Ion transit timing for instrument troubleshooting

Abstract

In one aspect, a method for identifying an operating condition of a mass spectrometer is disclosed, which includes measuring at least one transit time associated with passage of at least one target ion through at least one ion optic positioned in an ion path extending from an orifice of the mass spectrometer to an ion detector of thereof, and evaluating an operating condition associated with said at least one optic based on said at least one transit time.

Description

ION TRANSIT TIMING FOR INSTRUMENT TROUBLESHOOTINGRelated Applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 560,247 filed on March 1, 2024 and U.S. Provisional Application No. 63 / 559,345 filed on February 29, 2024, the contents of both of which are incorporated herein by reference in their entireties.Technical Field

[0002] The present disclosure relates generally to systems and methods for performing mass spectrometry, and more particularly to such systems and methods for identifying the source of a variation (e.g., a degradation) observed in the performance of a mass spectrometer.Background

[0003] The present disclosure relates generally to methods and systems for evaluating one or more operating conditions of a mass spectrometer, and more particularly to such methods and systems that allow identifying a deviation of one or more operating parameters of one or more components of a mass spectrometer from desired target value(s) and utilizing the measured deviation(s) to determine the cause of a variation in the mass spectrometer’s performance.

[0004] Mass spectrometry (MS) is an analytical technique for determining the structure of test chemical substances with both qualitative and quantitative applications. MS can be useful for identifying unknown compounds, determining the composition of atomic elements in a molecule, determining the structure of a compound by observing its fragmentation, and quantifying the amount of a particular chemical compound in a mixed sample. Mass spectrometers detect chemical entities as ions such that a conversion of the analytes to charged ions must occur.

[0005] The performance of a mass spectrometer may be influenced by a variety of factors, such as contamination of one or more components of the mass spectrometer. Users typically notice a decline in the performance of a mass spectrometer when a mass signal associated with an assay measurement drops below a certain threshold. Determining the cause of such a reduction in measurement sensitivity can be difficult. For example, it can be difficult to determine if the sensitivity reduction is due to contamination or other issues. A mass spectrometer charging test is sometimes used to determine if the sensitivity reduction is due to contamination in the mass spectrometer ion path. This test is, however, time consuming, e.g., itcan require 12-30 minutes for completion. Moreover, this test cannot be used to determine the location of the contamination along the ion path.

[0006] Thus, there is a need for enhanced methods and systems for diagnosing the cause of a variation in performance of a mass spectrometer.Summary

[0007] In one aspect, a method for identifying an operating condition of a mass spectrometer is disclosed, which includes measuring at least one transit time associated with passage of at least one target ion through at least one component of the mass spectrometer positioned in an ion path extending from an orifice of the mass spectrometer to an ion detector thereof, and evaluating an operating condition associated with the at least one component based on the measured transit time.

[0008] By way of example, the step of evaluating the operating condition can include determining that the at least one component for which the transit time has been measured is contaminated. Alternatively, or in addition, the step of evaluating the operating condition can include determining a misalignment of one or more elements associated with the at least one component. By way of example, when the component is an ion guide, a mass filter or a mass analyzer having a set of multipole rods, the measured transit time through such a component may be utilized to identify a misalignment of one or more of the rods relative to one another. By way of another example, the step of evaluating the operating condition based on one or more measured transit times can include determining whether at least one voltage applied to one or more elements associated with the at least one component for which the ion transit time has been measured is outside a target range. By way of example, in some cases, such a voltage can be applied to one or more rods of a multipole rod set and / or an ion lens of a mass spectrometer, all by way of example. Further, in some embodiments, the step of evaluating the operating condition can include determining whether a pressure within a chamber associated with the component for which the ion transit time has been measured is outside a target range.

[0009] In some cases, an ion transit time through at least a portion of an ion path extending from an orifice of the mass spectrometer to its ion detector can be measured by substantially emptying, and preferably completely emptying, that portion of the ion path from at least onetarget ion and subsequently introducing the target ion into that portion of the ion path and detecting one or more mass signals associated with that target ion. The time variation of the mass signals as a function of time can be utilized to compute the transit time. For example, a transit time can be defined as the time required for the mass signal to reach a baseline mass signal. By way of example, the measured mass signals can correspond to MRM transitions associated with a parent ion.

[0010] In some cases, at least a portion of the ion path can be emptied by adjusting any of a DC voltage and an RF voltage applied to at least one component positioned in that portion of the ion path to inhibit passage of a target ion through that component. In this manner, the component and other components that are positioned downstream from that component can be emptied of the target ion.

[0011] In various embodiments, a variety of components of the mass spectrometer can be examined via the measurement of the ion transit time through those components. By way of example, and without limitation, the mass spectrometer component can be any of an ion guide, a mass filter and a mass analyzer. By way of example, such an ion guide, mass filter and / or mass analyzer can include a plurality of rods, e.g., positioned relative to one another in a multipole configuration, to which at least one DC voltage and / or at least one RF voltage can be applied. The transit time can then be evaluated, e.g., via comparison with a threshold value, to determine whether one or more of the rods are contaminated and / or whether one or more voltages applied to the rods are outside a target (desired) range. In addition or alternatively, the ion transit time can be evaluated to determine whether a pressure of a chamber in which the ion guide, the mass filter or the mass analyzer is positioned is within a target (desired) pressure range. Further, as noted above, in some cases, the ion transit time can be evaluated to determine whether any of the plurality of rods is misaligned.

[0012] In various embodiments, a programmed digital data processor can be utilized to determine an ion transit time based, e.g., on variation of mass signals acquired subsequent to emptying at least a portion of the ion path. Further, the digital data processor can be programmed to evaluate the measured ion transit time, e.g., via a comparison of the measured transit time with an expected value or an expected range, to indicate whether an operatingcondition of a component is not optimal, e.g., whether one or more elements of a component are contaminated.

[0013] In a related aspect, a mass spectrometer is disclosed, which includes an ion source for generating a plurality of ions, an ion path extending from an orifice, which is configured to receive the ions, to an ion detector, which is configured to generate ion detection data in response to detection of ions incident thereon, an analysis module in communication with said ion detector to receive the ion detection data and generate mass signals, said analysis module being configured to determine a degradation of performance of the mass spectrometer based on analysis of said mass signals, a controller in communication with said analysis module to receive a signal indicative of degradation of performance of the mass spectrometer, where the controller is configured to initiate measurement of at least one ion transit time associated with at least a portion of said ion path and is further configured to analyze said measured ion transit time to evaluate one or more operating conditions of at least one component positioned in said at least a portion of said ion path.

[0014] The mass spectrometer can further include at least one DC voltage and / or at least one RF voltage source operating under control of the controller for applying DC and / or RF voltages to said at least one component of the mass spectrometer. The controller can initiate the measurement of the at least one ion transit time via sending control signal(s) to the DC and RF voltage sources for adjusting the DC and / or RF voltage(s) applied to the component.

[0015] In a related aspect, a mass spectrometer is disclosed, which includes an ion source for generating a plurality of ions, an ion path extending from an orifice, which is configured to receive the ions, to an ion detector, which is configured to generate ion detection data in response to detection of ions incident thereon. The mass spectrometer can include an analysis module in communication with said ion detector to receive the ion detection data and generate mass signals, said analysis module being configured to determine a degradation of performance of the mass spectrometer based on analysis of said mass signals, a controller in communication with said analysis module to receive a signal indicative of degradation of performance of the mass spectrometer. The controller is configured to initiate measurement of at least one ion transit time associated with at least a portion of said ion path and is further configured to analyze saidmeasured ion transit times to evaluate one or more operating conditions of at least one component positioned in said at least a portion of said ion path.

[0016] The mass spectrometer can further include any of at least one DC voltage source and at least one RF voltage source for application of DC and / or RF voltages to said at least one component, which operate under the control of a controller. The controller can initiate the measurement of the at least one ion transit time via adjusting at least one of the DC voltage and the RF voltage.

[0017] Further understanding of various aspects of the present teachings can be obtained by reference to the following detailed description in conjunction with the associated drawings, which are described briefly below.Brief Description of the Drawings

[0018] FIG. 1 is a flow chart depicting various steps in an embodiment of a method according to the present teachings,

[0019] FIG. 2 is an example of a triple quadrupole mass spectrometer to which diagnostic methods according to various embodiments of the present teachings can be applied,

[0020] FIG. 3A is an example of an ion guide in which LINAC and T-bar electrodes are incorporated, where the ion guide can be incorporated in a variety of mass spectrometers such as the mass spectrometer depicted in FIG. 2,

[0021] FIG. 3B is a schematic end view of the ion guide depicted in FIG. 3A,

[0022] FIG. 3C schematically depicts the LINAC and the T-bar electrodes employed in the ion guide of FIG. 3A,

[0023] FIG. 4A shows a set of operating parameters that was utilized in an example of an embodiment of the present teachings for measuring ion transit time through an ion guide of a triple quadrupole mass spectrometer,

[0024] FIG. 4B presents, in addition to a base line signal, mass recovery signal data acquired using the operating parameters depicted in FIG. 4A,

[0025] FIG. 5 presents, in addition to a base line signal, mass recovery signal data acquired according to an embodiment for measuring the ion transit time through an ion guide and a collision cell of a triple quadrupole mass spectrometer,

[0026] FIG. 6 presents mass signal intensities relative to a baseline, where the mass signals correspond to recovery of signals associated with a target ion having an m / z of 1522 for different states of LINAC potentials of Q0 ion guide and different vacuum pressures,

[0027] FIG. 7 shows mass data recovery signals obtained at two voltages applied to an ion lens positioned between the ion guide Q0 and the mass filter QI of a triple quadrupole mass spectrometer,

[0028] FIG. 8A presents data corresponding to mass signal recovery after emptying the ion path extending from Q0 to the ion detector, with both Tbar and LINAC electrodes in an “on” state,

[0029] FIG. 8B presents data corresponding to mass signal recovery after emptying the ion path extending from Q0 to the ion detector, with both Tbar and LINAC electrodes in an “off’ state,

[0030] FIG. 9 shows, in addition to a baseline signal, mass recovery signals obtained after emptying an ion path from an ion guide Q0 to the ion detector and after emptying an ion path from a collision cell Q2 to the ion detector, by varying the potential difference between IQ0 lens and Q0 ion guide, and

[0031] FIG. 10 is an example of an implementation of a controller / analyzer suitable for use in various embodiments of the present teachings.Detailed Description

[0032] It will be appreciated that for clarity, the following discussion will explicate various aspects of embodiments of the applicant’s teachings, while omitting certain specific details wherever convenient or appropriate to do so. For example, discussion of like or analogous features in alternative embodiments may be somewhat abbreviated. Well-known ideas or concepts may also, for brevity, not be discussed in any great detail. The skilled person will recognize that some embodiments of the applicant’s teachings may not require certain of thespecifically described details in every implementation, which are set forth herein only to provide a thorough understanding of the embodiments. Similarly, it will be apparent that the described embodiments may be susceptible to alteration or variation according to common general knowledge without departing from the scope of the disclosure. The following detailed description of embodiments is not to be regarded as limiting the scope of the applicant’s teachings in any manner.

[0033] As used herein, the terms "about" and "substantially equal" refer to variations in a numerical quantity that can occur, for example, through measuring or handling procedures in the real world; through inadvertent error in these procedures; through differences in the manufacture, source, or purity of compositions or reagents; and the like. Typically, the terms "about" and "substantially" as used herein means 10% greater or less than the value or range of values stated or the complete condition or state. For instance, a concentration value of about 30% or substantially equal to 30% can mean a concentration between 27% and 33%. The terms also refer to variations that would be recognized by one skilled in the art as being equivalent so long as such variations do not encompass known values practiced by the prior art.

[0034] As used herein the term "and / or" includes any and all combinations of one or more of the associated listed items and may be abbreviated as " / ".

[0035] The term “mass recovery signal” refers to a mass signal (or signals) that is observed in response to reintroducing ions into at least one region of an ion path that had been previously emptied of target ions.

[0036] The term “component of a mass spectrometer” refers to a device, unit, and / or subassembly associated with the mass spectrometer. Some examples of a component of a mass spectrometer can include, without limitation, an ion guide, a mass filter, or a mass analyzer, etc.

[0037] The present disclosure is generally related to methods and systems for diagnosing the cause of a change (typically a degradation) in the performance of a mass spectrometer relative to a target (desired) performance. As noted above, though a degradation in the performance of a mass spectrometer can be readily observed by users, e.g., via observing a reduction in signal intensity, the cause of such performance degradation can be difficult to ascertain.

[0038] In various embodiments, the methods according to the present teachings measure the transit time of at least a target ion through one or more regions of an ion path of a mass spectrometer and utilize the measured transit time(s) to diagnose the cause of a degradation in the performance of the mass spectrometer. For example, in some embodiments, the time required to re-establish an ion signal associated with at least one target ion after emptying different regions of the ion path from the target ion(s) can be employed to determine the ion transit time through those regions.

[0039] By way of example, with reference to the flow chart of FIG. 1, in one method according to an embodiment for determining a cause of performance variation of a mass spectrometer, at least one transit time associated with the passage of at least one target ion through at least one mass spectrometer component positioned in an ion path extending from an orifice of the mass spectrometer to an ion detector thereof is measured. The measured transit time(s) can then be utilized to evaluate an operating condition associated with the at least one component, e.g., to determine the cause of a performance variation.

[0040] In some embodiments, the ion transit time associated with a particular ion path region may be measured by emptying different portions of the ion path and measuring the time it takes to re-establish ion mass signals subsequent to the emptying steps. For example, in a triple quadrupole mass spectrometer, the transit time of a target ion through a mass filter can be determined by first measuring the ion transit time from the inlet of a first ion guide positioned downstream of the mass spectrometer’s orifice, and upstream of the mass filter, to an ion detector of the mass spectrometer and subsequently, measuring the ion transit time through an ion path region that extends from the inlet of the mass filter to the ion detector. A difference between the two ion transit times provides an estimate of the time required for an ion to pass through the mass filter.

[0041] The step of emptying various regions of the ion path can be achieved in a variety of different ways. By way of example, the voltages applied to a set of multipole rods associated with a mass filter and / or a mass analyzer can be adjusted so as to inhibit passage of one or more target ions through the mass filter and / or mass analyzer to downstream components of the mass spectrometer. Instead or in addition, voltages applied to ion lenses positioned between various components of a mass spectrometer can be adjusted to inhibit passage of one or more target ionsto an ion path region positioned downstream of the ion lens, thereby emptying the downstream ion path region of the target ion(s).

[0042] The measured ion time(s) can be used to evaluate a variety of operating conditions. Some examples of such operating conditions include, without limitation, contamination of a component of the mass spectrometer, misalignment of one or more elements of a component (such as one or more rods of a multipole rod set), the pressure of a chamber associated with a component, a deviation of one or more voltages (such as DC or RF voltages) applied to one or more elements of a component from target values, among others.

[0043] In various embodiments, the transit times are measured under similar ion population conditions. This can be important in performing diagnostic tests according to various embodiments as space charge effects in a mass spectrometer component, e.g., due to an increase in charge density beyond a threshold, can impact the transit time of ions through that component. For example, if the transit times are measured under ion population conditions that sufficiently differ from the ion population conditions during normal operation of the mass spectrometer such that space charge effects would cause changes in the measured transit times, the observed changes may be incorrectly attributed to issues with one or more components of the mass spectrometer, such as contamination of those components.

[0044] By way of further illustration, some factors that can affect the transmission of ions through a mass spectrometer component can be, for example, the charge of ions and the flux of ions being introduced into that component. Generally, as the ion charge increases, the transit time of the ions through a mass spectrometer component decreases. Further, generally, as the flux of ions entering a mass spectrometer component increases, the ion transit time through that component decreases. Thus, in various embodiments, the ion transit time is measured for the same ions under similar ion flux conditions.

[0045] Without limiting the applicability of the present teachings to any particular type of mass spectrometer, and only for purposes of illustration, various features of the present teachings will be described with respect to a triple quadrupole mass spectrometer illustrated in FIG. 2. More specifically, FIG. 2 shows a triple quadrupole mass spectrometer 100 to which various diagnostic methods according to the present teachings can be applied. The mass spectrometer100 includes an ion source 102 for generating a plurality of ions. A variety of ion sources can be employed in the practice of the present teachings. Some examples of suitable ion sources can include, without limitation, an electrospray ionization device, a nebulizer assisted electrospray device, a chemical ionization device, a nebulizer assisted atomization device, a chemical ionization device, a matrix-assisted laser desorption / ionization (MALDI) ion source, a photoionization device, a laser ionization device, a thermospray ionization device, an inductively coupled plasma (ICP) ion source, a sonic spray ionization device, a glow discharge ion source, and an electron impact ion source, among others.

[0046] The generated ions pass through an orifice 104a of a curtain plate 104 and an orifice 106a of an orifice plate 106, which is positioned downstream of the curtain plate 104 and is separated from the curtain plate 104 such that a gas curtain chamber is formed between the orifice plate 106 and the curtain plate 104. A curtain gas supply (not shown) can provide a curtain gas flow (e.g., of N2) between the curtain plate 104 and the orifice plate 106 to help keep the downstream sections of the mass spectrometer 100 clean by declustering and repelling large neutral particles. The gas curtain chamber can be maintained at an elevated pressure (e.g., a pressure greater than the atmospheric pressure) while the downstream sections of the mass spectrometer 100 can be maintained at one or more selected pressures via evacuation through one or more vacuum pumps (not shown).

[0047] In this embodiment, the ions pass through the orifice 106a of the orifice plate 106 to be received, via passage through an orifice of a skimmer 107, by an ion optic QJet, which includes four rods (two of which are shown in the figure) arranged in a quadrupole configuration to which RF voltages can be applied to generate a quadrupolar electric field in the space between the rods. The QJet optic can capture and focus the ions using a combination of gas dynamics and radio frequency fields.

[0048] The ions are then transmitted via an ion lens IQ0 into an ion guide Q0, which comprises four rods 108 (two of which are visible in this figure) that are arranged in a quadrupole configuration to form an ion beam for transmission to downstream components of the mass spectrometer.

[0049] The ion beam exits the QO ion guide and is focused via an ion lens IQ1 and a quadrupole prefilter lens STI into a subsequent ion mass filter QI, which includes four rods 110 (two of which are visible in this figure) that are arranged in a quadrupole configuration and to which RF voltages as well as a DC resolving voltage can be applied for radially focusing the ions and selecting ions having a target m / z ratio (herein referred to as precursor ions) as they pass through the QI mass filter. In other embodiments, other multipole configurations, such as a hexapole or an octupole configuration, can be utilized.

[0050] More specifically, in this embodiment, the quadrupole rod set QI can be operated as a conventional transmission RF / DC quadrupole mass filter for selecting ions having an m / z value of interest or m / z values within a range of interest. By way of example, the quadrupole rod set QI can be provided with RF / DC voltages suitable for operation in a mass-resolving mode. For example, parameters of the applied RF and DC voltages can be selected so that QI establishes a transmission window of chosen m / z ratios, such that these ions can traverse QI largely unperturbed. Ions having m / z ratios falling outside the window, however, do not attain stable ion trajectories within the quadrupole and can be prevented from traversing the quadrupole rod set QI. It should be appreciated that this mode of operation is but one possible mode of operation for QI. In this embodiment, the Q0 ion guide and the QI mass filter are disposed in differentially pumped vacuum chambers 151 and 152, respectively. By way of example, the vacuum chamber 151 can be maintained at a pressure in a range of about 3 to about 12 mTorr, and the vacuum chamber 152 can be maintained at a pressure in a range of about 1 to about 50 pTorr.

[0051] The ions passing through the QI mass analyzer are focused via a quadrupole prefilter lens ST2 and an ion lens IQ2A into a collision cell Q2. The collision cell Q2 includes four rods 112 (two of which are visible in this figure) that are arranged in a quadrupole configuration and to which RF voltages can be applied for providing radial confinement of the ions. The rods 112 are disposed within an enclosure 113 such that the pressure within the collision cell can be increased relative to the other stages, e.g., via introduction of a gas (e.g., nitrogen) into the enclosure. While in some embodiments the collision cell Q2 is employed to cause fragmentation of the ions received by the collision cell, in other embodiments, the collision cell Q2 is not utilized for ion fragmentation, but rather for causing, for example, collisional cooling of the ions.

[0052] The fragment ions exiting the collision cell are received by a downstream Q3 quadrupole mass analyzer 116 and are separated based on their m / z ratios to be detected via an ion detector 118. The Q3 quadrupole mass analyzer includes four rods that are arranged in a quadrupole configuration and to which RF and DC voltages can be applied.

[0053] An analysis module 119 is in communication with the ion detector 118 to receive ion detection signals (e.g., electrical pulses) generated by the ion detector 118 and to process those signals to generate a mass spectrum of the detected ions.

[0054] An RF voltage source 115a and a DC voltage source 115b operating under the control of a controller 117 can apply the requisite RF and DC voltages to various components of the mass spectrometer 100. By way of example, the RF voltage source 115a can apply RF voltages to the quadrupole rods of Q0 ion guide. In this embodiment, the QI mass filter, Q2 collision cell, and Q3 mass analyzer are capacitively coupled to the rods of the Q0 ion guide to receive RF voltages via such capacitive coupling. The RF voltages applied to the rods of the Q0 ion guide, the QI mass filter and the Q2 collision cell provide an electromagnetic field for causing radial confinement of the ions and / or selecting ions with desired m / z ratios to pass through the quadrupole rods. The DC voltage source 115b can apply a DC discriminating voltage to the quadrupole rods of the QI mass filter for selecting ions having m / z ratios of interest.

[0055] In various embodiments, different components of the above mass spectrometer 100 can be evaluated to determine whether an observed change in the mass spectrometer’s performance, e.g., a reduction in signal sensitivity, is due to an operating condition associated with a particular component. By way of example, the Q0 region (ion guide) includes several electro-mechanical components, e.g., rods, lenses, and in other embodiments T-bars and LINAC electrodes, that can be contaminated and hence contribute to a change in the mass spectrometer’s performance. Even in absence of contamination, voltages applied to the rods or lenses and / or the pressure of the chamber in which the electrodes, lenses, etc., are positioned can be outside target (desired) ranges. The transit time of ions through the Q0 can be measured by emptying the ion path that extends from the orifice 104 of the mass spectrometer to ion detector 118 of ions and subsequently determining the time required to re-establish a mass signal.

[0056] By way of example, an m / z of 5 Da and a bandpass of about 0.7 Da on the mass filter QI and / or the mass analyzer Q3 can be utilized to empty the ion path of all ions. In other words, the DC and RF voltages applied to the rods of the mass filter QI and / or the mass analyzer Q3 can be set such that only ions with an m / z of 5 Da can pass through QI and / or Q3. In this embodiment, the Q0 ion guide and the QI mass filter are capacitively coupled. Accordingly, configuring the QI mass filter to pass only ions with an m / z ratio of 5 Da will result in the same restriction in the passage of ions through the Q0 mass filter. As such, these components and any components positioned downstream of these components can be emptied of all ions of interest. Subsequently, the bandpass of Q0, QI and / or Q3 can be shifted to higher m / z ratios corresponding to one or more target ions that can be introduced into the mass spectrometer and detected.

[0057] For example, in various embodiments, repeated MRM measurements of a target (desired) ion, e.g., an ion having an m / z ratio of 1522, can be performed with minimal pause and dwell time, e.g., a pause and dwell time of about 0.5 msec, without performing ion emptying steps in between. Initially, no signal will be observed as the ion path is empty of ions, but as ions traverse through the ion path and reach the ion detector, mass signals will be detected. In this manner, the time required for ions to traverse the ion path can be measured. Finally, in some cases, an MRM measurement with a longer dwell time (typically about 100 msec) can be performed and used as a baseline signal to obtain the intensity of the full signal. In various embodiments, the entire measurement can be performed in only a couple of hundred milliseconds. Further, in various embodiments, the measurements can be repeated many times, e.g., over a minute, to improve the measurement statistics. By altering which parts of the ion path are emptied, it is possible to measure the ion transit time between different parts of the ion path.

[0058] For example, in order to measure the ion transit time through mass analyzer Q3, the RF and DC voltages applied to the rods of mass filter QI can be set so as to allow passage of a target ion while the RF and DC voltages applied to the rods of the mass analyzer Q3 can be set to about 5 Da, as discussed above. This leads to the emptying of ions from mass analyzer Q3. Following emptying of mass analyzer Q3 from ions, the RF and DC voltages applied to the rods of mass analyzer Q3 can be adjusted to allow passage of the target ion through the mass analyzerQ3 and thus re-establishing the mass signal. The time required for re-establishing the mass signal can be attributed to the ion transit time through mass analyzer Q3.

[0059] In some mass spectrometers, an ion guide, e.g., the above Q0 ion guide, can include accelerating and / or auxiliary electrodes. In some cases, the degradation of the performance of such mass spectrometers may be due to contamination, misalignment and / or application of sub- optimal voltages to such elements. Again, in various embodiments, the transmit time through such a component can be utilized as a diagnostic tool to identify the cause of the performance degradation.

[0060] With reference to FIGS. 3A, 3B, and 3C, an ion guide 1000 according to an embodiment, which can be employed as the Q0 ion guide in the above mass spectrometer 100, can include an inlet 1000a for receiving ions generated by an upstream ion source (not shown) and an outlet 1000b through which ions can exit the ion guide.

[0061] The ion guide 1000 includes a set of rods 1040, which are arranged according to a multipole configuration and are spaced apart to provide an ion passageway through which ions can travel. In this embodiment, the rod set 1040 includes four rods that are arranged according to a quadrupole configuration. In this embodiment, each of the rods 1040 extends, as a continuous element, from a proximal end to a distal end, where the proximal ends of the quadrupole rods 1040 are positioned at or in proximity of the inlet 1000a of the ion guide 1000 and the distal ends of the quadrupole rods 1040 are positioned at or in proximity of the outlet 1000b of the ion guide.

[0062] An RF voltage source 2000 operating under control of a controller 2020 applies RF voltages, e.g., at a frequency in a range of about 0.1 MHz to about 5 MHz and an amplitude in a range of about 10 volts to about 5 kilovolts, to the quadrupole rods 1040.

[0063] A DC voltage source 2040, also operating under control of the controller 2020, can apply offset DC voltages to the quadrupole rods so as to provide an offset DC voltage between the quadrupole rods and an upstream and / or a downstream ion optic (e.g., a downstream ion mass filter).

[0064] With continued reference to FIG. 3A, 3B, and 3C, a plurality of auxiliary electrodes 3000a, 3000b, 3000c, and 3000d, which are herein collectively referred to as the T-shapedauxiliary electrodes or T-shaped electrodes or T-bars 3000, is interspersed between the quadrupole rod set such that each auxiliary electrode is interposed between two of the quadrupole rods. In this embodiment, the auxiliary electrodes have a T-shaped configuration characterized by a base that extends parallel to the quadrupole rods and a stem that extends orthogonally from the base toward the ion passageway. In this embodiment, the auxiliary electrodes 3000 can be grouped into two pairs, which are herein referred to as T-bar A and T-bar B.

[0065] The pair of the auxiliary electrodes 3000a / 3000b forms one pole of the auxiliary electrodes (herein referred to as the B-pole) and the pair 3000c / 3000d (herein referred to as the A-pole) forms the other pole of the auxiliary electrodes.

[0066] In this embodiment, the auxiliary electrodes 3000 do not extend across the entire length of the ion guide 1000. In other words, the length of the base of the T-shaped electrodes 3000 is less than the longitudinal length of the ion guide 1000. The auxiliary electrodes 3000 may be positioned in a region of the ion guide that is closer to the ion guide’s inlet 1000a than its outlet 1000b.

[0067] As noted above, the ions entering the ion guide pass through the first region 1001a of the ion guide 1000 in which they are subjected only to the radial confining field generated by the voltage(s) applied to the multipole rods. The DC voltage source can apply DC voltages to the T- shaped auxiliary electrodes 3000 such that the DC potential difference between the auxiliary electrodes 3000 (as well as the potential difference between the auxiliary electrodes and the quadrupole rods) can generate a DC field (e.g., an octupolar DC field distribution) within the second region 1001b of the ion passageway that can cause a reduction in ion confinement experienced by a subset of ions (herein also referred to as the first subset) having m / z ratios within a target range that are received by the ion guide 1000, thereby inhibiting the passage of those ions through the ion guide 1000, while allowing other ions received by the ion guide 1000 to continue propagating through the ion passageway. For example, the reduction in the ion confinement of the first subset of ions can result in those ions following trajectories that result in the ions being attracted to the auxiliary electrodes 3000 and striking those electrodes, thereby being removed from the set of ions propagating toward the outlet of the ion guide 1000. The T- bar electrodes 3000 can be used to establish a high mass cut off (HMCO) and the RF voltageapplied to the multipole rods can be used to establish a low mass cut off (LMCO) such that the combination of the HMCO and the LMCO provides a bandpass filter that allows transmission of ions with m / z ratios within an m / z range while inhibiting the passage of ions with m / z ratios outside of that m / z range.

[0068] With particular reference to FIG. 3C, the ion guide 1000 further includes four LINAC electrodes 4000 (two of which 4000a and 4000b are visible in the figure) that extend along a portion 1001c of the length of the ion guide 1000. The application of DC voltages via the DC voltage source 2040 can generate an axial electric field that can accelerate the ions passing through the ion guide 1000.

[0069] In some embodiments, the ion transit time through the ion guide 1000 having the LINAC and T-bar electrodes 4000 and 3000 can be measured to evaluate the operational condition of the T-bar and / or the LINAC electrodes. For example, in the case of detecting a change in the ion transit time that is indicative of a degradation of the performance of the ion guide 1000, the voltages applied to the LINAC electrodes 4000 can be adjusted to determine whether the adjustment would affect the transit time. Generally, it is expected that increasing the voltages applied to the LINAC electrodes 4000 should result in a faster ion transit time through a component, such as a mass filter, in which the LINAC electrodes 4000 are incorporated, due to establishment of an accelerating electric field. A change in the voltage(s) applied to the LINAC electrodes 4000 that does not produce an expected change in the ion transit time can be an indication that the operating condition of one or more of the LINAC electrodes 4000 is not optimal (e.g., the electrode is contaminated).

[0070] In some embodiments, the process of determining the cause of a change in performance of a mass spectrometer can be automated. For example, in response to observing a degradation of the mass spectrometer’s performance, a controller can execute pre-loaded instructions for measuring ion transit times through various regions of an ion path extending from the orifice of the mass spectrometer to its ion detector. By way of example, with reference to FIG. 2, controller 117 can be programmed to adjust the voltages applied to various rods of the ion guide Q0, the mass analyzer QI, the collision cell Q2, and / or the quadrupole mass analyzer Q3 to determine ion transit times through these components in a manner discussed above. The controller can compare the ion transit times to target transit times to identify one or morecomponents that may be contributing to the degradation of the mass spectrometer’s performance. In some cases, the analysis module 119 can be programmed to automatically compare, e.g., on a periodic basis, one or more pre-defined target performance criteria with the measurements of the respective criteria to identify a degradation in the performance of the mass spectrometer. For example, the analysis module may be programmed to compare a signal intensity corresponding to a particular MRM transition signal with a target intensity (e.g., expected intensity) to determine if the degradation of the signal has occurred. When the analysis module detects such a degradation, the analysis module can transmit a signal to the controller 117 to begin the process of determining the cause of the performance degradation, as discussed above.

[0071] The controller and / or the analysis module can be implemented in hardware, firmware and / or software in a manner known in the art as informed by the present teachings. By way of illustration, FIG. 10 schematically depicts an example of an implementation of a controller or an analyzer suitable for use in the practice of the present teachings, such as the above controller and analyzer. This implementation includes a digital processor 10, a random-access-memory (RAM) module 12, a permanent memory module 14, a communications interface 16 and a communications bus 18, which allows the device to communicate with external devices. The instructions for determining whether a degradation of the mass spectrometer’s performance has occurred and / or for determining the cause of such a degradation, in a manner described herein, can be stored in the permanent memory module 14 and can be transferred via the processor 10 during runtime to the RAM module for execution.

[0072] The following examples are provided for further elucidation of various aspects of the present teachings. The examples do not necessarily provide optimal ways of practicing the present teachings or optimal results that may be obtained.

[0073] Examples

[0074] In the following examples, a Sciex 7500 triple quadrupole mass spectrometer similar to the mass spectrometer depicted in FIG. 2 with a Q0 ion guide as discussed in connection with FIGS. 3A-3C was employed for acquiring the mass data. Thus, the same terminology as that employed to discuss the mass spectrometer and the ion guide depicted, respectively, in FIG. 2 and FIGS. 3A-3C is employed to describe the following examples. The mass spectrometer further included a set of LINAC electrodes and a set of T-bar electrodes in the Q0 ion guide. ForY1the purposes of the following experiments, the mass filter QI and the mass analyzer Q3 were set to pass the same ion. Thus, no fragment ions were made or detected in these experiments.

[0075] Example 1

[0076] With reference to FIGS. 4A and 4B, the ion guide Q0 and the mass filter QI were configured to allow only the passage of ions with an m / z ratio of 5 Da, thereby emptying the ion path extending from the ion guide Q0 to the ion detector of all ions of interest. It is noted that as the ion guide Q0 and the mass filter QI were capacitively coupled, configuring the mass filter QI to allow only the passage of ions with an m / z ratio of 5 Da resulted in the same restriction of the passage of ions through the ion guide Q0. FIG. 4A provides the values of various mass spectrometer parameters that were utilized in the experiment (EP denotes the entrance potential, CE denotes the ion collision energy and CXP denotes the collision cell exit potential).

[0077] The emptying of the ion path took place over a time period of 20 msec. Subsequently, the ion guide Q0, the mass filter QI and the mass analyzer Q3 were configured to allow the passage of an ion with an m / z ratio of 922. A series of mass signals was measured as shown in FIG. 4B to determine the time required to recover the mass signal. Further, a baseline measurement of the mass signal for the ion at m / z of 922 was also made.

[0078] Defining the ion transit time as the 80% of the time required for the recovered mass signal to reach the signal height associated with the baseline signal, an ion transit time of about 7 msec was estimated for the transmission of ions from the ion guide Q0 to the ion detector.

[0079] Example 2

[0080] In this example, a target ion having an m / z ratio of 1522 was employed for obtaining the ion transit times through an ion path extending from the ion guide Q0 to the mass spectrometer’s ion detector as well as the ion transit time from the mass filter QI to the ion detector. The ion path from Q0 to the ion detector was emptied of ions by adjusting the RF and DC voltages applied to the rods of mass filter QI and mass analyzer Q3 to allow passage of only ions having an m / z ratio of 5 Da, in a manner discussed above in connection with Example 1. The ion emptying step took about 20 msec. Subsequently, the RF and DC voltages applied to the rods of mass filter QI and mass analyzer Q3 were adjusted to allow observing mass signalsassociated with the target ion having an m / z ratio of 1522. A baseline signal for the ion at the m / z ratio of 1522 was also acquired.

[0081] Again, defining the ion transit time as the time required for the recovered mass signal to reach about 80% of the baseline signal, the resultant mass data presented in the left portion of FIG. 5 can be used to estimate an ion transit time of about 6 msec for the ion path extending from the ion guide Q0 to the ion detector.

[0082] Subsequently, the ion path from collision cell Q2 (which was not used in this example for ion dissociation) to the ion detector was emptied by adjusting the QI mass and the Q3 mass by 20Da. This was followed by adjusting the QI and Q3 masses back to ions of interest to allow passage of the ions through the collision cell to be detected by the downstream ion detector. The recovered mass signals depicted in the right portion of the data presented in FIG. 5 can be utilized to estimate an ion transit time of about 3 msec along the ion path extending from the Q2 to the ion detector.

[0083] Using the transit times associated with ion transit from Q0 to the ion detector and Q2 to the ion detector, the transit time of ions from Q0 to Q2 was estimated to be about 3 msec.

[0084] Example 3

[0085] A 7500 Sciex mass spectrometer was employed to acquire the data presented in this example. The mass spectrometer included a set of LINAC electrodes in the Q0 region for accelerating ions passing through this region, in a manner similar to that depicted in FIGS. 3A - 3C. The recovery of a mass signal at 1522 was measured subsequent to emptying the ion path from Q0 to the ion detector. The data for “on” and “off’ states of the LINAC electrodes at several pressures of the Q0 chamber was acquired. For an “on” state of the LINAC electrodes, a voltage of -160 volts (V) was applied to the LINAC electrodes to generate an axial electric field for accelerating the ions.

[0086] The data presented in FIG. 6 shows that the use of the LINAC electrodes for accelerating the target ion having m / z of 1522 at a LINAC voltage of -160 V can result in a reduction of the ion transit time through the Q0 region by about 5 - 10 msec when a T-bar bandpass of HMCO at m / z 1622 was applied.

[0087] Example 4

[0088] The present teachings can also be utilized to evaluate whether an observed performance degradation of a mass spectrometer is due to contamination of one or more ion lenses. If altering a voltage offset applied to an ion lens positioned between the Q0 region and QI region (typically referred to as IQ1 lens) would result in a change in ion transit time, it could be an indication that the ion lens is contaminated.

[0089] FIG. 7 shows similar data as that in FIG. 4B but with two different offset voltages applied to the IQ1 lens positioned between the Q0 and QI regions. At an operating IQ1 offset voltage of -0.5 V, the data shows a significant change in the ion transit time through the Q0 region (See, solid intensity lines). Shifting the IQ1 offset voltage to an optimal value of -1.5 V helps partially recover the transit time (i.e., reduce the transit time).

[0090] Example 5

[0091] FIG. 8A shows data corresponding to the recovery of a mass signal associated with an ion having an m / z ratio of 1522 acquired after emptying the ion path from Q0 to the ion detector. Tbar and LINAC voltages were tuned following a tuning procedure. Tbar voltages were set to create a HMCO of lOODa higher than QI mass and LINAC voltages were optimized to either -110 V or -160 V. In contract, FIG. 8B shows the same mass signal recovery data but with both the Tbar and the LINAC electrodes in an “off’ state.

[0092] A comparison between the data presented in FIGS. 8A and 8B shows that the transit time along the ion path from the Q0 ion guide to the ion detector is significantly faster when the Tbar and the LINAC electrodes are both in the “on” state.

[0093] Example 6

[0094] Mass signal data was obtained for a target ion having an m / z of 1522 in a manner discussed in connection with Example 2 to assess how altering the voltage applied to Q0D ion lens (i.e., DC voltage between IQ0 and Q0) impacts Q0 timing measurements. The data presented in FIG. 9 shows that changing the Q0D voltage from -10 V (white lines) to 20 V (solid black lines) leads to the recovery of the ion transit time, that is, it reduces ion transit time,through the Q0 region. Such a change in the ion transmit time is indicative of IQ0 contamination.

[0095] Depending on certain implementation requirements, embodiments of the invention can be implemented in hardware and / or in software. The implementation can be performed using a non- transitory storage medium such as a digital storage medium, for example a floppy disc, a DVD, a Blu-Ray, a CD, a ROM, a PROM, and EPROM, an EEPROM or a FLASH memory, having electronically readable control signals stored thereon, which cooperate (or are capable of cooperating) with a programmable computer system such that the respective method is performed. Therefore, the digital storage medium may be computer readable.

[0096] While various embodiments have been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive; embodiments of the present disclosure are not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing embodiments of the present disclosure, from a study of the drawings, the disclosure, and the appended claims.

[0097] In the claims, the word “comprising” does not exclude other elements or steps, and the indefinite article “a” or “an” does not exclude a plurality. A single processor or other processing unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measured cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0098] Those having ordinary skill in the art will appreciate that various changes can be made to the above embodiments without departing from the scope of the present teachings.

Claims

What is claimed is:

1. A method for identifying an operating condition of a mass spectrometer, comprising: measuring at least one transit time associated with passage of at least one target ion through at least one component of the mass spectrometer positioned in an ion path extending from an orifice of the mass spectrometer to an ion detector of thereof; and evaluating an operating condition associated with said at least one component based on said at least one transit time.

2. The method of Claim 1 , wherein the step of evaluating the operating condition comprises determining contamination of said at least one component.

3. The method of Claim 1, wherein the step of evaluating the operating condition comprises determining a misalignment of one or more elements associated with said at least one component, wherein optionally said one or more elements comprise a plurality of rods of a multipole rod set.

4. The method of Claim 1 , wherein the step of evaluating the operating condition comprises determining whether at least one voltage applied to one or more elements associated with said at least one component is outside a target range, wherein optionally said one or more elements comprise any of one or more rods of a multipole rod set and one or more ion lenses.

5. The method of Claim 1, wherein the step of evaluating the operating condition comprises determining whether a pressure within a chamber associated with said component is outside a target range.

6. The method of any one of Claims 1-5, wherein the step of measuring the at least one transit time comprises substantially emptying said at least one component from said at least one target ion and subsequently introducing said at least one target ion into said component and measuring a temporal period between the subsequent introduction of theat least one target ion into the component and detection of a mass signal associated with the target ion via a downstream detector of the mass spectrometer.

7. The method of Claim 6, wherein said mass signal corresponds to an MRM transition of said target ion.

8. The method of Claim 6, wherein the step of substantially emptying said at least one component comprises switching an ion lens positioned upstream of the at least one component from one state to another so as to inhibit passage of the target ion into the at least one component while the target ion previously introduced into the component is removed.

9. The method of Claim 6, wherein the step of substantially emptying said at least one component comprises adjusting any of a DC voltage and an RF voltage applied to one or more rods of said component to inhibit passage of ions therethrough.

10. The method of any one of Claims 1-5 and 7-9, wherein said at least one component comprises any of an ion guide, a mass filter and a mass analyzer.

11. The method of Claim 10, wherein any of said ion guide, said mass filter and said mass analyzer comprises a plurality of rods to which any of at least one DC voltage and at least one RF voltage can be applied, wherein optionally said rods are arranged in a multipole configuration.

12. The method of Claim 11, wherein the step of evaluating the operating condition comprises evaluating contamination of one or more of said plurality of rods.

13. The method of Claim 11, wherein the step of evaluating the operating condition comprises evaluating whether any of said at least one DC voltage and said at least one RF voltage is within a target range.

14. The method of Claim 10, wherein the step of evaluating the operating condition comprises evaluating whether a pressure of a chamber in which any of said ion guide, said mass filter and said mass analyzer is positioned is within a target pressure range.

15. The method of Claim 11, wherein the step of evaluating the operating condition comprises evaluating whether any of said one or more plurality of rods is misaligned.

16. A mass spectrometer, comprising: an ion source for generating a plurality of ions; an ion path extending from an orifice, which is configured to receive the ions, to an ion detector, which is configured to generate ion detection data in response to detection of ions incident thereon; an analysis module in communication with said ion detector to receive the ion detection data and generate mass signals, said analysis module being configured to determine a degradation of performance of the mass spectrometer based on analysis of said mass signals; and a controller in communication with said analysis module to receive a signal indicative of degradation of performance of the mass spectrometer, wherein the controller is configured to initiate measurement of at least one ion transit time associated with at least a portion of said ion path and is further configured to analyze said measured ion transit times to evaluate one or more operating conditions of at least one component positioned in said at least a portion of said ion path.

17. The mass spectrometer of Claim 16, further comprising any of at least one DC voltage source and at least one RF voltage source operating under control of said controller for applying at least a DC and at least an RF voltage to said at least one component.

18. The mass spectrometer of Claim 16, wherein said controller initiates the measurement of the at least one ion transit time via adjusting at least one of said at least a DC voltage and said at least an RF voltage.

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