Mass spectrometer signal optimisation

Abstract

Method and system for operating a mass spectrometer comprising the steps of a) setting a static parameter for the mass spectrometer. b) Obtaining a plurality of mass spectrometer signals from one or more analytes with the mass spectrometer set at the static parameter. c) Determining a variability of the mass spectrometer signals for each of the one or more analytes obtained with the mass spectrometer set at the static parameter. d) Repeating steps a)-c) with a plurality of different static parameters. e) Determining a static parameter providing a lowest variability of mass spectrometer signal for each of the one or more analytes. Method and system for operating a mass spectrometer comprising the steps of operating the mass spectrometer set at a first parameter value. Obtaining one or more mass spectrometer signal from one or more analytes with the mass spectrometer set at the first parameter value. Determining if the one or more mass spectrometer signals obtained with the mass spectrometer set at the first parameter value is above a threshold. If the one or more mass spectrometer signals obtained with the mass spectrometer set at the first parameter value is not above a threshold then increasing or decreasing the parameter value until the one or more mass spectrometer signals is above the threshold.

Description

[0001] Mass Spectrometer Signal Optimisation

[0002] Field of the Invention

[0003] The present invention relates to a system and method for optimising mass spectrometer signals. In particular, a configuration of a mass spectrometer is found and set to reduce or minimise mass spectrometer signal variability and optimise other signal properties.

[0004] Background of the Invention

[0005] Inductively coupled plasma mass spectrometers (ICP-MS) have a well-known operation. ICP-MS instruments can provide sensitive elemental analysis of samples. Samples investigated by ICP-MS devices are usually in the form of a liquid solution or suspension and are supplied to the plasma by a nebuliser in the form of an aerosol in a carrier gas, which may be argon or helium, for example. The nebulised sample passes into a plasma torch, which may comprise a number of concentric tubes forming respective channels. The sample is directed downstream towards a helical induction coil. A plasma gas, typically argon, flows in an outer channel and an electric discharge is applied, which ionise some of the plasma gas. A radio frequency (RF) electric current is supplied to the helical induction coil producing an alternating magnetic field, which causes free electrons to be accelerated causing further ionisation of the plasma gas. This process continues until a steady plasma state is achieved, at temperatures typically between 5,000 K and 10,000 K. The carrier gas and nebulised sample flow through a central torch channel and pass into a central region of the plasma, where the temperature is high enough to cause atomization and then ionization of the sample. The sample ions in the plasma are formed into an ion beam. Ion separation and detection by the mass spectrometer may be provided by a quadrupole mass analyser, a magnetic and / or electric sector mass analyser, a time-of-flight mass analyser, or an ion trap mass analyser, for example.

[0006] In an ICP-MS, ions are formed under atmospheric pressure or a relatively high pressure (e.g., over 100 mbar). This is external to a main vacuum system of the mass spectrometer. For most mass analysers, a vacuum having a pressure of < 5x10-5mbar may be required. An interface region is therefore provided that regulates the transfer of ions from the atmospheric pressure ion source to the high vacuum mass analyser. This may involve a number of stages of pressure reduction, extraction of the ions from the plasma, and ion beam formation. A first stage of pressure reduction may be achieved by sampling the plasma through a first aperture in a vacuum interface, typically provided by a sampler cone having a tip with an aperture, which may have an inner diameter in the range 0.5 mm to 1 .5 mm. The sampler cone can interface with the plasma source at atmospheric pressure, or a relatively high (>100 mbar), pressure compared with the pressure within the mass analyser. The plasma expands downstream of the first aperture into an evacuated expansion chamber, where the pressure is typically a few mbar (e.g., 1-10 mbar). The central portion of the expanding plasma then passes through a second aperture, typically provided by a skimmer cone, and into a second evacuation chamber having a higher degree of vacuum than the expansion chamber. As the plasma expands through the skimmer cone, its density reduces sufficiently to allow extraction of the ions to form an ion beam. This is achieved using strong electric fields generated by ion lenses downstream of the skimmer cone. The resulting ion beam may be deflected and / or guided towards the mass analyser by one or more ion deflectors, ion lenses, and / or ion guides, which may operate with static or time-varying electric fields.

[0007] Changes in the plasma and / or interface configurations can affect ion transport efficiency and so the signal output of the mass spectrometer. For example, changes made by replacing sampling components, such as the inner diameter of the aperture of the sampler and skimmer cones, changing between hot and cold plasma conditions, and the use of organic solvents can have a direct impact on the interface characteristics, which affects ion transport efficiency.

[0008] When collecting data using a mass spectrometer it can be important to reduce the variability in the collected signal data. This can be especially important when the data are used to generate quantitative results, as a variation in signal can lead to erroneous or unreliable data. For example, the relative standard deviation of the signals should be as low as possible, but this is not always achievable with current techniques.

[0009] GB2572819A describes a process for configuring an inductively coupled plasma mass spectrometer (ICP-MS) to maximise signal intensities, which can be important for certain investigations. However, signal stability and variability can remain a problem. Therefore, there is required a method and system that overcomes these problems.

[0010] Summary of the Invention

[0011] Mass spectrometers may be operated by setting various different parameters. For example, at an interface between an ion source and an entrance (e.g., a skimmer cone) to a mass analyser, a pressure is maintained by a pump. This pressure is an intermediate pressure between atmospheric pressure, at which the ion source is maintained, and a low or vacuum pressure of the mass analyser. The intermediate pressure can affect mass spectrometer signals obtained from the mass analyser. The intermediate pressure may be one such parameter. Other parameters that can affect signal variability may include pressures or vacuum levels to other parts of the mass spectrometer (e.g., at an ion source or mass analyser), pump speeds used to set these pressures of vacuum levels, liquid sample flow rates, argon gas dilution (AGD) flow rate, and / or the electric potentials applied to various components of the mass spectrometer, including ion lenses, extraction components, and / or a skimmer cone.

[0012] Theory predicts that the variability, or more precisely the relative standard deviation RSD of a signal / that is created out of a process determined by Poisson statistics will obey the well-known law: with

[0013] Here < / > is the average number of statistical events corresponding to the number of ions detected per time interval, therefore corresponding to the signal intensity. This implies that the relative standard deviation becomes smaller when the signal intensity increases. In this case, finding the parameter for maximum intensity means simultaneously finding the parameter for minimum variability of the signal. However, when tuning an analytical instrument such as a mass spectrometer, this is not generally the case. For some parameters such as for example a simple electrostatical focus lens voltage this relation (1 ) might be valid, but there are others where the relation is only true for a small fraction of the available parameter range.

[0014] Examples for such parameters are the pressure between the interface cones of an ICP-MS or the liquid sample flow (e. g. generated by using a peristaltic pump) supplied to a nebulizer for creating an aerosol to be ionized in the ICP. The behaviour of the signal RSD when varying those parameters will be shown in the following. More such parameters might be a) the inert gas flow supplied to the nebulizer creating the aerosol or b) the extraction voltage that is used in the entry stage of the ICP mass spectrometer to extract ions from the plasma, or c) in case the skimmer cone of the ICP interface can be held at an electric potential other than zero, the supply voltage of the skimmer cone.

[0015] Generally, parameters that control complex processes are most likely to deviate from the ideal behaviour described by equation (1 ), because different noise spectra are contributing. For analytical instruments, the settings that enable the lowest signal RSDs are closely related with the lowest detection limits that can be achieved with this instrument. They can be improved when instrument optimization is not only following the common path of signal maximization, but is simultaneously considering signal variability as well by minimizing the RSD.

[0016] The variability or RSD of mass spectrometer signals varies as these parameters are varied (e.g., as interface pressure changes). For example, for some parameter settings, the signals obtained for the different analytes of the same concentration may vary by a greater amount (e.g., absolute or relative signal) than for other parameter values. A minimum signal RSD may be found by repeating an investigation or signal acquisition with the same or different analytes across a range of parameters (e.g., intermediate pressures of 1 to 10 mbar or preferably 1 to 3 mbar, or skimmer cone potential of + / - 5 V). A selection of analytes may be used across a range of ion masses (e.g., m / z = 7 to 238 u). These may include a selection of test samples.

[0017] Once the optimum parameter value is found to minimise variability then this optimum parameter value may be set when obtaining results from further samples. The optimum parameter value or values may be found for different instrument configurations or after maintenance has been conducted (e.g., replacing the skimmer cone) or the peripheral pump tubing). Finding and using this optimum value is especially beneficial for parameters which bring in a noise component that is characterized in that it is not smallest for the highest signal intensity, but whose contribution differs from such expected behaviour.

[0018] The optimum parameter value for the mass spectrometer and / or for particular configurations may be stored, retrieved and set on the mass spectrometer (e.g., as applied by a controller varying a pump speed, gas or liquid flow and / or electric potential) when mass spectra are acquired requiring the least variability in test results (e.g., when conducting quantitative investigations). As mentioned previously, the parameter value (or parameter values) providing the minimum variability may not necessarily coincide with a parameter value used to maximise signal intensity (e.g., that found by following the methods described in GB2572819). For some samples at this parameter value (e.g., intermediate pressure, gas flow, and / or electric potential), the signal level or signal to noise ratio may be too low to provide useful results. Therefore, the parameter (value) may be varied in small increments. For example, this may be achieved by varying the intermediate pressure in 0.1 mbar intervals above and / or below the minimum variability intermediate pressure found using the method described above or by varying the electric potential in 0.1 V increments. Whatever parameter or parameters are used, they may be varied until the signal or signal to noise ratio is sufficient for the particular investigation, such as a scientific experiment. In this way a best compromise parameter value or set of parameter values (e.g., intermediate pressure, gas flow rate, electric potential, etc.) can be found that provides the lowest variation in signal and also provides a sufficient signal level.

[0019] Furthermore, whilst the lowest variability may be used in some investigations, there may be an acceptable variability or threshold variability that may be used successfully in a particular investigation. Changing the parameter or parameters may increase both the variability but also the signal (or reduce the signal to noise ratio). Therefore, the parameter may be varied so that the variability is both within the acceptable variability range or below the variability threshold and maximising the mass spectrometer signal.

[0020] The method may be used with an inductively coupled plasma (ICP), microwave induced plasma (MEP), or laser-induced plasma, ion source, for example.

[0021] In accordance with a first aspect there is provided a method for operating a mass spectrometer comprising the steps of: a) setting at least one static parameter value(s) for the mass spectrometer (and preferably a plurality of static parameter values); b) obtaining a plurality of mass spectrometer signals from one or more analytes with the mass spectrometer set at the at least one static parameter value; c) determining a variability of the mass spectrometer signals for each of the one or more analytes obtained with the mass spectrometer set at the at least one static parameter value(s); d) repeating steps a)-c) with a plurality of different static parameter values; and e) determining a static parameter value providing a lowest variability of mass spectrometer signal for each of the one or more analytes. Therefore, improved quantitative results may be obtained from the mass spectrometer. The operating parameter value(s) of the mass spectrometer may be used to provide these improved results in future investigations. The parameter value may be formed from separate parameters or components.

[0022] Preferably, the method may further comprise the steps of: storing the determined static parameter value; retrieving the stored static parameter value; using a pump to provide the retrieved static parameter value; and obtaining one or more mass spectrometer signals with the mass spectrometer set at the (retrieved) static parameter value. Therefore, the original calibration settings or parameters of the mass spectrometer can be set without having to repeat the steps of finding the optimum parameters for operating the mass spectrometer with the lowest variability in signal results.

[0023] Optionally, the method may further comprise the steps of: determining if the one or more mass spectrometer signals obtained with the mass spectrometer set at the (retrieved) static parameter value is above a threshold; and if the one or more mass spectrometer signals obtained with the mass spectrometer set at the retrieved static parameter value is not above the threshold, then adjusting the parameter value until the one or more mass spectrometer signals is above the threshold. This provides sufficient signal quality with acceptable variability. This also avoids prioritising signal variability over signal strength (where the threshold is an intensity or amplitude value) so that a reduction in variability is obtained without reducing the signal to an unusable level. The threshold may be determined for signals of one or more m / z values (or an average), for example.

[0024] Optionally, the method may further comprise the steps of: obtaining one or more mass spectrometer signals from the one or more analytes with the mass spectrometer set with a parameter above or below the retrieved static parameter value; determining a variability of the mass spectrometer signals for each of the one or more analytes obtained with the mass spectrometer set at a static parameter value at each of the plurality of static parameters above or below the retrieved static parameter value; and determining one of the plurality of static parameter values above or below the retrieved static parameter value that provides a maximum mass spectrometer signal for the one or more analytes with the variability of the one or more mass spectrometer signal at or below a variability threshold. Therefore, a compromise or balance can be set having settings or parameters of the mass spectrometer that provide both an acceptable variability in results (e.g., a predetermined maximum variability) and sufficient signal levels for particular investigations or experiments.

[0025] Optionally, the variability threshold may be: a threshold received from a user input; a predetermined threshold; a limit of detection value of the mass spectrometer; and / or a signal sensitivity value of the mass spectrometer. Other thresholds may be used.

[0026] Optionally, the variability of the mass spectrometer signals for each of the plurality of analytes obtained with the mass spectrometer set at the at least one static parameter value(s) may be determined for different m / z values (and preferably a plurality of static parameter values for each of the different m / z values). Therefore, the mass spectrometer can be optimised across a great range of m / z values. For example, there may be a static parameter value that reduces variability for more m / z values rather than providing a minimum variability for a single m / z value.

[0027] According to a second aspect, there is provided a method for operating a mass spectrometer comprising the steps of: operating the mass spectrometer set to at least one first parameter value(s); obtaining one or more mass spectrometer signals from one or more analytes with the mass spectrometer set at the first parameter value; determining if the one or more mass spectrometer signals obtained with the mass spectrometer set at the first parameter value is above a threshold; and if the one or more mass spectrometer signals obtained with the mass spectrometer set at the first parameter value is not above the threshold then increasing or decreasing the parameter value until the one or more mass spectrometer signals is above the threshold. Therefore, an initial parameter value (which may be formed of separate parameters or components) can be set (e.g., one determined by using any of the previously described methods) and the settings of the mass spectrometer can be tuned so that an acceptable signal level or signal to noise ratio is achieved. These settings may be stored and retrieved when for use in the same mass spectrometer or for similar or identical devices. The threshold may be an absolute threshold (e.g., signal level) and range of values, an acceptable signal to noise ratio or a combination of signal value (amount) and signal to noise ratio, for example.

[0028] Optionally, the threshold may be: a threshold received from a user input; a predetermined threshold; a signal intensity threshold; a limit of detection value of the mass spectrometer; and / or a signal sensitivity value of the mass spectrometer. Other thresholds may be used.

[0029] Optionally, the first value of the parameter may be determined by: a) setting the mass spectrometer at a static parameter value; b) obtaining a plurality of mass spectrometer signals from one or more analytes with the mass spectrometer set at the static parameter value; c) determining a variability of the mass spectrometer signals for each of the one more analytes obtained with the mass spectrometer set at the static parameter value; d) repeating steps a)-c) with a plurality of different static parameter values; e) determining the static parameter providing a lowest variability of mass spectrometer signal for each of the one or more analytes; and f) storing the determined static parameter value as the first value. Optionally, determining the variability of the mass spectrometer signal may further comprise the steps of: repeating the mass spectrometer measurements with the same analyte or different analytes at the same static parameter value; and determining a value corresponding to a standard deviation of the repeated mass spectrometer measurements. Other metrics may be used to measure the variability of the signal or signals.

[0030] Optionally, the mass spectrometer may have a pump configured to provide a variable interface pressure at an interface between an ion source and a mass analyser of the mass spectrometer, and further wherein the static parameter is an interface pressure at an interface between an ion source and a mass analyser of the mass spectrometer. The pump or pumps may be used to set or vary the interface or other pressures or vacuum levels in the mass spectrometer.

[0031] Optionally, the parameter may be one or more comprising of: speed of a pump configured to vary a pressure at an interface between an ion source and a mass analyser of the mass spectrometer; a sample gas flow value; and an electric potential applied to a skimmer cone and / or a sample extraction aperture of the mass spectrometer. The gas flow rate may be set by values and / or gas flow sensors. The electric potential may be set by one or more power supplies or circuit(s) .

[0032] According to a third aspect, there is provided a mass spectrometer comprising: an ion source; a mass analyser; and and a controller adapted to execute the steps according to any previous claim. The controller may include one or more electrical circuits, processors, wiring, memory, firmware or other software, for example.

[0033] Optionally, the mass spectrometer may further comprise a pump configured to vary an interface pressure of the between the ion source and the mass analyser, wherein the parameter is the interface pressure. Optionally, the controller may comprise a computer processor and an electronic interface with the pump.

[0034] Optionally, the pump may be configured to vary the interface pressure between 0.1 mbar and 10 mbar. Other pressure settings or parameter values may be used.

[0035] Optionally, the ion source may be an inductively coupled plasma (ICP) source. Other mass spectrometers may be used.

[0036] Optionally, the mass spectrometer may further comprise a pressure sensor configured to measure the interface pressure and in electrical communication with the controller.

[0037] Preferably, the pressure sensor may be a Pirani sensor. Other pressure sensors may be used.

[0038] Optionally, the mass spectrometer may be an inductively coupled plasma mass spectrometer (ICP-MS).

[0039] In accordance with a fourth aspect, there is provided computer program product comprising instructions which, when the program is executed by a computer, causes the computer to carry out the method or methods described above.

[0040] In accordance with a further aspect, there is provided a method for operating a mass spectrometer having a variable gas flow rate for generating a plasma ion source and / or variable lens voltages, the method comprising the steps of: a) providing a static configuration of gas flow and / or lens voltage or voltages; b) obtaining a plurality of mass spectrometer signals from one or more analytes with the static configuration; c) determining a variability of the mass spectrometer signals for each of the one or more analytes obtained with the static configuration; d) repeating steps a)-c) with a plurality of different static configurations (i.e., varying the gas flow rate to a new static gas flow rate and / or varying the lens voltage or voltages to new static voltage(s)); and e) determining a static configuration providing a lowest variability of mass spectrometer signal for each of the one or more analytes. Other parameters may be tested. Similar variations of this method may be carried out according to any variation described above.

[0041] In accordance with a further aspect, there is provided a method for operating a mass spectrometer having a variable gas flow rate for generating a plasma ion source and / or variable lens voltages, the method comprising the steps of: operating the pump to provide an initial static configuration (e.g., gas flow rate and / or ion lens voltage(s)); obtaining one or more mass spectrometer signals from one or more analytes with the initial static configuration; determining if the one or more mass spectrometer signals obtained with the initial static configuration; and if the one or more mass spectrometer signals obtained with the initial static configuration is not above a threshold, then varying the configuration (e.g., increasing or decreasing the gas flow rate and / or ion lens voltage(s)) until the one or more mass spectrometer signals is above the threshold. Similar variations this this method may be carried out according to any variation described above.

[0042] In accordance with a further aspect, there is provided a method for operating a mass spectrometer comprising the steps of: a) setting at least one static parameter value for the mass spectrometer; b) obtaining a plurality of mass spectrometer signals from a plurality of analytes with the mass spectrometer set at the at least one static parameter value; c) determining a variability of the mass spectrometer signals for each of the plurality of analytes obtained with the mass spectrometer set at the static parameter value; d) repeating steps a)-c) with a plurality of different static parameter values; and e) determining a static parameter value providing a lowest variability of mass spectrometer signal for the plurality of analytes.

[0043] The methods described above may be implemented as a computer program comprising program instructions to operate a computer. The computer program may be stored on a computer-readable medium, including a non-transitory computer-readable medium. The computer system may include a processor or processors (e.g., local, virtual or cloud-based) such as a Central Processing Unit (CPU), and / or a single or a collection of Graphics Processing Units (GPUs). The processor may execute logic in the form of a software program. The computer system may include a memory including volatile and nonvolatile storage medium. A computer-readable medium (CRM) may be included to store the logic or program instructions. For example, embodiments may include a non-transitory computer-readable medium (CRM) storing software comprising instructions executable by one or more computers which, upon such execution, cause the one or more computers to perform the disclosed methods. Non-transitory CRM may refer to a CRM that stores data for short periods or in the presence of power such as a memory device or Random Access Memory (RAM). For example, a non-transitory computer-readable medium may include storage components, such as, a hard disk (e.g., a magnetic disk, an optical disk, a magneto-optic disk, and / or a solid-state disk), a compact disc (CD), a digital versatile disc (DVD), a floppy disk, a cartridge, and / or a magnetic tape. The different parts of the system may be connected using a network (e.g., wireless networks and wired networks). The computer system may include one or more interfaces. The computer system may contain a suitable operating system such as UNIX, Windows (RTM), macOS (RTM) or Linux, for example.

[0044] It should be noted that any feature described above may be used with any particular aspect or embodiment of the invention.

[0045] Brief description of the Figures

[0046] The present invention may be put into practice in a number of ways and embodiments will now be described by way of example only and with reference to the accompanying drawings, in which:

[0047] FIG. 1 shows a schematic diagram of a portion of a mass spectrometer, including an interface region;

[0048] FIG. 2 shows a flowchart of a method for optimising the configuration of the mass spectrometer of Figure 1 ;

[0049] FIG. 3 shows a flowchart of a method for operating the mass spectrometer of Figure

[0050] 1 ; FIG. 4 shows a graph of measured RSD values obtained by carrying out the method of Figure 2;

[0051] FIG. 5 shows a graph of measured intensities corresponding to Figure 4 obtained by carrying out the method of Figure 2 on the parameter of interface pressure.

[0052] FIG. 6 shows a graph of measured intensities obtained by carrying out the method of Figure 2 on the parameter of peristaltic pump speed.

[0053] FIG. 7 shows a graph of measured RSD values corresponding to Figure 6 obtained by carrying out the method of Figure 2; and

[0054] FIG 8 shows a schematic diagram of a computer system used to carry out the methods of Figures 2 and 3.

[0055] It should be noted that the figures are illustrated for simplicity and are not necessarily drawn to scale. Like features are provided with the same reference numerals.

[0056] Detailed description of the preferred embodiments

[0057] Figure 1 shows a schematic diagram of components of a mass spectrometer 10. A plasma torch 15 generates a plasma flame 20, which provides a plasma to a central aperture 25 of a sampling cone 30. The sampling cone 30 is used to sample the atmospheric pressure plasma flame 20 that extends from the end of the plasma torch 15.

[0058] The plasma flame 20 is within a region maintained at a high or atmospheric pressure. A pump 40, such as a fore vacuum pump or roughing pump, is used to evacuate an interface region 35 between the sampling cone 30 and a skimmer cone 45.

[0059] The sampling cone 30 has a central aperture 25 having an inner diameter of approximately 1 mm, which allows an interface pressure (Pi) of approximately 1 -5 mbar in the interface region 35 between the sampling cone 30 and the skimmer cone 45. The pump 40 may provide an example pumping speed of 5-15 l / s. These conditions determine a correct position of an aperture of the skimmer cone 45 inside a “zone of silence” of the extracted plasma. A typical distance between the tips of the sampling cone 30 and the skimmer cone 45 can be around 10 mm. An extracted jet beam forms a concentric shock wave structure, which ends in a shock wave front called the Mach disk. The region within this shock wave structure is named the zone of silence and contains the ions, electrons and neutrals, of which the ions are transferred to the mass analyser 60. This means that the aperture of the skimmer cone 25 should be placed within the zone of silence for adequate extraction of analyte ions. The sampler cone 30 and skimmer cone 45 are static and the interface pressure (Pi) in the interface region 35 must be low enough to position the Mach disk behind the aperture of the skimmer cone 45.

[0060] The mass analyser 60 and focusing optics or ion extraction optics 55 are behind the skimmer cone 45 and their environment is evacuated to a strong vacuum by one or more further pumps (not shown in this figure).

[0061] Beyond the interface region 35, the plasma is subjected to an ion extraction field by ion extraction optics 55, which draws positive ions from the plasma into an ion beam, repelling electrons and allowing neutral components to be pumped away. The ion beam is then transported downstream for mass analysis by the mass analyser 60 (not shown in detail). The ion beam may be deflected and / or guided from the extraction optics 55 towards the mass analyser 60 by one or more ion deflectors, ion lenses, and / or ion guides (not shown), which may operate with static or time-varying fields. A collision / reaction cell may be located upstream of the mass analyser 60, optionally with a mass filter located upstream of the collision / reaction cell (the latter configuration may be provided by a triple quadrupole arrangement as in the Thermo Scientific (RTM) iCAPTM TQ ICP-MS, for example).

[0062] A pressure sensor 60, such as a Pirani sensor, a thermocouple sensor or a cold cathode gauge (in particular for lower pressures), is located within the interface region 35 and provides pressure readings to a controller 50. The controller 50 is also in electrical communication with the pump 40. Therefore, the controller can obtain feedback from the pressure sensor 60, maintain a static interface pressure or vary the interface pressure over a pressure range (e.g., 1 -10 mbar, 1 -5 mbar or 1 -3 mbar).

[0063] The controller 50 may also include one or more voltage supplies or the controller 50 may have an electrical connection to voltage supplies external to the controller 50 (not shown in this figure). The voltage supplies can output voltages controlled by the controller 50. The sampler cone 30 may have an electrical connection 51 to one voltage supply and the skimmer cone may have another electrical connection 52 to the same or a separate voltage supply. In this way electric potentials applied to various parts of the mass spectrometer may be controlled by the controller 50. Varying these electric potentials may affect mass spectrometer signal variability and / or signal level in the same way as varying the interface pressure. These contribute to operating parameters of the mass spectrometer 10.

[0064] The mass spectrometer 10 can included any suitable device or component(s) able to vary the interface pressure or other parameters of the mass spectrometer 10. One such device is described in detail in GB2572819 but other apparatus can be used. The controller 50 preferably automatically sets and maintains the interface pressure and any other parameters. The pressure, voltage, gas flow rate or other parameter or parameters may be determined according to the following methods.

[0065] Parameter settings or settings for operating the mass spectrometer 10 can be determined so that signal stability is optimised, i.e., the relative standard deviation of analyte signals is as low as possible. The interface pressure of an ICP-MS or another mass spectrometer type strongly affects the signal intensity and stability of the ion signals, as can other parameters.

[0066] The following describes how to achieve a mass spectrometer parameter setting or settings that results in the best analyte signal stability. In this example, the interface pressure is the parameter being determined but similar processes can be used by varying the other example parameters (e.g., electric potentials, pump speeds, gas flow rates, etc.).

[0067] The pump 40 (e.g., a fore vacuum pump with a variable speed) may be operated at different speeds (static during data acquisition) and several analyte signals of ions with different masses or m / z are recorded simultaneously. The pump speed and corresponding interface pressure, as recoded by pressure sensor 60, where the relative standard deviation (RSD) of the measured signals is lowest throughout the mass range of the analytes is determined. This interface pressure provides the best or optimum setting for achieving the lowest signal variability. Other parameters may also be set and maintained in a static state while mass spectra are acquired.

[0068] Figure 2 shows a flowchart of a method 100 for determining the optimum parameter, e.g., an interface pressure of the interface region 35 where variability of mass spectrometer signals for one analyte or a range of analytes is minimised. At step 110, (a value of) an initial parameter (e.g., pressure, pump speed or voltage) is set by the controller 50. The pump speed or voltage is increased or decreased by the controller 50. This may be based on pressure readings from the pressure sensor 65 to maintain a static interface pressure, for example. The controller may select an initial parameter as an initial pressure as the lower or upper pressure in a predetermined range, for example.

[0069] Mass spectrometer data are collected from the mass spectrometer 10 with the parameter (e.g., interface pressure) maintained at the static initial value (step 120). These results may be more than one result from the same analyte, a plurality of results from different analytes having different m / z values or preferably, a combination of both (i.e., multiple analytes with multiple results obtained from each analyte).

[0070] From the collected data, a variability (e.g., a standard variation) of signal values is determined for the particular static parameter (step 130). For example, for the same concentration of analytes, different signal intensity values may be observed in the mass spectrum. Such results are illustrated graphically in Figure 4 with the interface pressure as the parameter in these example results.

[0071] At step 140, the measurements are repeated for all analytes after setting the parameter to a new static parameter value (e.g., the controller 50 setting the pump 40 to a new pressure). The measuring, determining, and setting steps (120, 130, 140) are repeated until the full parameter range (e.g., pressure range) has been investigated. For example, the pressure range may be 1 to 3 mbar with pressure changes between measurements of 0.1 or 0.2 mbar.

[0072] The variation in signal intensities may be lowest at a particular parameter value. In Figure 4, this is observed at around 2 mbar, as recorded by a Pirani pressure sensor. This lowest variation or variability parameter is determined at step 150. In other words, for similar or the same concentration of analyte, each different mass provides the most similar intensity value at this particular parameter value. It should be realised that determining the variability of the mass spectra signals for each parameter value (step 130) can be carried out after all of the mass spectra have been acquired across the full parameter range or in between parameter value(s) changes, as shown in Figure 2.

[0073] Figure 3 shows a flowchart of a method 200 for operating the mass spectrometer 10. This operation is optimised to minimise the variation in signals across different analytes or the same analytes at the same concentration. At step 210, the mass spectrometer is set with an initial parameter value (e.g., a pressure of the interface region on the mass spectrometer 10). The initial value may be selected by the controller 50 based on results obtained by following method 100 (e.g., calibration results for a particular mass spectrometer 10 or for a particular configuration of the mass spectrometer 10).

[0074] Mass spectrometer results are obtained at step 220. However, the parameter value can also affect signal level (as well as signal variability) and an optimum value for reducing or minimising variability may also reduce the signal level. For particular analytes, the parameter value may reduce the signal level (or signal to noise ratio) below an acceptable level. At step 230 a determination is made by comparing the signal level and a threshold (e.g., a predetermined threshold, a user-selected threshold, or a limit of detection value for the mass spectrometer 10). If the signal is greater than the threshold, then the method may end (240). Otherwise, the parameter value applied to the mass spectrometer 10 may be altered away from the optimum value for minimizing variability (e.g., by 0.1 mbar, 0.1 V or 0.1 l / m flow rate). The new parameter is set at step 250.

[0075] The method 200 repeats until the results with sufficient signal values or signal to noise ratios are obtained (as well as acceptable variability).

[0076] Figure 4 shows an example set of results from the method 100 used to find an optimum interface pressure for the interface region 35 of the mass spectrometer 10. It is noted that changing the configuration of the mass spectrometer 10 (e.g., replacing the skimmer cone 45) may result in a variation in results and a different optimum interface pressure. As can be seen from the graph of Figure 4, setting the interface pressure of the mass spectrometer (e.g., using the controller 50 and pump 40) to around 2 mbar results in a minimum variation (e.g., relative standard deviation, RSD) of most of the signals of different analytes. However, at this pressure the absolute signal values are low. This can be seen from the signal intensity data extracted from the same data set, which is shown in Figure 5. Therefore, this pressure is not ideal for low concentration analytes.

[0077] At around 1 .6 mbar, a considerable increase in signal can be seen. However, this interface pressure produces higher variation in measured signal values (RDS) and so may be unsuitable for certain types of quantitative investigations. For low concentrations or low signal analytes, a compromise interface pressure may be found by calibrating the mass spectrometer 10 (in a particular configuration) to find the interface pressure producing the lowest variation using method 100. When the actual measurements are required then method 200 may be used starting with the parameter (e.g., interface pressure) determined by method 100. Therefore, the parameter value closest to the optimum value (minimising variation but providing a high enough signal or signal to noise ratio) may be found. It may not be necessary to repeat these methods each time, as the optimum parameter value for particular mass spectrometer configurations, analytes and / or analyte concentrations may be determined in advance, and stored and retrieved when required. Furthermore, one parameter value may compensate for another. Therefore, it may be possible to keep the interface pressure value at the optimum value for minimising signal variability and alter other parameters (e.g., skimmer potential) until the signal value reaches an acceptable or threshold value (e.g., above the noise).

[0078] As can be seen in Figure 4, the RSD of an analyte signal is also a function of analyte mass. However, these example results show that all analytes in this investigation are most stable around a Pirani-measured N-calibrated interface pressure of approximately 2.0 mbar. A correction factor for true Ar-pressures of the displayed values is 2.25 in this example. Therefore, in this example the true optimised interface pressure for obtaining results with the lowest RSD is 4.5 mbar.

[0079] The following describes for details of the use of multiple signals for the optimisation of mass spectrometer settings. If more than one quantity is used for optimisation, there is a need to set individual signals in relation to each other. There are multiple possibilities for doing so. Three examples are described here.

[0080] 1. Equal weighting

[0081] 2. Preferential mass region weighting

[0082] 3. Individual weighting

[0083] Equal weighting:

[0084] Equal weighting is equivalent to using a certain multiplier for each single quantity. In the case of mass spectrometer signals, signals generally have various strengths. To achieve equal weighting, one option is to use normalised signals, i. e., divide the signal by its maximum, as found at a specific parameter setting. Every quantity then has the same importance in the optimisation of a parameter. If the quantities used for optimisation are RSD values, a slightly different type of normalisation may be provided by the definition of the RSD. For example, the expression to be optimised (minimised) can be the sum of the individual RSD values of the (n + 1) different signals that are considered:

[0085] [ RSD(7Li) + RSD(59Co) + RSD (115 In) + RSD (209 Bi)]

[0086] (3)

[0087] Preferential mass region weighting:

[0088] Preferential region weighting allows the user to name an arbitrary mass as most important for the optimisation and then use, for example, binomial coefficients to define the weighting multipliers for all signals used in this optimisation. For example, if the most important mass for the optimisation were to be selected or determined as 89Y, and the (n + 1 ) available signals for the optimisation are 7Li, 59Co, 1151 n and 209Bi, the corresponding weighting factors may be:

[0089] © 2n

[0090] The terms of the expression would then be r l 3 3 1

[0091] - RSD(7Li) + - RSD(59Co) + - RSD(U5In) + - RSD(209Bi)

[0092] .8 8 8 8

[0093] (4) and for optimisation for example, the sum of those four terms, may be minimised.

[0094] Individual weighting:

[0095] Individual weighting can be used to assign an arbitrary multiplier a, to the individual quantity and, for example, use the sum of all weighted quantities for optimisation. Therefore, a completely individual weighting pattern can be determined by the user by minimising the expression: If all quantities are normalised with their individual maximum in the considered parameter range, even mixing the weights of relative RSD values with relative signal strengths is possible:

[0096] This allows for an expression that balances a low RSD on some signals / while simultaneously emphasizing other signal strengths / '.

[0097] This example prefers low RSD on 59Co over high 7Li signal, while low RSD of 115ln and high signal on 209Bi is subordinated:

[0098] Other ions can be used in such optimisation techniques but these are provided as examples.

[0099] Another example of a quantity that can be better determined with the methods described in Fig. 2 and Fig. 3 instead of by following standard signal maximization is the liquid sample flow delivered to the instrument. Figure 6 shows the intensity of various analyte signals as a function of pressure. Similar to those in Figure 5, they increase monotonously with the instrument parameter, the peristaltic pump rotation speed. No specific feature is visible in the data which points to a best choice value, so that the highest value would be chosen by a maximum signal tuning approach. However, considering the signal variation expressed in terms of signal RSD, the best choice for liquid sample flow is found at about 30 rpm of the peristaltic pump of the system. This will provide the minimum relative fluctuation in the measured signals following the method described in Fig. 2. and therefore provides the best efficiency in using the available measurement time for highest precision. Figure 7 shows a graph of measured RSD values corresponding to Figure 6 obtained by carrying out the described method.

[0100] Once the optimised parameter value (e.g., interface pressure) for a particular mass spectrometer 10 and its configuration has been determined then it can be expected to be the same optimum parameter for systems having a similar or an identical design. Therefore, this parameter value (e.g., interface pressure and / or associated pump speed used to obtain this pressure) may be provided as a predetermined preset value for achieving best signal stability in mass spectrometers having the same or similar designs and configurations. The method 100 described with regards to Figure 2 may be carried out so that the optimum parameter value can be determined for other mass spectrometer configurations or types. These other settings or presets may be used in different system designs.

[0101] If for some reason the signal at this setting is too low, for example because it is very weak compared to other common analyte signals, then the method described in Figure 3 can be executed to increase the signal by leaving the parameter range that guarantees the lowest relative variation towards higher intensities. Such a new parameter setting that will be found this way is characterized in that it combines a required signal level with the minimum of signal fluctuations or variation that can be realized with the given system and configuration.

[0102] It is important to achieve more stable analyte signals in certain circumstances as this can provide a more achievable limit of detection (LOD) within a limited measurement time. Furthermore, reducing variation in signal intensity can reduce the time to achieve a targeted analytical precision level. Therefore, the time efficiency for obtaining analytical results may be improved, and in certain cases, where non-zero background levels are present, the LOD levels may also be improved.

[0103] The use of the method 100 that optimises signal RSD may be achieved using instrument software code. Therefore, the software can have a real-world effect on mass spectrometer operation, efficiency, reliability and repeatability of results. The use of this optimised parameter value could be achieved from existing instrument parameter sets and calibration specifications. The controller 60 comprises a computer system that is used to implement the described methods. As shown in Figure 8, the computer system 800 includes a number of components including communication interfaces 820, system circuitry 830, input / output (I / O) circuitry 840, display circuitry and interfaces 850, and a datastore 870. The system circuitry 820 can include one or more processors or CPUs 880 and memory 890. The system circuitry 830 may include any combination of hardware, software, firmware, and / or other circuitry. The system circuitry 830 may be implemented, with one or more systems on a chip (SoC), application specific integrated circuits (ASIC), microprocessors, and / or analogue and digital circuits.

[0104] The display circuitry may provide one or more graphical user interfaces (GUIs) 860 and the I / O interface circuitry 840 may include touch sensitive or non-touch displays, sound, voice or other recognition inputs, buttons, switches, speakers, sounders, and other user interface elements. The I / O interface circuitry 840 may include microphones, cameras, headset and microphone input / output connectors, Universal Serial Bus (USB) connectors, and SD or other memory card sockets. The I / O interface circuitry 840 may further include data media interfaces (e.g., a CD-ROM or DVD drive) and other bus and display interfaces.

[0105] The memory 890 may include volatile (RAM) or non-volatile memory (e.g., ROM or Flash memory). The memory may store the operating system 892 of the computer system 800, applications or software 894, dynamic data 896, and / or static data 898. The datastore or data source 870 may include one or more databases 872, 874 and / or a file store or file system, for example.

[0106] The method and system may be implemented in hardware, software, or a combination of hardware and software. The method and system may be implemented either as a server comprising a single computer system or as a distributed network of servers connected across a network. Any kind of computer system or other electronic apparatus may be adapted to carry out the described methods.

[0107] As used throughout, including in the claims, unless the context indicates otherwise, singular forms of the terms herein are to be construed as including the plural form and vice versa. For instance, unless the context indicates otherwise, a singular reference herein including in the claims, such as "a" or "an" (such as an ion multipole device) means "one or more" (for instance, one or more ion multipole device). Throughout the description and claims of this disclosure, the words "comprise", "including", "having" and "contain" and variations of the words, for example "comprising" and "comprises" or similar, mean "including but not limited to", and are not intended to (and do not) exclude other components. Also, the use of “or” is inclusive, such that the phrase “A or B” is true when “A” is true, “B is true”, or both “A” and “B” are true.

[0108] The use of any and all examples, or exemplary language ("for instance", "such as", "for example" and like language) provided herein, is intended merely to better illustrate the disclosure and does not indicate a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0109] The terms “first” and “second” may be reversed without changing the scope of the disclosure. That is, an element termed a “first” element may instead be termed a “second” element and an element termed a “second” element may instead be considered a “first” element.

[0110] Any steps described in this specification may be performed in any order or simultaneously unless stated or the context requires otherwise. Moreover, where a step is described as being performed after a step, this does not preclude intervening steps being performed.

[0111] It is also to be understood that, for any given component or embodiment described throughout, any of the possible candidates or alternatives listed for that component may generally be used individually or in combination with one another, unless implicitly or explicitly understood or stated otherwise. It will be understood that any list of such candidates or alternatives is merely illustrative, not limiting, unless implicitly or explicitly understood or stated otherwise.

[0112] Unless otherwise described, all technical and scientific terms used throughout have a meaning as is commonly understood by one of ordinary skill in the art to which the various embodiments described herein belongs. As will be appreciated by the skilled person, details of the above embodiment may be varied without departing from the scope of the present invention, as defined by the appended claims.

[0113] For example, the interface pressure is one parameter that has been described, as well as the sample flow in terms of the peristaltic pump speed, but also other parameters might be preset, tuned, tested or calibrated using similar methods 100, 200 described above to obtain the lowest signal variability or RSD. One further example may be a nebuliser flow rate, or other source-related parameters. For example, other candidates for RSD or variability minimisation may include an extraction voltage.

[0114] Whilst a single parameter value has been described as being determined (e.g., calibrated) and applied to the mass spectrometer, the parameter may be a composite value. For example, the parameter may be a combination of any two or more of interface value, electric potential applied to the sampler cone, electric potential applied to the skimmer cone, electric potential applied to the ion optics, operating parameter of the mass analyser, gas flow rates or other mass spectrometer operating characteristics. Additionally, or alternatively, the parameter may be a composite value of two or more instances of a signal, for example multiple signals representing multiple analytes. Finding an optimum combination of operating characteristics forming the optimum parameter or setting of the mass spectrometer may require keeping one or more static while varying one characteristic at a time and obtaining mass spectrometer results for every combination. This process may be automated by the controller.

[0115] Many combinations, modifications, or alterations to the features of the above embodiments will be readily apparent to the skilled person and are intended to form part of the invention. Any of the features described specifically relating to one embodiment or example may be used in any other embodiment by making the appropriate changes.

Claims

CLAIMS:1 . A method for operating a mass spectrometer comprising the steps of: a) setting at least one static parameter value for the mass spectrometer; b) obtaining a plurality of mass spectrometer signals from one or more analytes with the mass spectrometer set at the at least one static parameter value; c) determining a variability of the mass spectrometer signals for each of the one or more analytes obtained with the mass spectrometer set at the static parameter value; d) repeating steps a)-c) with a plurality of different static parameter values; and e) determining a static parameter value providing a lowest variability of mass spectrometer signal for each of the one or more analytes.

2. The method of claim 1 further comprising the steps of: storing the determined static parameter value; retrieving the stored static parameter value; using a pump to provide the retrieved static parameter value; and obtaining one or more mass spectrometer signals with the mass spectrometer set at the static parameter value.

3. The method of claim 2 further comprising the steps of: determining if the one or more mass spectrometer signals obtained with the mass spectrometer set at the static parameter value is above a threshold; and if the one or more mass spectrometer signals obtained with the mass spectrometer set at the retrieved static parameter value is not above the threshold, then adjusting the parameter value until the one or more mass spectrometer signals is above the threshold.

4. The method of claim 2 or claim 3 further comprising the steps of: obtaining one or more mass spectrometer signals from the one or more analytes with the mass spectrometer set with a parameter above or below the retrieved static parameter value; determining a variability of the mass spectrometer signals for each of the one or more analytes obtained with the mass spectrometer set at a static parameter value at each of the plurality of static parameter values above or below the retrieved static parameter value; anddetermining one of the plurality of static parameter values above or below the retrieved static parameter value that provides a maximum mass spectrometer signal for the one or more analytes with the variability of the one or more mass spectrometer signal at or below a variability threshold.

5. The method of claim 4, wherein variability threshold is: a threshold received from a user input; a predetermined threshold; a limit of detection value of the mass spectrometer; and / or a signal sensitivity value of the mass spectrometer.

6. The method according to any previous claim, wherein the variability of the mass spectrometer signals for each of the plurality of analytes obtained with the mass spectrometer set at the static parameter value is determined for different m / z values.

7. A method for operating a mass spectrometer comprising the steps of: operating the mass spectrometer set to at least one first parameter value; obtaining one or more mass spectrometer signals from one or more analytes with the mass spectrometer set at the first parameter value; determining if the one or more mass spectrometer signals obtained with the mass spectrometer set at the first parameter value is above a threshold; and if the one or more mass spectrometer signals obtained with the mass spectrometer set at the first parameter value is not above the threshold then increasing or decreasing the parameter value until the one or more mass spectrometer signals is above the threshold.

8. The method of claim 7, wherein the threshold is: a threshold received from a user input; a predetermined threshold; a signal intensity threshold; a limit of detection value of the mass spectrometer; and / or a signal sensitivity value of the mass spectrometer.

9. The method of claim 7 or claim 8, wherein the first value of the parameter is determined by: a) setting the mass spectrometer at a static parameter value;b) obtaining a plurality of mass spectrometer signals from one or more analytes with the mass spectrometer set at the static parameter value; c) determining a variability of the mass spectrometer signals for each of the one more analytes obtained with the mass spectrometer set at the static parameter value; d) repeating steps a)-c) with a plurality of different static parameter values; e) determining the static parameter value providing a lowest variability of mass spectrometer signal for each of the one or more analytes; and f) storing the determined static parameter value as the first value.

10. The method according to any previous claim, wherein determining the variability of the mass spectrometer signal further comprises the steps of: repeating the mass spectrometer measurements with the same analyte or different analytes at the same static parameter value; and determining a value corresponding to a standard deviation of the repeated mass spectrometer measurements.11 . The method according to any previous claims, wherein the mass spectrometer has a pump configured to provide a variable interface pressure at an interface between an ion source and a mass analyser of the mass spectrometer, and further wherein the static parameter is an interface pressure at an interface between an ion source and a mass analyser of the mass spectrometer.

12. The method according to any of claims 1 to 10, wherein the parameter is any one or more comprising of: speed of a pump configured to vary a pressure at an interface between an ion source and a mass analyser of the mass spectrometer; a sample gas flow value; and an electric potential applied to a skimmer cone and / or a sample extraction aperture of the mass spectrometer.

13. A mass spectrometer comprising: an ion source; a mass analyser; and a controller adapted to execute the steps according to any previous claim.

14. The mass spectrometer of claim 13 further comprising a pump configured to vary an interface pressure of the between the ion source and the mass analyser, wherein the parameter is the interface pressure.

15. The mass spectrometer of claim 14, wherein the controller comprises a computer processor and an electronic interface with the pump.

16. The mass spectrometer of claim 14 or claim 15, wherein the pump is configured to vary the interface pressure between 0.1 mbar and 10 mbar.

17. The mass spectrometer according to any of claim 13 to 16, wherein the ion source is an inductively coupled plasma source.

18. The mass spectrometer according to any of claim 14 to 17 further comprising a pressure sensor configured to measure the interface pressure and in electrical communication with the controller.

19. The mass spectrometer of claim 18, wherein the pressure sensor is a Pirani sensor.

20. The mass spectrometer according to any of claims 13 to 19, wherein the mass spectrometer is an inductively coupled plasma mass spectrometer (ICP-MS).21 . A computer program product comprising instructions which, when the program is executed by a computer, causes the computer to carry out the method of any of claims 1 to 12.

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