System for determining cleanliness of mass spectrometer ion optics

Abstract

A mass spectrometer comprising: an ion detector; ion optics for guiding ions to the ion detector; one or more voltage sources for supplying voltage to the ion optics; control circuitry for controlling the one or more voltage sources to switch the ion optics between operating in a first mode in which the ion optics are unable to transmit ions having a first mass to charge ratio or a first polarity to the ion detector and operating in a second mode in which the ion optics are able to transmit ions having the first mass to charge ratio or first polarity to the ion detector for a period of time; and to repeatedly switch between the first mode and the second mode a plurality of times; and a processor and circuitry configured to: (i) determine an intensity of an ion signal detected by the detector at a first time in each of the periods of time in which the ion optics are in the second mode; and (ii) determine an intensity of an ion signal detected by the detector at a second, later time in each of the periods of time in which the ion optics are in the second mode.

Description

[0001] Cross-references to related applications

[0002] This patent application claims priority and benefit to UK Patent Application No. 2013325.2, filed on 26 August 2020. The entire contents of this application are incorporated herein by reference. Technical Field

[0003] The present invention relates generally to mass spectrometers, and more particularly to systems and methods for determining the cleanliness of ion optics within a mass spectrometer. Background Technology

[0004] Ion guiding devices are used in various types of mass spectrometers to deliver ions along a given path. For example, one or more ion guiding devices can be arranged to guide ions from one region of the spectrometer to another region held at a different pressure. The two regions held at different pressures can be separated by a pressure gauge orifice. The ion guiding device can be arranged on one side of the orifice to guide ions toward and through the orifice, and the ion guiding device can be arranged on the other side of the orifice to receive and guide ions that have already passed through the orifice. Alternatively, a single ion guiding device can be arranged within the orifice and can extend upstream and downstream thereto to guide ions through the orifice.

[0005] Ion guiding devices in a spectrometer, and possibly any differential orifices, can become contaminated over time (e.g., due to impacts of ions and / or non-ionic substances on their surfaces). This contamination can affect the transit time of ions through the ion guiding device (and / or orifice), and therefore the transit time of a given ion can vary depending on the degree of contamination of the ion guiding device (or orifice). Consequently, the ion signal intensity profile derived from the given ion can vary depending on the degree of contamination. More specifically, the transit time of ions can increase with increasing contamination, and therefore, at least for the initial portion of the ion signal, the intensity of the ion signal in a spectrometer with a contaminated ion guiding device can be lower than that in a spectrometer with a cleaner ion guiding device.

[0006] Users of spectrometers often run system suitability tests before analysing a sample of interest in order to confirm that the system is fit for purpose before it is used to analyse the sample. This includes analysing a quality control sample and checking that the resulting ion signals detected have the expected sensitivity. However, the occurrence of cleanliness issues is difficult to detect because the ion signals detected are averaged for a given mass to charge ratio and compared to the expected value. If only the initial part of the ion signal is relatively low due to contamination, this can not reduce the average signal from the expected value enough for it to be determined that there is a contamination issue. A dirty ion guide can therefore not be detected by system suitability tests or by analysing a quality control sample. As a result, without a system failure in the middle of a batch, the user would then proceed to analyse their sample of interest, resulting in a loss of time, solvent and sample. Contamination is often only detected when a final quality control is analysed at the end of the whole batch, for example. SUMMARY

[0007] According to a first aspect, the present application provides a mass spectrometer comprising: an ion detector; ion optics for guiding ions to the ion detector; one or more voltage sources for supplying a voltage to the ion optics; control circuitry for controlling the one or more voltage sources to switch the ion optics between operating in a first mode in which the ion optics are unable to transmit ions having a first mass to charge ratio or first polarity to the ion detector and operating in a second mode in which the ion optics are able to transmit ions having the first mass to charge ratio or first polarity to the ion detector for a period of time; and a processor and circuitry configured to: determine an intensity of the ion signal at a first time in the period of time; determine an intensity of the ion signal at a second, later time in the period of time; determine whether there is a difference between the intensity at the first time and the intensity at the second time; and produce a first output indicating that the ion optics are dirty if the difference is above a threshold or a rate of change of the intensity over time is below a threshold rate.

[0008] The processor and circuitry can be configured to produce a different, second output indicating that the ion optics are clean if the difference is below a threshold or the rate of change of the intensity over time is above a threshold rate.

[0009] The spectrometer can comprise or be connected to a display screen such that the first output can cause the screen to display a notification that the ion optics require maintenance, such as cleaning. The second output can cause the screen to display a notification that the ion optics are clean, e.g. that they do not require maintenance.

[0010] For the avoidance of doubt, each step of determining the intensity of an ion signal comprises determining the intensity of an ion detected by an ion detector.

[0011] Advantageously, in the second mode, the ion optics are able to transmit only ions having said first mass-to-charge ratio or first polarity to the ion detector.

[0012] The ion optics can comprise a mass filter, and the control circuitry can be configured to control the mass filter so that it is unable to transmit ions having said first mass-to-charge ratio in the first mode, and is able to transmit only ions having said first mass-to-charge ratio in the second mode.

[0013] The control circuitry can be configured to control the mass filter so as to be able to transmit only ions having said first mass-to-charge ratio in the second mode, and to transmit only ions having a different, second mass-to-charge ratio in the first mode.

[0014] For example, the checking of the cleanliness of the ion optics can be performed as part of a step of switching the mass filter between two different mass transmission windows, for example in an MRM experiment. For example, the spectrometer can be a triple quadrupole mass analyser, in which the last quadrupole is the mass filter operated in the first and second modes.

[0015] The ion optics can comprise one or more ion guides and / or differential pumping apertures upstream of the mass filter.

[0016] The first output can indicate that the ion guide and / or differential pumping aperture is dirty if the difference between the intensity at the first time and the intensity at the second time is above a threshold or the rate of change of the intensity over time is below a threshold rate. On the other hand, the second output can indicate that the ion guide and / or differential pumping aperture is clean if the difference between the intensity at the first time and the intensity at the second time is below a threshold or the rate of change of the intensity over time is above a threshold rate.

[0017] The ion optics can comprise a mass filter and an ion guide arranged upstream of the mass filter; and the control circuitry can be configured to vary a voltage applied to the mass filter so that it is able to transmit ions having different mass-to-charge ratios at different times, and to vary a voltage applied to the ion guide in synchrony with the mass filter so that at a given time the ion guide is optimised for transmitting ions having a mass-to-charge ratio corresponding to the mass-to-charge ratio that the mass filter is set to transmit.

[0018] The ion guide can be an RF-only ion guide, and the control circuitry can vary an RF voltage applied to the RF-only ion guide in synchrony with the variation of the voltage applied to the mass filter.

[0019] The ion optics can comprise a mass filter and an ion gate or ion guide arranged upstream of the mass filter; wherein the control circuitry can be configured to: (i) control the mass filter so that it is able to transmit ions having the first mass-to-charge ratio in both the first mode and the second mode; and (ii) control the ion gate or ion guide so as to prevent the transmission of ions to the mass filter in the first mode and to allow the transmission of ions to the mass filter in the second mode.

[0020] For example, when there is an ion gate, the control circuitry can cause one or more voltages to be supplied to the ion gate in the first mode so that ions are not transmitted through the ion gate to the mass filter, and cause one or more different voltages to be supplied to the ion gate in the second mode so that ions are transmitted through the ion gate to the mass filter. Similarly, when there is an ion guide, the control circuitry can control the voltages supplied to the ion guide so that ions are not transmitted through the ion guide to the mass filter in the first mode but are transmitted through the ion guide to the mass filter in the second mode. For example, an RF voltage can be supplied to the ion guide in the second mode so as to radially confine the ions and direct them downstream to the mass filter, whereas the RF voltage cannot be supplied in the first mode so that the ions are not radially confined and are not transmitted to the ion guide.

[0021] The spectrometer can comprise a source of the ions having the first mass-to-charge ratio arranged upstream of the ion optics.

[0022] The control circuitry can be configured to switch to the second mode at a certain time and to hold the ion optics in the second mode for substantially the entire time period so that if the ion optics are clean, the ions having the first mass-to-charge ratio will reach the mass filter through the ion optics held in the second mode for substantially the entire time period; whereas if the ion optics are not clean, the ions having the first mass-to-charge ratio will reach the mass filter through the ion optics held in the second mode for at least an initial portion of the time period with a lower intensity

[0023] The spectrometer can comprise a source of the ions having the first mass-to-charge ratio, wherein the source and ion optics are configured so that if the ion optics are clean, the ion current to the mass filter of ions having the first mass-to-charge ratio is substantially constant through substantially the entire time period.

[0024] In contrast, if the ion optics are dirty, the ion current to the mass filter of ions having the first mass-to-charge ratio is not constant and can increase over time through the time period.

[0025] The spectrometer can comprise a separator for separating analyte molecules or ions upstream of the mass filter, such that ions of different mass-to-charge ratios are fed to the mass filter at different times.

[0026] According to the spectrometer described herein, the step of determining the intensity of the ion signal at the first time in the time period can comprise: a) determining the average intensity of the ion signal over a first segment of the time period, and the step of determining the intensity of the ion signal at the later second time in the time period comprises determining the average intensity of the ion signal over a later second segment of the time period; or b) determining the average intensity of the ion signal over a first segment at or near the beginning of the time period, and the step of determining the intensity of the ion signal at the later second time in the time period comprises determining the average intensity of the ion signal over the entire time period.

[0027] For the avoidance of doubt, a first segment positioned near the beginning of the time period is a segment (in its entirety) that is positioned before the end of the time period (e.g. before half way through the time period).

[0028] Alternatively, the step of determining the intensity of the ion signal at the first time in the time period can comprise determining the instantaneous intensity of the ion signal at that time (i.e. not an average), and the step of determining the intensity of the ion signal at the later second time can comprise determining the instantaneous intensity of the ion signal at that time (i.e. not an average).

[0029] The first time in the time period can be a time spaced apart from the beginning of the time period.

[0030] The present invention also provides a method of mass spectrometry, the method comprising: providing a mass spectrometer as described above; and determining the cleanliness of the ion optics by: switching the ion optics from a first mode to a second mode, such that the ion optics are able to transmit ions having the first mass-to-charge ratio or first polarity to the ion detector for a time period; determining the intensity of the ion signal at a first time in the time period; determining the intensity of the ion signal at a later second time in the time period; determining whether there is a difference between the intensity at the first time and the intensity at the second time; and producing a first output indicating that the ion optics are dirty if the difference is above a threshold or if the rate of change of the intensity over time is below a threshold rate.

[0031] A second aspect of the application provides a mass spectrometer comprising: an ion detector; ion optics for guiding ions to the ion detector; one or more voltage sources for supplying voltages to the ion optics; control circuitry for controlling the one or more voltage sources to switch the ion optics between operating in a first mode in which the ion optics are unable to transmit ions having a first mass-to-charge ratio or a first polarity to the ion detector and operating in a second mode in which the ion optics are able to transmit ions having the first mass-to-charge ratio or the first polarity to the ion detector for a period of time; and to repeatedly switch between the first mode and the second mode a plurality of times; and a processor and circuitry configured to: (i) determine an intensity of an ion signal detected by the detector at a first time in each of the periods of time in which the ion optics are in the second mode; and (ii) determine an intensity of an ion signal detected by the detector at a second, later time in each of the periods of time in which the ion optics are in the second mode.

[0032] The processor and circuitry can be configured to: determine how the intensities obtained in step (i) vary with time; determine how the intensities obtained in step (ii) vary with time; determine whether the intensities obtained in step (i) vary with time differently from the intensities obtained in step (ii); and in response to determining that the intensities vary with time differently, produce a first output.

[0033] The first output can be indicative of an undesirable condition in the spectrometer, such as the ion optics being dirty.

[0034] The control circuitry can be configured to control the one or more voltage sources to repeatedly switch the ion optics between operating in the first mode and operating in the second mode a plurality of times during a single experimental run.

[0035] For example, the control circuitry can be configured to switch the ion optics between the first mode and the second mode ≥ 2 times, ≥ 3 times, ≥ 4 times, ≥ 5 times, ≥ 6 times, ≥ 7 times, ≥ 8 times, ≥ 9 times, ≥ 10 times, ≥ 15 times, ≥ 20 times, ≥ 25 times or ≥ 30 times, for example when a source of analyte is continuously supplying analyte to the ion source of the spectrometer. The ion optics can be switched so many times over a period of time selected from: ≤ 10 minutes; ≤ 9 minutes; ≤ 8 minutes; ≤ 7 minutes; ≤ 6 minutes; ≤ 5 minutes; ≤ 4 minutes; ≤ 3 minutes; ≤ 2 minutes; ≤ 1 minute; ≤ 30 seconds; ≤ 20 seconds; ≤ 10 seconds; ≤ 5 seconds; or ≤ 1 second. For example, the ion optics can be switched from one mode to the other every few milliseconds or over a longer timescale.

[0036] The processor and circuitry can be configured to determine that the intensity obtained in step (i) varies with time in the same way as the intensity obtained in step (ii) and to generate a second output. For example, the second output can indicate a desired condition in the spectrometer, such as that the ion optics are sufficiently clean

[0037] The processor and circuitry can be configured such that: step (i) comprises determining that the ion signal varies with time as a peak; step (ii) comprises determining that the ion signal varies with time as a peak; step (iii) comprises determining that the peak area determined in step (i) is different to the peak area determined in step (ii); and step (iv) comprises generating said first output.

[0038] The above step (iii) can determine that the peak area determined in step (i) is less than the peak area determined in step (ii). Alternatively, the above step (iii) can determine that the peak area determined in step (ii) is less than the peak area determined in step (i).

[0039] Alternatively or additionally, the processor and circuitry can be configured such that: step (i) comprises determining that the ion signal varies with time as a peak; step (ii) comprises determining that the ion signal varies with time as a peak; step (iii) comprises determining that the time at which the peak determined in step (i) is detected is different to the time at which the peak determined in step (ii) is detected; and step (iv) comprises generating said first output. Step (iii) can determine that the time at which the peak determined in step (i) is detected is later than the time at which the peak determined in step (ii) is detected. The time at which a peak is detected can be determined from the time of the centre of the peak (e.g. the centre of the FWHM), or alternatively from the start or end time of the peak.

[0040] The processor and circuitry can be configured such that: step (i) comprises determining a gradient of the ion signal in the intensity profile at a first time; step (ii) comprises determining a gradient of the ion signal in the intensity profile at a time corresponding to said first time; step (iii) comprises determining that the gradient determined in step (i) is less than the gradient determined in step (ii); and step (iv) comprises generating said first output.

[0041] The processor and circuitry can be prompted manually to perform steps (i)-(iv). Alternatively, the processor and circuitry can be configured to perform steps (i)-(iv) automatically.

[0042] The spectrometer can comprise or be connected to a display screen, such that the first output can cause the screen to display a notification that the ion optics require maintenance (such as cleaning). The second output can cause the screen to display a notification that the ion optics are clean (e.g. that they do not require maintenance).

[0043] Advantageously, in the second mode, the ion optics are able to transmit only ions having said first mass-to-charge ratio or first polarity to the ion detector.

[0044] The ion optics can comprise a mass filter, and the control circuitry can be configured to control the mass filter so that it is unable to transmit ions having said first mass-to-charge ratio in the first mode, and is able to transmit only ions having said first mass-to-charge ratio in the second mode.

[0045] The control circuitry can be configured to control the mass filter so as to be able to transmit only ions having said first mass-to-charge ratio in the second mode, and to transmit only ions having a different, second mass-to-charge ratio in the first mode.

[0046] For example, the checking of the cleanliness of the ion optics can be performed as part of a step of switching the mass filter between two different mass transmission windows, for example in an MRM experiment. For example, the spectrometer can be a triple quadrupole mass analyser, in which the last quadrupole is the mass filter operated in the first and second modes.

[0047] The ion optics can comprise one or more ion guides and / or differential pumping apertures upstream of the mass filter. The first output can indicate that the ion guides and / or differential pumping apertures are dirty. On the other hand, the second output can indicate that the ion guides and / or differential pumping apertures are clean.

[0048] Although embodiments are envisaged in which the mass filter is switched between a transmission mode and a non-transmission mode, it is envisaged that the ion optics can comprise a mass filter and an ion gate or ion guide arranged upstream of the mass filter; wherein the control circuitry is configured to: (i) control the mass filter so that it is able to transmit ions having said first mass-to-charge ratio in both the first and second modes; and (ii) control the ion gate or ion guide so as to prevent the transmission of ions to the mass filter in the first mode, and to allow the transmission of ions to the mass filter in the second mode.

[0049] For example, when an ion gate is present, the control circuit can cause one or more voltages to be supplied to the ion gate in the first mode such that ions are not transmitted through the ion gate to the mass filter, and one or more different voltages to be supplied to the ion gate in the second mode such that ions are transmitted through the ion gate to the mass filter. Similarly, when an ion guide is present, the control circuit can control the voltage supplied to the ion guide such that ions are not transmitted through the ion guide to the mass filter in the first mode but are transmitted through the ion guide to the mass filter in the second mode. For example, an RF voltage can be supplied to the ion guide in the second mode in order to radially confine ions and direct them downstream to the mass filter, whereas the RF voltage cannot be supplied in the first mode such that ions are not radially confined and are not transmitted to the ion guide.

[0050] The spectrometer can comprise a source of said ions having a first mass-to-charge ratio arranged upstream of the ion optics.

[0051] In embodiments in which the mass filter is switched between a transmission mode and a non-transmission mode (in the first and second modes), for example, the control circuit can be configured to switch to the second mode at a certain time and to hold the ion optics in that second mode for a period of time such that if the ion optics are clean, said ions having the first mass-to-charge ratio will reach the mass filter throughout the period of time for which the ion optics are held in the second mode; whereas if the ion optics are not clean, said ions having the first mass-to-charge ratio will reach the mass filter with lower intensity throughout at least an initial portion of the period of time for which the ion optics are held in the second mode.

[0052] The spectrometer can comprise a source of said ions having said first mass-to-charge ratio, wherein the source and ion optics are configured to cause the ion current to the mass filter of ions having said first mass-to-charge ratio to vary with time.

[0053] The spectrometer can comprise a separator for separating analyte molecules or ions upstream of the ion optics.

[0054] For example, the spectrometer disclosed herein can comprise a liquid or gas chromatography separator for separating analytes and supplying the analytes to the ion source. Additionally or alternatively, an ion mobility or mass separator can be provided for separating ions upstream of said ion optics.

[0055] The separator can cause ions having different physico-chemical properties, such as mass-to-charge ratios, to reach the ion optics at different times.

[0056] Ions having each mass-to-charge ratio, for example said first mass-to-charge ratio, can reach the ion optics (for example the mass filter) with an intensity that varies with time.

[0057] The step of determining the intensity of the ion signal at the first time in each of the time periods can comprise determining the average intensity of the ion signal over a first segment of the time period, and the step of determining the intensity of the ion signal at the later second time in each of the time periods can comprise determining the average intensity of the ion signal over a later second segment of the time period.

[0058] Alternatively, the step of determining the intensity of the ion signal at the first segment in each of the time periods can comprise determining the average intensity of the ion signal over a first segment at or near the beginning of the time period, and the step of determining the intensity of the ion signal at the later second time in each of the time periods comprises determining the average intensity of the ion signal over the entire time of the time period. For the avoidance of doubt, a first segment positioned near the beginning of the time period is a segment (in its entirety) positioned before the end of the time period (e.g. before half way through the time period).

[0059] Alternatively, the step of determining the intensity of the ion signal at the first time in each of the time periods can comprise determining the instantaneous intensity of the ion signal at that time (i.e. not an average), and the step of determining the intensity of the ion signal at the later second time can comprise determining the instantaneous intensity of the ion signal at that time (i.e. not an average).

[0060] The application can also provide a method of mass spectrometry, the method comprising providing a mass spectrometer as described above in relation to the second aspect of the application. The method comprises repeatedly switching the ion optics between the first mode and the second mode a plurality of times; (i) determining the intensity of the ion signal detected by the detector at a first time in each of the time periods in which the ion optics are in the second mode; and (ii) determining the intensity of the ion signal detected by the detector at a later second time in each of the time periods in which the ion optics are in the second mode.

[0061] The method can comprise determining how the intensity obtained in step (i) varies with time; determining how the intensity obtained in step (ii) varies with time; determining whether the intensity obtained in step (i) varies with time in a different manner to the intensity obtained in step (ii); and in response to determining that the intensities vary with time in said different manner, producing a first output.

[0062] According to a third aspect, the present application also provides a mass spectrometer comprising: an ion detector; ion optics for guiding ions to the ion detector; and a processor and circuitry configured to: (i) control the ion optics so as to perform a plurality of operational cycles successively during a single experimental run, wherein each operational cycle comprises: transmitting ions of a first species for a first dwell time, followed by transmitting ions of a different second species for a second dwell time, and followed by transmitting ions of the first species for a third dwell time; (ii) determine an intensity of an ion signal detected by the detector during the first dwell time in each of the plurality of cycles; and (iii) determine an intensity of an ion signal detected by the detector during the third dwell time in each of the plurality of cycles.

[0063] The third aspect of the application can have features as described in relation to the second aspect of the application.

[0064] Each operational cycle can further comprise transmitting ions of the second species for a fourth dwell time, wherein the fourth dwell time is between the second dwell time and the third dwell time or after the third dwell time.

[0065] Each operational cycle can comprise transmitting ions of a third or further species during at least one further dwell time.

[0066] The processor and circuitry can be configured to: determine how the intensity obtained in step (ii) varies with time; determine how the intensity obtained in step (iii) varies with time; determine whether the intensity obtained in step (ii) varies with time differently to the intensity obtained in step (iii); and in response to determining that the intensity varies with time differently, produce a first output.

[0067] The first output can be indicative of an undesirable condition in the spectrometer, such as the ion optics being dirty.

[0068] The spectrometer can comprise a separator for separating analyte molecules in an analytical sample or separating analyte ions from an analytical sample, wherein the processor and circuitry are configured to control the ion optics so as to perform said plurality of operational cycles successively during peaks eluting from the separator.

[0069] The separator can be a chromatographic separator, such as a liquid or gas chromatographic analysis separator.

[0070] The application also provides a method of mass spectrometry, the method comprising: providing a mass spectrometer as described above in relation to the third aspect; (i) performing a plurality of operational cycles during a single experimental run, wherein each operational cycle comprises: transporting ions of a first species for a first dwell time, then transporting ions of a different second species for a second dwell time, and then transporting ions of the first species for a third dwell time; (ii) determining the intensity of the ion signal detected by the detector during the first dwell time in each of the plurality of cycles; and (iii) determining the intensity of the ion signal detected by the detector during the third dwell time in each of the plurality of cycles.

[0071] The method can comprise: determining how the intensity obtained in step (ii) varies with time; determining how the intensity obtained in step (iii) varies with time; determining whether the intensity obtained in step (ii) varies with time in a different manner to the intensity obtained in step (iii); and in response to determining that the intensity varies with time in said different manner, producing a first output. BRIEF DESCRIPTION OF DRAWINGS

[0072] Various embodiments will now be described, by way of example only, and with reference to the accompanying drawings, in which:

[0073] Figure 1 A schematic diagram of a triple quadrupole mass spectrometer according to a first embodiment of the application is shown;

[0074] Figures 2A-2B Ion signals of a spectrometer with clean and dirty ion optics are shown respectively;

[0075] Figure 3 A plot illustrating how ion signal intensity profiles as a function of LC elution time can be affected by contamination of the ion optics is shown;

[0076] Figure 4 A schematic diagram of a triple quadrupole mass spectrometer according to a second embodiment of the application is shown;

[0077] Figure 5 A further plot illustrating how ion signal intensity profiles as a function of LC elution time can be affected by contamination of the ion optics is shown; and

[0078] Figure 6 A further plot illustrating how ion signal intensity profiles as a function of LC elution time can be affected by strong ion species is shown. DETAILED DESCRIPTION

[0079] Figure 1A triple quadrupole mass spectrometer is shown, comprising a first quadrupole rod set 2 arranged in a first chamber, a second quadrupole rod set 3 arranged in a second chamber, and a third quadrupole rod set 4 arranged in a third chamber. An ion detector 5 is positioned downstream of the third quadrupole rod set 4. The first and second chambers are separated by a wall having a differential pumping aperture 6 therein, and the second and third chambers are separated by a wall having a differential pumping aperture 7 therein. The first and third chambers can be evacuated by one or more vacuum pumps, as indicated by the arrows, while gas can be provided into the second chamber through a port 8. Thus, the first and third chambers are maintained at a relatively low pressure when compared to the second chamber, so that the second chamber can be used to fragment ions, as will be discussed further below.

[0080] In use, ions 1 from an ion source (not shown) are fed to the first quadrupole rod set 2, which has RF and DC voltages applied to it so that it operates as a mass filter. The quadrupole rod mass filter 2 can be arranged so as to selectively transmit only parent ions or precursor ions having a particular mass-to-charge ratio. These selected parent ions or precursor ions are thus directed by the first quadrupole 2 towards and through the differential pumping aperture 6, so that they enter the second quadrupole 3 arranged in the second chamber. As noted above, the second chamber can be arranged at a relatively high pressure, and the selected precursor ions can be accelerated into the second chamber so that at least some of them collide with background gas therein and form fragment or product ions. Voltages are applied to the second quadrupole 3 so that it radially confines the resulting fragment or product ions (and optionally any unfragmented precursor ions). For example, the quadrupole 3 can be an RF-only ion guide. The second quadrupole 3 acts as an ion guide which directs these radially confined ions towards and through the differential pumping aperture 7, so that they enter the third quadrupole 4 arranged in the third chamber. One or more voltage sources 9 supply RF and DC voltages to the third quadrupole 4 so that it operates as a mass filter. A control circuit 10 controls the one or more voltage sources 9 so that the voltages applied to the quadrupole mass filter 4 at any given time are such that only ions having a particular mass-to-charge ratio (or a particular range of mass-to-charge ratios) can be guided by the quadrupole mass filter 4 to the ion detector 5, while ions having other mass-to-charge ratios that are present will be filtered out by the quadrupole mass filter 4. The voltages applied to the quadrupole mass filter 4 can be varied by the control circuit 10, for example in a step-wise manner over time, so that the quadrupole mass filter 4 is able to transmit different particular mass-to-charge ratios (or different particular ranges of mass-to-charge ratios) to the ion detector 5 at different times.

[0081] A triple quadrupole mass spectrometer can be used to perform a selected reaction monitoring (SRM) or multiple reaction monitoring (MRM) experiment, in which the quadrupole rod mass filter 2 is set so as to transmit only a particular precursor ion, i.e. only an ion having a particular mass-to-charge ratio. This precursor ion is guided by the quadrupole rod 2 into the second chamber, where it fragments or reacts so as to form fragment or product ions. These fragment or product ions are then guided by the quadrupole rod 3 into the third chamber and into the quadrupole rod mass filter 4. The quadrupole rod mass filter 4 can be set to monitor one or more particular fragment or product ions of interest. This can be performed by the control circuit 10 setting the voltage applied to the quadrupole rod mass filter 4 so that it can only transmit ions having a mass-to-charge ratio corresponding to one of the particular fragment or product ions of interest. Then, if an ion is detected at the ion detector 5, it is determined that the particular fragment or product ion of interest is present and has been produced from the precursor ion transmitted by the quadrupole rod mass filter 2. As described above, the quadrupole rod mass filter 4 can be stepped over time so that it can (only) transmit ions having different mass-to-charge ratios at different times. Accordingly, the voltage applied to the quadrupole rod mass filter 4 can be switched so that it can only transmit ions having a different mass-to-charge ratio corresponding to another of the particular fragment or product ions of interest. Then, if an ion is detected at the ion detector 5, it is determined that the other particular fragment or product ion of interest is present and has been produced from the precursor ion transmitted by the quadrupole rod mass filter 2. The quadrupole rod mass filter 4 can be further switched in this way one or more times in order to determine whether one or more further fragment or product ions of interest have been produced.

[0082] The ion optics of a spectrometer can become dirty / polluted over time, e.g. due to ions and / or non-ionic species impacting their surfaces. For example, one or more of the quadrupole rod sets 2 to 4 guiding the ions, and possibly one or more of the differential apertures 6 to 7, can become dirty. This contamination can affect the transit time of ions through the ion optics, and thus the transit time of a given ion through the spectrometer can vary depending on the degree of contamination of the ion optics. Thus, the ion signal intensity profile recorded for the given ion, or for ions originating from the given ion, can vary depending on the degree of contamination of the ion optics. More specifically, at least for the initial part of the ion signal, the transit time of the ion can increase with increasing degree of contamination, and thus the intensity of the ion signal in a spectrometer having contaminated ion optics can be lower than the intensity of the ion signal in a spectrometer having cleaner ion optics.

[0083] For example, in a spectrometer such as a mass spectrometer, the ion signal intensity profile recorded for a given ion can vary depending on the degree of contamination of the ion optics of the spectrometer. For example, the degree of contamination of the ion optics can affect the transit time of the ion through the ion optics, and thus the ion signal intensity profile recorded for the given ion can vary depending on the degree of contamination of the ion optics. More specifically, at least for the initial part of the ion signal, the transit time of the ion can increase with increasing degree of contamination, and thus the intensity of the ion signal in a spectrometer having contaminated ion optics can be lower than the intensity of the ion signal in a spectrometer having cleaner ion optics. Figure 1In an MRM (multiple reaction monitoring) experiment performed on a device such as that described above, the mass-to-charge ratio that the quadrupole mass filter 4 is able to transmit can also be varied by the control circuit 10 over time, so that the mass filter 4 is able to transmit different ions of interest or product ions at different times, as already described above. In order to determine whether these different ions of interest or product ions are present, the quadrupole mass filter 4 must be operated so as to be able to transmit these different ions at the times at which they are expected to reach the quadrupole mass filter 4. For example, in order to be able to detect the presence of a first ion of interest or product ion, the voltage applied to the quadrupole mass filter 4 is held at a value such that ions having the mass-to-charge ratio of the first ion of interest or product ion are able to be transmitted to the detector 5 for a period of time (referred to as a dwell time). Similarly, in order to be able to detect the presence of a different second ion of interest or product ion, the voltage applied to the quadrupole mass filter 4 is switched to a different value such that ions having the mass-to-charge ratio of the second ion of interest or product ion are able to be transmitted to the detector 5. Again, the voltage is held at this value for a period of time (referred to as a dwell time). The voltage can be switched and held (for a dwell time) one or more further times to allow one or more further ions of interest or product ions to be detected, respectively.

[0084] It will be appreciated that, during the period of time in which an ion of interest or product ion is expected to reach the quadrupole mass filter 4, the voltage applied to the quadrupole mass filter 4 must be switched and held for a dwell time, otherwise they cannot be detected even if they are generated from a precursor ion. However, the time at which an ion reaches the quadrupole mass filter 4 depends on the cleanliness of the upstream ion optics, for example on the cleanliness of the quadrupoles 2, 3 or differential pumping apertures 6, 7. Therefore, in order for the experiment to be reliable, it is important to determine when the ion optics have become excessively contaminated.

[0085] By way of example, the mass spectrometer can be set such that when it has clean ion optics and a constant ion current, the detected ion signal will be constant over each dwell time of the quadrupole filter 4 (assuming the presence of the corresponding fragment or product ions of interest). In other words, when the quadrupole filter 4 is switched to a new mass transmission window, the fragment or product ions of interest can be received and transmitted over the entire dwell time that they are held at that mass transmission window by the quadrupole filter 4 (assuming the ions are present). If the ion current is constant, then the ion signal is constant over the entire dwell time. By contrast, if the ion optics of the mass spectrometer are dirty / contaminated, then the transit time of the ions through those ion optics can be slower than if the ion optics were clean. Thus, the fragment or product ions of interest can arrive later than expected at the quadrupole filter 4, and so when the mass transmission window of the quadrupole filter 4 is switched to a new mass-to-charge ratio, the fragment or product ions having that mass-to-charge ratio can not yet have arrived at the quadrupole filter 4. Thus, the intensity of the fragment or product ion signal that reaches the quadrupole filter 4 and hence the ion detector 5 can increase during the dwell time (e.g. before the ion signal reaches a constant intensity if the ion current is constant).

[0086] Figure 2A The ion signal 12 detected for the fragment or product ions of interest transmitted by the quadrupole filter 4 during the dwell time is shown for a mass spectrometer with clean ion optics. Figure 2B The ion signal 12 detected for the same fragment or product ions of interest transmitted by the quadrupole filter 4 during the dwell time is shown for a mass spectrometer with contaminated ion optics. As noted above, when the ion optics are clean, the ion signal 12 is substantially constant (for a constant ion current), whereas when the ion optics are contaminated, the ion signal 12 rises and then becomes constant.

[0087] Conventionally, the ion signal recorded by the mass spectrometer for the ions of interest will be the average of the signal over the entire respective dwell time, which is shown by the line 14 in Figure 2A and Figure 2B It can be seen from Figure 2A and Figure 2B that these average signals 14 have very similar amplitudes, although the signal profile of the clean mass spectrometer shown in Figure 2A is very different from the signal profile of the dirty mass spectrometer shown in Figure 2B Thus, it is conventionally difficult to determine from these average ion signals 14 whether the ion optics of the mass spectrometer were dirty before the ion optics had become excessively dirty and caused problems.

[0088] For example, users of spectrometers typically run a system suitability test before analyzing a sample of interest in order to confirm that the system is fit for purpose before they use it in analyzing a sample of interest. This includes analyzing a quality control sample and checking that the resulting ion signals detected have the expected sensitivity. However, the onset of ion optics cleanliness problems is difficult to detect because for quadrupole instruments, for example in multiple reaction monitoring or selected ion monitoring (selected ion recording) modes, the signal is averaged over the entire dwell time and so if the ion optics are only slightly dirty, this cannot be detected by analyzing a quality control sample. Thus, without a system failure in between batches, the user would then proceed to analyze their batch of samples of interest, thus resulting in a waste of time, solvent and samples. Such a failure is often only detected by a final quality control analysis at the end of the entire batch.

[0089] It has been demonstrated that for a constant ion current in a spectrometer with clean ion optics, the ion signal will be relatively constant over each entire dwell time. However, when the ion optics become contaminated, the ion signal at the beginning of the dwell time can be significantly different from the ion signal at the end of the dwell time, even if the ion current from the ion source is constant.

[0090] Embodiments of the present invention seek to address this problem by monitoring whether the detected ion signal 12 changes over a single dwell time. The ion signal corresponding to one position or segment in a dwell time can be compared to the ion signal corresponding to another position or segment in the same dwell time. Alternatively, the ion signal corresponding to one position in a dwell time can be compared to the average ion signal for at least a portion of the dwell time. Alternatively, the average ion signal for one segment of a dwell time can be compared to the average ion signal for a different sized segment of the dwell time or the entire dwell time.

[0091] If the difference between these ion signals is below a threshold, it can be determined that the ion optics are relatively clean, e.g. such that the spectrometer can be used to analyse a sample of interest without requiring prior maintenance / cleaning of the spectrometer. The spectrometer can be configured to produce an output for indicating this case, e.g. to a display screen. On the other hand, if the difference between these ion signals is above a threshold, it can be determined that the ion optics are relatively dirty, e.g. such that the spectrometer cannot be used to analyse a sample of interest without prior maintenance / cleaning of the spectrometer. The spectrometer can be configured to produce a different output for indicating this case, e.g. to a display screen. By determining whether the ion signal changes significantly over the dwell time, rather than using conventional techniques which compare the average signal to an expected average value, embodiments of the present invention enable the spectrometer to determine when its ion optics are dirty before they become highly dirty. This enables the user to know that the ion optics need cleaning before starting an experimental run, and thus prevents unexpected downtime, wastage of solvent and sample. Embodiments of the present invention thus recognise that the process of switching the quadrupole mass filter to different masses can be used to determine the cleanliness of the ion optics.

[0092] For example, with reference to Figures 2A-2B , the x-axis represents a single dwell time, and the y-axis represents the intensity of the ion signal detected over the dwell time. According to embodiments, the dwell time can be considered to be formed from a plurality of dwell time segments, with these segments represented as regions between the vertical lines arranged on the x-axis. An average value of the ion signal detected during one of these segments 16 can be determined, as represented by the intensity line 18 in Figure 2B . This intensity 18 can then be compared to an average value of the ion signal detected during another of the segments (or to the average intensity over the entire dwell time 14) in order to determine whether the ion signal changed significantly over the dwell time. It will be apparent that this is not the case for a scenario in which the spectrometer has clean ion optics, as shown in Figure 2A . However, as can be seen from Figure 2B , the average ion signal 18 for the first segment of the dwell time is significantly different to the average ion signal for the last segment of the dwell time 20 (and significantly different to the average intensity over the entire dwell time 14). This relatively large difference in the average ion signal detected over a single dwell time indicates that the ion optics have become dirty.

[0093] Although Figure 2BThe average ion signal is shown for the first segment 16 and the last segment 20, but it will be appreciated that the average ion signal can be compared for two different segments. Furthermore, although the dwell time is shown as being divided into eight dwell time segments in the illustrated embodiment, it is envisaged that each of the dwell time segments used in the comparison step can have other durations (i.e. not necessarily one eighth of the entire dwell time).

[0094] It is also envisaged that rather than comparing the average ion signal from different dwell time segments, the spectrometer can instead compare the instantaneous ion signal at one point in the dwell time with the instantaneous ion signal at another point in the dwell time (i.e. not the average ion signal).

[0095] According to an embodiment, the spectrometer analyses the ion signal intensity recorded multiple times within the dwell time, and determines the duration taken for the signal intensity to become constant. If this duration is below a threshold, the spectrometer can determine that the ion optics are clean, whereas if this duration is above the threshold, the spectrometer can determine that the ion optics are dirty / contaminated. The spectrometer can comprise electronic circuitry which then controls a user interface to indicate that the ion optics require maintenance / cleaning.

[0096] The embodiments described herein are particularly beneficial in experiments in which ions having different physico-chemical properties (such as different mass, polarity or mobility) are transmitted to the mass filter sequentially (for example during a multiple reaction monitoring method). This is because when the ion optics are dirty, the ions can not have reached the mass filter by the time they are switched to a new mass transmission window. A dirty ion optics therefore typically results in a loss of ion signal (relative to a spectrometer with clean ion optics) which occurs over a period of time corresponding primarily to the start of the new mass transmission window.

[0097] It is also envisaged embodiments in which the ion current supplied by the ion source of interest is not constant but varies over time. For example, the spectrometer can comprise a chromatographic separator (e.g. a liquid or gas chromatographic analysis separator) or other separator for separating analyte molecules in a sample or separating analyte ions from a sample. In such embodiments, the ion signal detected over each dwell time can not be constant (even if the ion optics are clean) because the ions received by the mass filter during the dwell time can be or can result from ions that have eluted from the separator during the rising or falling slope of a peak eluting from the separator. However, embodiments of the application are still able to determine whether the ion optics are dirty / contaminated from the detected ion signal. For example, this can be achieved by taking into account the ion signal intensity either side of the detected eluting peak.

[0098] According to embodiments having a separator, the quadrupole filter repeatedly performs an operating cycle while molecules or ions are eluting from the separator. Each operating cycle comprises holding the voltage applied to the filter 4 at a value such that only ions having a first mass-to-charge ratio are able to be transmitted to the detector 5 for a first dwell time, and subsequently switching the voltage applied to the filter 4 and holding it at a different value such that only ions having a different second mass-to-charge ratio are able to be transmitted to the detector 5 for a second dwell time. Although the quadrupole filter 4 has been described as being switched twice in each cycle, it can be further switched one or more times in this way during each cycle. Alternatively, the spectrometer can be switched such that each cycle comprises only the transmission of the first ions and not the transmission of ions. This cycle can be performed multiple times during each peak of eluting ions from the separator.

[0099] The data recorded by the spectrometer can be processed to determine how the ion signal intensity of one of the ion types (e.g. the first ions or the second ions) varies as a function of elution time from the separator. This can be performed by determining the ion signal intensity from cycles corresponding to one of the ion types, and determining how these ion signal intensities vary as a function of elution time from the separator. The ion signal intensity of one of the ion types is determined from the ion signal detected during the dwell time in which the filter is operated so as to transmit one of the ion types.

[0100] When the ion signal intensity is determined from the intensity at only the initial portion of the dwell time, the spectrometer can determine how the ion signal intensity of one of the ion types (e.g. the first ions or the second ions) varies as a function of elution time from the separator. When the ion signal intensity is determined from the intensity at only the later portion of the dwell time (or when each ion signal intensity is determined as an average intensity over each dwell time), the mass spectrometer can also determine how the ion signal intensity of that ion type varies as a function of elution time from the separator. This data can then be used to determine whether the ion optics are clean or dirty, as will be described below in relation to Figure 3

[0101] Figure 3 A plot 22 is shown of how the ion signal intensity of the first type of ions varies with the elution time of the separator when the ion signal intensity is determined from the intensity at only the initial portion of the dwell time (e.g. from the first dwell time period 16 in Figure 2B Figure 3 A plot 24 is also shown of how the ion signal intensity of the first type of ions varies with the elution time of the separator when the ion signal intensity is determined from the intensity at only the later portion of the dwell time (e.g. from the second dwell time period 18 in Figure 2B ​​determined as the average intensity of each ion signal strength over each dwell time (e.g. as in Figure 2B a curve 24 of how the ion signal strength of the first type of ion varies with the change in elution time of the separator. As can be seen from Figure 3 the two curves 22, 24 vary differently in amplitude with time, which indicates that the intensity of the ion signal varies over each dwell time and that the ion optics can be dirty. By contrast, if the ion optics are clean (e.g. as in Figure 2A determined at an initial portion of a given dwell time will be substantially the same as the ion intensity at a later portion of that dwell time (over a short timescale of the dwell time), or the same as the average over the dwell time, and in that case the curves 22, 24 will be identical. Thus, the spectrometer can determine the cleanliness of the ion optics by comparing the data of curve 22 with the data of curve 24.

[0102] For varying source currents (such as from the separator), the peak areas in curve 22 can be calculated and compared with the peak areas in curve 24. If the ion optics are clean, the areas under the peaks will be substantially the same, whereas if the ion optics are dirty, the peak areas will be significantly different. Thus, the spectrometer can determine the cleanliness of the ion optics from the peak areas. Similarly, if the optics are dirty, the position of the peaks can be different, as the ions can be received at a later offset time. Similarly, if the ion optics are dirty, the gradient of the intensity profile can be different. Thus, the spectrometer can determine the gradient of the different curves 22, 24 at the same elution time, compare these gradients and determine the cleanliness of the ion optics from the comparison.

[0103] The described embodiments for checking the cleanliness of the ion optics can be performed as a standalone test (e.g. using an instrument jet, an LC solvent peak, etc.) which can perform an evaluation of the system cleanliness on demand of the user.

[0104] Alternatively, embodiments for checking the cleanliness of the ion optics can be performed as part of a system suitability test. System suitability tests are typically user-defined tests that the user runs prior to starting an experimental assay to analyze a sample of interest. The test is typically similar to the batch that will be run and includes quality control, sensitivity acceptance criteria, etc. (that the spectrometer must pass in order to be considered suitable to start an experimental assay). In the method of checking the cleanliness of the ion optics described herein, it can be set as an acceptance criterion that needs to be met. For example, the quality controlled ion signal can be monitored according to the embodiments in order to determine whether the ion optics are clean or dirty, which is advantageous because the approximate ion current of the quality control is known.

[0105] Alternatively, embodiments can not perform a separate experiment to determine the cleanliness of the ion optics, but instead can determine the cleanliness of the ion optics from data obtained during an experimental assay to analyze a sample of interest. In such techniques, two intensity values are obtained during each dwell time in the manner described herein during the experimental assay to analyze a sample of interest.

[0106] In Figure 4 Embodiments are shown that are the same as the embodiments shown in Figure 1 Embodiments are shown that are the same as the embodiments shown in

[0107] In use, ions 1 from an ion source (not shown) are fed to the ion guide 11 which has an RF voltage applied to it such that it guides the ions towards and through the differential pumping aperture 13 and into the quadrupole mass filter 2. The spectrometer can then be operated as described above in relation to Figure 1 The spectrometer has been described as already.

[0108] In Figure 1 and Figure 4In both embodiments of the implementation, one or more voltage sources 15 supply RF and DC voltages to the quadrupole mass filter 2 so that it filters ions according to mass-to-charge ratio. The control circuit 17 controls the one or more voltage sources 15 so that the voltages applied to the quadrupole mass filter 2 at any given time are such that only ions having a particular mass-to-charge ratio (or a particular range of mass-to-charge ratios) can be guided by the quadrupole mass filter 2 towards the ion detector 5 and onward transmission, while ions having other mass-to-charge ratios that are present will be filtered out by the quadrupole mass filter 2. The voltages applied to the quadrupole mass filter 2 can be varied by the control circuit 17 over time, for example in a step-wise fashion, so that the quadrupole mass filter 2 is able to transmit (only) different particular mass-to-charge ratios (or different particular ranges of mass-to-charge ratios) at different times.

[0109] The spectrometer can operate in a MS mode in which substantially only parent ions are analysed. In this mode, components of the spectrometer are controlled so that parent ions are not significantly fragmented, but are instead transmitted to the ion detector 5. In this mode, the voltages applied to the quadrupole set 4 can be such that it operates as an all-pass ion guide rather than a mass filter. The voltages applied to the quadrupole mass filter 2 can be held for a period of time (dwell time) in order to transmit only ions having a particular mass-to-charge ratio. This can be performed by the control circuit 17 setting the voltages applied by the voltage sources 15. If ions are then detected at the ion detector 5, it is determined that ions having the mass-to-charge ratio for which the mass filter 2 was set to transmit were present. As described above, the quadrupole mass filter 2 can be stepped over time so that it is able to transmit (only) ions having different mass-to-charge ratios at different times. Accordingly, the voltages applied to the quadrupole mass filter 2 can be switched by the circuit 17 so that it is able to transmit only ions having a different mass-to-charge ratio corresponding to another parent ion. The voltages are then held for a period of time (dwell time). If ions are detected at the ion detector 5, it is determined that the other parent ion was present. The quadrupole mass filter 2 can be further switched in this way one or more times in order to determine whether one or more further parent ions were present.

[0110] As described above in relation to Figure 1 It is also envisaged that MS / MS analysis can be performed using the quadrupole mass filter 2 to select a parent ion, fragment the parent ion in the quadrupole mass filter 3 and analyse the resulting fragment ions using the quadrupole mass filter 4. It is envisaged that the quadrupole mass filter 2 can be switched between transmitting different parent ions at different times in order to perform MS / MS analysis using different parent ions.

[0111] The amplitude and / or frequency of the RF voltage applied to the ion guide 11 in order to guide ions through the ion guide 11 can be selected based on the mass-to-charge ratio being transmitted by the mass filter 2 at the time, in order to optimize the transmission of ions 1 from the ion guide 11 into the mass filter 2. Thus, when the voltage applied to the mass filter 2 is switched in order to transmit a different mass-to-charge ratio of parent ions, the RF voltage applied to the ion guide 11 is also changed at the corresponding time (i.e. synchronously). Immediately after these voltage changes to the ion guide 11 and the mass filter 2, the ion current exiting the mass filter 2 and being detected can be relatively low, because the voltages are no longer optimized to transmit many of the ions within the ion guide 11 at the time of the switch. However, after the voltage changes, ions for which the voltages are now optimized will reach the ion guide 11 and be efficiently transmitted along the ion guide 11 and into the mass filter 2. Thus, the ion current exiting the mass filter 2 and being detected will increase during the dwell time for which the voltage applied to the mass filter 2 is held. As mentioned above, the transit time of a given ion through the mass spectrometer will vary depending on the degree of contamination of the ion optics, e.g. depending on the degree of contamination of the ion guide 11 and / or the differential pumping aperture 13. Thus, the rate at which the ion signal strength increases after the voltage switch (and during the dwell time) will vary depending on the degree of contamination of the ion guide 11 and / or the differential pumping aperture 13.

[0112] For example, if the ion optics are clean, the ion signal strength for a substantially constant current source can increase very rapidly, so that it is relatively constant throughout the entire dwell time, as shown in Figure 2A By contrast, if the ion optics are dirty, the ion signal strength for a substantially constant current source can increase relatively slowly, so that it varies as shown in Figure 2B Thus, the cleanliness of the ion optics can be determined from the profile of the ion signal, as described above in relation to Figures 2A-2B

[0113] ​As described above, embodiments in which the ion current supplied by the source varies over time are also envisioned. For example, the spectrometer may include a chromatographic separator (e.g., a liquid or gas chromatographic analyzer separator) or other separators for separating analyte molecules from a sample or separating analyte ions from a sample. According to an embodiment with a separator, the quadrupole mass filter 2 may repeatedly perform operating cycles as molecules or ions elute from the separator. This cycle may be repeated multiple times for each peak eluted from the separator. Each operating cycle includes: maintaining the voltage applied to the mass filter 2 at a value such that only ions with a first mass-to-charge ratio can be transported toward the detector 5 for a first residence time, and subsequently switching the voltage applied to the mass filter 2 and maintaining it at different values ​​such that only ions with a different second mass-to-charge ratio can be transported toward the detector 5 for a second residence time. Although the quadrupole mass filter 2 has been described as being switched twice in each cycle, it may be further switched once or more in this manner during each cycle. Alternatively, the spectrometer may be switched such that each cycle includes only the transport of the first ion and not the transport of other ions.

[0114] Data recorded by a spectrometer can be processed to determine how the ion signal intensity of one ion type (e.g., a first or second ion) varies as a function of elution time from the separator. This can be performed by determining the ion signal intensity from a cycle corresponding to one of the ion types, and determining how these ion signal intensities vary as a function of elution time from the separator. The ion signal intensity of one ion type is determined from the ion signal detected during the residence time of the mass filter for transmitting that ion type.

[0115] When the ion signal intensity is determined from the intensity at the initial portion of the residence time only, the spectrometer can determine how the ion signal intensity of one ion type (e.g., the first or second ion) varies as a function of elution time from the separator. When the ion signal intensity is determined from the intensity at a later portion of the residence time only (or when each ion signal intensity is determined as the average intensity over each residence time), the mass spectrometer can also determine how the ion signal intensity of one ion type varies as a function of elution time from the separator. This data can then be used to correlate with... Figure 3 The same method described above is used to determine whether an ion optics device is clean or dirty.

[0116] Figure 5 It shows the relationship with Figure 3The curve is similar to the one shown, but with multiple peaks at different times. Curve 26 shows how the ion signal intensity changes with the elution time of the separator when the intensity is determined from the initial portion of the residence time alone. Figure 5 The diagram also shows how the ion signal intensity varies with the elution time of the separator when the ion signal intensity is determined from the intensity at a later part of the residence time (or when each ion signal intensity is determined as the average intensity over each residence time).

[0117] As from Figure 5 As can be seen, curves 26 and 28 vary in magnitude for each peak, indicating that the intensity of the ion signal varies with each peak over each residence time, and the instrument may therefore suffer from unwanted charge buildup on the ion optics. In contrast, if such charging were absent, the ion intensity determined at the initial portion of a given residence time would be substantially the same as the ion intensity at a later portion of that residence time, and in this case, curves 26 and 28 would be substantially identical. Therefore, the spectrometer can determine the presence of a problem, such as unwanted charging of the ion optics, by comparing the data from curve 26 with the data from curve 28 and, for example, determining that curves 26 and 28 differ in intensity for multiple peaks. Alternatively, problematic charging of the ion optics can occur only when a relatively high ion flux is present, for example, as... Figure 6 As shown.

[0118] Figure 6 The curve 30 shows how the ion signal intensity changes with the elution time of the separator when the ion signal intensity is determined from the intensity at the initial part of the residence time only. Figure 6 The curve 32 also shows how the ion signal intensity varies with the elution time of the separator when the ion signal intensity is determined from the intensity at a later portion of the residence time (or when each ion signal intensity is determined as the average intensity over each residence time). As shown from... Figure 6 As can be seen, the two curves 30 and 32 differ only in amplitude for the relatively strong peak at the center, while they are essentially the same for the other relatively low-intensity peaks.

[0119] When it is determined that the intensity of only some of the peaks varies differently in amplitude, these peaks can be marked or labeled as inaccurate to prevent analysis or further use of the data.

[0120] Although the invention has been described with reference to preferred embodiments, those skilled in the art will understand that various changes in form and detail may be made without departing from the scope of the invention as set forth in the appended claims.

[0121] For example, although a triple quadrupole mass spectrometer has been described for performing the MRM experiment, the application is not limited to such spectrometers and can be performed on any instrument having a mass filter. Similarly, the mass filter is not limited to a quadrupole mass filter.

[0122] Although embodiments have been described in which the dwell time for which the ion signal is held at a certain mass transmission window before being switched to another mass transmission window is varied to determine the cleanliness of the ion guide, it is envisaged that instead the mass transmission window of the filter can be held constant and can simply allow ions to pass to the filter for a period of time defined as the "dwell time" during which the spectrometer is able to transmit ions to the detector. For example, the RF voltage on the upstream ion guide which radially confines the ions can be switched off in order to prevent ions reaching the filter and then switched on in order to allow ions to pass to the filter. Alternatively, an ion gate can be provided to prevent ions reaching the filter and then switched to allow ions to pass to the filter. The ion gate can provide a DC or pseudo-potential barrier which is switched on and off.

[0123] As described herein, the spectrometer can automatically determine from the detected intensities that the ion optics are contaminated. The spectrometer can then control a user interface to indicate this to the user, such as by controlling a visual display unit or an alarm. Alternatively or additionally, when the spectrometer determines that the ion optics are contaminated, it can apply one or more compensation voltages to the ion optics in order to compensate for the effects of the contamination on the ions passing through the ion optics.

[0124] It is envisaged that when the spectrometer determines that the ion optics are contaminated, it can automatically control a heater in order to heat the ion optics (e.g. the ion optics which are most susceptible to contamination) in order to burn off the contamination.

[0125] Embodiments have been described in which the intensity of one species of ion is determined twice in each dwell time in order to determine whether the ion optics are contaminated (or alternatively more generally to determine that there is a cause for a change in sensitivity for that species as it can be caused by a problem other than contamination of the ion optics). However, it is envisaged that the intensity of that species of ion can instead be determined only once in each dwell time (but in multiple dwell times).

[0126] For example, the quadrupole filter 2 can repeatedly perform an operating cycle during an experimental run. Each operating cycle can comprise holding the voltage applied to the filter 2 at a value such that only ions having a first mass-to-charge ratio (species A) can be transmitted towards the detector 5 for a first dwell time, then switching the voltage applied to the filter 2 and holding it at a different value such that only ions having a different second mass-to-charge ratio (species B) can be transmitted towards the detector 5 for a second dwell time, and then switching the voltage applied to the filter 2 and holding it at a value such that only ions having the first mass-to-charge ratio (species A) can be transmitted towards the detector 5 for a third dwell time. This cycle is repeated during the experimental run.

[0127] Although the quadrupole filter 2 has been described as being switched so as to transmit species A twice in each cycle and to transmit species B only once in each cycle (i.e. in the sequence ABA), it is envisaged that species B can also be transmitted twice in each cycle. For example, each cycle can transmit the species in the sequence ABAB or ABBA as follows. Additionally or alternatively, one or more further species can be transmitted during each cycle. For example, six species A to F can be transmitted sequentially in each cycle, for example in the sequence ABBACDDCEFFE as follows.

[0128] Embodiments are envisaged in which the spectrometer comprises a chromatographic separator (e.g. a liquid or gas chromatographic analytical separator) or other separator for separating analyte molecules in a sample or separating analyte ions from a sample. The above-described cycle can then be repeated multiple times for each peak eluted from the separator.

[0129] Data recorded by the spectrometer can be processed to determine how the ion signal intensity of one of the ion types (e.g. any of species A to F) varies with time (e.g. with elution time from the separator) during the experimental run. This can be performed by determining the ion signal intensity from cycles corresponding to the one of the ion types, and determining how these ion signal intensities vary as a function of time during the experimental run. The ion signal intensity of the one of the ion types is determined from ion signals detected during the dwell times in which the filter is operated so as to transmit the one of the ion types.

[0130] The spectrometer can determine how the ion signal intensity of one of the ion types varies with time using only the ion signal intensities determined for that ion type during an initial portion of the cycle. For example, if each cycle includes the sequence A1B1B2A2 (where the subscript integers indicate how many times the species has been transmitted in the cycle), the spectrometer can determine how the ion signal intensity of species A varies with time using only the intensity values from A1 (and not A2) from multiple cycles. The spectrometer can also determine how the ion signal intensity of one of the ion types varies with time using only the ion signal intensities determined for that ion type during a later portion of the cycle. For example, in the example where each cycle includes the sequence A1B1B2A2, the spectrometer can determine how the ion signal intensity of species A varies with time using only the intensity values from A2 (and not A1) from multiple cycles. This data can then be used to determine whether the ion optics are clean or dirty (or whether there is another issue causing a change in sensitivity for that species) in the same manner as described above with respect to Figure 3 the ion signal intensity of one of the ion types varies with time using only the ion signal intensities determined for that ion type during an initial portion of the cycle. For example, if each cycle includes the sequence A1B1B2A2 (where the subscript integers indicate how many times the species has been transmitted in the cycle), the spectrometer can determine how the ion signal intensity of species A varies with time using only the intensity values from A1 (and not A2) from multiple cycles. The spectrometer can also determine how the ion signal intensity of one of the ion types varies with time using only the ion signal intensities determined for that ion type during a later portion of the cycle. For example, in the example where each cycle includes the sequence A1B1B2A2, the spectrometer can determine how the ion signal intensity of species A varies with time using only the intensity values from A2 (and not A1) from multiple cycles. This data can then be used to determine whether the ion optics are clean or dirty (or whether there is another issue causing a change in sensitivity for that species) in the same manner as described above with respect to

Claims

1. A mass spectrometer comprising: an ion detector; ion optics for guiding ions to the ion detector; one or more voltage sources for supplying voltage to the ion optics; control circuitry for controlling the one or more voltage sources so as to switch the ion optics between operating in a first mode in which the ion optics are unable to transmit ions having a first mass-to-charge ratio or first polarity to the ion detector and operating in a second mode in which the ion optics are able to transmit ions having the first mass-to-charge ratio or first polarity to the ion detector for a period of time; and so as to repeatedly switch between the first mode and the second mode a plurality of times; and a processor and circuitry configured to determine a cleanliness of the ion optics by: (i) determining intensities of ion signals detected by the detector at a first time in each of the periods of time in which the ion optics are in the second mode, and determining that these intensities vary with time; (ii) determining intensities of ion signals detected by the detector at a later second time in each of the periods of time in which the ion optics are in the second mode, and determining that these intensities vary with time; and (iii) determining that the intensities obtained in step (i) vary with time in a different manner to the intensities obtained in step (ii), and in response to determining that the intensities vary with time in the different manner, producing a first output.

2. The mass spectrometer of claim 1, wherein the processor and circuitry are configured such that: step (i) comprises determining that ion signals vary with time to a peak; step (ii) comprises determining that ion signals vary with time to a peak; step (iii) comprises determining that the area of the peak determined in step (i) is different to the area of the peak determined in step (ii); and step (iv) comprises producing the first output.

3. The mass spectrometer of claim 2, wherein step (iii) determines that the area of the peak determined in step (i) is less than the area of the peak determined in step (ii); or wherein step (iii) determines that the area of the peak determined in step (ii) is less than the area of the peak determined in step (i).

4. The mass spectrometer of claim 1, wherein the processor and circuitry are configured such that: step (i) comprises determining a gradient of ion signals in an intensity profile at a first time; step (ii) comprises determining a gradient of the ion signals in the intensity profile at a time corresponding to the first time; step (iii) comprises determining that the gradient determined in step (i) is less than the gradient determined in step (ii); and step (iv) comprises producing the first output.

5. The mass spectrometer of claim 1, wherein the processor and circuitry are configured to: determining how the intensity obtained in step (i) varies with time; determining how the intensity obtained in step (ii) varies with time; determining whether the intensity obtained in step (i) varies with time in the same way as the intensity obtained in step (ii); and and in response to determining that the intensity varies with time in the same way, generating a second output.

6. The mass spectrometer of claim 1, comprising a separator for separating analyte molecules or ions upstream of the ion optics.

7. The mass spectrometer of claim 1, wherein the control circuitry is configured to control the one or more voltage sources to repeatedly switch the ion optics between operating in the first mode and operating in the second mode a plurality of times during a single experimental run.

8. A method of mass spectrometric analysis, the method comprising: providing a mass spectrometer according to claim 1; and determining a cleanliness of the ion optics in the mass spectrometer by: repeatedly switching the ion optics between the first mode and the second mode a plurality of times; (i) determining an intensity of an ion signal detected by the detector at a first time in each of the time periods in which the ion optics are in the second mode, and determining how these intensities vary with time; (ii) determining an intensity of an ion signal detected by the detector at a later second time in each of the time periods in which the ion optics are in the second mode, and determining how these intensities vary with time; and (iii) determining that the intensities obtained in step (i) vary with time in a different way to the intensities obtained in step (ii), and in response to determining that the intensities vary with time in the different way, generating a first output.

9. A mass spectrometer, the mass spectrometer comprising: an ion detector; ion optics for guiding ions to the ion detector; and a processor and circuitry configured to determine a cleanliness of the ion optics by: (i) controlling the ion optics so as to perform a plurality of operational cycles successively during a single experimental run, wherein each operational cycle comprises: transmitting a first species of ions for a first residence time, followed by transmitting a different second species of ions for a second residence time, and followed by transmitting the first species of ions for a third residence time; (ii) determining an intensity of an ion signal detected by the detector during the first residence time in each of the plurality of operational cycles, and determining how these intensities vary with time; (iii) determining an intensity of an ion signal detected by the detector during the third residence time in each of the plurality of operational cycles, and determining how these intensities vary with time; and (iv) determining that the intensities obtained in step (ii) vary with time in a different manner to the intensities obtained in step (iii), and in response to determining that the intensities vary with time in the different manner, generating a first output.

10. The mass spectrometer of claim 9, wherein each operational cycle further comprises transmitting ions of the second species for a fourth dwell time, wherein the fourth dwell time is between the second dwell time and the third dwell time or after the third dwell time.

11. The mass spectrometer of claim 9, wherein each operational cycle comprises transmitting ions of a third or further species for at least one further dwell time.

12. The mass spectrometer of claim 9, comprising a separator for separating analyte molecules in an analysis sample or separating analyte ions from an analysis sample, wherein the processor and circuitry are configured to control the ion optics so as to perform the plurality of operational cycles successively during peaks eluting from the separator.

13. A method of mass spectrometry analysis, the method comprising: providing a mass spectrometer according to claim 9; and determining the cleanliness of the ion optics in the mass spectrometer, in the following manner: (ii) performing a plurality of operational cycles during a single experimental run, wherein each operational cycle comprises: transmitting ions of a first species for a first dwell time, followed by transmitting a different second species of ions for a second dwell time, and followed by transmitting the first species of ions for a third dwell time; (ii) determining the intensities of ion signals detected by the detector during the first dwell time in each of the plurality of operational cycles, and determining how these intensities vary with time; (iii) determining the intensities of ion signals detected by the detector during the third dwell time in each of the plurality of operational cycles, and determining how these intensities vary with time; (iv) determining that the intensities obtained in step (ii) vary with time in a different manner to the intensities obtained in step (iii), and in response to determining that the intensities vary with time in the different manner, generating a first output.

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