Techniques for checking the status of the analyzer

Abstract

The present disclosure relates to an automated method for monitoring the state of an analyzer including a mass spectrometer MS, wherein the mass spectrometer has an electrospray ionization (ESI) source coupled to a liquid chromatography (LC) flow, the method comprising: monitoring the electrospray ionization current of the ESI source and identifying one of a plurality of conditions of the analyzer based on the monitored ionization current of the ESI source, one of the conditions being the presence of a dead volume in the liquid chromatography flow of the analyzer downstream of an LC column of the LC flow.

Description

Technical Field

[0001] The present disclosure relates to an automated method for monitoring the status of a mass spectrometer (MS) having an electrospray ionization (ESI) source of an automated analyzer. Background Art

[0002] Automated analyzers (e.g., in vitro analyzers) are widely used in today's laboratory and hospital environments. These devices tend to become increasingly complex due to added functionality, increased throughput, and the requirement to perform analytical tasks in an automated manner. As a result, errors and failures may occur in multiple components, which may result in reduced productivity of the analyzer or reduced reliability of measurement results. In some examples, it may take hours or even days for external service personnel to discover and repair the error, during which time the analyzer or a portion of it may be unusable. Summary of the invention

[0003] In one general aspect, the present invention relates to an automated method of monitoring the status of an analyzer including a mass spectrometer (MS) having an electrospray ionization (ESI) source coupled to a liquid chromatography (LC) flow. The method comprises: monitoring an electrospray ionization current of the ESI source; and identifying one of a plurality of conditions of the analyzer based on the monitored ionization current of the ESI source. One of the conditions is the presence of a dead volume in the liquid chromatography flow of the analyzer downstream of an LC column of the LC flow.

[0004] In a second aspect, an automated method of monitoring the status of an analyzer including a mass spectrometer (MS) having an electrospray ionization (ESI) source includes: monitoring an electrospray ionization current of the ESI source; and identifying a condition of a component of the analyzer based on the monitored ionization current of the ESI source.

[0005] In a third aspect, the invention relates to a computer system configured to perform the steps of the technique of the first aspect.

[0006] The techniques of the first to third aspects can have advantageous technical effects.

[0007] First, the monitoring technique of the first aspect of the present disclosure may allow for the identification of dead volume downstream of an LC column in an LC flow (also referred to in the present disclosure as "post-column dead volume"). It may be difficult to detect that the post-column dead volume is erroneous when other parameters of the LC flow are taken into account. For example, Figure 3b As shown in , monitoring the pressure of the LC stream may not be helpful because the post-column dead volume may have little or no effect on the pressure curve. Figure 3aAs can be seen in Figure 2, chromatographic characteristics (e.g., retention time, peak width, or peak height) change due to post-column dead volume. However, similar changes in column characteristics may also be caused by other conditions other than the presence of post-column dead volume. For example, column aging may result in changes in chromatographic characteristics such as Figure 3a Thus, the technique of the present disclosure allows for more precise identification of the conditions of the analyzer, taking into account the electrospray ionization current of the ESI source (also referred to as ESI current in the present disclosure).

[0008] Secondly, accurate identification of the post-column dead volume may help make any inspection or maintenance operations more efficient. An operator or other service personnel can quickly check or take action based on the determined condition without having to check too many sources of error. In addition, accurate identification of the post-column dead volume may allow less experienced personnel to perform inspection or maintenance operations. In some cases, downtime of the analyzer (or its modules) may be reduced as a result. For example, in some examples, it may not be necessary to bring in external service personnel.

[0009] Third, the monitoring techniques of the present disclosure can be used to distinguish between different conditions of the analyzer and trigger specific responses. In this way, the detection and / or monitoring techniques can make more efficient use of resources (e.g., operator time or outside service personnel) because the understanding of the analyzer status can be improved, thereby allocating these resources more accurately.

[0010] Fourth, in some examples, the monitoring technique can be seamlessly integrated into an existing analyzer workflow. For example, the monitoring technique can be performed as part of the analyzer initialization workflow. It may be necessary to add an ESI current sensing device to the ESI source to monitor the ESI current. However, this may have no impact on the performance (e.g., throughput) of the analyzer, and in some examples can be accomplished using well-known and relatively inexpensive components.

[0011] Several terms with specific meanings are used in this disclosure.

[0012] In this disclosure, the term "dead volume" refers to the additional volume experienced by solutes as they pass through an LC flow, specifically any unswept volume that is exposed to the mobile phase flow.

[0013] The term "condition" refers to any specific state of an analyzer or its parts (e.g., an LC column or an ESI source or one of their subcomponents). A condition may be an error or defect in the analyzer or its parts (e.g., an LC column or an ESI source or one of their subcomponents). However, according to the present disclosure, the term "condition" also includes acceptable conditions (e.g., conditions that allow operation within the specification range, also referred to as "normal operation" in this document) or conditions that are still acceptable (e.g., aging conditions of a component of the analyzer that bring the component close to an unacceptable range). In addition, in some cases, it may not be possible to clearly distinguish between "normal operation" or an error.

[0014] According to the present disclosure, a "time series" refers to at least two values ​​of a specific parameter value (e.g., a specific parameter value of the ionization current of an ESI source) at two different time points (e.g., at least one earlier time point and at least one later time point). In some examples, a time series may contain (much) more than two values ​​at corresponding time points. The term "time point" shall not limit the measurement window used to obtain the measurement values ​​contained in the time series to a specific accuracy. For example, according to the present disclosure, averaged measurement values ​​obtained by averaging multiple measurement values ​​of a parameter may also be included in the time series. A time series may include values ​​at equidistant time points or non-equidistant time points. In the present disclosure, the term "time series" refers to both "raw data" (e.g., retrieved from a current sensor) and processed raw data (e.g., by using signal processing techniques), as long as the processing step still reflects the time dependence of the monitored parameter (e.g., the ionization current of an ESI source).

[0015] According to the present disclosure, the term "automated" or "automatically" refers to an operation performed by a machine without user interaction. An automated step may be part of a method that also includes steps that require user interaction. For example, a user may schedule or trigger an automated step of the technology of the present disclosure.

[0016] According to the present disclosure, an "analyzer" is a device dedicated to performing an analytical function. In some examples, the analyzer may be configured to perform analysis of a sample (e.g., a sample for in vitro diagnosis). For example, the analyzer may be a clinical diagnostic system for performing in vitro diagnosis. The analyzer of the present disclosure includes at least one liquid chromatography (LC) flow connected to a mass spectrometer (MS) having an electrospray ionization source.

[0017] Depending on the needs and / or the desired workflow, the analyzer of the present disclosure may have different configurations. Additional configurations may be obtained by coupling multiple devices and / or modules together. A "module" is a working unit with a dedicated function, usually smaller than the entire analyzer. This function may be an analytical function, but may also be a pre-analytical function or a post-analytical function, or may be an auxiliary function of any of the pre-analytical function, the analytical function, or the post-analytical function. Specifically, a module may be configured to cooperate with one or more other modules for performing a dedicated task of a sample processing workflow, for example, by performing one or more pre-analytical steps and / or analytical steps and / or post-analytical steps.

[0018] In particular, an analyzer may include one or more analysis devices designed to perform corresponding workflows optimized for certain types of analysis.

[0019] The analyzer may include analytical equipment for one or more of clinical chemistry, immunochemistry, coagulation, hematology, etc.

[0020] Thus, the analyzer may comprise an analysis device or a combination of any such analysis devices with a corresponding workflow, wherein the pre-analysis module and / or the post-analysis module may be coupled to a separate analysis device or may be shared by a plurality of analysis devices. In an alternative, the pre-analysis function and / or the post-analysis function may be performed by a unit integrated in the analysis device. The analyzer may comprise functional units, such as a liquid handling unit for pipetting and / or pumping and / or mixing samples and / or reagents and / or system fluids, and functional units for sorting, storing, transporting, identifying, separating, detecting.

[0021] The term "sample" refers to a biological material suspected of containing one or more analytes of interest and whose detection, identification and / or quantification may be associated with a particular condition (eg, a clinical condition).

[0022] The sample may be from any biological source, such as physiological fluids, including blood, saliva, lens fluid, cerebrospinal fluid, sweat, urine, milk, ascites, mucus, synovial fluid, peritoneal fluid, amniotic fluid, tissue, cells, etc. The sample may be pre-treated before use, such as preparing plasma from blood, diluting viscous liquids, lysing, etc.; the treatment method may involve filtration, centrifugation, distillation, concentration, inactivation of interfering components, and addition of reagents. In some cases, the sample may be used directly as obtained from the source or may be used following a pre-treatment and / or sample preparation workflow to modify the characteristics of the sample (e.g., after adding an internal standard, after dilution with another solution, or after mixing with a reagent), for example: to enable one or more in vitro diagnostic tests, or for enrichment (extraction / separation / concentration) of the target analyte and / or removal of matrix components that may interfere with the detection of the target analyte.

[0023] The term "sample" is intended to refer to a sample before sample preparation, a sample after sample preparation, or a sample before and after sample preparation. For example, the term "sample" may refer to a sample in mobile phase before injection into an LC stream and a sample after injection into an LC stream.

[0024] In general, examples of analytes of interest are vitamin D, drugs of abuse, therapeutic drugs, hormones, and metabolites. However, this list is not exhaustive.

[0025] Specifically, the analyzer may include a sample preparation station for automatically preparing samples. "Sample preparation station" is a pre-analysis module coupled to one or more analytical devices or units in an analytical device, which is designed to perform a series of sample processing steps, which are intended to remove or at least reduce interfering matrix components in the sample and / or enrich the target analyte in the sample. Such processing steps may include any one or more of the following processing operations performed sequentially or in parallel or staggered on one or more samples: pipetting (suction and / or distribution) fluid, pumping fluid, mixing with reagents, cultivating at a certain temperature, heating or cooling, centrifuging, separating, filtering, screening, drying, washing, resuspending, equal parts, transferring, storing ...).

[0026] For example, the sample can be provided in a sample container, such as a sample tube (including primary and secondary tubes), a multi-well plate, or any other sample carrying support. Reagents can be arranged, for example, in the form of containers or boxes containing individual reagents, reagent groups, and placed in a suitable receptacle or position in a storage compartment or conveyor. Other types of reagents or system fluids can be provided in bulk containers or via pipelines.

[0027] Unless otherwise specified in the respective context, the term "about" in relation to a parameter value means including a deviation of + / - 10% relative to the specified value in the present disclosure. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 is a flow chart of the monitoring technique of the present disclosure.

[0029] Figure 2 An exemplary time series of electrospray ionization current of an ESI source that may be monitored according to the present disclosure is shown.

[0030] Figure 3a and Figure 3b The chromatogram is shown ( Figure 3a ) and the pressure in the LC flow ( Figure 3b )’s exemplary time series.

[0031] Figure 4 is a schematic diagram of the current measurement setup of the ESI source.

[0032] Figure 5a and Figure 5b shows a plurality of LC flows ( Figure 5a ) of an exemplary system, wherein the multiple LC streams are coupled to an ESI source ( Figure 5b ).

[0033] Figure 6 is a flow chart of an exemplary monitoring technique that includes evaluating ESI current and various additional monitored parameters.

[0034] Figure 7 is a table summarizing how changes in different monitored parameters relate to the analyzer's responses in different conditions and examples according to the present disclosure. DETAILED DESCRIPTION

[0035] First, combine Figures 1 to 4 An overview of the monitoring technology disclosed in the present invention is given. Figure 5a to Figure 5b Various aspects of analyzers, particularly ESI sources, that can use the monitoring techniques disclosed herein are discussed. Figure 6 and Figure 7 Additional aspects and specific examples of the monitoring techniques of the present disclosure are discussed.

[0036] General Overview

[0037] Figure 1 is a flow chart of the monitoring technique of the present disclosure.

[0038] An automated method for monitoring the status of an analyzer includes: monitoring an electrospray ionization current of an ESI source 101; and identifying one of a plurality of conditions of the analyzer based on the monitored ionization current of the ESI source 107. One of the conditions is the presence of a dead volume in a liquid chromatography flow of the analyzer downstream of an LC column in the LC flow.

[0039] These steps are discussed in detail in the subsequent subsections.

[0040] The step of monitoring the ESI current may include using any suitable sensor to generate a time series of ESI current values. For example, a current measuring device may be connected to the ESI source to measure the ESI current of the ESI source.

[0041] In some examples, the ESI current is sampled at a minimum sampling frequency greater than 1 Hz (eg, greater than 5 Hz or greater than 10 Hz). A sampling rate with this minimum sampling frequency ensures that certain changes are reflected in the time series, thereby allowing multiple conditions to be identified.

[0042] Figure 4Schematic depiction of a current measuring device for an ESI source. The ESI source comprises two electrodes 2, 5 to apply a high voltage (e.g., by a high voltage source 1 coupled to the first electrode 2) so that the ESI source can generate ions for input into a mass spectrometer (described below in conjunction with Figure 5b Further details on possible configurations of ESI sources are discussed).

[0043] exist Figure 4 In the example of FIG. 1 , the first electrode 2 is included in an ESI source that can atomize a mobile phase that is transferred from an LC column to the ESI source. The second electrode 5 is arranged adjacent to a sampling device 5a (e.g., a sampling capillary) that is configured to collect ions generated in the ESI source (e.g., Figure 4 ) as shown in the opposing plate depicted in FIG.

[0044] Now, during operation of the ESI source, as the nebulized sample is continuously ionized, a current flows between the electrodes 2, 5 (depending on the sign of the applied voltage, negatively or positively charged ions are produced and the ESI current flows in one direction or the opposite direction). This ESI current can be detected by the current measuring device 3 of the ESI source. Figure 4 In the example of , the current measuring device is coupled to the resistive element 4, which is inserted in the conductor that couples the second electrode 5 and the second voltage source 6a. For example, two terminals of the current measuring device are electrically connected to two corresponding terminals of the resistive element 4 (e.g., to detect a voltage drop across the resistive element 4 indicating the ESI current).

[0045] exist Figure 4 In the example of FIG. 1 , the current measuring device 3 includes a voltage clamping circuit for processing the detected signal (eg, an amplifier and a low-pass filter for pre-processing the signal and an analog-to-digital converter ("ADC") circuit for converting the signal into the digital domain).

[0046] Figure 4 The configuration in is merely exemplary. In other examples, the ESI current may be detected in different ways and using different devices. For example, the current measuring device may be coupled to different parts of the ESI source. In addition, any parameter indicative of the ESI current (e.g., Figure 4 In this regard, the ESI current can be sensed directly or indirectly.

[0047] Furthermore, the expression "monitored ionization current" as used in the present disclosure does not mean that monitoring involves quantification of current values ​​(e.g., in amperes). While this may be the case in some examples, in other examples, a parameter indicative of the ESI current may be detected (e.g., a voltage proportional to the ESI current). It is only required that the monitored parameter carries information about the ESI current. In the subsequent paragraphs, for ease of explanation, the monitored ionization current of the ESI source is measured as a time series of current values.

[0048] In some examples, the time series carrying information about the ESI may be subjected to one or more signal processing steps. For example, a single time series of system pressure may be smoothed or outliers may be eliminated. Additionally or alternatively, multiple time series (e.g., each time series spanning at least a portion of a single injection process) may be averaged. The averaged time series may then be further processed. In other examples, one or more portions of a time series may be removed.

[0049] The monitored time series of ionization currents may span a specific portion of the injection process of the sample into the LC column and / or an LC gradient having specific pressure characteristics after the sample injection process. In some cases, the monitored time series of ionization currents may span substantially the entire LC gradient (e.g., more than 90% of the duration of the LC gradient). In other examples, the monitored ionization currents may span a specific portion of the LC gradient and / or the injection process (e.g., a window covering 20% ​​or less or 10% or less of the duration of the LC gradient).

[0050] Figure 2 An exemplary time series 20 of the electrospray ionization current of an ESI source that can be monitored according to the present disclosure is shown. It can be seen that the first time series 21 monitored during normal operation and the second time series 22 recorded when there is a dead volume downstream of the LC column have significantly different characteristics. These differences can be used to identify whether there is a dead volume downstream of the LC column.

[0051] In some examples, identifying whether there is a dead volume downstream of the LC column includes evaluating a change in the time series compared to a previously monitored time series or compared to a reference time series. Additionally or alternatively, identifying whether there is a dead volume downstream of the LC column includes evaluating a global feature or a local feature of the time series.

[0052] Evaluating changes in the time series compared to a previously monitored time series or compared to a reference time series may include determining one or more of: a decrease in ESI current, an increase in ESI current, a fluctuation in ESI current, a shift in the profile of the time series of ESI current (i.e., the profile of the time series remains substantially unchanged but moves in time relative to a reference time point), and a change in the profile of the time series of ESI current (e.g., the time series starts or stops to show oscillatory behavior or shows a different change in the profile of the time series). The determination may be a binary or qualitative assessment of the change in the time series (e.g., "has decreased") or a quantitative assessment ("has decreased by XXX").

[0053] Global or local characteristics of the evaluation time series may include one or more of the following: the amplitude of the signal drop or rise, the speed of the signal drop or rise, the signal value at a specific point, a local or global minimum or maximum, or a spectral characteristic (e.g., the energy content in a specific frequency band).

[0054] In some examples, identifying whether a dead volume exists in the liquid chromatography flow based on the monitored ionization current of the ESI source includes evaluating a profile shift in the time series of the monitored ionization current of the ESI source. In this case, if the time shift in the time series of the monitored ionization current of the ESI source (compared to the reference time series) is greater than a predetermined threshold time shift (e.g., greater than 5 seconds or greater than 10 seconds), it can be identified whether a dead volume exists in the liquid chromatography flow. Figure 2 As shown, the time shift in the time series of the monitored ionization current can be a suitable characteristic for identifying the dead volume downstream of the LC column. It can be seen that the first time series 21 and the second time series 22 have relatively similar shapes or profiles, but are offset in time by a certain amount. However, even though the time shift of the time series can be a particularly suitable characteristic for identifying the dead volume downstream of the LC column, in other examples, other characteristics of the ESI current can also be used alternatively or additionally.

[0055] In some examples, identifying whether a dead volume exists in a liquid chromatography flow of an analyzer downstream of an LC column of the LC flow includes determining whether a waveform of an electrospray ionization current has a phase shift compared to a reference waveform.

[0056] A profile shift of a time series (or any other change in the time series discussed herein) may be determined by comparing the monitored time series to a reference time series. The reference time series may be static (e.g., a time series recorded after installation of the analyzer or a maintenance operation) or may be dynamically updated during operation of the analyzer (e.g., a reference time series monitored during operation of the analyzer at an earlier point in time than the current time series).

[0057] In other examples, evaluating the ESI current (or any other monitored parameter discussed in the present disclosure) may include comparing a single measurement of the corresponding parameter (e.g., a measurement at a particular reference time point). For example, it may be evaluated whether the ESI current or other parameter decreases, increases, or remains constant at a particular reference time point.

[0058] In the monitoring technique of the present disclosure, in addition to the ESI current, additional further parameters may be monitored. This will be discussed below.

[0059] Additional monitored parameters

[0060] In some examples, the monitoring techniques of the present disclosure also include monitoring one or more additional parameters, including pressure in a liquid chromatography (LC) flow of the analyzer: identification of a condition of the analyzer is also based on the monitored pressure in the LC flow to distinguish between multiple conditions.

[0061] For example, the monitoring techniques of the present disclosure also include monitoring one or more additional parameters, including one or more chromatographic features of a chromatogram of a liquid chromatography (LC) stream of an analyzer. In these cases, identification of a condition is also based on the monitored chromatographic features to distinguish between multiple conditions.

[0062] The chromatographic characteristic may be selected from the list consisting of a peak width parameter (eg, FWHM peak width or 1 / e peak width), a retention time parameter, a peak height parameter, a peak area parameter, and a peak symmetry parameter.

[0063] In identifying the condition of the analyzer, other parameters may be processed in the same manner as the ESI current discussed above. For example, relative changes may be evaluated as discussed above.

[0064] In some examples, the time series is monitored for multiple (e.g., each) additional parameters. Identification of a condition can include evaluating a change in the time series compared to a previously monitored time series or compared to a reference time series. Additionally or alternatively, identification of a condition can include evaluating a global or local feature of the time series.

[0065] The additional parameter being monitored may be measured on an internal standard or another sample of known composition. However, in other examples, the additional parameter being monitored may also be measured on a sample of unknown composition (eg, a patient sample).

[0066] In one example, identification of a condition is based at least on the monitored ESI current, the monitored pressure, and two or more chromatographic features (e.g., retention time, peak height, and peak width). Figure 7 Discuss a specific example of a set of parameters.

[0067] Figure 3aTwo exemplary time series of chromatograms are shown. The first time series 31a is a chromatogram when the analyzer is operating normally (within the specification range) (e.g., a chromatogram of an internal standard substance). The second time series 31b is a chromatogram when there is a dead volume downstream of the LC column (e.g., a chromatogram of the same substance as the first time series 31a of the internal standard substance). It can be seen that when there is a dead volume after the column, different chromatographic features (e.g., peak height and peak width) are different between the first time series 31a and the second time series 31b. Therefore, in addition to the ESI current, chromatographic features can also be used to identify the dead volume after the column. However, as discussed above, there may be other reasons for the changes between the first time series 31a and the second time series 31b, so using them alone may not be enough to clearly identify the dead volume after the column.

[0068] Figure 3b Two exemplary time series of pressure and LC gradient during the injection process are shown. The first time series 32a is taken when the analyzer is operating normally (within specifications). The second time series 32b is taken when there is dead volume downstream of the LC column. Also as discussed above, when there is a post-column dead volume, the pressure time series is essentially unchanged. However, the pressure time series can be used to identify other conditions of the analyzer, as discussed below.

[0069] Analyzer Hardware

[0070] In the following sections, we will combine Figure 5a and Figure 5b Additional aspects of an analyzer including a mass spectrometer (MS) having an electrospray ionization source coupled to a liquid chromatography (LC) stream in which the monitoring techniques of the present disclosure may be employed are discussed.

[0071] Figure 5a and Figure 5b shows a plurality of LC flows ( Figure 5a ) of an exemplary system wherein the multiple LC streams are coupled to an ESI source ( Figure 5b ).

[0072] exist Figure 5a In the example of FIG. 1 , each LC stream includes: a loading pump 7a, 7b; an injection assembly 8a, 8b, which includes a rotary valve; and an LC column 9a, 9b. Multiple LC streams are connected to a stream selection valve 12, which can connect each stream to an ESI source (and a mass spectrometer), such as Figure 5b As depicted in .

[0073] In operation, the loading pumps 7a, 7b provide a mobile phase (e.g., a mixture of aqueous and organic liquids) to the respective injection assemblies 8a, 8b. The injection assemblies 8a, 8b include an injection port 10 for injecting a sample into the LC stream and a sample loop 11 for receiving the injected sample. The components of the LC stream may be connected by capillaries or other fluid connectors.

[0074] Now, if Figure 5a As depicted in , different dead volumes may occur in the fluid path of the LC flow. For example, Figure 5a Shown are possible positions upstream of the LC column 9a, where a pre-column dead volume 14 may occur, and possible positions of a post-column dead volume 13 downstream of the LC column 9a (which position may change over time during operation of the LC flow).

[0075] In some examples, the monitoring techniques of the present disclosure may be used to detect conditions (eg, post-column dead volume) in each of multiple LC streams of an analyzer having multiple streams.

[0076] Figure 5a Only examples of configurations of LC flows of analyzers in which the monitoring techniques of the present invention may be employed are shown. In some examples, the analyzer has additional LC flows. In addition, the injection assemblies 8a, 8b may be used with Figure 5a Different arrangements are shown.

[0077] The fluid path of the analyzer continues downstream of the stream selection valve through the capillary 16 connecting the stream selection valve 12 and the ESI source 45, as shown in FIG. Figure 5b shown.

[0078] Figure 5b An ESI source 45 is depicted with an orthogonal arrangement of a nebulizer and a sampling capillary. In this example, the LC flow exiting one of the LC columns is directed through an ESI probe 17, which includes a spray needle 18. In this way, the LC flow is nebulized in a volume downstream of the spray needle 18, where ionization occurs and the ionized species are converted to the gas phase (also as discussed above). A sampling device 19 (e.g., a sampling capillary) is provided to collect ions in the gas phase 43. Figure 5b In the example of FIG. 1 , the ESI probe 17 and the sampling device 19 are arranged orthogonally. In other examples, the ESI probe and the sampling device may be arranged coaxially.

[0079] The ESI source 45 also includes an assembly 42 to provide a curtain gas (eg, N2) that reduces background ions (eg, solvent clusters) entering the MS. The assembly may have a curtain plate 41 and an orifice assembly 42 for providing the curtain gas.

[0080] As discussed above, a high voltage is applied, for example, between the spray needle 18 and the curtain plate 41. The ESI current flowing between these elements may be monitored (eg, by the means discussed above) and used in the identification of the state of the analyzer.

[0081] The ESI current of other ESI sources can also be monitored using appropriate hardware.

[0082] Conditions and Responses

[0083] In subsequent subsections, different additional conditions of an analyzer (besides the presence of post-column dead volume) that can be identified using the techniques of the present disclosure will be discussed.

[0084] Generally, the condition may include one or more of the following: aging of a particular component of the analyzer or an error or defect in a particular component of the analyzer. The component may be selected from the list consisting of: an LC column, an LC column heater, a valve included in the flow path of the LC stream or one of its parts (e.g., a sample loop), an ESI source or one of its parts (e.g., an ion source or a spray needle). In other examples, the component may be a combination of Figure 5a or Figure 5b One of the components described.

[0085] For example, the plurality of conditions may include one or more of the following: presence of pre-column dead volume, valve error, aging of the spray needle, column defect, column aging, column heater defect, and unstable spray conditions.

[0086] This error may be caused by components of the analyzer (for example, Figure 5a or Figure 5b For example, this condition may be related to contamination of the ion source or contamination of the spray needle of the ESI source.

[0087] In other examples, the condition may be a blockage or leak in the fluid path of the LC flow. In some examples, the condition may include a blockage or leak in a specific portion of the path of the LC flow. Other exemplary conditions that can be identified using the monitoring techniques of the present disclosure are discussed below.

[0088] The monitoring techniques of the present disclosure include triggering one or more selected responses of a plurality of responses based on the determined condition of the analyzer. Generally speaking, the triggered response may include notifying an operator or a third person about the identified condition. Additionally or alternatively, the triggered response may include a triggering measure for resolving an error or defect.

[0089] For example, the plurality of responses includes a response that includes recording the determined condition of the analyzer (e.g., in a log of the analyzer or in a central log of a laboratory or other unit employing the analyzer). Additionally or alternatively, the response may include setting a flag indicating that a particular condition of the plurality of conditions has been identified.

[0090] Additionally or alternatively, the plurality of responses include generating an error message. For example, the error message may be displayed on a graphical user interface of the analyzer. Additionally or alternatively, the error message may be sent to a remote site (e.g., a site of an external service provider).

[0091] Additionally or alternatively, the plurality of responses includes a response that includes initiating or scheduling an automatic maintenance operation.

[0092] Additionally or alternatively, multiple responses include requiring the operator to perform a predetermined inspection or maintenance operation. For example, the response may include requiring the operator to confirm that a specific error has occurred. In other examples, the response may include requiring the operator to resolve a specific error of the analyzer. In some examples, instructions (e.g., in the form of a checklist and / or tutorial) are provided to the operator or a third person on how to perform the corresponding inspection or maintenance operation.

[0093] Additionally or alternatively, multiple responses include scheduling preventive maintenance operations. For example, the identified conditions (or trends in the identified conditions) may be evaluated to determine a point in time when a more serious error may exist in the analyzer. Based on this information, the techniques of the present disclosure may include scheduling a corresponding maintenance operation (e.g., by notifying an external service provider) before the determined point in time.

[0094] Inspection or maintenance operations may include cleaning, reconfiguring, or replacing components of the analyzer (e.g., as discussed above or in combination with Figure 5a or Figure 5b For example, the inspection or maintenance operation may be one of the following: reconnecting a capillary of the ESI source, replacing a column of an LC flow of the analyzer, cleaning an ion source of the ESI source, and cleaning or replacing a capillary of the ESI source or cleaning or replacing a spray needle of the ESI source.

[0095] As discussed above, determining the condition of the analyzer may include identifying an error with the analyzer, optionally one of a plurality of predetermined errors.

[0096] In some examples, one of a plurality of potential errors is identified based on determining whether an electrospray ionization current of an ESI source and, optionally, one or more measured additional parameters of an analyzer are within or outside of an accepted range.

[0097] For example, the error may be an error in the capillary leading to the spray needle of the ESI source (e.g., the error may include a leak in the capillary). Additionally and alternatively, the error may be an instability in the spray of the spray needle of the ESI source. Additionally and alternatively, the error may be an error caused by column aging of the LC column. Additionally and alternatively, the error may be an error caused by aging of the ESI spray needle of the ESI source.

[0098] Evaluation of the electrospray ionization current and optionally one or more additional measured parameters of the analyzer may involve any suitable numerical techniques to identify a number of conditions of the analyzer.

[0099] In some examples, determining the condition of the analyzer based on the electrospray ionization current and optionally one or more measured additional parameters of the analyzer includes using a classifier that identifies one of a plurality of error classes corresponding to the plurality of conditions. The classifier can be a classifier trained by a machine learning algorithm (e.g., an artificial neural network).

[0100] In some examples, the monitoring techniques of the present disclosure may include predicting the development of the electrospray ionization current and optionally one or more measured additional parameters over time based on the monitored electrospray ionization current and optionally one or more measured additional parameters. The method may also include triggering a response based on the predicted electrospray ionization current and optionally one or more measured additional parameters. For example, the prediction of the ESI current may result in an increase in the ESI current (e.g., at a specific constant or non-constant rate). The monitoring techniques of the present disclosure may compare the monitored parameters at a specific time point with the predicted values ​​of the corresponding parameters as part of identifying the condition of the analyzer.

[0101] Figure 6 is a flow chart of an exemplary monitoring technique that includes evaluating ESI current and various other monitored parameters.

[0102] In a first step, sample injection is initiated 71. ESI current and a plurality of chromatographic features are monitored 72. Based on the monitored parameters (including ESI current and a plurality of chromatographic features), the condition of the analyzer is identified 73. Figure 6 In the example, six condition classes are identified:

[0103] The first category involves conditions under which the analyzer is operating normally (ie, within specifications).If the evaluation of the ESI current and the various chromatographic features conclude that the analyzer is operating normally, the triggered response may be to record this result.

[0104] The second category involves a condition in which a leak exists in the capillary connected to the ESI needle. If the evaluation of the ESI current and the plurality of chromatographic features results in the second category, the triggered response may be to trigger an operator to reconnect the capillary of the LC flow (e.g., by displaying corresponding information on a graphical user display and / or sending a message including the corresponding information).

[0105] The third category relates to the presence of post-column dead volume as discussed above. If the evaluation of the ESI current and the plurality of chromatographic features yields the third category, the triggered response may be to trigger an operator to check the capillary dead volume (e.g., by displaying corresponding information on a graphical user display and / or sending a message including the corresponding information).

[0106] The fourth category relates to the column aging condition of the LC column. If the evaluation of the ESI current and the plurality of chromatographic features results in the fourth category, the triggered response may be to trigger an operator to replace the corresponding LC column (e.g., by displaying corresponding information on a graphical user display and / or sending a message including the corresponding information).

[0107] The fifth category involves an unstable spray condition of the ESI source. If the evaluation of the ESI current and the plurality of chromatographic features results in the fifth category, the triggered response may be to trigger an operator to clean the ion source of the ESI source (e.g., by displaying corresponding information on a graphical user display and / or sending a message including corresponding information).

[0108] The sixth category involves the occurrence of an electrical discharge in the ESI source. If the evaluation of the ESI current and the multiple chromatographic features yields the sixth category, the triggered response may be to call an external service to perform a maintenance operation.

[0109] The seventh category relates to aging of the spray needle in the ESI source. If the evaluation of the ESI current and the plurality of chromatographic features yields the seventh category, the triggered response may be to trigger an operator to clean or replace the spray needle (e.g., by displaying corresponding information on a graphical user display and / or sending a message including corresponding information).

[0110] In other examples, the monitoring techniques of the present disclosure may include identifying only Figure 6 A subset of the classes depicted in (e.g., only classes 0 to 3).

[0111] Additionally or alternatively, instead of triggering an operator to perform a particular inspection or maintenance operation, the response may also include triggering an automated inspection or maintenance operation (eg, cleaning the ion source or spray needle of an ESI source).

[0112] Example Conditional Logic Table

[0113] Figure 7is a table summarizing how changes in different monitored parameters may be related to different conditions and responses of the analyzer in examples according to the present disclosure.

[0114] exist Figure 7 In the table below, eighteen different error classes are listed with exemplary responses. Figure 7 In the example of , the recognition process includes determining whether a particular parameter decreases (v), increases (^), fluctuates or oscillates (~), remains constant (–), or undergoes a profile shift (Δ). In each case, the change is only recorded if it is above a predetermined threshold ("decreases by at least x"). In some examples, two or more of the aforementioned behaviors may be detected in combination (e.g., a parameter may decrease and oscillate at the same time). As can be seen, Figure 7 Examples of use relative metrics (as discussed above) to compare a monitored parameter or time series with earlier measurements of the same parameter or same time series.

[0115] exist Figure 7 In the example of , seven different parameters are monitored: ESI current ("x1i"), LC flow pressure ("x2p"), four chromatographic features including a peak width parameter ("x3Δ"), a peak area parameter ("x4A"), a retention time parameter ("x5RT"), and a peak height parameter ("x6H"). The chromatographic parameters are determined based on an internal standard, the expected parameters of which are known. In other examples, only a subset of these parameters may be used in the identification process.

[0116] Now, Figure 7 Specify the decision logic used to identify conditions for the analyzer. The behavior of each parameter monitored is evaluated as shown in the corresponding columns, each specifying a condition. Based on the detected behavior, the condition is identified. For example, a column aging condition can be identified if the ESI current and peak area are constant, the pressure is constant or increasing, the peak area is increasing, the peak height is decreasing, and the retention time is increasing or decreasing. Appropriate responses can be triggered, including setting a flag, triggering a maintenance operation to change the corresponding LC column, and running a quality control sample.

[0117] It can be seen that in Figure 7 In some examples, expression rules are defined to identify specific conditions based on the behavior of the monitored parameters. In other examples, such expression rules are not defined. For example, a machine learning classifier can receive a monitored parameter (or one or more features extracted from a time series of the monitored parameter) and identify a corresponding condition.

[0118] return Figure 7 , which lists eighteen conditions that can be identified based on the set of parameters discussed above. These conditions will be briefly discussed in the subsequent subsections.

[0119] An LC column defect can be identified if the ESI current remains constant, the monitored pressure remains constant or increases, the monitored peak area increases, the monitored peak area remains constant, the monitored retention time increases or decreases, and the monitored peak height decreases.

[0120] If the ESI current profile shifts, the monitored pressure profile shifts, the monitored peak area remains constant, the monitored retention time increases, and the monitored peak height remains constant or decreases, then the pre-column dead volume can be identified.

[0121] Post-column dead volume can be identified if the ESI current profile shifts, the monitored pressure remains constant, the monitored peak area increases, the monitored peak area and monitored retention time remain constant, and the monitored peak height decreases.

[0122] An eluent composition error can be identified if the ESI current profile shifts, the monitored pressure decreases or increases and the profile shifts, the monitored peak area increases, the monitored peak area remains constant or decreases, the monitored retention time decreases or increases and the monitored peak height decreases or remains constant.

[0123] A leak upstream of the LC column ("pre-leak") can be identified if the ESI current decreases, the monitored pressure remains constant or shows a profile shift, the monitored peak area increases, the monitored peak area decreases or remains constant, the monitored retention time decreases or increases, and the monitored peak height decreases or remains constant.

[0124] Additionally or alternatively, a leak upstream of the LC column ("pre-leak") can be identified if the ESI current decreases, the monitored pressure increases, the monitored peak area increases, the monitored peak area remains constant, the monitored retention time increases and the monitored peak height decreases.

[0125] A leak downstream of the LC column ("post leak") can be identified if the ESI current decreases, the monitored pressure remains constant, the monitored peak area remains constant, the monitored peak area decreases, the monitored retention time remains constant and the monitored peak height decreases.

[0126] If the ESI current decreases and the monitored pressure increases, a fluid path blockage may be identified.

[0127] A valve error (e.g., in the analyzer's loading pump) can be identified if the ESI current shows a profile shift, the monitored pressure decreases and oscillates, the monitored peak area increases, the monitored peak area remains constant, the monitored retention time decreases or increases, and the monitored peak height decreases.

[0128] Additionally or alternatively, a valve error (e.g., in the analyzer's loading pump) can be identified if the ESI current decreases, the monitored pressure decreases, the monitored peak area increases, the monitored peak area remains constant, the monitored retention time decreases or increases, and the monitored peak height decreases.

[0129] The presence of air in the LC stream can be identified if the ESI current decreases and oscillates, the monitored pressure decreases and oscillates, the monitored peak area increases, the monitored peak area remains constant, the monitored retention time increases and the monitored peak height decreases.

[0130] An LC column heater error may be identified if the ESI current remains constant, the monitored pressure increases, the monitored peak area increases, the monitored peak area remains constant, the monitored retention time increases, and the monitored peak height decreases.

[0131] Unstable ESI spray conditions can be identified if the ESI current oscillates, the monitored pressure remains constant, the monitored peak area remains constant, the monitored peak area decreases, the monitored retention time remains constant, and the monitored peak height decreases.

[0132] Aging of the ESI needle can be identified if the ESI current oscillates and decreases, the monitored pressure remains constant, the monitored peak area remains constant, the monitored peak area decreases, the monitored retention time remains constant, and the monitored peak height decreases.

[0133] A source contamination condition may be identified if the monitored pressure remains constant, the monitored peak area remains constant, the monitored peak area decreases, the monitored retention time remains constant, and the monitored peak height decreases.

[0134] A mass shift condition can be identified if the ESI current and monitored pressure remain constant, the monitored peak area remains constant, the monitored peak area decreases, the monitored retention time remains constant, and the monitored peak height decreases.

[0135] A flow controller error may be identified if the ESI current decreases and the monitored pressure remains constant, the monitored peak area remains constant, the monitored peak area decreases, the monitored retention time remains constant and the monitored peak height decreases.

[0136] It can be seen that the techniques of the present disclosure may include determining whether the ESI current and one or more additional monitored parameters exhibit one of two or more qualitative behaviors (e.g., increases, decreases, remains constant, oscillates, or shows a profile shift or a combination of two or more of these behaviors), and identifying a condition based on the determined behavior.

[0137] In the examples of the present disclosure, in addition to the post-column dead volume, the multiple conditions may also include binding Figure 7 Each of the conditions discussed or a combination of two or more of the conditions (and specific ways of identifying them based on the monitored parameters) may also be used in a method of monitoring a state of an analyzer that does not include a dead volume in a liquid chromatography flow of the analyzer downstream of an LC column of the LC flow, as in one of the conditions identified in some examples, as will be discussed below.

[0138] Figure 7 Specific responses that can be triggered when the corresponding conditions are detected are also defined. The responses have been explained in detail above and will not be repeated for the sake of brevity.

[0139] Alternative Condition Identification Techniques

[0140] In the previous section, techniques according to the present disclosure have been discussed where one of the conditions identified was the presence of dead volume in the liquid chromatography flow of an analyzer downstream of an LC column in the LC flow. However, the present disclosure also encompasses other examples where other conditions other than post-column dead volume of components of the analyzer are detected (and where post-column dead volume is not one of the conditions detected).

[0141] Generally speaking, an automated method of monitoring the status of an analyzer including a mass spectrometer (MS) having an electrospray ionization source may include: monitoring an electrospray ionization current of the ESI source; and identifying a condition of a component of the analyzer based on the monitored ionization current of the ESI source.

[0142] The method may use any of the techniques discussed above and below in the context of monitoring techniques, necessarily including that one of the identified conditions is post-column dead volume, as long as that particular aspect is not specific to post-column dead volume detection.

[0143] For example, the conditions may include one or more of the following: aging of a particular component of the analyzer or an error or defect in a particular component of the analyzer. In some examples, the plurality of conditions may include one or more of the following: presence of a dead volume before the column, a valve error, aging of the spray needle, a column defect, column aging, spray instability, blockage, leakage, and ion source contamination. In other examples, the conditions may include the above in combination with Figure 7 One of the conditions in question.

[0144] In some examples, the automated method may include monitoring one or more additional parameters, wherein the one or more additional parameters include pressure in a liquid chromatography (LC) flow of the analyzer (e.g., one or more chromatographic features of a chromatogram of the liquid chromatography (LC) flow of the analyzer and / or pressure in the liquid chromatography (LC) flow of the analyzer), and identification of the condition is also based on the monitored additional parameters to distinguish between multiple conditions.

[0145] Computer Implementation

[0146] The present disclosure also relates to a computer system configured to execute techniques for a state of an analyzer including a mass spectrometer (MS) having an electrospray ionization source coupled to a liquid chromatography (LC) flow.

[0147] In some examples, the computer system may be a controller of the analyzer (or a portion thereof). However, in other examples, the computer system may only be connected to the analyzer via a network and may not be part of the controller of the analyzer. For example, the computer system may be a hospital or laboratory management system, or a computer system of a supplier or service provider of the analyzer.

[0148] The computer system is only required to obtain a time series of the system pressure of the injection assembly of the liquid chromatography flow. This may mean that the computing system receives this information over a network. However, in other examples, as discussed above, the computing system also controls the functions of the analyzer (e.g., measuring pressure or triggering a response), which means that the computing system is the controller of the analyzer.

[0149] The computing system of the present disclosure is not limited to a specific software or hardware configuration. As long as the software or hardware configuration is capable of performing the technical steps according to the present disclosure for monitoring the status of an analyzer including a mass spectrometer (MS) having an electrospray ionization source coupled to a liquid chromatography (LC) flow, the computing system may have such software or hardware configuration.

[0150] The present disclosure also relates to a computer-readable medium having instructions stored thereon, which, when executed by a computer system, prompt the computer system to perform technical steps according to the present disclosure for monitoring the status of an analyzer including a mass spectrometer (MS), the mass spectrometer having an electrospray ionization source coupled to a liquid chromatography (LC) flow.

[0151] Further disclosed and proposed is a computer program comprising computer executable instructions, which, when executed on a computer or a computer network, are used to perform the method according to the present disclosure in one or more embodiments attached hereto. In particular, the computer program can be stored on a computer readable data carrier. Therefore, in particular, one, more than one or even all method steps as disclosed herein can be performed by using a computer or a computer network, preferably by using a computer program.

[0152] A computer program product with program code is further disclosed and proposed, so that when the program is executed on a computer or a computer network, the method according to the present disclosure is performed in one or more embodiments attached hereto. Specifically, the program code can be stored on a computer-readable data carrier.

[0153] Further disclosed and proposed is a data carrier having a data structure stored thereon, which after being loaded into a computer or a computer network, such as after being loaded into a working memory or a main memory of the computer or the computer network, can execute a method according to one or more embodiments disclosed herein.

[0154] Further disclosed and proposed is a computer program product having program code stored on a machine-readable carrier, so that when the program is executed on a computer or a computer network, a method according to one or more embodiments disclosed herein is performed. As used herein, a computer program product refers to a program that is a tradable product. The product can generally exist in any format (such as paper format) or on a computer-readable data carrier. Specifically, the computer program product can be distributed on a data network.

[0155] Further disclosed and proposed is a modulated data signal containing instructions readable by a computer system or a computer network for executing a method according to one or more embodiments disclosed herein.

[0156] With reference to the computer-implemented aspects of the present disclosure, one or more method steps or even all method steps of the method according to one or more embodiments disclosed herein may be performed using a computer or a computer network. Therefore, generally speaking, any method step including providing and / or processing data may be performed using a computer or a computer network. Generally speaking, these method steps may include any method step other than method steps that typically require manual work (such as providing samples and / or performing certain aspects of measurements).

[0157] A computer or a computer network is further disclosed and proposed, the computer or the computer network comprising at least one processor, wherein the processor is adapted to execute the method according to one of the embodiments described in this specification.

[0158] A computer-loadable data structure is further disclosed and proposed, which is suitable for executing a method according to one of the embodiments described in this specification when the data structure is executed on a computer.

[0159] A storage medium is further disclosed and proposed, wherein a data structure is stored on the storage medium and wherein the data structure, after being loaded into a main storage device and / or a working storage device of a computer or a computer network, is suitable for executing a method according to one of the embodiments described in the present specification.

[0160] Other aspects

[0161] In the previous subsections, various aspects of the disclosed techniques for monitoring the state of an analyzer including a mass spectrometer (MS) having an electrospray ionization source coupled to a liquid chromatography (LC) flow have been discussed. In addition, the disclosed techniques for monitoring the state of an analyzer including a mass spectrometer (MS) having an electrospray ionization source coupled to a liquid chromatography (LC) flow may also be performed according to the following aspects.

[0162] 1. An automated method of monitoring the status of an analyzer comprising a mass spectrometer (MS) having an electrospray ionization (ESI) source coupled to a liquid chromatography (LC) stream, the method comprising:

[0163] monitoring the electrospray ionization current of the ESI source; and

[0164] identifying one of a plurality of conditions of the analyzer based on the monitored ionization current of the ESI source,

[0165] One of the conditions described is the presence of a dead volume in the liquid chromatography flow of the analyzer downstream of the LC column in the LC flow.

[0166] 2. An automated method of monitoring the status of an analyzer comprising a mass spectrometer (MS) having an electrospray ionization (ESI) source, the method comprising:

[0167] monitoring an electrospray ionization current of the ESI source; and

[0168] The conditions of components of the analyzer are identified based on the monitored ionization current of the ESI source.

[0169] 3. The method according to aspect 1 or 2 further comprises monitoring one or more additional parameters, wherein the one or more additional parameters comprise pressure in a liquid chromatography (LC) flow of the analyzer, wherein identification of a condition is also based on the monitored additional parameters to distinguish between multiple conditions.

[0170] 4. A method according to any one of aspects 1 to 3, further comprising monitoring one or more additional parameters, wherein the one or more additional parameters include one or more chromatographic features of a chromatogram of a liquid chromatography (LC) flow of an analyzer, wherein identification of a condition is also based on the monitored additional parameters to distinguish between multiple conditions.

[0171] 5. The method according to aspect 4, wherein the chromatographic characteristics are selected from the list consisting of a peak width parameter, a retention time parameter, a peak height parameter, a peak area parameter and a peak symmetry parameter.

[0172] 6. The method according to any one of aspects 1 to 5, wherein the condition comprises one or more of: aging of a specific component of the analyzer or an error or defect in a specific component of the analyzer.

[0173] 7. The method according to any one of aspects 1 to 6, wherein the plurality of conditions further comprises the following

[0174] One or more of:

[0175] There is dead volume before the column;

[0176] Valve error;

[0177] Spray needle aging;

[0178] Column defects;

[0179] Column aging;

[0180] The spray is unstable;

[0181] Blockage;

[0182] leakage;

[0183] Ion source contamination.

[0184] 8. A method according to any one of aspects 1 to 7, wherein identification of one of the multiple conditions includes determining one or more of the following: a decrease in the monitored parameter, an increase in the monitored parameter, a fluctuation in the monitored parameter, a shift in the time series of the monitored parameter, and a profile change in the time series of the monitored parameter.

[0185] 9. The method of aspect 8, wherein identifying whether a dead volume exists in the liquid chromatography flow based on the monitored ionization current of the ESI source comprises evaluating a profile shift in a time series of the monitored ionization current of the ESI source.

[0186] 10. The method of aspect 9, wherein the presence of a dead volume in the liquid chromatography flow is identified if a profile shift in the monitored time series of the ionization current of the ESI source is greater than a predetermined threshold profile shift.

[0187] 11. The method according to any one of aspects 2 to 10, wherein the additional parameter measured is measured with an internal standard.

[0188] 12. The method according to any one of aspects 1 to 11, further comprising:

[0189] One or more selected responses of a plurality of responses are triggered based on the determined analyzer condition.

[0190] 13. The method of aspect 12, wherein the plurality of responses includes a response that records the determined status of the analyzer.

[0191] 14. The method of clause 12 or clause 13, wherein the plurality of responses comprises a response to initiate or schedule an automatic maintenance operation.

[0192] 15. The method of any one of aspects 12 to 14, wherein the plurality of responses comprises generating an error message.

[0193] 16. The method of any one of aspects 12 to 15, wherein the plurality of responses comprises requesting an operator to perform a predetermined maintenance operation.

[0194] 17. The method of any one of aspects 12 to 16, wherein the plurality of responses comprises notifying a service provider.

[0195] 18. The method of any one of aspects 12 to 17, wherein the plurality of responses comprises scheduling a preventive maintenance operation.

[0196] 19. The method of aspects 14, 16 or 18, wherein the maintenance operation is one of: reconnecting a capillary of an ESI source; replacing a column of an LC flow of an analyzer; cleaning an ion source of an ESI source; and cleaning or replacing a capillary of an ESI source.

[0197] 20. The method according to any of aspects 1 to 19, wherein determining the condition of the analyser comprises identifying an error of the analyser, optionally identifying one of a plurality of predetermined errors.

[0198] 21. A method according to any one of aspects 1 to 20, wherein identifying whether a dead volume exists in the liquid chromatography flow of the analyzer downstream of the LC column of the LC flow includes determining whether the waveform of the electrospray ionization current has a phase shift compared to a reference waveform.

[0199] 22. The method according to any one of aspects 20 to 21, wherein the error is an error in a capillary leading to a spray needle of the ESI source, optionally a leak in the capillary.

[0200] 23. The method according to any one of aspects 20 to 22, wherein the error is spray instability of a spray needle of the ESI source.

[0201] 24. The method according to any one of aspects 20 to 23, wherein the error is caused by column aging of the LC column.

[0202] 25. The method according to any one of aspects 20 to 24, wherein the error is caused by aging of an ESI spray needle of the ESI source.

[0203] 26. The method according to any one of aspects 1 to 25, wherein determining the condition of the analyser comprises determining whether an electrospray ionisation current of the ESI source and optionally one or more measured additional parameters of the analyser are within or outside respective acceptance ranges.

[0204] 27. A method according to aspect 26, wherein one or more acceptance ranges are defined based on reference data for the corresponding parameters.

[0205] 28. A method according to aspect 26 or aspect 27, wherein an error among a plurality of potential errors is identified based on determining whether the electrospray ionization current of the ESI source and optionally one or more measured additional parameters of the analyser are within or outside an accepted range.

[0206] 29. The method of any one of aspects 1 to 28, wherein determining the condition of the analyzer based on the electrospray ionization current and optionally one or more measured additional parameters of the analyzer comprises using a classifier that identifies one of a plurality of error classes.

[0207] 30. The method of clause 29, wherein the classifier is a classifier trained by a machine learning algorithm.

[0208] 31. The method according to any one of aspects 1 to 30, further comprising predicting the development of the electrospray ionization current and optionally one or more measured additional parameters over time based on the monitored electrospray ionization current and optionally one or more measured additional parameters.

[0209] 32. The method according to aspect 31, further comprising:

[0210] A response is triggered based on the development of the predicted electrospray ionization current and, optionally, one or more measured additional parameters.

[0211] 33. The method according to any one of the preceding aspects 1 to 32, wherein the electrospray ionization current is the current flowing between the spray needle and the counter electrode.

[0212] 34. A computer system configured to perform the steps of any of the methods of aspects 1 to 33.

[0213] 35. The computer system of aspect 34, wherein the computer system is a controller of the analyzer.

[0214] 36. A computer-readable medium having instructions stored thereon, which, when executed by a computer system, prompt the computer system to perform the steps of any one of the methods of aspects 1 to 33.

Claims

1. An automated method of monitoring the status of an analyzer comprising a mass spectrometer (MS) having an electrospray ionization (ESI) source (ESI source) (45) coupled to a liquid chromatography (LC) flow (LC flow), the method comprising: monitoring (101) the electrospray ionization current of the ESI source (45); as well as identifying (107) one of a plurality of conditions of the analyzer based on the monitored ionization current of the ESI source (45), wherein one of the plurality of conditions is that in the LC column (9a; 9b) There is a post-column dead volume (13) in the liquid chromatography flow downstream of the analyzer, wherein identifying whether there is a post-column dead volume (13) in the liquid chromatography flow based on the monitored ionization current of the ESI source (45) includes evaluating a curve shift in the time series of the monitored ionization current of the ESI source (45).

2. The method of claim 1 , further comprising monitoring one or more additional parameters, the one or more additional parameters comprising pressure in a liquid chromatography (LC) flow of the analyzer, wherein identification of a condition is further based on the monitored additional parameters to distinguish between the multiple conditions.

3. The method of claim 1 , further comprising monitoring one or more additional parameters, the one or more additional parameters comprising one or more chromatographic features of a chromatogram of a liquid chromatography (LC) flow of the analyzer, wherein the identification of a condition is further based on the monitored additional parameters to distinguish between the multiple conditions.

4. The method of claim 3, wherein the chromatographic characteristic is selected from the list consisting of a peak width parameter, a retention time parameter, a peak height parameter, a peak area parameter, and a peak symmetry parameter.

5. The method of claim 1, wherein the condition comprises one or more of: aging of a particular component of the analyzer, or an error or defect in a particular component of the analyzer.

6. The method of claim 1, wherein the plurality of conditions further comprises one or more of the following: There is dead volume before the column (14); Valve error; Spray needle aging; Column defects; Column aging; The spray is unstable; Blockage; leakage; Ion source contamination.

7. The method of claim 1, wherein the identification of a condition among the plurality of conditions comprises determining one or more of: a decrease in a monitored parameter, an increase in a monitored parameter, a fluctuation in a monitored parameter, a time series of a monitored parameter (21; 22; 31a; 31b; 32a; 32b) and the curve change of the time series (21; 22; 31a; 31b; 32a; 32b) of the monitored parameters.

8. The method according to any one of claims 2 to 4, wherein the additional parameter measured is measured with an internal standard.

9. The method according to claim 1, further comprising: One or more selected responses from a plurality of responses are triggered based on the determined condition of the analyzer (74).

10. The method of claim 9, wherein the plurality of responses comprises one or more of: recording the determined status of the analyzer; Start or schedule automatic maintenance operations; Generates error messages; Request operators to perform scheduled maintenance operations; Notify the service provider; as well as Scheduling preventive maintenance operations.

11. The method according to claim 10, wherein the maintenance operation is one of the following: reconnecting the capillary of the ESI source (45); replacing the LC column (9a; 9b) of the LC flow of the analyzer; cleaning the ion source of the ESI source (45); and cleaning or replacing the capillary of the ESI source (45).

12. The method of claim 1, further comprising predicting the development of the electrospray ionization current and optionally one or more measured additional parameters over time based on the monitored electrospray ionization current and optionally one or more measured additional parameters, and A response is triggered based on the predicted development of the electrospray ionization current and optionally one or more measured additional parameters.

13. A computer system configured to perform the steps of any of the methods of claims 1 to 12.

14. A computer readable medium having instructions stored thereon, which, when executed by a computer system, prompt the computer system to perform the steps of any one of the methods of claims 1 to 12.

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