyte-specific, robustness deficiencies can be observed, particularly when compared to the peak area ratio between the analyte and the internal standard. Furthermore, significant differences can exist between different instruments and between temporal drift and temporal shift. For laboratory devices, target values for this ratio are typically defined after development or during validation or verification on a specific instrument. To overcome robustness deficiencies, wide acceptance ranges can be applied, or the target needs to be adjusted with each batch calibration. This approach may be impractical and unsuitable for fully automated in vitro diagnostic runs on multiple instruments.

[0005] Common adjustment and calibration procedures for mass spectrometry instruments are outlined in the following article by Fabio Garofolo: "LC-MS Instrument Calibration: Chemical / Analytical Validation" in "Analytical Method Validation and Instrument Performance Verification," John Wiley & Sons, Inc., Hoboken, NJ, USA, ISBN: 978-0-471-25953-4, pp. 197-220, DOI: 10.1002 / 0471463728.ch13. The following document by Ludwig Huber et al. provides an overview of equipment qualification and validation: "Equipment Qualification and Computer System Validation" in "Analytical Method Validation and Instrument Performance Verification: Chemical / Analytical Validation," January 15, 2004, John Wiley & Sons, Inc., Hoboken, NJ, USA, ISBN: 978-0-471-25953-4, pp. 255-276, DOI: 10.1002 / 0471463728.ch17.

[0006] Issues to be resolved

[0007] Therefore, an object of the present invention is to provide a method and a device for performing a quantitative factor-directive factor ratio calibration which avoids the above-mentioned disadvantages of the known methods and devices. In particular, the method and the device should allow a reliable and fully automated analysis of a sample using a mass spectrometer. Summary of the Invention

[0008] This problem is solved by a computer-implemented method, a computer program and a mass spectrometry system having the features of the independent claims. In the dependent claims and throughout the description, advantageous embodiments are listed which can be realized individually or in any combination.

[0009] As used hereinafter, the terms "having," "including," or "comprising," or any of their arbitrary grammatical variations, are used in a non-exclusive manner. Thus, these terms may refer both to situations in which, apart from the features introduced by these terms, no further features are present in the entity described in that context, and to situations in which one or more further features are present. As an example, the expressions "A has B," "A includes B," and "A contains B" may refer both to situations in which, apart from B, no further elements are present in A (i.e., situations in which A consists solely and exclusively of B), and to situations in which, apart from B, one or more further elements (such as element C, element C and element D, or even further elements) are present in entity A.

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

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

[0012] In a first aspect of the present invention, a computer-implemented method for calibrating a customer mass spectrometry instrument for a quantifier-qualifier ratio check is disclosed.

[0013] As used herein, the term "computer-implemented method" is a broad term and is given the ordinary and customary meaning for a person skilled in the art, and is not limited to a special or customary meaning. The term may specifically refer to, but is not limited to, a method involving at least one computer and / or at least one computer network. The computer and / or computer network may include at least one processor that is configured to perform at least one of the method steps of the method according to the present invention. Preferably, several method steps are performed by the computer and / or computer network. The method may be performed partially or fully automatically (particularly, without user interaction). As used herein, the term "automatically" is a broad term and is given the ordinary and customary meaning for a person skilled in the art, and is not limited to a special or customary meaning. The term may specifically refer to, but is not limited to, a process that is performed entirely with the aid of at least one computer and / or at least one computer network and / or at least one machine, in particular, without the need for manual operation and / or interaction with a user.

[0014] The term "calibration" or "calibrating" is a broad term and is given a common and customary meaning to one of ordinary skill in the art and is not limited to a special or customary meaning. These terms may specifically refer to, but are not limited to, an operation or process of determining the relationship between a measured value delivered by a device and a measured value of a calibration standard (specifically a calibration function). In particular, calibration can be a relationship between a measured value and a target value. Calibration can be a relationship between a target value for a quantitative factor-qualifier ratio from a measurement determined using a customer's mass spectrometer and a target value for a quantitative factor-qualifier ratio of a calibration standard (particularly determined at the manufacturer's site).

[0015] As used herein, the term "mass spectrometry (MS) instrument" is a broad term and is to be given the ordinary and customary meaning to those of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically refers to, but is not limited to, a mass analyzer configured to detect at least one analyte based on mass-to-charge ratio. A mass spectrometer can be or can include at least one quadrupole mass spectrometer. The MS instrument can be a tandem mass spectrometer (MS / MS) instrument or a triple quadrupole MS / MS. In particular, the mass spectrometer can be configured for multiple reaction monitoring (MRM).

[0016] Mass spectrometer can be specifically or can include liquid chromatography mass spectrometry device.As used herein, term " liquid chromatography mass spectrometry device " is a broad term and is given common and customary meaning for those of ordinary skill in the art, and is not limited to special or customized meaning.This term specifically can refer to but is not limited to the combination of liquid chromatography and mass spectrometry.Liquid chromatography mass spectrometry device can be or can include at least one high performance liquid chromatography (HPLC) device or at least one microfluidic liquid chromatography (μLC) device.Liquid chromatography mass spectrometry device can include liquid chromatography (LC) device and mass spectrometry (MS) device, wherein LC device and MS are coupled via at least one interface.The interface coupling liquid chromatography device and MS can include at least one ionization source, and this ionization source is configured for generating molecular ions and for molecular ions being transferred to gas phase.As used herein, term " liquid chromatography (LC) device " is a broad term and is given common and customary meaning for those of ordinary skill in the art, and is not limited to special or customized meaning. The term may specifically refer to, but is not limited to, an analytical module configured to separate one or more target analytes of a sample from other components of the sample for detection of the one or more analytes using a mass spectrometer. The LC device can be based on any separation principle deemed suitable by the skilled person; in one embodiment, the LC device can be reverse phase chromatography, hydrophobic interaction chromatography, ion exchange chromatography, size exclusion chromatography, affinity chromatography, or chiral chromatography; in another embodiment, the LC device is reverse phase chromatography. The LC device may include at least one LC column. For example, the LC device may be a single column LC device or a multi-column LC device having 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 transport the target analyte.

[0017] As used herein, the term "multiple reaction monitoring," also denoted as multi-transition monitoring, is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically may refer to, but is not limited to, methods used in mass spectrometry, particularly tandem mass spectrometry, in which multiple product ions from one or more precursor ions are monitored. As used herein, the term "monitoring" is a broad term and is given its ordinary and customary meaning to one of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically may refer to, but is not limited to, the determination and / or detection of multiple product ions.

[0018] As used herein, the term "customer" is a broad term and is to be given the ordinary and customary meaning to one of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically may refer to, but is not limited to, the owner or operator of a mass spectrometer instrument, particularly one obtained from one or more of a seller, distributor, or supplier. As used herein, the term "customer mass spectrometer instrument" is a broad term and is to be given the ordinary and customary meaning to one of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically may refer to, but is not limited to, the customer's mass spectrometer instrument.

[0019] As used herein, the term "quantitative factor," also denoted as "quantitative ion," is a broad term and has a common and customary meaning for those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, an ion that characterizes a target compound. Generally speaking, the most abundant and / or most reliably detected transition or fragment is used to quantify the compound. Specifically, the quantitative ion may be the peak with the maximum signal intensity on the compound's mass spectrum. As used herein, the term "qualitative factor," also denoted as "qualitative ion," is a broad term and has a common and customary meaning for those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, another ion that characterizes the target compound having a different mass-to-charge ratio than the quantitative ion. The quantitative factor can be used to confirm the identity of a compound. Generally speaking, a second transition or second fragment serves as the quantitative factor. As used herein, the term "quantitative factor-qualitative factor ratio," also denoted as the quantitative factor-qualitative factor peak area ratio, is a broad term and has a common and customary meaning for those skilled in the art, and is not limited to a specific or customary meaning. The term may specifically refer to, but is not limited to, the ratio between the signal intensity of the peak of the qualifier ion and the signal intensity of the peak of the quantifier ion and / or the ratio between the peak area of the peak of the quantifier ion and the peak area of the peak of the qualifier ion.

[0020] As used herein, the term "quantitative factor-qualitative factor ratio verification" is a broad term and will be given the common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customized meaning. The term can specifically refer to, but is not limited to, a quality control measure for peak identity and interference in a verification sample. Using the quantitative factor-qualitative factor ratio is a perfect method for liquid chromatography-mass spectrometry and is considered by many guidelines (such as the "Guide to Quality Control of Forensic Toxicological Analysis" (GTFCh) issued by the "Toxicology and Forensic Chemistry Association" of the Clinical and Laboratory Standards Institute (CLSI) C62-A). For the quantitative factor-qualitative factor ratio verification, the quantitative factor-qualitative factor ratio determined is compared with the target value of the quantitative factor-qualitative factor ratio and is verified according to at least one acceptance criterion.

[0021] As used herein, the term "quality control" is known to the skilled person. In one embodiment, quality control is the process of ensuring that the processes performed by an entity and / or the goods produced meet predefined quality standards. In a further embodiment, quality control in sample measurements, in particular in the measurement of medical samples (such as patient samples), for example in clinical diagnostics and / or clinical chemistry, includes ensuring that the analytical results obtained using a particular measurement method correspond to the results obtained using a gold standard method, and thus, in one embodiment, correspond to the results theoretically obtainable within a pre-specified range.

[0022] The method comprises the following steps, which, as an example, may be performed in the order given. However, it should be noted that different orders are also possible. Furthermore, one or more method steps may be performed once or repeatedly. Furthermore, two or more method steps may be performed simultaneously or in a timely overlapping manner. The method may include further method steps that are not listed. As used herein, the term "step" is a broad term and will be given the ordinary and customary meaning for a person of ordinary skill in the art and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, a work step, a process step, or a stage of an operation or procedure.

[0023] The method comprises the following steps:

[0024] a) at least one manufacturer's on-site standardization, wherein a set of subject samples and a set of calibrator samples are measured in multiple replicates on multiple mass spectrometry instruments, wherein each measurement comprises multiple reaction monitoring by quantifier and qualifier transitions for an analyte and an internal standard, wherein at least three adjustment factors are determined from the multiple measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α is dependent on the difference between the analyte and the internal standard, wherein a second adjustment factor β is dependent on the difference in the ratio of the quantifier to the qualifier for the analyte between the subject sample and the calibrator sample, and wherein a third adjustment factor γ is dependent on the difference in the ratio of the quantifier to the qualifier for the internal standard between the subject sample and the calibrator sample;

[0025] b) at least one transmission step, wherein the adjustment factors are electronically transmitted to a customer mass spectrometer;

[0026] c) at least one customer on-site calibration, wherein the customer on-site calibration comprises at least one calibration measurement, wherein a set of calibrator samples are measured on the customer mass spectrometer instrument and quantifier-qualifier ratios are determined from the set of calibrator samples, wherein target values for the quantifier-qualifier ratios for the analyte and for the internal standard are set by applying an adjustment factor to the determined quantifier-qualifier ratios.

[0027] In order to perform a quality check based on the quantitative factor-qualifier ratio, at least one target value is used and compared with the measured quantitative factor-qualifier ratio. However, the target value may vary or be different due to the difference in mass spectrometry instruments. Therefore, for quality check, it may be advantageous to use the target value for a specific customer mass spectrometry instrument. Even temporal changes are possible. Therefore, for quality check, it may be advantageous to use a target value that can be adjusted or adapted repeatedly at the customer site in a timely manner. In addition, for calibration, a small amount of calibrator samples are usually measured, and the composition of these calibrator samples may be different compared to the subject sample. Therefore, the quality check based on the quantitative factor-qualifier ratio may be strongly affected by measurement imprecision and may produce deviations due to the matrix differences between the calibrator and the subject sample. In order to overcome these problems, the present invention proposes a data transmission method. At the manufacturer's site, a group of subject samples and calibrator samples can be measured with multiple repetitions on multiple instruments during step a). Three adjustment factors can be determined in step a), and can be electronically transmitted to the customer mass spectrometry instrument in step b). At the customer site, in step c), calibration measurements can be performed on the calibrator sample, and initial target values for the quantitative factor-qualifier ratio for the analyte and for the internal standard can be determined. The adjustment factor can be applied to the initial target value to calculate the adjusted target value for the quantitative factor-qualifier ratio of the analyte and the quantitative factor-qualifier ratio of the internal standard. The adjusted target value is instrument-specific, traceable to the subject sample, and has better accuracy due to the use of multiple data points. Due to the determination of the specific calibration frequency, time drift and time displacement can be corrected regularly. For subsequent sample analysis, at least one acceptance criterion can be used to verify the measured quantitative factor-qualifier ratio. The acceptance criterion or multiple acceptance criteria can be determined during the determination development. At least one acceptance criterion may be neither instrument-specific nor change over time. At least one acceptance criterion can be electronically transmitted to the customer instrument by applying a parameter file.

[0028] As used herein, the term "manufacturer" is a broad term and is given a common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customized meaning. The term can specifically refer to, but is not limited to, at least one manufacturer of a mass spectrometer. The term "manufacturer" can also refer to a single manufacturer and / or multiple manufacturers that produce all parts of a mass spectrometer, such as suppliers of specific components of a mass spectrometer. The manufacturer can be the final manufacturer that provides the final product for use by the customer. As used herein, the term "manufacturer site" is a broad term and is given a common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customized meaning. The term can specifically refer to, but is not limited to, all processes performed by the manufacturer before providing the mass spectrometer to the customer. All reagents, chromatographic columns, calibrators, system reagents, and disposables can be produced by or for the manufacturer. In contrast, at the customer site, the customer can place the subject's sample and control sample on the instrument as non-manufacturer components.

[0029] As used herein, the term "standardization" is a broad term and will be given the ordinary and customary meaning for those of ordinary skill in the art and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, the following process: determining an estimate of the imprecision of the measured quantitative factor-qualifier ratio and the bias caused by matrix differences between the calibrator and the subject's sample and providing corrections for this. Standardization may include: determining a chromatogram for each measurement of the sample. The term "chromatogram" is well known to technicians. In one embodiment, the term relates to a correlation diagram of the quantitative measure of a signal obtained from a sample and determined by an MS instrument over time, such as retention time and / or elution volume, and the progress of the chromatographic separation. In one embodiment, the quantitative measure of the signal is associated with the concentration of at least a portion of the sample components, in particular the concentration of the analyte; therefore, the quantitative measure of the signal can be in particular signal intensity. The chromatogram can be an MS chromatogram, and in another embodiment, an MS / MS chromatogram. As will be understood by the technician, the above representation can be, but not necessarily, a graphical representation; However, the representation can also be provided, for example, as a list of value pairs (e.g., elution time / quantitative factor value pairs and / or elution time / qualitative factor value pairs) or as a mathematical model. The quantitative measurement of the signal may include analyte signal intensity and / or internal standard signal intensity. The quantitative measurement of the signal includes analyte quantitative factor, internal standard quantitative factor, analyte qualitative factor and / or internal standard qualitative factor. Therefore, in one embodiment, particularly when MS is a tandem MS, determining at least one chromatogram includes measuring at least one of the analyte quantitative factor, internal standard quantitative factor, analyte qualitative factor and / or internal standard qualitative factor as specified above over time and / or elution time. As will be understood by the technician, elution time can be replaced by any other LC measure that the technician thinks is suitable, particularly replaced by elution volume or retention time.

[0030] As used herein, the term "sample" is a broad term and is given the ordinary and customary meaning to those of ordinary skill in the art and is not limited to a specific or customized meaning. The term specifically refers to, but is not limited to, any arbitrary sample, such as a biological sample. In one embodiment, the sample is a liquid sample, and in further embodiments, an aqueous sample. In one embodiment, the sample can be selected from the group consisting of: physiological fluids, including blood, serum, plasma, saliva, lens fluid, tears, cerebrospinal fluid, sweat, urine, breast milk, ascites, mucus, synovial fluid, peritoneal fluid, and amniotic fluid; lavage fluid; tissue, cells, etc. However, the sample can also be a natural or industrial liquid, particularly surface or groundwater, sewage, industrial wastewater, process fluid, soil eluate, etc. In one embodiment, the sample includes or is suspected of including at least one target chemical compound, i.e., the chemical substance to be determined, which is referred to as the "analyte." The sample may include one or more additional chemical compounds that are not determined and are generally referred to as the "matrix." The sample can be used directly as obtained from the corresponding source, or it can be subjected to one or more pretreatment and / or sample preparation steps. Thus, the sample can be pretreated by physical and / or chemical methods, in one embodiment, by centrifugation, filtration, mixing, homogenization, chromatography, precipitation, dilution, concentration, contact with a binding agent and / or a detection reagent, and / or any other method deemed appropriate by the skilled person. During the sample preparation step, i.e., before, during and / or after the sample preparation step, one or more internal standards can be added to the sample. The sample may be spiked with an internal standard. For example, an internal standard can be added to the sample at a predefined concentration. The internal standard can be selected so that it can be easily identified under normal operating conditions of the mass spectrometer. The concentration of the internal standard can be predetermined and significantly higher than the concentration of the analyte.

[0031] As used herein, the term "internal standard" relates, in one embodiment, to an analyte that is present in a sample at a defined concentration. Thus, in one embodiment, the concentration of the internal standard is known; however, it is also conceivable that the concentration of the internal standard is unknown, but is the same for at least the sample of interest and at least one calibration sample; in this case, in one embodiment, the concentration of the internal standard is the same for all analyzed samples. In one embodiment, the internal standard is structurally similar to the analyte, and in a further embodiment, is structurally identical to the analyte. In particular in the latter case, in one embodiment, the internal standard is an isotopically labeled molecule, in particular an isotopically labeled form of the analyte, such as 2 H (deuterated), 15 N and / or 13 The internal standard sample may be a sample comprising at least one internal standard substance with a known (eg predetermined) concentration. For more detailed information on standard samples, see, for example, EP 3 425 369 A1.

[0032] As used herein, the term "subject" is a broad term and will be given its common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customary meaning. The term specifically refers to, but is not limited to, mammals. In an embodiment of the present invention, the subject is a human. Specifically, the subject can be a patient. According to the present invention, a patient may generally suffer from or be suspected of having a disease, that is, they may have shown some or all of the negative symptoms associated with the disease. As used herein, the term "subject sample" is a broad term and will be given its common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customary meaning. The term specifically refers to, but is not limited to, a biological sample of a subject. A group of patient samples can include multiple different samples from at least one subject. The group of patient samples can be a group of representative samples. Typically, the group of patient samples can include 5 to 30 samples. However, the group of patient samples can include more than 30 samples.

[0033] The term "calibrator sample" is a broad term and is given a common and customary meaning to those of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically refers to, but is not limited to, any sample having a known concentration of the substance of the calibrator sample. For example, the concentration value of the calibrator sample can be determined by a reference laboratory. For example, the calibrator sample can be at least one commercial calibrator. A set of calibrator samples can include a plurality of different calibrator samples. The calibrator sample can be or can include a sample with a specified target value. For example, a set of calibrator samples can include two to three calibrator samples. A set of calibrator samples can include at least one calibrator sample. A set of calibrator samples can include 4 to 10 calibrator samples.

[0034] The term "adjustment factor" is a broad term and is to be given the ordinary and customary meaning to one of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically refers to, but is not limited to, a factor used to correct the initial target value of the quantifier-qualifier ratio for the analyte and / or for the internal standard determined on the customer's mass spectrometer instrument for measurement imprecision and bias due to matrix differences between calibrators and subject samples.

[0035] The method comprises determining at least three adjustment factors from measurements of a set of subject samples and a set of calibrator samples. The method may comprise evaluating a determined chromatogram and determining a quantitative factor-qualitative factor ratio from the chromatogram. The evaluation may comprise determining the peak area of the quantitative peak of the chromatogram and determining the peak area of the qualitative peak of the chromatogram. The evaluation may comprise determining the ratio of the peak area of the quantitative peak to the peak area of the qualitative peak. Step a) may comprise determining the median quantitative factor-qualitative factor ratio for the analyte and the internal standard for the calibrator sample and the subject sample for each of a plurality of mass spectrometers. The adjustment factor may be determined by using an inter-instrument average. The first adjustment factor α depends on the difference, in particular the relationship, between the analyte and the internal standard. In step a), the first adjustment factor α may be determined by the following formula: α=R 平均值，AQN / AQL / R 平均值，IQN / IQL , where R 平均值，AQN / AQL is the average value of the quantitative factor-qualifier ratio of the analyte measured multiple times in step a), and R 平均值，IQN / IQL is the average of the internal standard quantitative factor-qualifier ratios of the multiple measurements in step a). The second adjustment factor β depends on the difference in the quantitative factor-qualifier ratio for the analyte between the subject sample and the calibrator sample. In step a), the second adjustment factor β can be determined by the following formula: β = R 平均值，患者，AQN / AQL / R 平均值，校准品，AQN / AQL , where R 平均值，患者，AQN / AQL is the average value of the quantitative factor-qualifier ratio of the analyte measured multiple times for the subject sample in step a), and R 平均值，校准品，AQN / AQL is the average of the quantification factor-qualification factor ratios of the analyte measured multiple times for the calibrator sample in step a). The third adjustment factor γ depends on the difference between the subject sample and the calibrator sample for the internal standard quantification factor-qualification factor ratio. In step a), the third adjustment factor γ can be determined by the following formula: γ = R 平均值，患者，IQN / IQL / R 平均值，校准品，IQN / IQL , where R 平均值，患者，IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of multiple measurements of the subject sample in step a), and R 平均值，校准品，IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of multiple measurements of the calibrator sample in step a).

[0036] The term "transmission" is a broad term and has a common and customary meaning for those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, one-way or two-way information exchange, particularly data exchange. Transmission can include the transmission of information from a computing device (e.g., a computer), such as to send or output the information to, for example, another device. The transmission can be performed via at least one communication interface. As used herein, the term "communication interface" is a broad term and has a common and customary meaning for those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, items or elements that form a boundary configured for transmitting information. In particular, a communication interface can be configured to transmit information from a computing device (e.g., a computer), such as to send or output the information to, for example, another device. Additionally or alternatively, a communication interface can be configured to transmit information to a computing device (e.g., a computer), such as to receive information. A communication interface can specifically provide a means for transmitting or exchanging information. In particular, a communication interface can provide a data transmission connection, such as Bluetooth, NFC, inductive coupling, etc. As an example, the communication interface may be or may include at least one port, which includes one or more of a network or Internet port, a USB port, and a disk drive. The communication interface may be at least one Web interface. The term "electronically transmitted" is a broad term and will be given the common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customized meaning. The term specifically may refer to, but is not limited to, transmission using at least one electronic data transmission technology, in particular, using at least one transmission protocol. Specifically, electronic transmission may include: downloading at least one parameter file from a dedicated database at least once. Transmission may include: the customer mass spectrometer retrieving information from the manufacturer. As used herein, the term "retrieval" is a broad term and is given the common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customized meaning. The term specifically may refer to, but is not limited to, such as receiving data and / or downloading data from a data server.

[0037] The term "customer site" is a broad term and has the ordinary and customary meaning for those skilled in the art, and is not limited to a specific or customary meaning. The term specifically refers to, but is not limited to, calibration performed by the customer. Thus, such calibration may be performed without the manufacturer's knowledge. However, the manufacturer may provide support to the customer if necessary.

[0038] The present invention proposes to divide calibration into two parts. In the first part, standardization can be performed at the manufacturer's site, and in the second part, calibration is performed on the customer's mass spectrometer. Standardization can be performed before performing customer site calibration. Customer site calibration includes at least one calibration measurement, wherein a group of calibration samples are measured on the customer's mass spectrometer. A group of calibration samples for customer site calibration can be the same as a group of calibration samples for manufacturer site standardization. A group of calibration samples can be provided by the manufacturer. The calibration measurement can include multiple measurements (such as multiple calibration samples in a group of calibration samples) and multiple repetitions. The calibration measurement can include: performing multiple reaction monitoring by quantitative factor and qualitative factor transitions for analyte and / or internal standard. The calibration measurement can include: determining at least one chromatogram for each measurement of the sample. The calibration measurement can include: determining the initial target value for the quantitative factor-qualitative factor ratio for the analyte and for the internal standard. The initial target value can be determined by evaluating the chromatogram and determining the quantitative factor-qualitative factor ratio from the chromatogram.

[0039] The target values for the quantifier-qualifier ratios for the analyte and for the internal standard, also referred to as initial target values, are set by applying adjustment factors to the determined quantifier-qualifier ratios. In step c), all quantifier-qualifier ratios determined during the calibration measurements can be used to set the target values. In particular, all calibrator levels and all calibrator replicates for the analyte and the internal standard can be used to set the target values. Quantifier-qualifier ratios for the analyte quantifier AQN and the analyte qualifier AQL The target value can be set by the following formula:

[0040]

[0041] Where R is the quantifier-qualifier peak area ratio of a single measurement, IQN is the internal standard quantifier, IQL is the internal standard qualifier, and N is the total number of quantifier-qualifier ratios used for calculation. Quantifier-qualifier ratios for internal standard quantifier IQN and internal standard qualifier IQL The target value of is set by:

[0042]

[0043] Where R is the quantifier-qualifier peak area ratio for a single measurement, AQN is the analyte quantifier, AQL is the analyte qualifier, and N is the total number of quantifier-qualifier ratios used in the calculation. These target values can be instrument-specific, can be based on natural patient samples, and can have better accuracy due to the use of multiple data points. With assay-specific calibration frequency, time variations can be corrected regularly.

[0044] In another aspect, a computer-implemented method for calibrating a quantifier-qualifier ratio on a customer mass spectrometer is disclosed. The method includes performing calibration of the customer mass spectrometer according to a computer-implemented method for calibrating a customer mass spectrometer for a quantifier-qualifier ratio calibration according to the present invention. Therefore, for definitions and embodiments of the method for calibrating a quantifier-qualifier ratio, reference is made to definitions and embodiments of the method for calibrating a customer mass spectrometer for a quantifier-qualifier ratio calibration according to the present invention, as described in detail above or in more detail below.

[0045] The method comprises at least one sample measurement performed using a customer mass spectrometer. The method further comprises at least one sample analysis step, wherein during sample analysis for each sample measurement, a quantifier-qualifier ratio for the analyte and / or internal standard is determined and compared to a target value taking into account at least one acceptance criterion.

[0046] As used herein, the term "sample measurement" is a broad term and is given its ordinary and customary meaning to those of ordinary skill in the art, and is not limited to a special or customary meaning. The term specifically may refer to, but is not limited to, the process of measuring a sample using a mass spectrometer. As used herein, the term "sample analysis" is a broad term and is given its ordinary and customary meaning to those of ordinary skill in the art, and is not limited to a special or customary meaning. The term specifically may refer to, but is not limited to, the process of evaluating the signals of a mass spectrometer. Sample analysis may include determining at least one chromatogram. Sample analysis may include evaluating the chromatogram and determining at least one quantitative factor-qualitative factor ratio.

[0047] As used herein, the term "acceptance criteria" is a broad term and will be given the common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customized meaning. The term specifically refers to, but is not limited to, any standard that characterizes a quantitative factor-qualifier ratio as acceptable or rejected. The acceptance criteria or multiple acceptance criteria can be determined during assay development. At least one acceptance criteria may not be instrument-specific and may not change over time. At least one acceptance criteria can be electronically transmitted to the customer's instrument via an application parameter file. The acceptance criteria may include at least one tolerance limit or tolerance range. The acceptance criteria can be used for peak identity verification. The acceptance criteria can be used to distinguish between quantitative ions and interferences. The acceptance criteria can characterize whether the quantitative factor-qualifier ratio measured by the customer's mass spectrometer is appropriate. The quantitative factor-qualifier ratio below the tolerance limit or within the tolerance range can be verified. The method may further include: marking each sample measurement that does not meet the acceptance criteria in the sample measurement. The quantitative factor-qualifier ratio that is above the tolerance limit or not within the tolerance range may be marked and requires further review by the operator or user of the customer's mass spectrometer.

[0048] This document further discloses and proposes a computer program product having program code tools, wherein the program code tools can be stored on a storage medium or stored thereon for performing, when the program code tools are executed on a computer or computer network, a computer-implemented method for calibrating a customer's mass spectrometer for quantitative factor-qualifier ratio verification according to the present invention and / or a computer-implemented method for quantitative factor-qualifier ratio verification on a customer's mass spectrometer according to the present invention.

[0049] The present invention further discloses and proposes a computer program product having program code means, wherein the program code means can be stored on or stored on a storage medium for executing, when the program code means is executed on a computer or computer network, a computer-implemented method for calibrating a customer's mass spectrometer for a quantifier-qualifier ratio calibration according to the present invention and / or a computer-implemented method for quantifier-qualifier ratio calibration on a customer's mass spectrometer according to the present invention. Specifically, the program code means can be stored on a computer-readable data carrier and / or a computer-readable storage medium.

[0050] As used herein, the terms "computer-readable data carrier" and "computer-readable storage medium" may specifically refer to a non-transitory data storage device, such as a hardware storage medium having computer-executable instructions stored thereon. A computer-readable data carrier or storage medium may specifically be or may include a storage medium such as a random access memory (RAM) and / or a read-only memory (ROM).

[0051] Thus, in particular, one, more than one or even all method steps a) to c) as indicated above may be performed by using a computer or a computer network, preferably by using a computer program.

[0052] The present invention further discloses and proposes a data carrier having a data structure stored thereon, which, after being loaded into a computer or a computer network, such as after being loaded into a working memory or main memory of the computer or the computer network, can perform one or both methods according to one or more embodiments disclosed herein.

[0053] This document further discloses and proposes a computer program product having program code means stored on a machine-readable carrier, so that when the program is executed on a computer or computer network, one or both of the methods according to one or more embodiments disclosed herein are performed. As used herein, a computer program product refers to a program that is a tradable product. The product can generally be in any format (such as paper format) or on a computer-readable data carrier and / or computer-readable storage medium. Specifically, the computer program product can be distributed over a data network.

[0054] Finally, disclosed and proposed herein is a modulated data signal containing instructions readable by a computer system or computer network for executing one or both methods according to one or more embodiments disclosed herein.

[0055] With reference to the computer-implemented aspects of the present invention, one or more method steps or even all method steps of one or both methods according to one or more embodiments disclosed herein can be performed using a computer or a computer network. Thus, generally speaking, any method step including providing and / or processing data can be performed using a computer or a computer network. Generally speaking, these method steps can include any method step other than method steps that typically require manual operation (such as providing samples and / or performing certain aspects of the actual measurement).

[0056] In another aspect of the present invention, a mass spectrometry system for determining the concentration of at least one analyte in a sample is disclosed. The mass spectrometry system comprises:

[0057] - A manufacturing site calibration system comprising a plurality of mass spectrometry instruments configured to measure a set of subject samples and a set of calibrator samples in a plurality of replicates, wherein each of the mass spectrometry instruments is configured to perform multiple reaction monitoring with quantifier and qualifier transitions for an analyte and an internal standard, wherein the manufacturing site calibration system comprises at least one processing unit configured to determine at least three adjustment factors from the plurality of measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α depends on a difference between the analyte and the internal standard, wherein a second adjustment factor β depends on a difference in a ratio of the quantifier to the qualifier for the analyte between the subject samples and the calibrator samples, and wherein a third adjustment factor γ depends on a difference in a ratio of the quantifier to the qualifier for the internal standard between the subject samples and the calibrator samples;

[0058] - at least one communication interface configured to electronically transmit the adjustment factors from the manufacturing site calibration system to at least one customer mass spectrometer; and

[0059] at least one customer mass spectrometer, wherein the customer mass spectrometer is configured to perform at least one calibration measurement, wherein in the calibration measurement a set of calibrator samples are measured on the customer mass spectrometer, wherein the customer mass spectrometer comprises at least one evaluation device configured to determine a quantifier-qualifier ratio from the calibration measurement, wherein the evaluation device is configured to set a target value for the quantifier-qualifier ratio for the analyte and for the internal standard by applying an adjustment factor to the determined quantifier-qualifier ratio.

[0060] The mass spectrometry instrument may be a liquid chromatography mass spectrometry (LC-MS) device.

[0061] The customer mass spectrometer can be configured to perform at least one sample measurement. The evaluation device can be configured to perform at least one sample analysis, wherein during the sample analysis for each sample measurement, a quantifier-qualifier ratio for the analyte and / or the internal standard is determined and compared to a target value taking into account at least one acceptance criterion.

[0062] As used herein, the term "processing unit" is a broad term and is given the ordinary and customary meaning to those of ordinary skill in the art and is not limited to a special or customized meaning. The term may specifically refer to, but is not limited to, any device suitable for performing the method steps described above, in one embodiment by using at least one data processing device, and in other embodiments by using at least one processor and / or at least one application specific integrated circuit. Thus, as an example, at least one processing unit may include at least one data processing unit having software code stored thereon, the software code comprising a plurality of computer commands. The processing unit may provide one or more hardware elements for performing one or more indicated operations, and / or may provide one or more processors with software running thereon for performing one or more method steps.

[0063] As used herein, the term "evaluation device" is a broad term and is given the ordinary and customary meaning to those of ordinary skill in the art and is not limited to a special or customized meaning. The term specifically refers to, but is not limited to, any device suitable for performing the method steps described above, in one embodiment by using at least one data processing device, and in other embodiments by using at least one processor and / or at least one application specific integrated circuit. Thus, as an example, at least one evaluation device may include at least one data processing unit having software code stored thereon, the software code comprising a plurality of computer commands. The evaluation device may provide one or more hardware elements for performing one or more of the indicated operations, and / or may provide one or more processors with software for executing the one or more method steps.

[0064] The system can be configured to perform a computer-implemented method for calibrating a customer's mass spectrometer for quantifier-qualifier ratio calibration according to the present invention and / or a computer-implemented method for quantifier-qualifier ratio calibration on a customer's mass spectrometer according to the present invention. Therefore, for definitions and embodiments of the system, reference is made to the embodiments and definitions of the method according to the present invention as described above and in more detail below.

[0065] Summarizing and without excluding further possible embodiments, the following embodiments may be envisaged:

[0066] Example 1: A computer-implemented method for calibrating a customer's mass spectrometer for a quantifier-qualifier ratio calibration, the method comprising the following steps:

[0067] a) at least one manufacturer's on-site standardization, wherein a set of subject samples and a set of calibrator samples are measured in multiple replicates on multiple mass spectrometry instruments, wherein each measurement comprises multiple reaction monitoring by quantifier and qualifier transitions for an analyte and an internal standard, wherein at least three adjustment factors are determined from the multiple measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α is dependent on the difference between the analyte and the internal standard, wherein a second adjustment factor β is dependent on the difference in the ratio of the quantifier to the qualifier for the analyte between the subject sample and the calibrator sample, and wherein a third adjustment factor γ is dependent on the difference in the ratio of the quantifier to the qualifier for the internal standard between the subject sample and the calibrator sample;

[0068] b) at least one transmission step, wherein the adjustment factors are electronically transmitted to a customer mass spectrometer;

[0069] c) at least one customer on-site calibration, wherein the customer on-site calibration comprises at least one calibration measurement, wherein a set of calibrator samples are measured on the customer mass spectrometer instrument and quantifier-qualifier ratios are determined from the set of calibrator samples, wherein target values for the quantifier-qualifier ratios for the analyte and for the internal standard are set by applying an adjustment factor to the determined quantifier-qualifier ratios.

[0070] Embodiment 2: The method according to the preceding embodiment, wherein in step c), all quantifier-qualifier ratios determined during the calibration measurements are used for setting the target value, wherein all calibrator levels and all calibrator replicates for the analyte and the internal standard are used for setting the target value.

[0071] Embodiment 3: The method according to any one of the preceding embodiments, wherein the quantifier-qualifier ratio for the analyte quantifier AQN and the analyte qualifier AQL is The target value of is set by:

[0072]

[0073] where R is the quantifier-qualifier peak area ratio of a single measurement, IQN is the internal standard quantifier, IQL is the internal standard qualifier, and N is the total number of quantifier-qualifier ratios used for the calculation.

[0074] Embodiment 4: The method according to any one of the preceding embodiments, wherein the quantitative factor-qualifier ratio for the internal standard quantitative molecule IQN and the internal standard qualitative factor IQL The target value of is set by:

[0075]

[0076] where R is the quantifier-qualifier area ratio for a single measurement, AQN is the analyte quantifier, AQL is the analyte qualifier, and N is the total number of quantifier-qualifier ratios used in the calculation.

[0077] Embodiment 5: The method according to any one of the preceding embodiments, wherein in step a), the first adjustment factor α is determined by the following formula: α=R 平均值，AQN / AQL / R 平均值，IQN / IQL , where R 平均值，AQN / AQL is the average value of the quantitative factor-qualifier ratio of the analyte measured multiple times in step a), and R 平均值，IQN / IQL is the average value of the ratio of the internal standard quantitative factor to the qualitative factor measured multiple times in step a).

[0078] Embodiment 6: The method according to any one of the preceding embodiments, wherein in step a), the second adjustment factor β is determined by the following formula: β=R 平均值，患者，AQN / AQL / R 平均值，校准品，AQN / AQL , where R 平均值，患者，AQN / AQL is the average value of the quantitative factor-qualifier ratio of the analyte measured multiple times for the subject sample in step a), and R 平均值，校准品，AQN / AQL is the average of the quantification factor to qualifier ratios of the analyte from multiple measurements of the calibrator sample of step a).

[0079] Embodiment 7: The method according to any one of the preceding embodiments, wherein in step a), the third adjustment factor γ is determined by the following formula: γ=R 平均值，患者，IQN / IQL / R 平均值，校准品，IQN / IQL , where R 平均值，患者，IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of multiple measurements of the subject sample in step a), and R 平均值，校准品 , IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of multiple measurements of the calibrator sample in step a).

[0080] Embodiment 8: The method according to any one of the preceding embodiments, wherein step a) comprises determining, for each of a plurality of mass spectrometry instruments, the median quantifier-qualifier ratio for the analyte and the internal standard for the calibrator sample and the subject sample.

[0081] Embodiment 9: The method according to the preceding embodiment, wherein the adjustment factor is determined by using an inter-instrument average.

[0082] Embodiment 10: The method according to any one of the preceding embodiments, wherein the mass spectrometer used in step a) and step c) is a liquid chromatography mass spectrometer (LC-MS) device.

[0083] Example 11: A computer-implemented method for quantifier-qualifier ratio calibration on a customer mass spectrometer, wherein the method includes: performing calibration of the customer mass spectrometer according to the computer-implemented method for calibrating the customer mass spectrometer for quantifier-qualifier ratio calibration according to any one of the preceding embodiments, wherein the method includes: at least one sample measurement performed using the customer mass spectrometer, wherein the method further includes at least one sample analysis step, wherein during the sample analysis for each sample measurement, the quantifier-qualifier ratio for the analyte and / or internal standard is determined and compared with a target value taking into account at least one acceptance criterion.

[0084] Embodiment 12: The method according to the preceding embodiment, wherein the method further comprises: marking each sample measurement that does not meet the acceptance criteria.

[0085] Embodiment 13: The method according to the preceding embodiment, wherein the method further comprises: reviewing the labeled sample measurements.

[0086] Embodiment 14: A computer program product having a program code tool, wherein the program code tool can be stored on a storage medium or stored thereon for performing, when the program code tool is executed on a computer or on a computer network, a computer-implemented method for calibrating a customer mass spectrometer for quantitative factor-qualifier ratio verification according to any one of the aforementioned embodiments relating to a method for calibrating a customer mass spectrometer and / or a computer-implemented method for quantitative factor-qualifier ratio verification on a customer mass spectrometer according to any one of the aforementioned embodiments relating to a method for quantitative factor-qualifier ratio verification.

[0087] Embodiment 15: A computer program product having a program code tool, wherein the program code tool can be stored on a storage medium or stored thereon for performing, when the program code tool is executed on a computer or on a computer network, a computer-implemented method for calibrating a customer mass spectrometer for quantitative factor-qualifier ratio verification according to any one of the aforementioned embodiments relating to a method for calibrating a customer mass spectrometer and / or a computer-implemented method for quantitative factor-qualifier ratio verification on a customer mass spectrometer according to any one of the aforementioned embodiments relating to a method for quantitative factor-qualifier ratio verification.

[0088] Example 16: A mass spectrometry system for determining the concentration of at least one analyte in a sample, the mass spectrometry system comprising:

[0089] - A manufacturing site calibration system comprising a plurality of mass spectrometry instruments configured to measure a set of subject samples and a set of calibrator samples in a plurality of replicates, wherein each of the mass spectrometry instruments is configured to perform multiple reaction monitoring with quantifier and qualifier transitions for an analyte and an internal standard, wherein the manufacturing site calibration system comprises at least one processing unit configured to determine at least three adjustment factors from the plurality of measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α depends on a difference between the analyte and the internal standard, wherein a second adjustment factor β depends on a difference in a ratio of the quantifier to the qualifier for the analyte between the subject samples and the calibrator samples, and wherein a third adjustment factor γ depends on a difference in a ratio of the quantifier to the qualifier for the internal standard between the subject samples and the calibrator samples;

[0090] - at least one communication interface configured to electronically transmit the adjustment factors from the manufacturing site calibration system to at least one customer mass spectrometer; and

[0091] at least one customer mass spectrometer, wherein the customer mass spectrometer is configured to perform at least one calibration measurement, wherein in the calibration measurement a set of calibrator samples are measured on the customer mass spectrometer, wherein the customer mass spectrometer comprises at least one evaluation device configured to determine a quantifier-qualifier ratio from the calibration measurement, wherein the evaluation device is configured to set a target value for the quantifier-qualifier ratio for the analyte and for the internal standard by applying an adjustment factor to the determined quantifier-qualifier ratio.

[0092] Example 17: A system according to the preceding embodiments, wherein the system is configured to perform a computer-implemented method for calibrating a customer mass spectrometer for a quantifier-qualifier ratio calibration according to any one of the preceding embodiments involving methods for calibrating a customer mass spectrometer and / or a computer-implemented method for a quantifier-qualifier ratio calibration on a customer mass spectrometer according to any one of the preceding embodiments involving methods for calibrating a customer mass spectrometer.

[0093] Embodiment 18: The system according to any of the preceding embodiments directed to systems, wherein the mass spectrometry instrument is a liquid chromatography mass spectrometry (LC-MS) device. BRIEF DESCRIPTION OF THE DRAWINGS

[0094] Further optional features and embodiments will be disclosed in more detail in the subsequent description of embodiments, preferably in conjunction with the dependent claims. As will be appreciated by those skilled in the art, each optional feature may be implemented individually and in any feasible combination. The scope of the present invention is not limited by the preferred embodiments. Embodiments are schematically depicted in the accompanying drawings. Identical reference numerals in these drawings refer to identical or functionally equivalent elements.

[0095] In the attached figure:

[0096] Figure 1 An embodiment of a mass spectrometry system according to the present invention is shown;

[0097] Figure 2 A computer-implemented method for calibrating a customer's mass spectrometer for a quantifier-qualifier ratio calibration according to the present invention and a computer-implemented method for quantifier-qualifier ratio calibration on a customer's mass spectrometer according to the present invention are shown; and

[0098] Figure 3A and Figure 3B Experimental results. DETAILED DESCRIPTION

[0099] Figure 1Shown is an embodiment of a mass spectrometry system 110 according to the present invention. Mass spectrometry system 110 includes a manufacturing site calibration system 112, which includes a plurality of mass spectrometers 114 configured to measure a group of subject samples and a group of calibrator samples with multiple repetitions. Each of mass spectrometers 114 is configured to monitor multiple reactions by transitions of quantitative factors and qualitative factors for analytes and internal standards. Mass spectrometry (MS) instrument 114 can be a mass analyzer configured to detect at least one analyte based on mass-to-charge ratio. Each mass spectrometer in mass spectrometer 114 can be or can include at least one quadrupole mass spectrometry device. MS instrument 114 can be a tandem mass spectrometry (MS / MS) instrument or a triple quadrupole MS / MS. Specifically, mass spectrometer 114 can be configured to perform multiple reaction monitoring (MRM).

[0100] The mass spectrometer 114 may be specifically or may include a liquid chromatography mass spectrometer. The liquid chromatography mass spectrometer may be or may include at least one high performance liquid chromatography (HPLC) device or at least one microfluidic liquid chromatography (μLC) device. The liquid chromatography mass spectrometer may include a liquid chromatography (LC) device and a mass spectrometer (MS) device, wherein the LC device and the MS are coupled via at least one interface. The interface coupling the liquid chromatography device and the MS may include at least one ionization source configured to generate molecular ions and to transfer the molecular ions into the gas phase. The liquid chromatography (LC) device may be configured to separate one or more target analytes of a sample from other components of the sample for detection of the one or more analytes using the mass spectrometer 114. The LC device may be based on any separation principle deemed suitable by a skilled person; in one embodiment, the LC device may be reverse phase chromatography, hydrophobic interaction chromatography, ion exchange chromatography, size exclusion chromatography, affinity chromatography, or chiral chromatography; in another embodiment, the LC device is a reverse phase chromatography. The LC device may include at least one LC column. For example, the LC device can be a single-column LC device or a multi-column LC device having multiple LC columns.The LC column can have a stationary phase through which a mobile phase is pumped to separate and / or elute and / or transport the target analyte.

[0101] The manufacturer can be at least one producer of mass spectrometer 114. The manufacturer can also be a single manufacturer and / or multiple manufacturers that produce all parts of mass spectrometer 114, such as suppliers of specific components of mass spectrometer 114. The manufacturer can be the final manufacturer that provides the final product for use by the customer. As used herein, "manufacturer site" is a broad term and is given a common and customary meaning for those of ordinary skill in the art, and is not limited to a special or customized meaning. The term specifically can refer to, but is not limited to, all processes performed by the manufacturer before providing the mass spectrometer to the customer. All reagents, chromatographic columns, calibrators, system reagents, and disposables can be produced by or for the manufacturer. In contrast, at the customer site, the customer can place the subject's sample and control sample on the instrument as non-manufacturer parts.

[0102] The manufacturing site calibration system 112 includes at least one processing unit 116 configured to determine at least three adjustment factors from measurements of a set of subject samples and a set of calibrator samples. The processing unit 116 may be adapted to determine the three adjustment factors using at least one data processing device and, in another embodiment, using at least one processor and / or at least one application specific integrated circuit. Thus, as an example, the at least one processing unit 116 may include at least one data processing unit having software code stored thereon, the software code comprising a plurality of computer commands. The processing unit 116 may provide one or more hardware elements for performing one or more indicated operations and / or may provide one or more processors with software running thereon for performing the determination of the adjustment factors.

[0103] The adjustment factor can be determined during standardization at the manufacturer's site. Standardization can be or include the process of determining an estimate of the imprecision of the measured quantitative factor-qualifier ratio and bias due to matrix differences between the calibrator and the subject sample and providing corrections therefor. Standardization can include determining a chromatogram for each measurement of the sample. A chromatogram can be a correlation plot of a quantitative measure of a signal obtained from the sample and determined by the MS instrument 114, in one embodiment, over time, such as retention time and / or elution volume, and the progress of the chromatographic separation. In one embodiment, the quantitative measure of the signal is associated with the concentration of at least a portion of the sample components, particularly the concentration of the analyte; thus, the quantitative measure of the signal can be particularly signal intensity. The chromatogram can be an MS chromatogram, and in another embodiment, an MS / MS chromatogram. As will be understood by those skilled in the art, the above representation can be, but is not necessarily, a graphical representation; however, the representation can also be provided, for example, as a list of value pairs (e.g., elution time / quantitative factor value pairs and / or elution time / qualitative factor value pairs) or as a mathematical model. The quantitative measure of the signal can include analyte signal intensity and / or internal standard signal intensity. The quantitative measure of the signal comprises an analyte quantitative factor, an internal standard quantitative factor, an analyte qualitative factor and / or an internal standard qualitative factor. Thus, in one embodiment, particularly where the MS is a tandem MS, determining at least one chromatogram comprises measuring at least one of the analyte quantitative factor, internal standard quantitative factor, analyte qualitative factor and / or internal standard qualitative factor as specified above over time and / or elution time. As will be appreciated by the skilled person, elution time may be replaced by any other measure of LC progression deemed appropriate by the skilled person, particularly by elution volume or retention time.

[0104] Adjustment factors may be or include factors used to correct initial target values for the quantifier-qualifier ratio for the analyte and / or the internal standard, determined on the client mass spectrometer 118, for measurement imprecision and bias due to matrix differences between the calibrator and the subject sample. Processing unit 116 may be configured to determine at least three adjustment factors from measurements of a set of subject samples and a set of calibrator samples. Processing unit 116 may be configured to evaluate the determined chromatogram and determine the quantifier-qualifier ratio from the chromatogram. Processing unit 116 may be or include at least one evaluation device. Evaluation may include determining the peak area of a quantitative peak in the chromatogram and determining the peak area of a qualitative peak in the chromatogram. Evaluation may include determining the ratio of the peak area of the quantitative peak to the peak area of the qualitative peak. Processing unit 116 may be configured to determine, for each of the plurality of mass spectrometers, the median quantifier-qualifier ratio for the analyte and the internal standard for the calibrator sample and the subject sample. The adjustment factors may be determined by using an inter-instrument average. A first adjustment factor α depends on the difference between the analyte and the internal standard. The first adjustment factor α can be determined by the following formula: α = R 平均值，AQN / AQL / R 平均值，IQN / IQL , where R 平均值，AQN / AQL is the average value of the quantitative factor-qualifier ratio of the analyte measured multiple times, and R 平均值，IQN / IQL The second adjustment factor β depends on the difference between the quantitative factor and the qualitative factor ratio of the analyte between the subject sample and the calibrator sample. The second adjustment factor β can be determined by the following formula: β = R 平均值，患者，AQN / AQL / R 平均值，校准品，AQN / AQL , where R 平均值，患者，AQN / AQL is the average of the quantification factor-qualification factor ratios of the analyte from multiple measurements of the subject sample, and R 平均值，校准品，AQN / AQL The third adjustment factor γ depends on the difference between the quantitative factor and the qualitative factor ratio of the internal standard between the subject sample and the calibrator sample. The third adjustment factor γ can be determined by the following formula: γ = R 平均值，患者，IQN / IQL / R 平均值，校准品，IQN / IQL , where R 平均值，患者，IQN / IQL is the average value of the ratio of the internal standard quantitative factor to the qualitative factor of multiple measurements of the subject sample, and R 平均值，校准品，IQN / IQL The average value of the internal standard quantitative factor-qualifier ratio of multiple measurements of the calibrator sample.

[0105] The mass spectrometry system 110 includes at least one communication interface 120 configured to electronically transmit adjustment factors from the manufacturing site calibration system 112 to the customer mass spectrometry instrument 118. Figure 1In the figure, the communication interface 120 is represented by two dashed lines. Transmission can be a one-way or two-way information exchange, particularly data exchange. Transmission can include transmitting information from a computing device (e.g., a computer), such as to send or output the information to, for example, another device. The communication interface 120 can form a boundary configured for transmitting data. In particular, the communication interface 120 can be configured to transmit information from a computing device (e.g., a computer), such as to send or output the information to, for example, another device. Additionally or alternatively, the communication interface 120 can be configured to transmit information to a computing device (e.g., a computer), such as to receive information. The communication interface 120 can specifically provide a means for transmitting or exchanging information. In particular, the communication interface 120 can provide a data transmission connection, such as Bluetooth, NFC, inductive coupling, etc. As an example, the communication interface 120 can be or include at least one port, including one or more of a network or Internet port, a USB port, and a disk drive. The communication interface 120 can be at least one web interface. The electronic transmission can be performed using at least one electronic data transmission technology, particularly at least one transmission protocol. Specifically, the electronic transmission may include downloading at least one parameter file at least once from a dedicated database. The transmission may include the customer mass spectrometer 118 retrieving information from the manufacturer, such as by receiving data and / or such as by downloading data from a data server.

[0106] The mass spectrometry system 110 includes at least one customer mass spectrometry instrument 118. The customer mass spectrometry instrument 118 is located at a customer site 122. The customer mass spectrometry instrument 118 is configured to perform at least one calibration measurement, wherein a set of calibrator samples is measured on the customer mass spectrometry instrument 118 during the calibration measurement. The customer mass spectrometry instrument 118 includes at least one evaluation device 124 configured to determine a quantifier-qualifier ratio from the calibration measurement. The evaluation device 124 is configured to set target values for the quantifier-qualifier ratio for the analyte and for the internal standard by applying an adjustment factor to the determined quantifier-qualifier ratio.

[0107] The target values for the quantifier-qualifier ratios for the analyte and for the internal standard, also called initial target values, are set by applying adjustment factors to the determined quantifier-qualifier ratios. All quantifier-qualifier ratios determined during the calibration measurements can be used to set the target values. In particular, all calibrator levels and all calibrator replicates for the analyte and the internal standard can be used to set the target values. Quantifier-qualifier ratios for the analyte quantifier AQN and the analyte qualifier AQL The target value can be set by the following formula:

[0108]

[0109] Where R is the quantifier-qualifier peak area ratio of a single measurement, IQN is the internal standard quantifier, IQL is the internal standard qualifier, and N is the total number of quantifier-qualifier ratios used for calculation. Quantifier-qualifier ratios for internal standard quantifier IQN and internal standard qualifier IQL The target value of is set by:

[0110]

[0111] Where R is the quantifier-qualifier peak area ratio for a single measurement, AQN is the analyte quantifier, AQL is the analyte qualifier, and N is the total number of quantifier-qualifier ratios used in the calculation. These target values can be instrument-specific, can be based on natural patient samples, and can have better accuracy due to the use of multiple data points. With assay-specific calibration frequency, time variations can be corrected regularly.

[0112] The customer mass spectrometer 118 can be configured to perform at least one sample measurement. The evaluation device 124 can be configured to perform at least one sample analysis, wherein during the sample analysis for each sample measurement, a quantifier-qualifier ratio for the analyte and / or internal standard is determined and compared to a target value taking into account at least one acceptance criterion.

[0113] The mass spectrometry system 110 can be configured to perform a quality check based on the quantifier-qualifier ratio. For a quality check based on the quantifier-qualifier ratio, at least one target value is used and compared with the measured quantifier-qualifier ratio. However, the target value may vary or be different depending on the mass spectrometry instrument. Therefore, for quality check, it may be advantageous to use the target value for a specific customer's mass spectrometry instrument. Even temporal variations are possible. Therefore, for quality check, it may be advantageous to use a target value that can be adjusted or adapted repeatedly at the customer site in a timely manner. In addition, for calibration, a small amount of calibrator samples is usually measured, and the composition of these calibrator samples may be different compared to the subject samples. Therefore, a quality check based on the quantifier-qualifier ratio may be strongly affected by measurement inaccuracy and may be biased due to matrix differences between the calibrator and the subject samples. To overcome these problems, the present invention proposes a data transmission method. At the manufacturer's site 112, a set of subject samples and calibrator samples can be measured in multiple replicates on multiple instruments. Three adjustment factors can be determined and electronically transmitted to the customer's mass spectrometry instrument 118. At the customer site 122, calibration measurements can be performed on the calibrator sample, and initial target values for the quantitative factor-qualifier ratio for the analyte and for the internal standard can be determined. Adjustment factors can be applied to the initial target values to calculate adjusted target values for the quantitative factor-qualifier ratio for the analyte and the quantitative factor-qualifier ratio for the internal standard. The adjusted target values are instrument-specific, traceable to the subject sample, and have better accuracy due to the use of multiple data points. Due to the determination of a specific calibration frequency, time drift and time displacement can be regularly corrected. For subsequent sample analysis, at least one acceptance criterion can be used to verify the measured quantitative factor-qualifier ratio.

[0114] Acceptance criteria can characterize the quantitative factor-qualifier ratio as acceptable or rejected. Acceptance criteria or multiple acceptance criteria can be determined during assay development. At least one acceptance criterion may be neither instrument-specific nor time-varying. At least one acceptance criterion can be electronically transmitted to the customer instrument via an application parameter file. The acceptance criteria may include at least one tolerance limit or tolerance range. The acceptance criteria can be used for peak identity verification. The acceptance criteria can be used to distinguish quantitative ions from interferences. The acceptance criteria can characterize whether the quantitative factor-qualifier ratio measured by the customer mass spectrometer 118 is appropriate. The quantitative factor-qualifier ratio below the tolerance limit or within the tolerance range can be verified. The method may further include: marking each sample measurement that does not meet the acceptance criteria in the sample measurement. The quantitative factor-qualifier ratio that is above the tolerance limit or not within the tolerance range may be marked and requires further review by the operator or user of the customer mass spectrometer.

[0115] The present invention proposes to divide calibration into two parts. In the first part, standardization can be performed at the manufacturer's site 112, and in the second part, calibration can be performed on the customer's mass spectrometer 118. Standardization can be performed before performing customer site calibration. Customer site calibration includes at least one calibration measurement, wherein a group of calibration samples are measured on the customer's mass spectrometer 118. A group of calibration samples for customer site calibration can be the same as a group of calibration samples for manufacturer site standardization. A group of calibration samples can be provided by the manufacturer. The calibration measurement can include multiple measurements (such as multiple calibration samples in a group of calibration samples) and multiple repetitions. The calibration measurement can include: performing multiple reaction monitoring by quantitative factor and qualitative factor transitions for analyte and / or internal standard. The calibration measurement can include: determining at least one chromatogram for each measurement of the sample. The calibration measurement can include: determining the initial target value for the quantitative factor-qualifier ratio for the analyte and for the internal standard. The initial target value can be determined by evaluating the chromatogram and determining the quantitative factor-qualifier ratio from the chromatogram.

[0116] Figure 2 A computer-implemented method for calibrating a customer mass spectrometer 118 for quantifier-qualifier ratio calibration according to the present invention and a computer-implemented method for quantifier-qualifier ratio calibration on a customer mass spectrometer 118 according to the present invention are shown. The method includes the following steps:

[0117] a) (denoted by reference numeral 126) at least one manufacturer on-site standardization, wherein a set of subject samples and a set of calibrator samples are measured in multiple replicates on a plurality of mass spectrometer instruments 114, wherein each measurement comprises multiple reaction monitoring by quantifier and qualifier transitions for an analyte and an internal standard, wherein at least three adjustment factors are determined from the multiple measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α is dependent on a difference between the analyte and the internal standard, wherein a second adjustment factor β is dependent on a difference in a ratio of the quantifier to the qualifier for the analyte between the subject sample and the calibrator sample, and wherein a third adjustment factor γ is dependent on a difference in a ratio of the quantifier to the qualifier for the internal standard between the subject sample and the calibrator sample;

[0118] b) (denoted by reference numeral 128) at least one transmission step, wherein the adjustment factors are electronically transmitted to the customer mass spectrometer 118;

[0119] c) (denoted by reference numeral 130) at least one customer on-site calibration, wherein the customer on-site calibration comprises at least one calibration measurement, wherein a set of calibrator samples are measured on the customer mass spectrometer instrument 118 and quantifier-qualifier ratios are determined from the set of calibrator samples, wherein target values for the quantifier-qualifier ratios for the analyte and for the internal standard are set by applying adjustment factors to the determined quantifier-qualifier ratios.

[0120] The computer-implemented method for quantifier-qualifier ratio calibration on a customer mass spectrometer 118 includes steps a) through c). Furthermore, the method for quantifier-qualifier ratio calibration includes at least one sample measurement (indicated by reference numeral 132) performed using the customer mass spectrometer 118. The method further includes at least one sample analysis step (indicated by reference numeral 134), wherein during sample analysis for each sample measurement, a quantifier-qualifier ratio for the analyte and / or internal standard is determined and compared to a target value that takes into account at least one acceptance criterion.

[0121] Figure 3A and Figure 3B The experimental result of testosterone test case (particularly for the quantitative LCMS mensuration of testosterone in human serum or blood plasma) is shown.Automatic sample preparation is completed on robot workstation, LC separation is completed on commercial HPLC system, and by utilizing respectively for the quantitative factor and the qualitative factor transition of analyte and internal standard, multiple reaction monitoring is carried out to complete mass spectrometry detection.For the manufacturer's on-site standardization carried out on two mass spectrometers 114, calibrator and patient sample were measured with two days twice of repeated measurement.Intermediate value quantitative factor-qualitative factor ratio of calibrator and patient sample on two mass spectrometers 114 is calculated.

[0122]

[0123] By using the inter-instrument average, the adjustment factors α, β, and γ were determined:

[0124] -α=1.001

[0125] -β=1.003

[0126] -γ=0.998.

[0127] At the customer site 122, sample measurements were performed under customer conditions. Two calibrator levels were measured in triplicate on the customer's mass spectrometer 118 over one day and used for calibration and target value setting. Thirty patient samples were measured in multiple replicates over 10 days, and a quantifier-qualifier ratio calibration was applied.

[0128] QQ ratio verification Analytes Internal standard Target value 1.15 1.14 Acceptance range (±20%) ±0.23 ±0.23

[0129] Figure 3A and Figure 3B Experimental results for the testosterone test case are shown. Figure 3A The quantitative factor-qualifier ratio QQ of the analyte is shown ana Relative to Area Ratio. The Area Ratio is the ratio of the peak area of the quantifier of the analyte to the peak area of the quantifier of the internal standard. Figure 3B The quantitative factor-qualifier ratio QQ of the internal standard is shown ISTD Relative to the area ratio. The solid lines show a target value of 1.15 for the analyte and a target value of 1.14 for the internal standard. Additionally, an acceptance range of ±20% is depicted. This demonstrates that the target values of 1.15 for the analyte and 1.14 for the internal standard, determined using adjustment factors from the manufacturer's on-site standardization, are applicable over the entire measuring range of the customer's mass spectrometer.

[0130] Reference Signs List

[0131] 110 Mass Spectrometry System

[0132] 112 Manufacturer Site

[0133] 114 Mass Spectrometer

[0134] 116 processing units

[0135] 118 Mass Spectrometer

[0136] 120 Communication Interface

[0137] 122 Customer Site

[0138] 124 Evaluation Device

[0139] 126 Manufacturer Site Standardization

[0140] 128 transmission steps,

[0141] 130 Customer On-site Calibration

[0142] 132 Sample Measurement

[0143] 134 Sample Analysis Steps

Claims

1. A computer-implemented method for calibrating a customer mass spectrometer (118) for a quantifier-qualifier ratio calibration, the method comprising the steps of: a) at least one manufacturer's on-site standardization, wherein a set of subject samples and a set of calibrator samples are measured in multiple replicates on a plurality of mass spectrometry instruments (114), wherein each measurement comprises multiple reaction monitoring by quantitative factor and qualitative factor transitions for an analyte and an internal standard, wherein at least three adjustment factors are determined from the measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α is dependent on the difference between the analyte and the internal standard, wherein the first adjustment factor α is given by α=R 平均值,AQN / AQL / R 平均值,IQN / IQL OK, where R 平均值,AQN / AQL is the average value of the quantitative factor-qualifier ratio of the analyte measured multiple times in step a), and R 平均值,IQN / IQL is the average of the internal standard quantitative factor-qualifier ratios of the multiple measurements of step a), wherein the second adjustment factor β depends on the difference in the quantitative factor-qualifier ratio for the analyte between the subject sample and the calibrator sample, wherein the second adjustment factor β is β=R 平均值,患者,AQN / AQL / R 平均值,校准品,AQN / AQL OK, where R 平均值,患者,AQN / AQL is the average value of the quantifier-qualifier ratio of the analyte of the multiple measurements of the subject sample in step a), and R 平均值,校准品,AQN / AQL is the average of the multiple measured analyte quantitative factor-qualifier ratios of the calibrator sample of step a), wherein the third adjustment factor γ depends on the difference between the subject sample and the calibrator sample for the internal standard quantitative factor-qualifier ratio, wherein the third adjustment factor γ is given by γ=R 平均值,患者,IQN / IQL / R 平均值,校准品,IQN / IQL OK, where R 平均值,患者,IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of the multiple measurements of the subject sample in step a), and R 平均值,校准品,IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of the multiple measurements of the calibrator sample in step a); b) at least one transfer step, wherein the adjustment factor is electronically transferred to a customer mass spectrometer (118); c) at least one customer on-site calibration, wherein the customer on-site calibration comprises at least one calibration measurement, wherein a set of calibrator samples are measured on the customer mass spectrometer (118) and a quantifier-qualifier ratio is determined therefrom, wherein target values for the quantifier-qualifier ratio for the analyte and for the internal standard are set by applying the adjustment factor to the determined quantifier-qualifier ratio, wherein the quantifier-qualifier ratio The target values for the quantitative factor AQN and the qualitative factor AQL are set by the following formula: Where R is the quantifier-qualifier peak area ratio of a single measurement, IQN is the internal standard quantifier, IQL is the internal standard qualifier, and N is the total number of quantifier-qualifier ratios used for calculation, where the quantifier-qualifier ratio The target values for the internal standard quantitative factor IQN and the internal standard qualitative factor IQL are set by the following formula: where R is the quantifier-qualifier peak area ratio of a single measurement, AQN is the analyte quantifier, AQL is the analyte qualifier, and N is the total number of quantifier-qualifier ratios used in the calculation.

2. The method according to claim 1 , wherein in step c) all quantifier-qualifier ratios determined during the calibration measurements are used for setting the target value, wherein all calibrator levels and all calibrator replicates for the analyte and the internal standard are used for setting the target value.

3. The method according to any one of the preceding claims, wherein step a) comprises: For each of the plurality of mass spectrometry instruments, a median quantifier-qualifier ratio for the analyte and the internal standard is determined for the calibrator sample and the subject sample, wherein the adjustment factor is determined using an inter-instrument average.

4. A computer-implemented method for calibrating a quantifier-qualifier ratio on a customer mass spectrometer (118), wherein the method comprises: Calibration of a customer mass spectrometer (118) is performed according to a computer-implemented method for calibrating a customer mass spectrometer for quantifier-qualifier ratio verification according to any of the preceding claims, wherein the method comprises: at least one sample measurement performed using the customer mass spectrometer (118), wherein the method further comprises at least one sample analysis step, wherein during the sample analysis for each sample measurement, the quantifier-qualifier ratio for the analyte and / or internal standard is determined and compared with a target value taking into account at least one acceptance criterion.

5. The method according to claim 4, wherein the method further comprises: Each of the sample measurements that does not meet the acceptance criteria is flagged.

6. The method according to claim 4, wherein the method further comprises: Review the marked sample measurements.

7. A computer program product having program code means, wherein the program code means can be stored on or on a storage medium for performing, when the program code means is executed on a computer or on a computer network, a computer-implemented method for calibrating a customer mass spectrometer (118) for a quantitative factor-qualifier ratio calibration according to any one of the preceding claims relating to a method for calibrating a customer mass spectrometer (118) and / or a computer-implemented method for a quantitative factor-qualifier ratio calibration on a customer mass spectrometer (118) according to any one of the preceding claims relating to a method for a quantitative factor-qualifier ratio calibration.

8. A mass spectrometry system (110) for determining the concentration of at least one analyte in a sample, comprising: - A manufacturing site calibration system (112) comprising a plurality of mass spectrometry instruments (114) configured to measure a set of subject samples and a set of calibrator samples in a plurality of replicates, wherein each of the mass spectrometry instruments (114) is configured to perform multiple reaction monitoring with quantifier and qualifier transitions for an analyte and an internal standard, wherein the manufacturing site calibration system (112) comprises at least one processing unit (116) configured to determine at least three adjustment factors from the measurements of the set of subject samples and the set of calibrator samples, wherein a first adjustment factor α is dependent on a difference between the analyte and the internal standard, wherein the first adjustment factor α is given by α=R 平均值,AQN / AQL / R 平均值,IQN / IQL OK, where R 平均值,AQN / AQL is the average value of the quantitative factor-qualifier ratio of the analyte measured multiple times in step a), and R 平均值,IQN / IQL is the average of the internal standard quantitative factor-qualifier ratios of the multiple measurements of step a), wherein the second adjustment factor β depends on the difference in the quantitative factor-qualifier ratio for the analyte between the subject sample and the calibrator sample, wherein the second adjustment factor β is β=R 平均值,患者,AQN / AQL / R 平均值,校准品,AQN / AQL OK, where R 平均值,患者,AQN / AQL is the average value of the quantifier-qualifier ratio of the analyte of the multiple measurements of the subject sample in step a), and R 平均值,校准品,AQN / AQL is the average of the multiple measured analyte quantitative factor-qualifier ratios of the calibrator sample of step a), wherein the third adjustment factor γ depends on the difference between the subject sample and the calibrator sample for the internal standard quantitative factor-qualifier ratio, wherein the third adjustment factor γ is given by γ=R 平均值,患者,IQN / IQL / R 平均值,校准品,IQN / IQL OK, where R 平均值,患者,IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of the multiple measurements of the subject sample in step a), and R 平均值,校准品,IQN / IQL is the average value of the internal standard quantitative factor-qualifier ratio of the multiple measurements of the calibrator sample in step a); - at least one communication interface (120) configured to electronically transfer the adjustment factors from the manufacturing site calibration system (112) to at least one customer mass spectrometer (118); and - the at least one customer mass spectrometer (118), wherein the customer mass spectrometer (118) is configured to perform at least one calibration measurement, wherein in the calibration measurement a set of calibrator samples is measured on the customer mass spectrometer (118), wherein the customer mass spectrometer comprises at least one evaluation device (124) configured to determine a quantifier-qualifier ratio from the calibration measurement, wherein the evaluation device (124) is configured to set target values of the quantifier-qualifier ratio for the analyte and for the internal standard by applying the adjustment factor to the determined quantifier-qualifier ratio The target values for the quantitative factor AQN and the qualitative factor AQL are set by the following formula: Where R is the quantifier-qualifier peak area ratio of a single measurement, IQN is the internal standard quantifier, IQL is the internal standard qualifier, and N is the total number of quantifier-qualifier ratios used for calculation, where the quantifier-qualifier ratio The target values for the internal standard quantitative factor IQN and the internal standard qualitative factor IQL are set by the following formula: where R is the quantifier-qualifier peak area ratio of a single measurement, AQN is the analyte quantifier, AQL is the analyte qualifier, and N is the total number of quantifier-qualifier ratios used in the calculation.

9. A mass spectrometry system (110) according to the preceding claims, wherein the mass spectrometry system (110) is configured to perform a computer-implemented method for calibrating a customer mass spectrometry instrument (118) for quantifier-qualifier ratio verification according to any one of the preceding claims relating to a method for calibrating a customer mass spectrometry instrument (118) and / or a computer-implemented method for quantifier-qualifier ratio verification on a customer mass spectrometry instrument (118) according to any one of the preceding claims relating to a method for quantifier-qualifier ratio verification.

10. The mass spectrometry system (110) according to any one of the preceding claims relating to a system, wherein the mass spectrometry instrument (114, 118) is a liquid chromatography mass spectrometry (LC-MS) device.

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