BENCH-TOP TIME OF FLIGHT MASS SPECTROMETER

Abstract

A start-up routine for a mass spectrometer is performed automatically upon switching ON the mass spectrometer. The mass spectrometer comprises a plurality of functional modules connected thereto, each module operable to perform a predetermined function of the mass spectrometer in use. The start-up routine comprises detecting which functional modules are present in the set of a plurality of functional modules connected to the mass spectrometer, and performing one or more steps of the start-up routine based upon the results of the detection. The mass spectrometer automatically determines whether configuration information is stored locally in respect of each one of the detected functional modules, and, for the or each one of the detected functional modules for which such information is found to be stored locally, automatically uses the information in configuring the mass spectrometer, and, for any detected functional module(s) for which such information is not found to be stored locally, automatically obtains configuration information for the detected functional module(s) from a remote server, and uses the information in configuring the mass spectrometer.

Claims

1. A method of performing a start-up routine for a mass spectrometer, the start-up routine being performed automatically upon switching ON the mass spectrometer, wherein the mass spectrometer comprises a plurality of functional modules connected thereto, each module operable to perform a predetermined function of the mass spectrometer in use, and wherein the start-up routine comprises detecting which functional modules are present in the set of a plurality of functional modules connected to the mass spectrometer, and performing one or more steps of the start-up routine based upon the results of the detection.

2. The method of claim 1, wherein the method comprises configuring the mass spectrometer based on the detected functional modules.

3. The method of claim 2, wherein the method comprises the mass spectrometer automatically determining whether configuration information is stored locally in respect of each one of the detected functional modules, and, for the or each one of the detected functional modules for which such information is found to be stored locally, automatically using the information in configuring the mass spectrometer, and, for any one or ones of the detected functional modules for which such information is not found to be stored locally, automatically obtaining configuration information for the one or ones of the detected functional modules from a remote server, and using the information in configuring the mass spectrometer.

4. The method of claim 1, wherein each of the functional modules is individually addressable and connected in a network in use, and the mass spectrometer comprises a scheduler operable to introduce discrete packets of instructions to the network at predetermined times to instruct at least one functional module to perform a predetermined operation.

5. The method of claim 1, wherein the method comprises determining whether the detected functional modules correspond to an allowed combination of modules, and, where the detected functional modules do correspond to an allowed combination, continuing with the start-up routine, and, where the detected functional modules do not correspond to an allowed combination of modules, determining a fault state of the spectrometer.

6. A mass spectrometer comprising a control system which is arranged to automatically perform a start-up routine for the mass spectrometer upon switching ON the mass spectrometer, wherein the mass spectrometer comprises a plurality of functional modules connected thereto, each module operable to perform a predetermined function of the mass spectrometer in use, and wherein the start-up routine comprises detecting which functional modules are present in the set of a plurality of functional modules connected to the mass spectrometer, and performing one or more steps of the start-up routine based upon the results of the detection.

7. A method of performing a start-up routine for a mass spectrometer, the start-up routine being performed automatically upon switching ON the mass spectrometer, wherein the mass spectrometer comprises a mass analyser and ion optics for guiding ions from an ion source to the mass analyser in use; wherein the start-up routine comprises, when a first set of one or more conditions is met, putting the mass spectrometer into a power save mode, wherein the power save mode is a mode in which voltage is supplied to one or more components of the mass analyser, and voltage is not supplied to one or more components of the ion optics between the ion source and the mass analyser.

8. The method of claim 7, wherein the mass spectrometer is automatically switched to the power save mode before a pressure of a vacuum chamber housing the mass analyser has reached an operating level.

9. The method of claim 7, comprising pumping a vacuum chamber housing the mass analyser to reduce the pressure therein before switching the spectrometer to the power save mode, and continuing to pump the vacuum chamber after switching to the power save mode.

10. The method of claim 7, wherein the first set of one or more conditions includes a requirement that a pressure within a vacuum chamber housing the mass analyser has fallen below a first predetermined threshold, for example 1×10.sup.−5 mbar.

11. The method of claim 7, further comprising, subsequently, if a further set of one or more conditions is met, automatically putting the mass spectrometer into an operating mode, in which voltage is supplied to one or more components of both the mass analyser and the ion optics between the source and the mass analyser.

12. The method of claim 11, wherein the further set of one or more conditions includes a requirement that there is no fault detected within the mass analyser within a predetermined period after the voltage supply to the one or more components of the mass analyser is switched on based on automatically monitoring of the current associated with one or more components of the mass analyser, wherein the method comprises automatically monitoring the current associated with one or more components of the mass analyser for a predetermined period after the voltage supply to the one or more components of the mass analyser is switched on to ensure there is no fault within the mass analyser.

13. The method of claim 11, wherein the mass spectrometer is automatically switched from the power save mode to the operating mode when the pressure within a vacuum chamber housing the mass analyser falls below a second predetermined threshold, wherein the second predetermined threshold is lower than the first predetermined threshold, for example wherein the second predetermined threshold is 1×10.sup.−6 mbar.

14. The method of claim 7 wherein the mass spectrometer is configured such that it may be switched to a standby mode in which voltage is not supplied to any components of the mass analyser.

15. (canceled)

16. (canceled)

17. (canceled)

18. The method of claim 1, wherein the mass spectrometer comprises: a mass analyser and ion optics for guiding ions from an ion source to the mass analyser in use; a vacuum chamber housing at least a portion of the ion optics of the spectrometer, and a backing pump operable to pump the vacuum chamber; a pump associated with one or more other vacuum chambers of the spectrometer downstream of the vacuum chamber housing the at least a portion of the ion optics for reducing the pressure within the one or more other vacuum chambers, wherein the pump is operable to pump a vacuum chamber housing the mass analyser of the spectrometer, and one or more further vacuum chamber housing a respective further portion of the ion optics; the method comprising: operating the backing pump to reduce the pressure in the vacuum chamber housing the at least a portion of the ion optics; detecting when a backing pressure has decreased to a predetermined level, and then turning on the pump associated with the one or more other vacuum chambers of the spectrometer; the method further comprising putting the mass spectrometer into a power save mode when a first set of one or more conditions is met, wherein the power save mode is a mode in which voltage is supplied to one or more components of the mass analyser, and voltage is not supplied to one or more components of the ion optics between the source and the mass analyser; wherein the first set of one or more conditions includes a requirement that a pressure within the vacuum chamber housing the mass analyser has fallen below a first predetermined threshold; and automatically switching the mass spectrometer from the power save mode to an operating mode when it is determined that a further set of one or more conditions is met, wherein the further set of one or more conditions includes a requirement that the pressure within the vacuum chamber housing the mass analyser has fallen below a second predetermined threshold, wherein the second predetermined threshold is lower than the first predetermined threshold, wherein, in the operating mode, voltage is supplied to one or more components of the mass analyser and to one or more components of the ion optics between the source and the mass analyser.

19. The method of claim 11, wherein the further set of one or more conditions additionally includes a requirement that the voltage supplied to one or more components of the mass analyser has stabilised within a predetermined time period.

20. The method of claim 18, wherein the mass spectrometer further comprises a plurality of functional modules connected thereto, each module operable to perform a predetermined function of the mass spectrometer in use, and, when the pump associated with the one or more other vacuum chambers of the spectrometer reaches a predetermined speed, detecting which functional modules are present in the set of a plurality of functional modules connected to the mass spectrometer, and performing one or more steps of the start-up routine based upon the results of the detection.

21. The method of claim 18, wherein the pump associated with the one or more other vacuum chambers of the spectrometer is a turbo pump, optionally wherein the method comprises turning on a pressure gauge of the mass analyser when a speed of the turbo pump relative to a maximum speed of the pump exceeds a predetermined threshold.

22. The method of claim 21, wherein the step of detecting the functional modules present is performed when a speed of the turbo pump relative to a maximum speed of the pump exceeds a predetermined threshold.

23. The method of claim 18, further comprising automatically monitoring the current associated with one or more components of the mass analyser for a predetermined period after the voltage supply to the mass analyser is switched on to determine whether there is a fault within the mass analyser.

24. (canceled)

25. (canceled)

26. (canceled)

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0153] Various embodiments together with other arrangements given for illustrative purposes only will now be described, by way of example only, and with reference to the accompanying drawings in which:

[0154] FIG. 1 shows a perspective view of a bench-top Time of Flight mass spectrometer according to various embodiments coupled to a conventional bench-top liquid chromatography (“LC”) separation system;

[0155] FIG. 2A shows a front view of a bench-top mass spectrometer according to various embodiments showing three solvent bottles loaded into the instrument and a front display panel,

[0156] FIG. 2B shows a perspective view of a mass spectrometer according to various embodiments and FIG. 2C illustrates in more detail various icons which may be displayed on the front display panel in order to highlight the status of the instrument to a user and to indicate if a potential fault has been detected;

[0157] FIG. 3 shows a schematic representation of mass spectrometer according to various embodiments, wherein the instrument comprises an Electrospray Ionisation (“ESI”) or other ion source, a conjoined ring ion guide, a segmented quadrupole rod set ion guide, one or more transfer lenses and a Time of Flight mass analyser comprising a pusher electrode, a reflectron and an ion detector;

[0158] FIG. 4 shows a known Atmospheric Pressure Ionisation (“API”) ion source which may be used with the mass spectrometer according to various embodiments;

[0159] FIG. 5 shows a first known ion inlet assembly which shares features with an ion inlet assembly according to various embodiments;

[0160] FIG. 6A shows an exploded view of the first known ion inlet assembly, FIG. 6B shows a second different known ion inlet assembly having an isolation valve, FIG. 6C shows an exploded view of an ion inlet assembly according to various embodiments, FIG. 6D shows the arrangement of an ion block attached to a pumping block upstream of a vacuum chamber housing a first ion guide according to various embodiments, FIG. 6E shows in more detail a fixed valve assembly which is retained within an ion block according to various embodiments, FIG. 6F shows the removal by a user of a cone assembly attached to a clamp to expose a fixed valve having a gas flow restriction aperture which is sufficient to maintain the low pressure within a downstream vacuum chamber when the cone is removed and FIG. 6G illustrates how the fixed valve may be retained in position by suction pressure according to various embodiments;

[0161] FIG. 7A shows a pumping arrangement according to various embodiments, FIG. 7B shows further details of a gas handling system which may be implemented, FIG. 7C shows a flow diagram illustrating the steps which may be performed following a user request to the turn the Atmospheric Pressure Ionisation (“API”) gas ON and FIG. 7D shows a flow chart illustrating a source pressure test which may be performed according to various embodiments;

[0162] FIG. 8 shows in more detail a mass spectrometer according to various embodiments;

[0163] FIG. 9 shows a Time of Flight mass analyser assembly comprising a pusher plate assembly having mounted thereto a pusher electronics module and an ion detector module and wherein a reflectron assembly is suspended from an extruded flight tube which in turn is suspended from the pusher plate assembly;

[0164] FIG. 10A shows in more detail a pusher plate assembly, FIG. 10B shows a monolithic pusher plate assembly according to various embodiments and FIG. 100 shows a pusher plate assembly with a pusher electrode assembly or module and an ion detector assembly or module mounted thereto;

[0165] FIG. 11 shows a flow diagram illustrating various processes which occur upon a user pressing a start button on the front panel of the instrument according to various embodiments;

[0166] FIG. 12A shows in greater detail three separate pumping ports of a turbo molecular pump according to various embodiments and FIG. 12B shows in greater detail two of the three pumping ports which are arranged to pump separate vacuum chambers;

[0167] FIG. 13 shows in more detail a transfer lens arrangement;

[0168] FIG. 14A shows details of a known internal vacuum configuration and FIG. 14B shows details of a new internal vacuum configuration according to various embodiments;

[0169] FIG. 15A shows a schematic of an arrangement of ring electrodes and conjoined ring electrodes forming a first ion guide which is arranged to separate charged ions from undesired neutral particles, FIG. 15B shows a resistor chain which may be used to produce a linear axial DC electric field along the length of a first portion of the first ion guide and FIG. 15C shows a resistor chain which may be used to produce a linear axial DC electric field along the length of a second portion of the first ion guide;

[0170] FIG. 16A shows in more detail a segmented quadrupole rod set ion guide according to various embodiments which may be provided downstream of the first ion guide and which comprises a plurality of rod electrodes, FIG. 16B illustrates how a voltage pulse applied to a pusher electrode of a Time of Flight mass analyser may be synchronised with trapping and releasing ions from the end region of the segmented quadrupole rod set ion guide, FIG. 16C illustrates in more detail the pusher electrode geometry and shows the arrangement of grid and ring lenses or electrodes and their relative spacing, FIG. 16D illustrates in more detail the overall geometry of the Time of Flight mass analyser including the relative spacings of elements of the pusher electrode and associated electrodes, the reflectron grid electrodes and the ion detector, FIG. 16E is a schematic illustrating the wiring arrangement according to various embodiments of the pusher electrode and associated grid and ring electrodes and the grid and ring electrodes forming the reflectron, FIG. 16F illustrates the relative voltages and absolute voltage ranges at which the various ion optical components such as the Electrospray capillary probe, differential pumping apertures, transfer lens electrodes, pusher electrodes, reflectron electrodes and the detector are maintained according to various embodiments, FIG. 16G is a schematic of an ion detector arrangement according to various embodiments and which shows various connections to the ion detector which are located both within and external to the Time of Flight housing and FIG. 16H shows an illustrative potential energy diagram;

[0171] FIG. 17 shows an indication of a fault which may be provided on a computer device connected to the mass spectrometer in some embodiments;

[0172] FIG. 18A is a flow chart illustrating how calibration of the mass spectrometer may be performed in accordance with certain embodiments; and

[0173] FIG. 18B illustrates the process in more detail.

DETAILED DESCRIPTION

[0174] Various aspects of a newly developed mass spectrometer are disclosed. The mass spectrometer comprises a modified and improved ion inlet assembly, a modified first ion guide, a modified quadrupole rod set ion guide, improved transfer optics, a novel cantilevered time of flight arrangement, a modified reflectron arrangement together with advanced electronics and an improved user interface.

[0175] The mass spectrometer has been designed to have a high level of performance, to be highly reliable, to offer a significantly improved user experience compared with the majority of conventional mass spectrometers, to have a very high level of EMC compliance and to have advanced safety features.

[0176] The instrument comprises a highly accurate mass analyser and overall the instrument is small and compact with a high degree of robustness. The instrument has been designed to reduce manufacturing cost without compromising performance at the same time making the instrument more reliable and easier to service. The instrument is particularly easy to use, easy to maintain and easy to service. The instrument constitutes a next-generation bench-top Time of Flight mass spectrometer.

[0177] FIG. 1 shows a bench-top mass spectrometer 100 according to various embodiments which is shown coupled to a conventional bench-top liquid chromatography separation device 101. The mass spectrometer 100 has been designed with ease of use in mind. In particular, a simplified user interface and front display is provided and instrument serviceability has been significantly improved and optimised relative to conventional instruments. The mass spectrometer 100 has an improved mechanical design with a reduced part count and benefits from a simplified manufacturing process thereby leading to a reduced cost design, improved reliability and simplified service procedures. The mass spectrometer has been designed to be highly electromagnetic compatible (“EMC”) and exhibits very low electromagnetic interference (“EMI”).

[0178] FIG. 2A shows a front view of the mass spectrometer 100 according to various embodiments and FIG. 2B shows a perspective view of the mass spectrometer according to various embodiments. Three solvent bottles 201 may be coupled, plugged in or otherwise connected or inserted into the mass spectrometer 100. The solvent bottles 201 may be back lit in order to highlight the fill status of the solvent bottles 201 to a user.

[0179] One problem with a known mass spectrometer having a plurality of solvent bottles is that a user may connect a solvent bottle in a wrong location or position. Furthermore, a user may mount a solvent bottle but conventional mounting mechanisms will not ensure that a label on the front of the solvent bottle will be positioned so that it can be viewed by a user i.e. conventional instruments may allow a solvent bottle to be connected where a front facing label ends up facing away from the user. Accordingly, one problem with conventional instruments is that a user may not be able to read a label on a solvent bottle due to the fact that the solvent bottle ends up being positioned with the label of the solvent bottle facing away from the user. According to various embodiments conventional screw mounts which are conventionally used to mount solvent bottles have been replaced with a resilient spring mounting mechanism which allows the solvent bottles 201 to be connected without rotation.

[0180] According to various embodiments the solvent bottles 201 may be illuminated by a LED light tile in order to indicate the fill level of the solvent bottles 201 to a user. It will be understood that a single LED illuminating a bottle will be insufficient since the fluid in a solvent bottle 201 can attenuate the light from the LED. Furthermore, there is no good single position for locating a single LED.

[0181] The mass spectrometer 100 may have a display panel 202 upon which various icons may be displayed when illuminated by the instrument control system.

[0182] A start button 203 may be positioned on or adjacent the front display panel 202. A user may press the start button 203 which will then initiate a power-up sequence or routine. The power-up sequence or routine may comprise powering-up all instrument modules and initiating instrument pump-down i.e. generating a low pressure in each of the vacuum chambers within the body of the mass spectrometer 100.

[0183] According to various embodiments the power-up sequence or routine may or may not include running a source pressure test and switching the instrument into an Operate mode of operation.

[0184] According to various embodiments a user may hold the start button 203 for a period of time, e.g. 5 seconds, in order to initiate a power-down sequence.

[0185] If the instrument is in a maintenance mode of operation then pressing the start button 203 on the front panel of the instrument may initiate a power-up sequence. Furthermore, when the instrument is in a maintenance mode of operation then holding the start button 203 on the front panel of the instrument for a period of time, e.g. 5 seconds, may initiate a power-down sequence.

[0186] FIG. 2C illustrates in greater detail various icons which may be displayed on the display panel 202 and which may illuminated under the control of instrument hardware and/or software. According to various embodiments one side of the display panel 202 (e.g. the left-hand side) may have various icons which generally relate to the status of the instrument or mass spectrometer 100. For example, icons may be displayed in the colour green to indicate that the instrument is in an initialisation mode of operation, a ready mode of operation or a running mode of operation.

[0187] In the event of a detected error which may require user interaction or user input a yellow or amber warning message may be displayed. A yellow or amber warning message or icon may be displayed on the display panel 202 and may convey only relatively general information to a user e.g. indicating that there is a potential fault and a general indication of what component or aspect of the instrument may be at fault.

[0188] According to various embodiments it may be necessary for a user to refer to an associated computer display or monitor in order to get fuller details or gain a fuller appreciation of the nature of the fault and to receive details of potential corrective action which is recommended to perform in order to correct the fault or to place the instrument in a desired operational state.

[0189] A user may be invited to confirm that a corrective action should be performed and/or a user may be informed that a certain corrective action is being performed.

[0190] In the event of a detected error which cannot be readily corrected by a user and which instead requires the services of a skilled service engineer then a warning message may be displayed indicating that a service engineer needs to be called. A warning message indicating the need for a service engineer may be displayed in the colour red and a spanner or other icon may also be displayed or illuminated to indicate to a user that an engineer is required.

[0191] The display panel 202 may also display a message that the power button 203 should be pressed in order to turn the instrument OFF.

[0192] According to an embodiment one side of the display panel 202 (e.g. the right-hand side) may have various icons which indicate different components or modules of the instrument where an error or fault has been detected. For example, a yellow or amber icon may be displayed or illuminated in order to indicate an error or fault with the ion source, a fault in the inlet cone region, a fault with the fluidic systems, an electronics fault, a fault with one or more of the solvent or other bottles 201 (i.e. indicating that one or more solvent bottles 201 needing to be refilled or emptied), a vacuum pressure fault associated with one or more of the vacuum chambers, an instrument setup error, a communication error, a problem with a gas supply or a problem with an exhaust.

[0193] It will be understood that the display panel 202 may merely indicate the general status of the instrument and/or the general nature of a fault. In order to be able to resolve the fault or to understand the exact nature of an error or fault a user may need to refer to the display screen of an associated computer or other device. For example, as will be understood by those skilled in the art an associated computer or other device may be arranged to receive and process mass spectral and other data output from the instrument or mass spectrometer 100 and may display mass spectral data or images on a computer display screen for the benefit of a user.

[0194] According to various embodiments the status display may indicate whether the instrument is in one of the following states namely Running, Ready, Getting Ready, Ready Blocked or Error.

[0195] The status display may display health check indicators such as Service Required, Cone, Source, Set-up, Vacuum, Communications, Fluidics, Gas, Exhaust, Electronics, Lock-mass, Calibrant and Wash.

[0196] A “Hold power button for OFF” LED tile is shown in FIG. 2C and may remain illuminated when the power button 203 is pressed and may remain illuminated until the power button 203 is released or until a period of time (e.g. 5 seconds) has elapsed whichever is sooner. If the power button 203 is released before the set period of time (e.g. less than 5 seconds after it is pressed) then the “Hold power button for OFF” LED tile may fade out over a time period of e.g. 2 s.

[0197] The initialising LED tile may be illuminated when the instrument is started via the power button 203 and may remain ON until software assumes control of the status panel or until a power-up sequence or routine times out.

[0198] According to various embodiments an instrument health check may be performed and printer style error correction instructions may be provided to a user via a display screen of a computer monitor (which may be separate to the front display panel 202) in order to help guide a user through any steps that the user may need to perform.

[0199] The instrument may attempt to self-diagnose any error messages or warning status alert(s) and may attempt to rectify any problem(s) either with or without notifying the user.

[0200] Depending upon the severity of any problem the instrument control system may either attempt to correct the problem(s) itself, request the user to carry out some form of intervention in order to attempt to correct the issue or problem(s) or may inform the user that the instrument requires a service engineer.

[0201] In the event where corrective action may be taken by a user then the instrument may display instructions for the user to follow and may provide details of methods or steps that should be performed which may allow the user to fix or otherwise resolve the problem or error. A resolve button may be provided on a display screen which may be pressed by a user having followed the suggested resolution instructions. The instrument may then run a test again and/or may check if the issue has indeed been corrected. For example, if a user were to trigger an interlock then once the interlock is closed a pressure test routine may be initialised as detailed below.

[0202] FIG. 3 shows a high level schematic of the mass spectrometer 100 according to various embodiments wherein the instrument may comprise an ion source 300, such as an Electrospray Ionisation (“ESI”) ion source. However, it should be understood that the use of an Electrospray Ionisation ion source 300 is not essential and that according to other embodiments a different type of ion source may be used. For example, according to various embodiments a Desorption Electrospray Ionisation (“DESI”) ion source may be used. According to yet further embodiments a Rapid Evaporative Ionisation Mass Spectrometry (“REIMS”) ion source may be used.

[0203] If an Electrospray ion source 300 is provided then the ion source 300 may comprise an Electrospray probe and associated power supply.

[0204] The initial stage of the associated mass spectrometer 100 comprises an ion block 802 (as shown in FIG. 6C) and a source enclosure may be provided if an Electrospray Ionisation ion source 300 is provided.

[0205] If a Desorption Electrospray Ionisation (“DESI”) ion source is provided then the ion source may comprise a DESI source, a DESI sprayer and an associated DESI power supply. The initial stage of the associated mass spectrometer may comprise an ion block 802 as shown in more detail in FIG. 6C. However, according to various embodiments if a DESI source is provided then the ion block 802 may not enclosed by a source enclosure.

[0206] It will be understood that a REIMS source involves the transfer of analyte, smoke, fumes, liquid, gas, surgical smoke, aerosol or vapour produced from a sample which may comprise a tissue sample. In some embodiments, the REIMS source may be arranged and adapted to aspirate the analyte, smoke, fumes, liquid, gas, surgical smoke, aerosol or vapour in a substantially pulsed manner. The REIMS source may be arranged and adapted to aspirate the analyte, smoke, fumes, liquid, gas, surgical smoke, aerosol or vapour substantially only when an electrosurgical cutting applied voltage or potential is supplied to one or more electrodes, one or more electrosurgical tips or one or more laser or other cutting devices.

[0207] The mass spectrometer 100 may be arranged so as to be capable of obtaining ion images of a sample. For example, according to various embodiments mass spectral and/or other physico-chemical data may be obtained as a function of position across a portion of a sample. Accordingly, a determination can be made as to how the nature of the sample may vary as a function of position along, across or within the sample.

[0208] The mass spectrometer 100 may comprise a first ion guide 301 such as a conjoined ring ion guide 301 having a plurality of ring and conjoined ring electrodes. The mass spectrometer 100 may further comprise a segmented quadrupole rod set ion guide 302, one or more transfer lenses 303 and a Time of Flight mass analyser 304. The quadrupole rod set ion guide 302 may be operated in an ion guiding mode of operation and/or in a mass filtering mode of operation. The Time of Flight mass analyser 304 may comprise a linear acceleration Time of Flight region or an orthogonal acceleration Time of Flight mass analyser.

[0209] If the Time of Flight mass analyser comprises an orthogonal acceleration Time of Flight mass analyser 304 then the mass analyser 304 may comprise a pusher electrode 305, a reflectron 306 and an ion detector 307. The ion detector 307 may be arranged to detect ions which have been reflected by the reflectron 306. It should be understood, however, that the provision of a reflectron 306 though desirable is not essential.

[0210] According to various embodiments the first ion guide 301 may be provided downstream of an atmospheric pressure interface. The atmospheric pressure interface may comprises an ion inlet assembly.

[0211] The first ion guide 301 may be located in a first vacuum chamber or first differential pumping region.

[0212] The first ion guide 301 may comprise a part ring, part conjoined ring ion guide assembly wherein ions may be transferred in a generally radial direction from a first ion path formed within a first plurality of ring or conjoined ring electrodes into a second ion path formed by a second plurality of ring or conjoined ring electrodes. The first and second plurality of ring electrodes may be conjoined along at least a portion of their length. Ions may be radially confined within the first and second plurality of ring electrodes.

[0213] The second ion path may be aligned with a differential pumping aperture which may lead into a second vacuum chamber or second differential pumping region.

[0214] The first ion guide 301 may be utilised to separate charged analyte ions from unwanted neutral particles. The unwanted neutral particles may be arranged to flow towards an exhaust port whereas analyte ions are directed on to a different flow path and are arranged to be optimally transmitted through a differential pumping aperture into an adjacent downstream vacuum chamber.

[0215] It is also contemplated that according to various embodiments ions may in a mode of operation be fragmented within the first ion guide 301. In particular, the mass spectrometer 100 may be operated in a mode of operation wherein the gas pressure in the vacuum chamber housing the first ion guide 301 is maintained such that when a voltage supply causes ions to be accelerated into or along the first ion guide 301 then the ions may be arranged to collide with background gas in the vacuum chamber and to fragment to form fragment, daughter or product ions. According to various embodiments a static DC voltage gradient may be maintained along at least a portion of the first ion guide 301 in order to urge ions along and through the first ion guide 301 and optionally to cause ions in a mode of operation to fragment.

[0216] However, it should be understood that it is not essential that the mass spectrometer 100 is arranged so as to be capable of performing ion fragmentation in the first ion guide 301 in a mode of operation.

[0217] The mass spectrometer 100 may comprise a second ion guide 302 downstream of the first ion guide 302 and the second ion guide 302 may be located in the second vacuum chamber or second differential pumping region.

[0218] The second ion guide 302 may comprise a segmented quadrupole rod set ion guide or mass filter 302. However, other embodiments are contemplated wherein the second ion guide 302 may comprise a quadrupole ion guide, a hexapole ion guide, an octopole ion guide, a multipole ion guide, a segmented multipole ion guide, an ion funnel ion guide, an ion tunnel ion guide (e.g. comprising a plurality of ring electrodes each having an aperture through which ions may pass or otherwise forming an ion guiding region) or a conjoined ring ion guide.

[0219] The mass spectrometer 100 may comprise one or more transfer lenses 303 located downstream of the second ion guide 302. One of more of the transfer lenses 303 may be located in a third vacuum chamber or third differential pumping region. Ions may be passed through a further differential pumping aperture into a fourth vacuum chamber or fourth differential pumping region. One or more transfer lenses 303 may also be located in the fourth vacuum chamber or fourth differential pumping region.

[0220] The mass spectrometer 100 may comprise a mass analyser 304 located downstream of the one or more transfer lenses 303 and may be located, for example, in the fourth or further vacuum chamber or fourth or further differential pumping region. The mass analyser 304 may comprise a Time of Flight (“TOF”) mass analyser. The Time of Flight mass analyser 304 may comprise a linear or an orthogonal acceleration Time of Flight mass analyser.

[0221] According to various embodiments an orthogonal acceleration Time of Flight mass analyser 304 may be provided comprising one or more orthogonal acceleration pusher electrode(s) 305 (or alternatively and/or additionally one or more puller electrode(s)) and an ion detector 307 separated by a field free drift region. The Time of Flight mass analyser 304 may optionally comprise one or more reflectrons 306 intermediate the pusher electrode 305 and the ion detector 307.

[0222] Although highly desirable, it should be recognised that the mass analyser does not have to comprise a Time of Flight mass analyser 304. More generally, the mass analyser 304 may comprise either: (i) a quadrupole mass analyser; (ii) a 2D or linear quadrupole mass analyser; (iii) a Paul or 3D quadrupole mass analyser; (iv) a Penning trap mass analyser; (v) an ion trap mass analyser; (vi) a magnetic sector mass analyser; (vii) Ion Cyclotron Resonance (“ICR”) mass analyser; (viii) a Fourier Transform Ion Cyclotron Resonance (“FTICR”) mass analyser; (ix) an electrostatic mass analyser arranged to generate an electrostatic field having a quadro-logarithmic potential distribution; (x) a Fourier Transform electrostatic mass analyser; (xi) a Fourier Transform mass analyser; (xii) a Time of Flight mass analyser; (xiii) an orthogonal acceleration Time of Flight mass analyser; or (xiv) a linear acceleration Time of Flight mass analyser.

[0223] Although not shown in FIG. 3, the mass spectrometer 100 may also comprise one or more optional further devices or stages. For example, according to various embodiments the mass spectrometer 100 may additionally comprise one or more ion mobility separation devices and/or one or more Field Asymmetric Ion Mobility Spectrometer (“FAIMS”) devices and/or one or more devices for separating ions temporally and/or spatially according to one or more physico-chemical properties. For example, the mass spectrometer 100 according to various embodiments may comprise one or more separation stages for temporally or otherwise separating ions according to their mass, collision cross section, conformation, ion mobility, differential ion mobility or another physico-chemical parameter.

[0224] The mass spectrometer 100 may comprise one or more discrete ion traps or one or more ion trapping regions. However, as will be described in more detail below, an axial trapping voltage may be applied to one or more sections or one or more electrodes of either the first ion guide 301 and/or the second ion guide 302 in order to confine ions axially for a short period of time. For example, ions may be trapped or confined axially for a period of time and then released. The ions may be released in a synchronised manner with a downstream ion optical component. For example, in order to enhance the duty cycle of analyte ions of interest, an axial trapping voltage may be applied to the last electrode or stage of the second ion guide 302. The axial trapping voltage may then be removed and the application of a voltage pulse to the pusher electrode 305 of the Time of Flight mass analyser 304 may be synchronised with the pulsed release of ions so as to increase the duty cycle of analyte ions of interest which are then subsequently mass analysed by the mass analyser 304. This approach may be referred to as an Enhanced Duty Cycle (“EDC”) mode of operation.

[0225] Furthermore, the mass spectrometer 100 may comprise one or more collision, fragmentation or reaction cells selected from the group consisting of: (i) a Collisional Induced Dissociation (“CID”) fragmentation device; (ii) a Surface Induced Dissociation (“SID”) fragmentation device; (iii) an Electron Transfer Dissociation (“ETD”) fragmentation device; (iv) an Electron Capture Dissociation (“ECD”) fragmentation device; (v) an Electron Collision or Impact Dissociation fragmentation device; (vi) a Photo Induced Dissociation (“PID”) fragmentation device; (vii) a Laser Induced Dissociation fragmentation device; (viii) an infrared radiation induced dissociation device; (ix) an ultraviolet radiation induced dissociation device; (x) a nozzle-skimmer interface fragmentation device; (xi) an in-source fragmentation device; (xii) an in-source Collision Induced Dissociation fragmentation device; (xiii) a thermal or temperature source fragmentation device; (xiv) an electric field induced fragmentation device; (xv) a magnetic field induced fragmentation device; (xvi) an enzyme digestion or enzyme degradation fragmentation device; (xvii) an ion-ion reaction fragmentation device; (xviii) an ion-molecule reaction fragmentation device; (xix) an ion-atom reaction fragmentation device; (xx) an ion-metastable ion reaction fragmentation device; (xxi) an ion-metastable molecule reaction fragmentation device; (xxii) an ion-metastable atom reaction fragmentation device; (xxiii) an ion-ion reaction device for reacting ions to form adduct or product ions; (xxiv) an ion-molecule reaction device for reacting ions to form adduct or product ions; (xxv) an ion-atom reaction device for reacting ions to form adduct or product ions; (xxvi) an ion-metastable ion reaction device for reacting ions to form adduct or product ions; (xxvii) an ion-metastable molecule reaction device for reacting ions to form adduct or product ions; (xxviii) an ion-metastable atom reaction device for reacting ions to form adduct or product ions; and (xxix) an Electron Ionisation Dissociation (“EID”) fragmentation device.

[0226] The mass spectrometer 100 may comprise one or more mass filters selected from the group consisting of: (i) a quadrupole mass filter; (ii) a 2D or linear quadrupole ion trap; (iii) a Paul or 3D quadrupole ion trap; (iv) a Penning ion trap; (v) an ion trap; (vi) a magnetic sector mass filter; (vii) a Time of Flight mass filter; and (viii) a Wien filter.

[0227] The fourth or further vacuum chamber or fourth or further differential pumping region may be maintained at a lower pressure than the third vacuum chamber or third differential pumping region. The third vacuum chamber or third differential pumping region may be maintained at a lower pressure than the second vacuum chamber or second differential pumping region and the second vacuum chamber or second differential pumping region may be maintained at a lower pressure than the first vacuum chamber or first differential pumping region. The first vacuum chamber or first differential pumping region may be maintained at lower pressure than ambient. Ambient pressure may be considered to be approx. 1013 mbar at sea level.

[0228] The mass spectrometer 100 may comprise an ion source configured to generate analyte ions. In various particular embodiments, the ion source may comprise an Atmospheric Pressure Ionisation (“API”) ion source such as an Electrospray Ionisation (“ESI”) ion source or an Atmospheric Pressure Chemical Ionisation (“APCI”) ion source.

[0229] FIG. 4 shows in general form a known Atmospheric Pressure Ionisation (“API”) ion source such as an Electrospray Ionisation (“ESI”) ion source or an Atmospheric Pressure Chemical Ionisation (“APCI”) ion source. The ion source may comprise, for example, an Electrospray Ionisation probe 401 which may comprise an inner capillary tube 402 through which an analyte liquid may be supplied. The analyte liquid may comprise mobile phase from a LC column or an infusion pump. The analyte liquid enters via the inner capillary tube 402 or probe and is pneumatically converted to an electrostatically charged aerosol spray. Solvent is evaporated from the spray by means of heated desolvation gas. Desolvation gas may be provided through an annulus which surrounds both the inner capillary tube 402 and an intermediate surrounding nebuliser tube 403 through which a nebuliser gas emerges. The desolvation gas may be heated by an annular electrical desolvation heater 404. The resulting analyte and solvent ions are then directed towards a sample or sampling cone aperture mounted into an ion block 405 forming an initial stage of the mass spectrometer 100.

[0230] The inner capillary tube 402 is preferably surrounded by a nebuliser tube 403. The emitting end of the inner capillary tube 402 may protrude beyond the nebuliser tube 403. The inner capillary tube 402 and the nebuliser tube 403 may be surrounded by a desolvation heater arrangement 404 as shown in FIG. 4 wherein the desolvation heater 404 may be arranged to heat a desolvation gas. The desolvation heater 404 may be arranged to heat a desolvation gas from ambient temperature up to a temperature of around 600° C. According to various embodiments the desolvation heater 404 is always OFF when the API gas is OFF.

[0231] The desolvation gas and the nebuliser gas may comprise nitrogen, air or another gas or mixture of gases. The same gas (e.g. nitrogen, air or another gas or mixture of gases) may be used as both a desolvation gas, nebuliser gas and cone gas. The function of the cone gas will be described in more detail below.

[0232] The inner probe capillary 402 may be readily replaced by an unskilled user without needing to use any tools. The Electrospray probe 402 may support LC flow rates in the range of 0.3 to 1.0 mL/min.

[0233] According to various embodiments an optical detector may be used in series with the mass spectrometer 100. It will be understood that an optical detector may have a maximum pressure capability of approx. 1000 psi. Accordingly, the Electrospray Ionisation probe 401 may be arranged so as not to cause a back pressure of greater than around 500 psi, allowing for back pressure caused by other system components. The instrument may be arranged so that a flow of 50:50 methanol/water at 1.0 mL/min does not create a backpressure greater than 500 psi.

[0234] According to various embodiments a nebuliser flow rate of between 106 to 159 L/hour may be utilised.

[0235] The ESI probe 401 may be powered by a power supply which may have an operating range of 0.3 to 1.5 kV.

[0236] It should, however, be understood that various other different types of ion source may instead be coupled to the mass spectrometer 100. For example, according to various embodiments, the ion source may more generally comprise either: (i) an Electrospray ionisation (“ESI”) ion source; (ii) an Atmospheric Pressure Photo Ionisation (“APPI”) ion source; (iii) an Atmospheric Pressure Chemical Ionisation (“APCI”) ion source; (iv) a Matrix Assisted Laser Desorption Ionisation (“MALDI”) ion source; (v) a Laser Desorption Ionisation (“LDI”) ion source; (vi) an Atmospheric Pressure Ionisation (“API”) ion source; (vii) a Desorption Ionisation on Silicon (“DIOS”) ion source; (viii) an Electron Impact (“EI”) ion source; (ix) a Chemical Ionisation (“CI”) ion source; (x) a Field Ionisation (“FI”) ion source; (xi) a Field Desorption (“FD”) ion source; (xii) an Inductively Coupled Plasma (“ICP”) ion source; (xiii) a Fast Atom Bombardment (“FAB”) ion source; (xiv) a Liquid Secondary Ion Mass Spectrometry (“LSIMS”) ion source; (xv) a Desorption Electrospray Ionisation (“DESI”) ion source; (xvi) a Nickel-63 radioactive ion source; (xvii) an Atmospheric Pressure Matrix Assisted Laser Desorption Ionisation ion source; (xviii) a Thermospray ion source; (xix) an Atmospheric Sampling Glow Discharge Ionisation (“ASGDI”) ion source; (xx) a Glow Discharge (“GD”) ion source; (xxi) an Impactor ion source; (xxii) a Direct Analysis in Real Time (“DART”) ion source; (xxiii) a Laserspray Ionisation (“LSI”) ion source; (xxiv) a Sonicspray Ionisation (“SSI”) ion source; (xxv) a Matrix Assisted Inlet Ionisation (“MAII”) ion source; (xxvi) a Solvent Assisted Inlet Ionisation (“SAII”) ion source; (xxvii) a Desorption Electrospray Ionisation (“DESI”) ion source; (xxviii) a Laser Ablation Electrospray Ionisation (“LAESI”) ion source; (xxix) a Surface Assisted Laser Desorption Ionisation (“SALDI”) ion source; or (xxx) a Low Temperature Plasma (“LTP”) ion source.

[0237] A chromatography or other separation device may be provided upstream of the ion source 300 and may be coupled so as to provide an effluent to the ion source 300. The chromatography separation device may comprise a liquid chromatography or gas chromatography device. Alternatively, the separation device may comprise: (i) a Capillary Electrophoresis (“CE”) separation device; (ii) a Capillary Electrochromatography (“CEC”) separation device; (iii) a substantially rigid ceramic-based multilayer microfluidic substrate (“ceramic tile”) separation device; or (iv) a supercritical fluid chromatography separation device. The mass spectrometer 100 may comprise an atmospheric pressure interface or ion inlet assembly downstream of the ion source 300. According to various embodiments the atmospheric pressure interface may comprise a sample or sampling cone 406,407 which is located downstream of the ion source 401. Analyte ions generated by the ion source 401 may pass via the sample or sampling cone 406,407 into or onwards towards a first vacuum chamber or first differential pumping region of the mass spectrometer 100. However, according to other embodiments the atmospheric pressure interface may comprise a capillary interface.

[0238] As shown in FIG. 4, ions generated by the ion source 401 may be directed towards an atmospheric pressure interface which may comprise an outer gas cone 406 and an inner sample cone 407. A cone gas may be supplied to an annular region between the inner sample cone 407 and the outer gas cone 406. The cone gas may emerge from the annulus in a direction which is generally opposed to the direction of ion travel into the mass spectrometer 100. The cone gas may act as a declustering gas which effectively pushes away large contaminants thereby preventing large contaminants from impacting upon the outer cone 406 and/or inner cone 407 and also preventing the large contaminants from entering into the initial vacuum stage of the mass spectrometer 100.

[0239] FIG. 5 shows in more detail a first known ion inlet assembly which is similar to an ion inlet assembly according to various embodiments. The known ion inlet assembly as shown and described below with reference to FIGS. 5 and 6A is presented in order to highlight various aspects of an ion inlet assembly according to various embodiments and also so that differences between an ion inlet assembly according to various embodiments as shown and discussed below with reference to FIG. 6C can be fully appreciated.

[0240] With reference to FIG. 5, it will be understood that the ion source (not shown) generates analyte ions which are directed towards a vacuum chamber 505 of the mass spectrometer 100.

[0241] A gas cone assembly is provided comprising an inner gas cone or sampling cone 513 having an aperture 515 and an outer gas cone 517 having an aperture 521. A disposable disc 525 is arranged beneath or downstream of the inner gas cone or sampling 513 and is held in position by a mounting element 527. The disc 525 covers an aperture 511 of the vacuum chamber 505. The disc 525 is removably held in position by the inner gas cone 513 resting upon the mounting element 527.

[0242] As will be discussed in more detail below with reference to FIG. 6C, according to various embodiments the mounting element 527 is not provided in the preferred ion inlet assembly.

[0243] The disc 525 has an aperture or sampling orifice 529 through which ions can pass.

[0244] A carrier 531 is arranged underneath or below the disc 525. The carrier 531 is arranged to cover the aperture 511 of the vacuum chamber 505. Upon removal of the disc 525, the carrier 531 may remain in place due to suction pressure.

[0245] FIG. 6A shows an exploded view of the first known ion inlet assembly. The outer gas cone 517 has a cone aperture 521 and is slidably mounted within a clamp 535. The clamp 535 allows a user to remove the outer gas cone 517 without physically having to touch the outer gas cone 517 which will get hot during use.

[0246] An inner gas cone or sampling cone 513 is shown mounted behind or below the outer gas cone 517.

[0247] The known arrangement utilises a carrier 531 which has a 1 mm diameter aperture. The ion block 802 is also shown having a calibration port 550. However, the calibration port 550 is not provided in an ion inlet assembly according to various embodiments.

[0248] FIG. 6B shows an second different known ion inlet assembly as used on a different instrument which has an isolation valve 560 which is required to hold vacuum pressure when the outer cone gas nozzle 517 and the inner nozzle 513 are removed for servicing. The inner cone 513 has a gas limiting orifice into the subsequent stages of the mass spectrometer. The inner gas cone 513 comprises a high cost, highly precisioned part which requires routine removal and cleaning. The inner gas cone 513 is not a disposable or consumable item. Prior to removing the inner sampling cone 513 the isolation valve 560 must be rotated into a closed position in order to isolate the downstream vacuum stages of the mass spectrometer from atmospheric pressure. The isolation valve 560 is therefore required in order to hold vacuum pressure whilst the inner gas sampling cone 513 is removed for cleaning.

[0249] FIG. 6C shows an exploded view of an ion inlet assembly according to various embodiments. The ion inlet assembly according to various embodiments is generally similar to the first known ion inlet assembly as shown and described above with reference to FIGS. 5 and 6A except for a few differences. One difference is that a calibration port 550 is not provided in the ion block 802 and a mounting member or mounting element 527 is not provided.

[0250] Accordingly, the ion block 802 and ion inlet assembly have been simplified. Furthermore, importantly the disc 525 may comprise a 0.25 or 0.30 mm diameter aperture disc 525 which is substantially smaller diameter than conventional arrangements.

[0251] According to various embodiments both the disc 525 and the vacuum holding member or carrier 531 may have a substantially smaller diameter aperture than conventional arrangements such as the first known arrangement as shown and described above with reference to FIGS. 5 and 6A.

[0252] For example, the first known instrument utilises a vacuum holding member or carrier 531 which has a 1 mm diameter aperture. In contrast, according to various embodiments the vacuum holding member or carrier 531 according to various embodiments may have a much smaller diameter aperture e.g. a 0.3 mm or 0.40 mm diameter aperture.

[0253] FIG. 6D shows in more detail how the ion block assembly 802 according to various embodiments may be enclosed in an atmospheric pressure source or housing. The ion block assembly 802 may be mounted to a pumping block or thermal interface 600. Ions pass through the ion block assembly 802 and then through the pumping block or thermal interface 600 into a first vacuum chamber 601 of the mass spectrometer 100. The first vacuum chamber 601 preferably houses the first ion guide 301 which as shown in FIG. 6D and which may comprise a conjoined ring ion guide 301. FIG. 6D also indicates how ion entry 603 into the mass spectrometer 100 also represents a potential leak path. A correct pressure balance is required between the diameters of the various gas flow restriction apertures in the ion inlet assembly with the configuration of the vacuum pumping system.

[0254] FIG. 6E shows the ion inlet assembly according to various embodiments and illustrates how ions pass through an outer gas cone 517 and an inner gas cone or sampling cone 513 before passing through an apertured disc 525. No mounting member or mounting element is provided unlike the first known ion inlet assembly as described above.

[0255] The ions then pass through an aperture in a fixed valve 690. The fixed valve 690 is held in place by suction pressure and is not removable by a user in normal operation. Three O-ring vacuum seals 692a,692b,692c are shown. The fixed valve 690 may be formed from stainless steel. A vacuum region 695 of the mass spectrometer 100 is generally indicated.

[0256] FIG. 6F shows the outer cone 517, inner sampling cone 513 and apertured disc 525 having been removed by a user by withdrawing or removing a clamp 535 to which at least the outer cone 517 is slidably inserted. According to various embodiments the inner sampling cone 513 may also be attached or secured to the outer cone 517 so that both are removed at the same time.

[0257] Instead of utilising a conventional rotatable isolation valve, a fixed non-rotatable valve 690 is provided or otherwise retained in the ion block 802. An O-ring seal 692a is shown which ensures that a vacuum seal is provided between the exterior body of the fixed valve 690 and the ion block 802. An ion block voltage contact 696 is also shown. O-rings seals 692b,692c for the inner and outer cones 513,517 are also shown.

[0258] FIG. 6G illustrates how according to various embodiments a fixed valve 690 may be retained within an ion block 802 and may form a gas tight sealing therewith by virtue of an O-ring seal 692a. A user is unable to remove the fixed valve 690 from the ion block 802 when the instrument is operated due to the vacuum pressure within the vacuum chamber 695 of the instrument. The direction of suction force which holds the fixed valve 690 in a fixed position against the ion block 802 during normal operation is shown.

[0259] The size of the entrance aperture into the fixed valve 690 is designed for optimum operation conditions and component reliability. Various embodiments are contemplated wherein the shape of the entrance aperture may be cylindrical. However, other embodiments are contemplated wherein there may be more than one entrance aperture and/or wherein the one or more entrance apertures to the fixed valve 690 may have a non-circular aperture. Embodiments are also contemplated wherein the one or more entrance apertures may be angled at a non-zero angle to the longitudinal axis of the fixed valve 690.

[0260] It will be understood that total removal of the fixed valve 690 from the ion block 802 will rapidly result in total loss of vacuum pressure within the mass spectrometer 100.

[0261] According to various embodiments the ion inlet assembly may be temporarily sealed in order to allow a vacuum housing within the mass spectrometer 100 to be filled with dry nitrogen for shipping. It will be appreciated that filling a vacuum chamber with dry nitrogen allows faster initial pump-down during user initial instrument installation.

[0262] It will be appreciated that since according to various embodiments the internal aperture in the vacuum holding member or carrier 531 is substantially smaller in diameter than conventional arrangements, then the vacuum within the first and subsequent vacuum chambers of the instrument can be maintained for substantially longer periods of time than is possible conventionally when the disc 525 is removed and/or replaced.

[0263] Accordingly, the mass spectrometer 100 according to various embodiments does not require an isolation valve in contrast with other known mass spectrometers in order to maintain the vacuum within the instrument when a component such as the outer gas cone 517, the inner gas cone 513 or the disc 525 are removed.

[0264] A mass spectrometer 100 according to various embodiments therefore enables a reduced cost instrument to be provided which is also simpler for a user to operate since no isolation valve is needed. Furthermore, a user does not need to be understand or learn how to operate such an isolation valve.

[0265] The ion block assembly 802 may comprise a heater in order to keep the ion block 802 above ambient temperature in order to prevent droplets of analyte, solvent, neutral particles or condensation from forming within the ion block 802.

[0266] According to an embodiment when a user wishes to replace and/or remove either the outer cone 517 and/or the inner sampling cone 513 and/or the disc 525 then both the source or ion block heater and the desolvation heater 404 may be turned OFF. The temperature of the ion block 802 may be monitored by a thermocouple which may be provided within the ion block heater or which may be otherwise provided in or adjacent to the ion block 802.

[0267] When the temperature of the ion block is determined to have dropped below a certain temperature such as e.g. 55° C. then the user may be informed that the clamp 535, outer gas cone 517, inner gas sampling cone 513 and disc 525 are sufficiently cooled down such that a user can touch them without serious risk of injury.

[0268] According to various embodiment a user can simply remove and/or replace the outer gas cone 517 and/or inner gas sampling cone 513 and/or disc 525 in less than two minutes without needing to vent the instrument. In particular, the low pressure within the instrument is maintained for a sufficient period of time by the aperture in the fixed valve 690.

[0269] According to various embodiments the instrument may be arranged so that the maximum leak rate into the source or ion block 802 during sample cone maintenance is approx. 7 mbar L/s. For example, assuming a backing pump speed of 9 m.sup.3/hour (2.5 L/s) and a maximum acceptable pressure of 3 mbar, then the maximum leak rate during sampling cone maintenance may be approx. 2.5 L/s×3 mbar=7.5 mbar L/s.

[0270] The ion block 802 may comprise an ion block heater having a K-type thermistor. As will be described in more detail below, according to various embodiments the source (ion block) heater may be disabled to allow forced cooling of the source or ion block 802. For example, desolvation heater 404 and/or ion block heater may be switched OFF whilst API gas is supplied to the ion block 802 in order to cool it down. According to various embodiments either a desolvation gas flow and/or a nebuliser gas flow from the probe 401 may be directed towards the cone region 517,513 of the ion block 802. Additionally and/or alternatively, the cone gas supply may be used to cool the ion block 802 and the inner and outer cones 513,517. In particular, by turning the desolvation heater 404 OFF but maintaining a supply of nebuliser and/or desolvation gas from the probe 401 so as to fill the enclosure housing the ion block with ambient temperature nitrogen or other gas will have a rapid cooling effect upon the metal and plastic components forming the ion inlet assembly which may be touched by a user during servicing. Ambient temperature (e.g. in the range 18-25° C.) cone gas may also be supplied in order to assist with cooling the ion inlet assembly in a rapid manner. Conventional instruments do not have the functionality to induce rapid cooling of the ion block 802 and gas cones 521,513.

[0271] Liquid and gaseous exhaust from the source enclosure may be fed into a trap bottle. The drain tubing may be routed so as to avoid electronic components and wiring. The instrument may be arranged so that liquid in the source enclosure always drains out even when the instrument is switched OFF. For example, it will be understood that an LC flow into the source enclosure could be present at any time.

[0272] An exhaust check valve may be provided so that when the API gas is turned OFF the exhaust check valve prevents a vacuum from forming in the source enclosure and trap bottle. The exhaust trap bottle may have a capacity 5L.

[0273] The fluidics system may comprise a piston pump which allows the automated introduction of a set-up solution into the ion source. The piston pump may have a flow rate range of 0.4 to 50 mL/min. A divert/select valve may be provided which allows rapid automated changeover between LC flow and the flow of one or two internal set-up solutions into the source.

[0274] According to various embodiments three solvent bottles 201 may be provided. Solvent A bottle may have a capacity within the range 250-300 mL, solvent B bottle may have a capacity within the range 50-60 mL and solvent C bottle may have a capacity within the range 100-125 mL. The solvent bottles 201 may be readily observable by a user who may easily refill the solvent bottles.

[0275] According to an embodiment solvent A may comprise a lock-mass, solvent B may comprise a calibrant and solvent C may comprise a wash. Solvent C (wash) may be connected to a rinse port.

[0276] A driver PCB may be provided in order to control the piston pump and the divert/select valve. On power-up the piston pump may be homed and various purge parameters may be set.

[0277] Fluidics may be controlled by software and may be enabled as a function of the instrument state and the API gas valve state in a manner as detailed below:

TABLE-US-00001 Software control of Instrument state API gas valve fluidics Operate Open Enabled Operate Closed Disabled Over-pressure Open Enabled Over-pressure Closed Disabled Power Save Open Disabled Power Save Closed Disabled

[0278] When software control of the fluidics is disabled then the valve is set to a divert position and the pump is stopped.

[0279] FIG. 7A illustrates a vacuum pumping arrangement according to various embodiments.

[0280] A split-flow turbo molecular vacuum pump (commonly referred to as a “turbo” pump) may be used to pump the fourth or further vacuum chamber or fourth or further differential pumping region, the third vacuum chamber or third differential pumping region, and the second vacuum chamber or second differential pumping region. According to an embodiment the turbo pump may comprise either a Pfeiffer® Splitflow 310 fitted with a TC110 controller or an Edwards® nEXT300/100/100D turbo pump. The turbo pump may be air cooled by a cooling fan.

[0281] The turbo molecular vacuum pump may be backed by a rough, roughing or backing pump such as a rotary vane vacuum pump or a diaphragm vacuum pump. The rough, roughing or backing pump may also be used to pump the first vacuum chamber housing the first ion guide 301. The rough, roughing or backing pump may comprise an Edwards® nRV14i backing pump. The backing pump may be provided external to the instrument and may be connected to the first vacuum chamber which houses the first ion guide 301 via a backing line 700 as shown in FIG. 7A.

[0282] A first pressure gauge such as a cold cathode gauge 702 may be arranged and adapted to monitor the pressure of the fourth or further vacuum chamber or fourth or further differential pumping region. According to an embodiment the Time of Flight housing pressure may be monitored by an Inficon® MAG500 cold cathode gauge 702.

[0283] A second pressure gauge such as a Pirani gauge 701 may be arranged and adapted to monitor the pressure of the backing pump line 700 and hence the first vacuum chamber which is in fluid communication with the upstream pumping block 600 and ion block 802. According to an embodiment the instrument backing pressure may be monitored by an Inficon® PSG500 Pirani gauge 701.

[0284] According to various embodiments the observed leak plus outgassing rate of the Time of Flight chamber may be arranged to be less than 4×10.sup.−5 mbar L/s. Assuming a 200 L/s effective turbo pumping speed then the allowable leak plus outgassing rate is 5×10.sup.−7 mbar×200 L/s=1×10.sup.−4 mbar L/s.

[0285] A turbo pump such as an Edwards® nEXT300/100/100D turbo pump may be used which has a main port pumping speed of 400 L/s. As will be detailed in more detail below, EMC shielding measures may reduce the pumping speed by approx. 20% so that the effective pumping speed is 320 L/s. Accordingly, the ultimate vacuum according to various embodiments may be 4×10.sup.−5 mbar L/s/320 L/s=1.25×10.sup.−7 mbar.

[0286] According to an embodiment a pump-down sequence may comprise closing a soft vent solenoid as shown in FIG. 7B, starting the backing pump and waiting until the backing pressure drops to 32 mbar. If 32 mbar is not reached within 3 minutes of starting the backing pump then a vent sequence may be performed. Assuming that a pressure of 32 mbar is reached within 3 minutes then the turbo pump is then started. When the turbo speed exceeds 80% of maximum speed then the Time of Flight vacuum gauge 702 may then be switched ON. It will be understood that the vacuum gauge 702 is a sensitive detector and hence is only switched ON when the vacuum pressure is such that the vacuum gauge 702 which not be damaged.

[0287] If the turbo speed does not reach 80% of maximum speed within 8 minutes then a vent sequence may be performed.

[0288] A pump-down sequence may be deemed completed once the Time of Flight vacuum chamber pressure is determined to be <1×10.sup.−5 mbar.

[0289] If a vent sequence is to be performed then the instrument may be switched to a Standby mode of operation. The Time of Flight vacuum gauge 702 may be switched OFF and the turbo pump may also be switched OFF. When the turbo pump speed falls to less than 80% of maximum then a soft vent solenoid valve as shown in FIG. 7B may be opened. The system may then wait for 10 seconds before then switching OFF the backing pump.

[0290] It will be understood by those skilled in the art that the purpose of the turbo soft vent solenoid valve as shown in FIG. 7B and the soft vent line is to enable the turbo pump to be vented at a controlled rate. It will be understood that if the turbo pump is vented at too fast a rate then the turbo pump may be damaged.

[0291] The instrument may switch into a maintenance mode of operation which allows an engineer to perform service work on all instrument sub-systems except for the vacuum system or a subsystem incorporating the vacuum system without having to vent the instrument. The instrument may be pumped down in maintenance mode and conversely the instrument may also be vented in maintenance mode.

[0292] A vacuum system protection mechanism may be provided wherein if the turbo speed falls to less than 80% of maximum speed then a vent sequence is initiated. Similarly, if the backing pressure increases to greater than 10 mbar then a vent sequence may also be initiated. According to an embodiment if the turbo power exceeds 120 W for more than 15 minutes then a vent sequence may also be initiated. If on instrument power-up the turbo pump speed is >80% of maximum then the instrument may be set to a pumped state, otherwise the instrument may be set to a venting state.

[0293] FIG. 7B shows a schematic of a gas handling system which may be utilised according to various embodiments. A storage check valve 721 may be provided which allows the instrument to be filled with nitrogen for storage and transport. The storage check valve 721 is in fluid communication with an inline filter.

[0294] A soft vent flow restrictor may be provided which may limit the maximum gas flow to less than the capacity of a soft vent relief valve in order to prevent the analyser pressure from exceeding 0.5 bar in a single fault condition. The soft vent flow restrictor may comprise an orifice having a diameter in the range 0.70 to 0.75 mm.

[0295] A supply pressure sensor 722 may be provided which may indicate if the nitrogen pressure has fallen below 4 bar.

[0296] An API gas solenoid valve may be provided which is normally closed and which has an aperture diameter of not less than 1.4 mm.

[0297] An API gas inlet is shown which preferably comprises a Nitrogen gas inlet. According to various embodiments the nebuliser gas, desolvation gas and cone gas are all supplied from a common source of nitrogen gas.

[0298] A soft vent regulator may be provided which may function to prevent the analyser pressure exceeding 0.5 bar in normal condition.

[0299] A soft vent check valve may be provided which may allow the instrument to vent to atmosphere in the event that the nitrogen supply is OFF.

[0300] A soft vent relief valve may be provided which may have a cracking pressure of 345 mbar. The soft vent relief valve may function to prevent the pressure in the analyser from exceeding 0.5 bar in a single fault condition. The gas flow rate through the soft vent relief valve may be arranged so as not to be less than 2000 L/h at a differential pressure of 0.5 bar.

[0301] The soft vent solenoid valve may normally be in an open position. The soft vent solenoid valve may be arranged to restrict the gas flow rate in order to allow venting of the turbo pump at 100% rotational speed without causing damage to the pump. The maximum orifice diameter may be 1.0 mm.

[0302] The maximum nitrogen flow may be restricted such that in the event of a catastrophic failure of the gas handling the maximum leak rate of nitrogen into the lab should be less than 20% of the maximum safe flow rate. According to various embodiments an orifice having a diameter of 1.4 to 1.45 mm may be used.

[0303] A source pressure sensor may be provided.

[0304] A source relief valve having a cracking pressure of 345 mbar may be provided. The source relief valve may be arranged to prevent the pressure in the source from exceeding 0.5 bar in a single fault condition. The gas flow rate through the source relief valve may be arranged so as not to be less than 2000 L/h at a differential pumping pressure of 0.5 bar. A suitable valve is a Ham-Let® H-480-S-G-1/4-5 psi valve.

[0305] A cone restrictor may be provided to restrict the cone flow rate to 36 L/hour for an input pressure of 7 bar. The cone restrictor may comprise a 0.114 mm orifice.

[0306] The desolvation flow may be restricted by a desolvation flow restrictor to a flow rate of 940 L/hour for an input pressure of 7 bar. The desolvation flow restrictor may comprise a 0.58 mm orifice.

[0307] A pinch valve may be provided which has a pilot operating pressure range of at least 4 to 7 bar gauge. The pinch valve may normally be open and may have a maximum inlet operating pressure of at least 0.5 bar gauge.

[0308] When the instrument is requested to turn the API gas OFF, then control software may close the API gas valve, wait 2 seconds and then close the source exhaust valve.

[0309] In the event of an API gas failure wherein the pressure switch opens (pressure <4 bar) then software control of the API gas may be disabled and the API gas valve may be closed. The system may then wait 2 seconds before closing the exhaust valve.

[0310] In order to turn the API gas ON a source pressure monitor may be turned ON except while a source pressure test is performed. An API gas ON or OFF request from software may be stored as an API Gas Request state which can either be ON or OFF. Further details are presented below:

TABLE-US-00002 API Gas Request state API Gas Control state API gas valve ON Enabled Open ON Disabled Closed OFF Enabled Closed OFF Disabled Closed

[0311] FIG. 7C shows a flow diagram showing an instrument response to a user request to turn the API gas ON. A determination may be made as to whether or not software control of API gas is enabled. If software control is not enabled then the request may be refused. If software control of API gas is enabled then the open source exhaust valve may be opened. Then after a delay of 2 seconds the API gas valve may be opened. The pressure is then monitored. If the pressure is determined to be between 20-60 mbar then a warning message may be communicated or issued. If the pressure is greater than 60 mbar then then the API gas valve may be closed. Then after a delay of 2 seconds the source exhaust valve may be closed and a high exhaust pressure trip may occur.

[0312] A high exhaust pressure trip may be reset by running a source pressure test.

[0313] According to various embodiments the API gas valve may be closed within 100 ms of an excess pressure being sensed by the source pressure sensor.

[0314] FIG. 7D shows a flow diagram illustrating a source pressure test which may be performed according to various embodiments. The source pressure test may be commenced and software control of fluidics may be disabled so that no fluid flows into the Electrospray probe 401. Software control of the API gas may also be disabled i.e. the API is turned OFF. The pressure switch may then be checked. If the pressure is above 4 bar for more than 1 second then the API gas valve may be opened. However, if the pressure is less than 4 bar for more than 1 second then the source pressure test may move to a failed state due to low API gas pressure.

[0315] Assuming that the API gas valve is opened then the pressure may then be monitored. If the pressure is in the range 18-100 mbar then a warning message may be output indicating a possible exhaust problem. If the warning status continues for more than 30 seconds then the system may conclude that the source pressure test has failed due to the exhaust pressure being too high.

[0316] If the monitored pressure is determined to be less than 18 mbar then the source exhaust valve is closed.

[0317] The pressure may then again be monitored. If the pressure is less than 200 mbar then a warning message indicating a possible source leak may be issued.

[0318] If the pressure is determined to be greater than 200 mbar then the API gas valve may be closed and the source exhaust valve may be opened i.e. the system looks to build pressure and to test for leaks. The system may then wait 2 seconds before determining that the source pressure test is passed.

[0319] If the source pressure test has been determined to have been passed then the high pressure exhaust trip may be reset and software control of fluidics may be enabled. Software control of the API gas may then be enabled and the source pressure test may then be concluded.

[0320] According to various embodiments the API gas valve may be closed within 100 ms of an excess pressure being sensed by the source pressure sensor.

[0321] In the event of a source pressure test failure, the divert valve position may be set to divert and the valve may be kept in this position until the source pressure test is either passed or the test is over-ridden.

[0322] It is contemplated that the source pressure test may be over-ridden in certain circumstances. Accordingly, a user may be permitted to continue to use an instrument where they have assessed any potential risk as being acceptable. If the user is permitted to continue using the instrument then the source pressure test status message may still be displayed in order to show the original failure. As a result, a user may be reminded of the continuing failed status so that the user may continually re-evaluate any potential risk.

[0323] In the event that a user requests a source pressure test over-ride then the system may reset a high pressure exhaust trip and then enable software control of the divert valve. The system may then enable software control of the API gas before determining that the source pressure test over-ride is complete.

[0324] The pressure reading used in the source pressure test and source pressure monitoring may include a zero offset correction.

[0325] The gas and fluidics control responsibility may be summarised as detailed below:

TABLE-US-00003 Mode of operation Software Electronics Operate Gas and fluidics None Power save Gas Fluidics Standby Gas Fluidics SPT/Failure None Gas and fluidics Vacuum loss None Gas and fluidics Gas fail state None Gas and fluidics Operate gas OFF Gas Fluidics

[0326] A pressure test may be initiated if a user triggers an interlock.

[0327] The instrument may operate in various different modes of operation. If the turbo pump speed falls to less than 80% of maximum speed whilst in Operate, Over-pressure or Power save mode then the instrument may enter a Standby state or mode of operation.

[0328] If the pressure in the Time of Flight vacuum chamber is greater than 1×10.sup.−5 mbar and/or the turbo speed is less than 80% of maximum speed then the instrument may be prevented from operating in an Operate mode of operation.

[0329] According to various embodiments the instrument may be operated in a Power save mode. In a Power save mode of operation the piston pump may be stopped. If the instrument is switched into a Power save mode while the divert valve is in the LC position, then the divert valve may change to a divert position. A Power save mode of operation may be considered as being a default mode of operation wherein all back voltages are kept ON, front voltages are turned OFF and gas is OFF.

[0330] If the instrument switches from a Power save mode of operation to an Operate mode of operation then the piston pump divert valves may be returned to their previous states i.e. their states immediately before a Power save mode of operation was entered.

[0331] If the Time of Flight region pressure rises above 1.5×10.sup.−5 mbar while the instrument is in an Operate mode of operation then the instrument may enter an Over-pressure mode of operation or state.

[0332] If the Time of Flight pressure enters the range 1×10.sup.−8 to 1×10.sup.−5 mbar while the instrument is in an Over-pressure mode of operation then the instrument may enter an Operate mode of operation.

[0333] If the API gas pressure falls below its trip level while the instrument is in an Operate mode of operation then the instrument may enter a Gas Fail state or mode of operation. The instrument may remain in a Gas Fail state until both: (i) the API gas pressure is above its trip level; and (ii) the instrument is operated in either Standby or Power save mode.

[0334] According to an embodiment the instrument may transition from an Operate mode of operation to an Operate with Source Interlock Open mode of operation when the source cover is opened. Similarly, the instrument may transition from an Operate with Source Interlock Open mode of operation to an Operate mode of operation when the source cover is closed.

[0335] According to an embodiment the instrument may transition from an Over-pressure mode of operation to an Over-pressure with Source Interlock Open mode of operation when the source cover is opened. Similarly, the instrument may transition from an Over-pressure with Source Interlock Open mode of operation to an Over-pressure mode of operation when the source cover is closed.

[0336] The instrument may operate in a number of different modes of operation which may be summarised as follows:

TABLE-US-00004 API gas Mode of Analyser Front end Desolvation Source control operation voltages voltages heater heater state Standby OFF OFF OFF ON Enabled Operate ON ON ON ON Enabled Power Save ON OFF OFF ON Enabled Over- OFF ON ON ON Enabled pressure Gas Fail ON OFF OFF ON Disabled Operate ON OFF OFF OFF Disabled with Source Interlock Over- OFF OFF OFF OFF Disabled pressure with Source interlock Not OFF OFF OFF OFF Enabled Pumped

[0337] Reference to front end voltages relates to voltages which are applied to the Electrospray capillary electrode 402, the source offset, the source or first ion guide 301, aperture #1 (see FIG. 15A) and the quadrupole ion guide 302.

[0338] Reference to analyser voltages relates to all high voltages except the front end voltages.

[0339] Reference to API gas refers to desolvation, cone and nebuliser gases.

[0340] Reference to Not Pumped refers to all vacuum states except pumped.

[0341] If any high voltage power supply loses communication with the overall system or a global circuitry control module then the high voltage power supply may be arranged to switch OFF its high voltages. The global circuitry control module may be arranged to detect the loss of communication of any subsystem such as a power supply unit (“PSU”), a pump or gauge etc.

[0342] According to various embodiments the system will not indicate its state or mode of operation as being Standby if the system is unable to verify that all subsystems are in a Standby state.

[0343] As is apparent from the above table, when the instrument is operated in an Operate mode of operation then all voltages are switched ON. When the instrument transitions to operate in an Operate mode of operation then the following voltages are ON namely transfer lens voltages, ion guide voltages, voltages applied to the first ion guide 301 and the capillary electrode 402. In addition, the desolvation gas and desolvation heater are all ON.

[0344] If a serious fault were to develop then the instrument may switch to a Standby mode of operation wherein all voltages apart from the source heater provided in the ion block 802 are turned OFF and only a service engineer can resolve the fault. It will be understood that the instrument may only be put into a Standby mode of operation wherein voltages apart from the source heater in the ion block 802 are turned OFF only if a serious fault occurs or if a service engineer specifies that the instrument should be put into a Standby mode operation. A user or customer may (or may not) be able to place an instrument into a Standby mode of operation. Accordingly, in a Standby mode of operation all voltages are OFF and the desolvation gas flow and desolvation heater 404 are all OFF. Only the source heater in the ion block 802 may be left ON.

[0345] The instrument may be kept in a Power Save mode by default and may be switched so as to operate in an Operate mode of operation wherein all the relevant voltages and gas flows are turned ON. This approach significantly reduces the time taken for the instrument to be put into a useable state. When the instrument transitions to a Power Save mode of operation then the following voltages are ON—pusher electrode 305, reflectron 306, ion detector 307 and more generally the various Time of Flight mass analyser 304 voltages.

[0346] The stability of the power supplies for the Time of Flight mass analyser 304, ion detector 307 and reflectron 306 can affect the mass accuracy of the instrument. The settling time when turning ON or switching polarity on a known conventional instrument is around 20 minutes.

[0347] It has been established that if the power supplies are cold or have been left OFF for a prolonged period of time then they may require up to 10 hours to warm up and stabilise. For this reason customers may be prevented from going into a Standby mode of operation which would switch OFF the voltages to the Time of Flight analyser 304 including the reflectron 306 and ion detector 307 power supplies.

[0348] On start-up the instrument may move to a Power save mode of operation as quickly as possible as this allows the power supplies the time they need to warm up whilst the instrument is pumping down. As a result, by the time the instrument has reached the required pressure to carry out instrument setup the power supplies will have stabilised thus reducing any concerns relating to mass accuracy.

[0349] According to various embodiments in the event of a vacuum failure in the vacuum chamber housing the Time of Flight mass analyser 304 then power may be shut down or turned OFF to all the peripherals or sub-modules e.g. the ion source 300, first ion guide 301, the segmented quadrupole rod set ion guide 302, the transfer optics 303, the pusher electrode 305 high voltage supply, the reflectron 306 high voltage supply and the ion detector 307 high voltage supply. The voltages are primarily all turned OFF for reasons of instrument protection and in particular protecting sensitive components of the Time of Flight mass analyser 307 from high voltage discharge damage.

[0350] It will be understood that high voltages may be applied to closely spaced electrodes in the Time of Flight mass analyser 304 on the assumption that the operating pressure will be very low and hence there will be no risk of sparking or electrical discharge effects. Accordingly, in the event of a serious vacuum failure in the vacuum chamber housing the Time of Flight mass analyser 304 then the instrument may remove power or switch power OFF to the following modules or sub-modules: (i) the ion source high voltage supply module; (ii) the first ion guide 301 voltage supply module; (iii) the quadrupole ion guide 302 voltage supply module; (iv) the high voltage pusher electrode 305 supply module; (v) the high voltage reflectron 306 voltage supply module; and (vi) the high voltage detector 307 module. The instrument protection mode of operation is different to a Standby mode of operation wherein electrical power is still supplied to various power supplies or modules or sub-modules. In contrast, in an instrument protection mode of operation power is removed to the various power supply modules by the action of a global circuitry control module. Accordingly, if one of the power supply modules were faulty it would still be unable in a fault condition to turn voltages ON because the module would be denied power by the global circuitry control module.

[0351] FIG. 8 shows a view of a mass spectrometer 100 according to various embodiments in more detail. The mass spectrometer 100 may comprise a first vacuum PCB interface 801a having a first connector 817a for directly connecting the first vacuum interface PCB 801a to a first local control circuitry module (not shown) and a second vacuum PCB interface 801b having a second connector 817b for directly connecting the second vacuum interface PCB 801b to a second local control circuitry module (not shown).

[0352] The mass spectrometer 100 may further comprise a pumping or ion block 802 which is mounted to a pumping block or thermal isolation stage (not viewable in FIG. 8). According to various embodiments one or more dowels or projections 802a may be provided which enable a source enclosure (not shown) to connect to and secure over and house the ion block 802. The source enclosure may serve the purpose of preventing a user from inadvertently coming into contact with any high voltages associated with the Electrospray probe 402. A micro-switch or other form of interlock may be used to detect opening of the source enclosure by a user in order to gain source access whereupon high voltages to the ion source 402 may then be turned OFF for user safety reasons.

[0353] Ions are transmitted via an initial or first ion guide 301, which may comprise a conjoined ring ion guide, and then via a segmented quadrupole rod set ion guide 302 to a transfer lens or transfer optics arrangement 303. The transfer optics 303 may be designed in order to provide a highly efficient ion guide and interface into the Time of Flight mass analyser 304 whilst also reducing manufacturing costs.

[0354] Ions may be transmitted via the transfer optics 303 so that the ions arrive in a pusher electrode assembly 305. The pusher electrode assembly 305 may also be designed so as to provide high performance whilst at the same time reducing manufacturing costs.

[0355] According to various embodiments a cantilevered Time of Flight stack 807 may be provided. The cantilevered arrangement may be used to mount a Time of Flight stack or flight tube 807 and has the advantage of both thermally and electrically isolating the Time of Flight stack or flight tube 807. The cantilevered arrangement represents a significant design departure from conventional instruments and results in substantial improvements in instrument performance.

[0356] According to an embodiment an alumina ceramic spacer and a plastic (PEEK) dowel may be used.

[0357] According to an embodiment when a lock mass is introduced and the instrument is calibrated then the Time of Flight stack or flight tube 807 will not be subjected to thermal expansion. The cantilevered arrangement according to various embodiments is in contrast to known arrangements wherein both the reflectron 306 and the pusher assembly 305 were mounted to both ends of a side flange. As a result conventional arrangements were subjected to thermal impact.

[0358] Ions may be arranged to pass into a flight tube 807 and may be reflected by a reflectron 306 towards an ion detector 811. The output from the ion detector 811 is passed to a pre-amplifier (not shown) and then to an Analogue to Digital Converter (“ADC”) (also not shown). The reflectron 306 is preferably designed so as to provide high performance whilst also reducing manufacturing cost and improviding reliability.

[0359] As shown in FIG. 8 the various electrode rings and spacers which collectively form the reflectron subassembly may be mounted to a plurality of PEEK support rods 814. The reflectron subassembly may then be clamped to the flight tube 807 using one or more cotter pins 813. As a result, the components of the reflectron subassembly are held under compression which enables the individual electrodes forming the reflectron to be maintained parallel to each other with a high level of precision. According to various embodiments the components may be held under spring loaded compression.

[0360] The pusher electrode assembly 305 and the detector electronics or a discrete detector module may be mounted to a common pusher plate assembly 1012. This is described in more detail below with reference to FIGS. 10A-10C.

[0361] The Time of Flight mass analyser 304 may have a full length cover 809 which may be readily removed enabling extensive service access. The full length cover 809 may be held in place by a plurality of screws e.g. 5 screws. A service engineer may undo the five screws in order to expose the full length of the time of flight tube 807 and the reflectron 306.

[0362] The mass analyser 304 may further comprise a removable lid 810 for quick service access. In particular, the removable lid 810 may provide access to a service engineer so that the service engineer can replace an entrance plate 1000 as shown in FIG. 100. In particular, the entrance plate 1000 may become contaminated due to ions impacting upon the surface of the entrance plate 1000 resulting in surface charging effects and potentially reducing the efficiency of ion transfer from the transfer optics 303 into a pusher region adjacent the pusher electrode 305.

[0363] A SMA (SubMiniature version A) connector or housing 850 is shown but an AC coupler 851 is obscured from view.

[0364] FIG. 9 shows a pusher plate assembly 912, flight tube 907 and reflectron stack 908. A pusher assembly 905 having a pusher shielding cover is also shown. The flight tube 907 may comprise an extruded or plastic flight tube. The reflectron 306 may utilise fewer ceramic components than conventional reflectron assemblies thereby reducing manufacturing cost. According to various embodiments the reflectron 306 may make greater use of PEEK compared with conventional reflectron arrangements.

[0365] A SMA (SubMiniature version A) connector or housing 850 is shown but an AC coupler 851 is obscured from view.

[0366] According to other embodiments the reflectron 306 may comprise a bonded reflectron. According to another embodiment the reflectron 306 may comprise a metalised ceramic arrangement. According to another embodiment the reflectron 306 may comprise a jigged then bonded arrangement.

[0367] According to alternative embodiments instead of stacking, mounting and fixing multiple electrodes or rings, a single bulk piece of an insulating material such as a ceramic may be provided. Conductive metalised regions on the surface may then be provided with electrical connections to these regions so as to define desired electric fields. For example, the inner surface of a single piece of cylindrical shaped ceramic may have multiple parallel metalised conductive rings deposited as an alternative method of providing potential surfaces as a result of stacking multiple individual rings as is known conventionally. The bulk ceramic material provides insulation between the different potentials applied to different surface regions. The alternative arrangement reduces the number of components thereby simplifying the overall design, improving tolerance build up and reducing manufacturing cost. Furthermore, it is contemplated that multiple devices may be constructed this way and may be combined with or without grids or lenses placed in between. For example, according to one embodiment a first grid electrode may be provided, followed by a first ceramic cylindrical element, followed by a second grid electrode followed by a second ceramic cylindrical element.

[0368] FIG. 10A shows a pusher plate assembly 1012 comprising three parts according to various embodiments. According to an alternative embodiment a monolithic support plate 1012a may be provided as shown in FIG. 10B. The monolithic support plate 1012a may be made by extrusion. The support plate 1012a may comprise a horse shoe shaped bracket having a plurality (e.g. four) fixing points 1013. According to an embodiment four screws may be used to connect the horse shoe shaped bracket to the housing of the mass spectrometer and enable a cantilevered arrangement to be provided. The bracket may be maintained at a voltage which may be the same as the Time of Flight voltage i.e. 4.5 kV. By way of contrast, the mass spectrometer housing may be maintained at ground voltage i.e. 0V.

[0369] FIG. 100 shows a pusher plate assembly 1012 having mounted thereon a pusher electrode assembly and an ion detector assembly 1011. An entrance plate 1000 having an ion entrance slit or aperture is shown.

[0370] The pusher electrode may comprise a double grid electrode arrangement having a 2.9 mm field free region between a second and third grid electrode as shown in more detail in FIG. 16C.

[0371] FIG. 11 shows a flow diagram illustrating various processes which may occur once a start button has been pressed.

[0372] According to an embodiment when the backing pump is turned ON a check may be made that the pressure is <32 mbar within three minutes of operation. If a pressure of <32 mbar is not achieved or established within three minutes of operation then a rough pumping timeout (amber) warning may be issued.

[0373] FIG. 12A shows the three different pumping ports of the turbo molecular pump according to various embodiments. The first pumping port H1 may be arranged adjacent the segmented quadrupole rod set 302. The second pumping port H2 may be arranged adjacent a first lens set of the transfer lens arrangement 303. The third pumping port (which may be referred to either as the H port or the H3 port) may be directly connected to Time of Flight mass analyser 304 vacuum chamber.

[0374] FIG. 12B shows from a different perspective the first pumping port H1 and the second pumping port H2. The user clamp 535 which is mounted in use to the ion block 802 is shown. The first ion guide 301 and the quadrupole rod set ion guide 302 are also indicated. A nebuliser or cone gas input 1201 is also shown. An access port 1251 is provided for measuring pressure in the source. A direct pressure sensor is provided (not fully shown) for measuring the pressure in the vacuum chamber housing the initial ion guide 301 and which is in fluid communication with the internal volume of the ion block 802. An elbow fitting 1250 and an over pressure relief valve 1202 are also shown.

[0375] One or more part-rigid and part-flexible printed circuit boards (“PCBs”) may be provided. According to an embodiment a printed circuit board may be provided which comprises a rigid portion 1203a which is located at the exit of the quadrupole rod set region 302 and which is optionally at least partly arranged perpendicular to the optic axis or direction of ion travel through the quadrupole rod set 302. An upper or other portion of the printed circuit board may comprise a flexible portion 1203b so that the flexible portion 1203b of the printed circuit board has a stepped shape in side profile as shown in FIG. 12B.

[0376] According to various embodiments the H1 and H2 pumping ports may comprise EMC splinter shields.

[0377] It is also contemplated that the turbo pump may comprise dynamic EMC sealing of the H or H3 port. In particular, an EMC mesh may be provided on the H or H3 port.

[0378] FIG. 13 shows in more detail the transfer lens arrangement 303 and shows a second differential pumping aperture (Aperture #2) 1301 which separates the vacuum chamber housing the segmented quadrupole rod set 302 from first transfer optics which may comprise two acceleration electrodes. The relative spacing of the lens elements, their internal diameters and thicknesses according to an embodiment are shown. However, it should be understood that the relative spacing, size of apertures and thicknesses of the electrodes or lens elements may be varied from the specific values indicated in FIG. 13.

[0379] The region upstream of the second aperture (Aperture #2) 1301 may be in fluid communication with the first pumping port H1 of the turbo pump. A third differential pumping aperture (Aperture #3) 1302 may be provided between the first transfer optics and second transfer optics.

[0380] The region between the second aperture (Aperture #2) 1301 and the third aperture (Aperture #3) 1302 may be in fluid communication with the second pumping port H2 of the turbo pump.

[0381] The second transfer optics which is arranged downstream of the third aperture 1302 may comprises a lens arrangement comprising a first electrode which is electrical connection with the third aperture (Aperture #3) 1302. The lens arrangement may further comprise a second (transport) lens and a third (transport/steering) lens. Ions passing through the second transfer optics then pass through a tube lens before passing through an entrance aperture 1303. Ions passing through the entrance aperture 1303 pass through a slit or entrance plate 1000 into a pusher electrode assembly module.

[0382] The lens apertures after Aperture #3 1302 may comprise horizontal slots or plates. Transport 2/steering lens may comprise a pair of half plates.

[0383] The entrance plate 1000 may be arranged to be relatively easily removable by a service engineer for cleaning purposes.

[0384] One or more of the lens plates or electrodes which form a part of the overall transfer optics 303 may be manufactured by introducing an overcompensation etch of 5%. An additional post etch may also be performed. Conventional lens plates or electrodes may have a relatively sharp edge as a result of the manufacturing process. The sharp edges can cause electrical breakdown with conventional arrangements. Lens plates or electrodes which may be fabricated according to various embodiments using an overcompensation etching approach and/or additional post etch may have significantly reduced sharp edges which reduces the potential for electrical breakdown as well as reducing manufacturing cost.

[0385] FIG. 14A shows details of a known internal vacuum configuration and FIG. 14B shows details of a new internal vacuum configuration according to various embodiments.

[0386] A conventional arrangement is shown in FIG. 14A wherein the connection 700 from the backing pump to the first vacuum chamber of a mass spectrometer makes a T-connection into the turbo pump when backing pressure is reached. However, this requires multiple components so that multiple separate potential leak points are established. Furthermore, the T-connection adds additional manufacturing and maintenance costs.

[0387] FIG. 14B shows an embodiment wherein the backing pump 700 is only directly connected to the first vacuum chamber i.e. the T-connection is removed. A separate connection 1401 is provided between the first vacuum chamber and the turbo pump.

[0388] A high voltage supply feed through 1402 is shown which provides a high voltage (e.g. 1.1 kV) to the pusher electrode module 305. An upper access panel 810 is also shown. A Pirani pressure gauge 701 is arranged to measure the vacuum pressure in the vacuum chamber housing the first ion guide 301. An elbow gas fitting 1250 is shown through which desolvation/cone gas may be supplied. With reference to FIG. 14B, behind the elbow gas fitting 1250 is shown the over pressure relief valve 1202 and behind the over pressure relief valve 1202 is shown a further elbow fitting which enables gas pressure from the source to be directly measured.

[0389] FIG. 15A shows a schematic of the ion block 802 and source or first ion guide 301. According to an embodiment the source or first ion guide 301 may comprise six initial ring electrodes followed by 38-39 open ring or conjoined electrodes. The source or first ion guide 301 may conclude with a further 23 rings. It will be appreciated, however, that the particular ion guide arrangement 301 shown in FIG. 15A may be varied in a number of different ways. In particular, the number of initial ring electrodes (e.g. 6) and/or the number of final stage (e.g. 23) ring electrodes may be varied. Similarly, the number of intermediate open ring or conjoined ring electrodes (e.g. 38-39) may also be varied.

[0390] It should be understood that the various dimensions illustrated on FIG. 15A are for illustrative purposes only and are not intended to be limiting. In particular, embodiments are contemplated wherein the sizing of ring and/or conjoined ring electrodes may be different from that shown in FIG. 15A.

[0391] A single conjoined ring electrode is also shown in FIG. 15A.

[0392] According to various embodiment the initial stage may comprise 0-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50 or >50 ring or other shaped electrodes. The intermediate stage may comprise 0-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50 or >50 open ring, conjoined ring or other shaped electrodes. The final stage may comprise 0-5, 5-10, 10-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50 or >50 ring or other shaped electrodes.

[0393] The ring electrodes and/or conjoined ring electrodes may have a thickness of 0.5 mm and a spacing of 1.0 mm. However, the electrodes may have other thicknesses and/or different spacings.

[0394] Aperture #1 plate may comprise a differential pumping aperture and may have a thickness of 0.5 mm and an orifice diameter of 1.50 mm. Again, these dimensions are illustrative and are not intended to be limiting.

[0395] A source or first ion guide RF voltage may be applied to all Step 1 and Step 2 electrodes in a manner as shown in FIG. 15A. The source or first ion guide RF voltage may comprise 200 V peak-to-peak at 1.0 MHz.

[0396] Embodiments are contemplated wherein a linear voltage ramp may be applied to Step 2 Offset (cone).

[0397] The Step 2 Offset (cone) voltage ramp duration may be made equal to the scan time and the ramp may start at the beginning of a scan. Initial and final values for the Step 2 Offset (cone) ramp may be specified over the complete range of Step 2 Offset (cone).

[0398] According to various embodiments a resistor chain as shown in FIG. 15B may be used to produce a linear axial field along the length of Step 1. Adjacent ring electrodes may have opposite phases of RF voltage applied to them.

[0399] A resistor chain may also be used to produce a linear axial field along the length of Step 2 as shown in FIG. 15C. Adjacent ring electrodes may have opposite phases of RF voltage applied to them.

[0400] Embodiments are contemplated wherein the RF voltage applied to some or substantially all the ring and conjoined ring electrodes forming the first ion guide 301 may be reduced or varied in order to perform a non-mass to charge ratio specific attenuation of the ion beam. For example, as will be appreciated, with a Time of Flight mass analyser 304 the ion detector 307 may suffer from saturation effects if an intense ion beam is received at the pusher electrode 305. Accordingly, the intensity of the ion beam arriving adjacent the pusher electrode 305 can be controlled by varying the RF voltage applied to the electrodes forming the first ion guide 301. Other embodiments are also contemplated wherein the RF voltage applied to the electrodes forming the second ion guide 302 may additionally and/or alternatively be reduced or varied in order to attenuate the ion beam or otherwise control the intensity of the ion beam. In particular, it is desired to control the intensity of the ion beam as received in the pusher electrode 305 region.

[0401] FIG. 16A shows in more detail the quadrupole ion guide 302 according to various embodiments. The quadrupole rods may have a diameter of 6.0 mm and may be arranged with an inscribed radius of 2.55 mm. Aperture #2 plate which may comprise a differential pumping aperture may have a thickness of 0.5 mm and an orifice diameter of 1.50 mm. The various dimensions shown in FIG. 16A are intended to be illustrative and non-limiting.

[0402] The ion guide RF amplitude applied to the rod electrodes may be controllable over a range from 0 to 800 V peak-to-peak.

[0403] The ion guide RF voltage may have a frequency of 1.4 MHz. The RF voltage may be ramped linearly from one value to another and then held at the second value until the end of a scan.

[0404] As shown in FIG. 16B, the voltage on the Aperture #2 plate may be pulsed in an Enhanced Duty Cycle mode operation from an Aperture 2 voltage to an Aperture 2 Trap voltage. The extract pulse width may be controllable over the range 1-25 μs. The pulse period may be controllable over the range 22-85 μs. The pusher delay may be controllable over the range 0-85 μs.

[0405] FIG. 16C shows in more detail the pusher electrode arrangement. The grid electrodes may comprise Ø 60 parallel wire with 92% transmission (Ø 0.018 mm parallel wires at 0.25 mm pitch). The dimensions shown are intended to be illustrative and non-limiting.

[0406] FIG. 16D shows in more detail the Time of Flight geometry. The region between the pusher first grid, reflectron first grid and the detector grid preferably comprises a field free region. The position of the ion detector 307 may be defined by the ion impact surface in the case of a MagneTOF® ion detector or the surface of the front MCP in the case of a MCP detector.

[0407] The reflectron ring lenses may be 5 mm high with 1 mm spaces between them. The various dimensions shown in FIG. 16D are intended to be illustrative and non-limiting.

[0408] According to various embodiments the parallel wire grids may be aligned with their wires parallel to the instrument axis. It will be understood that the instrument axis runs through the source or first ion guide 301 through to the pusher electrode assembly 305.

[0409] A flight tube power supply may be provided which may have an operating output voltage of either +4.5 kV or −4.5 kV depending on the polarity requested.

[0410] A reflectron power supply may be provided which may have an operating output voltage ranging from 1625±100 V or −1625±100 V depending on the polarity requested.

[0411] FIG. 16E is a schematic of the Time of Flight wiring according to an embodiment. The various resistor values, voltages, currents and capacitances are intended to be illustrative and non-limiting.

[0412] According to various embodiments a linear voltage gradient may be maintained along the length of the reflectron 306. In a particular embodiment a reflectron clamp plate may be maintained at the reflectron voltage.

[0413] An initial electrode and associated grid 1650 of the reflectron 306 may be maintained at the same voltage or potential as the flight tube 807 and the last electrode of the pusher electrode assembly 305. According to an embodiment the initial electrode and associated grid 1650 of the reflectron 306, the flight tube 807 and the last electrode and associated grid of the pusher electrode assembly 305 may be maintained at a voltage or potential of e.g. 4.5 kV of opposite polarity to the instrument or mode of operation. For example, in positive ion mode the initial electrode and associated grid 1650 of the reflectron 306, the flight tube 807 and the last electrode and associated grid of the pusher electrode assembly 305 may be maintained at a voltage or potential of −4.5 kV.

[0414] The second grid electrode 1651 of the reflectron 306 may be maintained at ground or 0V.

[0415] The final electrode 1652 of the reflectron 306 may be maintained at a voltage or potential of 1.725 kV of the same polarity as the instrument. For example, in positive ion mode the final electrode 1652 of the reflectron 306 may be maintained at a voltage or potential of +1.725 kV.

[0416] It will be understood by those skilled in the art that the reflectron 306 acts to decelerate ions arriving from the time of flight region and to redirect the ions back out of the reflectron 306 in the direction of the ion detector 307.

[0417] The voltages and potentials applied to the reflectron 306 according to various embodiments and maintaining the second grid electrode 1651 of the reflectron at ground or 0V is different from the approach adopted in conventional reflectron arrangements.

[0418] The ion detector 307 may always be maintained at a positive voltage relative to the flight tube voltage or potential. According to an embodiment the ion detector 307 may be maintained at a +4 kV voltage relative to the flight tube.

[0419] Accordingly, in a positive ion mode of operation if the flight tube is maintained at an absolute potential or voltage of −4.5 kV then the detector may be maintained at an absolute potential or voltage of −0.5 kV.

[0420] FIG. 16F shows the DC lens supplies according to an embodiment. It will be understood that Same polarity means the same as instrument polarity and that Opposite polarity means opposite to instrument polarity. Positive means becomes more positive as the control value is increased and Negative means becomes more negative as the control value is increased. The particular values shown in FIG. 16F are intended to be illustrative and non-limiting.

[0421] FIG. 16G shows a schematic of an ion detector arrangement according to various embodiments. The detector grid may form part of the ion detector 307. The ion detector 307 may, for example, comprise a MagneTOF® DM490 ion detector. The inner grid electrode may be held at a voltage of +1320 V with respect to the detector grid and flight tube via a series of zener diodes and resistors. The ion detector 307 may be connected to a SMA 850 and an AC coupler 851 which may both be provided within or internal to the mass analyser housing or within the mass analyser vacuum chamber. The AC coupler 851 may be connected to an externally located preamp which in turn may be connected to an Analogue to Digital Converter (“ADC”) module.

[0422] FIG. 16H shows a potential energy diagram for an instrument according to various embodiments. The potential energy diagram represents an instrument in positive ion mode. In negative ion mode all the polarities are reversed except for the detector polarity. The particular voltages/potentials shown in FIG. 16H are intended to be illustrative and non-limiting.

[0423] The instrument may include an Analogue to Digital Converter (“ADC”) which may be operated in peak detecting ADC mode with fixed peak detecting filter coefficients. The ADC may also be run in a Time to Digital Converter (“TDC”) mode of operation wherein all detected ions are assigned unit intensity. The acquisition system may support a scan rate of up to 20 spectra per second. A scan period may range from 40 ms to 1 s. The acquisition system may support a maximum input event rate of 7×10.sup.6 events per second.

[0424] According to various embodiments the instrument may have a mass accuracy of 2-5 ppm may have a chromatographic dynamic range of 10.sup.4. The instrument may have a high mass resolution with a resolution in the range 10000-15000 for peptide mapping. The mass spectrometer 100 is preferably able to mass analyse intact proteins, glycoforms and lysine variants. The instrument may have a mass to charge ratio range of approx. 8000.

[0425] Instrument testing was performed with the instrument fitted with an ESI source 401. Sample was infused at a flow rate of 400 mL/min. Mass range was set to m/z 1000. The instrument was operated in positive ion mode and high resolution mass spectral data was obtained.

[0426] According to various embodiments the instrument may have a single analyser tune mode i.e. no sensitivity and resolution modes.

[0427] According to various embodiments the resolution of the instrument may be in the range 10000-15000 for high mass or mass to charge ratio ions such as peptide mapping applications. The resolution may be determined by measuring on any singly charged ion having a mass to charge ratio in the range 550-650.

[0428] The resolution of the instrument may be around 5500 for low mass ions. The resolution of instrument for low mass ions may be determined by measuring on any singly charged ion having a mass to charge ratio in the range 120-150.

[0429] According to various embodiments the instrument may have a sensitivity in MS positive ion mode of approx. 11,000 counts/second. The mass spectrometer 100 may have a mass accuracy of approx. 2-5 ppm

[0430] Mass spectral data obtained according to various embodiments was observed as having reduced in-source fragmentation compared with conventional instruments. Adducts are reduced compared with conventional instruments. The mass spectral data also has cleaner valleys (<20%) for mAb glycoforms.

[0431] As disclosed in US 2015/0076338 (Micromass), the contents of which are incorporated herein by reference, the instrument according to various embodiment may comprise a plurality of discrete functional modules. The functional modules may comprise, for example, electrical, mechanical, electromechanical or software components. The modules may be individually addressable and may be connected in a network. A scheduler may be arranged to introduce discrete packets of instructions to the network at predetermined times in order to instruct one or more modules to perform various operations. A clock may be associated with the scheduler.

[0432] The functional modules may be networked together in a hierarchy such that the highest tier comprises the most time-critical functional modules and the lowest tier comprises functional modules which are the least time time-critical. The scheduler may be connected to the network at the highest tier.

[0433] For example, the highest tier may comprise functional modules such as a vacuum control system, a lens control system, a quadrupole control system, an electrospray module, a Time of Flight module and an ion guide module. The lowest tier may comprise functional modules such as power supplies, vacuum pumps and user displays.

[0434] The mass spectrometer 100 according to various embodiments may comprise multiple electronics modules for controlling the various elements of the spectrometer. As such, the mass spectrometer may comprise a plurality of discrete functional modules, each operable to perform a predetermined function of the mass spectrometer 100, wherein the functional modules are individually addressable and connected in a network and further comprising a scheduler operable to introduce discrete packets of instructions to the network at predetermined times in order to instruct at least one functional module to perform a predetermined operation.

[0435] The mass spectrometer 100 may comprise an electronics module for controlling (and for supplying appropriate voltage to) one or more or each of: (i) the source; (ii) the first ion guide; (iii) the quadrupole ion guide; (iv) the transfer optics; (v) the pusher electrode; (vi) the reflectron; and (vii) the ion detector.

[0436] This modular arrangement may allow the mass spectrometer to be reconfigured straightforwardly. For example, one or more different functional elements of the spectrometer may be removed, introduced or changed, and the spectrometer may be configured to automatically recognised which elements are present and to configure itself appropriately.

[0437] The instrument may allow for a schedule of packets to be sent onto the network at specific times and intervals during an acquisition. This reduces or alleviates the need for a host computer system with a real time operating system to control aspects of the data acquisition. The use of packets of information sent to individual functional modules also reduces the processing requirements of a host computer.

[0438] The modular nature conveniently allows flexibility in the design and/or reconfiguring of a mass spectrometer. According to various embodiments at least some of the functional modules may be common across a range of mass spectrometers and may be integrated into a design with minimal reconfiguration of other modules. Accordingly, when designing a new mass spectrometer, wholesale redesign of all the components and a bespoke control system are not necessary. A mass spectrometer may be assembled by connecting together a plurality of discrete functional modules in a network with a scheduler.

[0439] Furthermore, the modular nature of the mass spectrometer 100 according to various embodiments allows for a defective functional module to be replaced easily. A new functional module may simply be connected to the interface. Alternatively, if the control module is physically connected to or integral with the functional module, both can be replaced.

[0440] In accordance with the disclosure, the mass spectrometer is arranged to automatically perform a start-up routine when the ON/start button is pressed. The start-up routine involves a sequence of steps which, in the absence of a fault, may result in the mass spectrometer being automatically brought to an operating state, ready for the user to submit a sample batch. No user intervention is required, in the absence of a fault. At various points, tests are automatically initiated, to ensure that no fault is present in relation to various parts of the spectrometer.

[0441] By way of example, FIG. 11 is a flow diagram illustrating various processes which may occur once the start button has been pressed. The term “ICS” refers to “Instrument Control System” software. The main steps in the start-up process shown in FIG. 11 will now be described.

[0442] When the start button of the mass spectrometer is pressed, the mass spectrometer (i.e. the control system thereof) will turn ON the backing pump. The mass spectrometer will also turn ON the turbo pump when the backing pressure reaches a defined value.

[0443] Once the turbo pump reaches 80% of its maximum speed then the mass spectrometer control system will turn ON the Time of Flight mass analyser pressure gauge.

[0444] As described above, the mass spectrometer includes a plurality of functional modules (the “Typhoon modules”). At 80% turbo speed the functional modules are turned ON and it is checked which modules are present. Assuming that an acceptable set of modules is present, and found to be in communication with the network, the mass spectrometer proceeds to determine whether appropriate configuration information for the modules is stored locally (i.e. within a controller of the mass spectrometer, or within a PC that is connected to the mass spectrometer, and used to control it); and if present, performs configuration of the mass spectrometer; and if not present, automatically downloads configuration data over the internet from a remote server, and uses the downloaded data to configure the mass spectrometer.

[0445] Once the pressure in the Time of Flight mass analyser vacuum chamber is below 1×10.sup.−5 mbar then the instrument is automatically moved to a power save mode (which is defined in more detail below).

[0446] On transition to the power save mode (power save state in FIG. 11), voltage is supplied to the following; the pusher electrode, the reflectron, flight tube and the ion detector of the Time of Flight mass analyser.

[0447] As shown in FIG. 11, automatic checks may be performed to ensure that the voltages set are settled within a given time for the ion detector, flight tube and the reflectron.

[0448] Checks may also be performed automatically to monitor the current for the reflectron and flight tube when first turned ON for a defined period of time to ensure there is no breakdown within the Time of Flight mass analyser. This is carried out without the intervention of the user.

[0449] Once pressure in the Time of Flight mass analyser vacuum chamber is below 1×10.sup.−6 mbar, the mass spectrometer moves automatically to an operating mode (operate state in FIG. 11). On transition to the operating mode the following voltages are additionally turned ON; transfer lens voltages, ion guide voltages, stepwave ion guide voltages, capillary tube of the source. The desolvation gas supply is turned on, and the desolvation gas heater is turned on.

[0450] Checks may be carried out to ensure that the temperature of the desolvation gas settles, the desolvation gas is turned ON and the voltages supplied to the various components upon transition to the operating mode have reached the required values. Once this is all completed, the mass spectrometer is in a ready to use state, being ready to acquire sample data. No user intervention is required other than the submission of a sample batch.

[0451] The various modes of the mass spectrometer will now be described in more detail.

[0452] It will be seen that when the start-up button is pressed, all gases, heaters and voltages are turned ON, but at different stages.

[0453] When transition to power save mode occurs, the following voltages are turned ON; pusher, reflectron, ion detector and flight tube.

[0454] When transition to operating mode occurs, the following voltages are additionally turned ON; transfer lens voltages, ion guide voltages, stepwave ion guide voltages, source capillary tube voltage. The desolvation gas heater is turned on, and the desolvation gas supply is turned on.

[0455] Thus, power save mode is a mode in which all back voltages are kept ON, front voltages are turned OFF and desolvation gas supply is OFF. In this mode the pusher, reflectron, ion detector and flight tube voltages are ON. The following voltages are OFF; transfer lens voltages, ion guide voltages, stepwave ion guide voltages, source capillary tube voltage. The desolvation gas heater and desolvation gas supply are OFF. The source heater is additionally ON.

[0456] In the operating mode, all voltages are ON, and the desolvation gas supply is ON. Thus, the front voltages are ON. In this mode, in addition to the pusher, reflectron, ion detector and Time of Flight mass analyser voltages, the following voltages are also ON; transfer lens voltages, ion guide voltages, stepwave ion guide voltages, and source capillary tube. The desolvation gas heater and desolvation gas supply are ON. In addition, the source heater is ON.

[0457] In embodiments of the disclosure, the mass spectrometer automatically transitions from power save mode to operating mode during the start-up routine, in the absence of a fault.

[0458] In embodiments of the disclosure, the mass spectrometer is maintained, as a default, in power save mode, and can be switched to operating mode where all the relevant voltages and gas flows are turned ON. By maintaining the spectrometer in power save mode as default, as described below, the time taken for the instrument to be put into a useable state is significantly reduced.

[0459] The mass spectrometer has a further state, a “standby mode”. The standby mode is a mode in which all voltages are OFF, and the desolvation gas supply and heater are OFF. Only the source heater is ON.

[0460] In accordance with embodiments of the disclosure, the standby mode is used if a serious fault occurs, in which case it would be entered automatically, or if an engineer specifies that the instrument should be put into a standby mode operation. In some embodiments the user may cause the mass spectrometer to enter the standby mode by pressing and holding the power button, while in other embodiments the user is prevented from being able to cause the spectrometer to enter standby mode. The standby mode corresponds to a mode previously known on Time of Flight mass analyser products as source standby. If a serious fault develops, which only a service engineer can resolve, then the mass spectrometer will automatically switch to standby.

[0461] The stability of the power supplies for the flight tube, detector and reflectron can affect the mass accuracy of the instrument. On previous products the settling time when turning ON or switching polarity was around 20 minutes. Data has found that if the supplies are cold or been left off for a prolonged period of time they will require 10 hours to warm up and stabilise.

[0462] For this reason, in embodiments of the disclosure on start-up the instrument moves to power save mode, and may be switched back to this mode by the user once the user has finished operating the mass spectrometer.

[0463] During the start-up routine, the mass spectrometer is put into the power save mode as soon as possible. This ensures that the voltages to the flight tube, detector and reflectron are turned on as soon as possible, maximising the time available for them to stabilise, and minimising delay in being able to enter the operating state. Pumping down of the mass spectrometer will continue after the spectrometer has entered the power save mode until a pressure in the vacuum chamber of the Time of Flight mass analyser has reached a level lower than a predetermined threshold. Thus, there will still be some time to wait before the spectrometer can be put into the operating mode. However, by putting the spectrometer into power save mode, stabilisation of the voltages to the mass analyser components may occur during this period of pumping down, minimising any additional delay. By the time the mass spectrometer has reached the required pressure to enter operating mode, and be ready for the user to carry out instrument setup, the voltage supplies will have stabilised, thus reducing the mass accuracy concerns.

[0464] Usability is a major contributor to the requirements and operation of the spectrometer. In embodiments, the mass spectrometer is intended to have the capability to self-diagnose all problems, and, depending on the effect that each problem has on the spectrometer, determine what, if any action can be taken to rectify the problem. According to various embodiments health checks are performed and printer style error correction instructions may be provided to a user.

[0465] The health check system may be used in bringing the mass spectrometer to readiness from a cold start, bringing the spectrometer to readiness after maintenance, and monitoring the mass spectrometer for issues on a periodic basis to make sure it remains fit to run experiments.

[0466] Referring to FIG. 11, in addition to the main steps of the start-up routine described above, it will be seen that checks are made at various points in the routine. For example, the backing pressure may be monitored. The pressure of the vacuum chamber housing the Time of Flight mass analyser may be checked periodically. The stability of various voltages may be checked. Many of these tests involve checking that a given requirement is met within a predetermined time period e.g. that a pressure has reached a given threshold, or that a voltage has stabilised within a given time period. At any time, one of these tests or checks may not be passed. This may result in a determination of a fault.

[0467] The mass spectrometer may be arranged to monitor various parameters and other features relating to the operation of the spectrometer, and assign a status to each. Monitoring may be carried out at predetermined intervals e.g. in operating mode, or may be triggered at particular points in a start-up routine, or when bringing the spectrometer back into operation after maintenance. Monitoring may be based on outputs from various sensors and/or the outcome of tests performed.

[0468] The status may be a fault or a non-fault status depending upon the outcome of the e.g. test. The fault and non-fault statuses may be selected from respective lists of multiple possible statuses. Monitoring may be carried out such that the status of each parameter or feature is regularly checked.

[0469] By way of example, in embodiments as illustrated in FIG. 11, when the backing pump is turned ON, a check may be made that the backing pressure is <32 mbar within three minutes of operation. If a pressure of <32 mbar is not achieved within this period, then a fault may be determined.

[0470] When a fault is determined, the mass spectrometer is arranged to determine what action, if any, may be taken to rectify the problem. In embodiments, a fault is put into one of three categories. In a first category, the fault is one that the mass spectrometer can attempt to rectify itself, and automatically, without intervention by a user. In a second category, the fault is one which the user may attempt to rectify. A third category of more serious faults may only be rectified by a service engineer. A fault may be categorised based on its severity. An initially less severe fault may be recategorised to a higher severity e.g. a higher category, if initial attempts to solve the problem have failed.

[0471] Where a fault is detected that the mass spectrometer may attempt to rectify itself, the spectrometer automatically takes the appropriate action. The spectrometer may then check again to determine whether the fault has been corrected, and if so, update the relevant status to a non-fault status.

[0472] Where a fault is detected that the user may attempt to rectify, the mass spectrometer causes an indication of the fault, and instructions as to how to attempt to rectify the fault, to be displayed to the user. Typically the information is displayed to the user via a computing device connected to the mass spectrometer. Some information may additionally be displayed on a display forming part of the mass spectrometer unit itself. This is discussed in more detail in relation to FIGS. 2A-C above. FIG. 17 illustrates an example of a fault indication which may be displayed to the user on a PC connected to the mass spectrometer. The fault is associated with an amber colour, indicating that it belongs to a category of fault that the user may attempt to rectify. The fault indication provides an indication of what is wrong “Source not fitted”, and instructs the user to “check mark II source enclosure is fitted and cable is secured”. In other embodiments, an instructional video or images may be provided to the user. In combination with this information displayed on the PC, as described above, some information may be displayed on the display panel 202 of the mass spectrometer unit e.g. indicating generally the area to which the fault relates.

[0473] Once the user has attempted to rectify the fault by following the instructions given, they may press/click on the resolve button 2000. When the mass spectrometer receives this indication that the user has performed the rectification steps, it performs a further check to see whether the fault has indeed been rectified. If the fault has been rectified, the mass spectrometer may pass to a ready status, being ready to acquire sample data once more.

[0474] If the fault has not been successfully rectified, the mass spectrometer may display another fault indication to the user, inviting them to try again to rectify the fault, together with the necessary instructions. If the fault remains unresolved after a predetermined number of allowed attempts by the user, the mass spectrometer escalates the fault to a category three fault, which may only be rectified by a service engineer.

[0475] Where a fault is detected which may only be rectified by an engineer i.e. a category three fault, whether or not escalated from a lower level fault, an indication similar to that of FIG. 17 may be given, indicating the nature of the fault, and this time instructing the user to call a service engineer. Instructions may be provided as to how to do this. The colour associated with the fault indication will be red, to indicate a more serious category of fault. It is envisaged that the spectrometer may be arranged to provide additional information to an engineer, when the engineer has presented necessary credentials.

[0476] Possible faults may be assigned a priority level, at least if they are faults which may be attempted to be rectified by a user. This will enable the spectrometer to determine which fault to indicate to the user first, where multiple faults occur simultaneously, which a user may attempt to rectify i.e. amber or category 2 faults. The faults may be presented simultaneously, in an ordered list, or sequentially, in order of priority. Multiple faults may be given the same priority if they are not expected to occur simultaneously. For example, in annex 1, priority 18 has three different warnings which are all related to the cone; no cone fitted, incorrect cone warning, either the 0.2 or 0.09 cone is fitted, which is not correct. Only one of these warnings can occur at the same time, but they are all as likely to happen, and therefore have the same priority number.

[0477] The table below illustrates different status indications which may be issued according to various embodiments in connection with the backing pump (rough pump as referred to in the table).

[0478] In the illustrated examples, the following non-fault statuses may be used;

[0479] Ready—the instrument is ready to acquire sample data. No user intervention is required other than submission of a sample batch.

[0480] Getting ready—the instrument is currently undertaking operations after which it is expected to transition towards the ready state. No user intervention is required.

[0481] The following fault statuses may be used:

[0482] Ready Blocked—the instrument has a warning/problem that is stopping it being ready for sample acquisition (not other forms of data acquisition such as tuning), but that can be resolved by the user, and does not require a system level shutdown.

[0483] Error—the instrument has a serious issue that is not recoverable by the user or requires a system level shutdown to occur.

[0484] Warning—this is generated when there is a problem that can be corrected through user intervention.

[0485] Problem—this occurs when there is something wrong with an easily accessible part of the instrument.

[0486] Critical—this is the most significant item in a list provided e.g. the most important issue that needs to be resolved out of a list of several.

[0487] Other statuses which may be used:

[0488] Information—this is text that is provided to inform the user.

[0489] Failed—this means that the test has not achieved the required levels as specified.

[0490] In the table below, the nature of the status is indicated under the column heading “type”. Here, where applicable for faults which may be attempted to be rectified by a user, it is stated which part of the mass spectrometer is affected (“status area”). This may be used in providing an indication as to which part(s) are affected by a fault on a display panel of the spectrometer as shown in FIG. 2C. In FIG. 2C, the left hand area includes general status indications for the spectrometer as a whole. These may indicate initialising, ready or running states of the spectrometer, which would be coloured green. The arrows show which is the current state. The attention state would be coloured amber indicating that the user may need to intervene. An arrow, arrow 3 then points to the right hand area of the display, to prompt the user to look at the icons indicating in more detail which part(s) of the spectrometer have a fault. Returning to the left hand side, the call service status is used when the user must call an engineer to resolve a fault, and is highlighted by a spanner icon. These would be coloured red. At the bottom is an icon which may be illuminated to prompt the user to hold the power button to turn the spectrometer off. This may be coloured green. On the right hand side are a series of icons, which may be illuminated to indicate the general part(s) of the spectrometer affected by a fault which the user may attempt to resolve. These would be coloured amber to attract the user's attention, and indicate a user rectifiable fault. In the embodiment of FIG. 2C, there are icons which may be illuminated to indicate faults with any one or ones of the source, cone, fluidics, electronics, setup, communications, refill, gas, vacuum or exhaust parts of the system.

[0491] The column “priority” indicates the priority assigned to a particular fault. The column “reason for generation” is self-explanatory. The column “resolution” indicates what action needs to be taken, by a user or service engineer (FSE), as applicable. The column “wording” indicates the instruction that is displayed to the user for category 2 faults. The column “outcome” indicates what action will be taken after the user has indicated that they have finished taking the requested action i.e. pressed the “resolve button”. The outcome for category 3 faults is that the engineer will fix them.

[0492] In some cases, for category 2 faults, a resolution 2 and outcome 2 is given. These indicate the action that is to be taken by the user if the first attempt to fix the fault i.e. outcome 1, fails. Outcome 2 indicates the action that will be taken once resolution 2 has been performed.

[0493] It will be seen that each outcome involves retesting the relevant e.g. parameter, and determining whether it is now passes the test initially failed. If the test is passed, then the backing pump is returned to a non-fault state. If it is failed again, then another attempt to resolve the fault is initiated, until a predetermined number of attempts has been made, at which point the fault is escalated to category 3, requiring an engineer to be called.

[0494] Category 2 faults, which the user may attempt to fix, are shaded pale grey (corresponding to amber faults), and are labelled “cat 2”. Category 3 faults, which require a service engineer to be called, are shaded darker grey (corresponding to red faults) and are labelled “cat 3”. Other statuses are on a white background and labelled “status”.

TABLE-US-00005 Reason for Name Type Priority generation Resolution Wording Outcome Rough Getting N/A Instrument (firmware) N/A N/A N/A Pumping Ready has switched on the (status) backing pump and the backing pressure is decreasing. (Turbo is off) Rough Ready 4 The backing pressure Resolution 1: Wording 1: Outcome 1: Pumping Blocked does not reach the Customer is “Check that the Instrument Timeout required 32 mbar asked to check following cables will try and Warning within 3 minutes and that the mains are connected turn backing (Status a the firmware supply cable to and switched pump on again area- generates either the backing pump on. and see if vacuum) Venting_BackingUnderange is fitted and Main cable is backing pump (Cat. 2) or switched on. plugged into gets to 32 Vented_BackingUnderange Customer is also rough pump mbar in 3 asked to check Pump cable is minutes. that the cable is attached Passes - fitted between the between Ready instrument and instrument and Fails - the backing rough pump.” Ready pump. PICTURE TO Blocked and Resolve button BE INCLUDED goes to available to press OF CABLES resolution 2 once completed. Wording 2: Outcome 2: Resolution 2: “Check the oil Instrument Customer is level in pump” will try and asked to check turn backing the oil level in the pump on again pump. If oil is not and see if within the shown backing pump levels for gets to 32 operation or mbar in 3 empty then top minutes. up with oil. Either: Resolve button Passes - available to press Ready once completed Fails (Issue remains) = Error - Rough Pumping Timeout Error Rough Error N/A Rough Pumping Timeout FSE will Call Service Fixed Pumping Warning resolutions investigate and Timeout have not fixed the once resolved Error problem and so an error issue will power (Cat. 3) has been generated. cycle instrument Unresolved Warning

[0495] The next table indicates illustrates different status indications which may be issued according to various embodiments in connection with the functional modules of the mass spectrometer, using the same terminology, shading, categories and headings.

TABLE-US-00006 Reason for Name Type Priority generation Resolution Wording Outcome Typhoon Getting N/A Typhoon N/A N/A N/A Module Ready modules Booting turned on (status) and time is less than 60 seconds since turned on Module Ready 7 Any of the Resolution 1: Wording 1: Outcome 1: Warning Blocked modules fail to Software will “Checking Passed - [include communicate rediscover the electronics All modules which within 60 network units” present module/ seconds. Resolution 2: Wording 2: Fails - Still modules [Source HT, Customer is asked “Electronics missing failed in StepWave to reboot the reboot modules - name] Ion Guide, electronics required” move to (Status Ion Guide 2, PICTURE resolution 2 area- Pusher, INCLUDED Outcome 2: electronics) Reflectron, FOR Passed - (cat 2) Detector, ELECTRONICS All modules ADC] REBOOT present BUTTON Fails - Still LOCATION missing modules - ERROR Module Ready 7 Any of the Resolution 1: Wording 1: Outcome 1: Warning Blocked modules Software will “Checking Passed - [include disappear rediscover the electronics All modules which from the network units” present module/ network at Resolution 2: Wording 2: Fails - Still modules any given Customer is asked “Electronics missing failed in time during to reboot the reboot modules - name] instrument electronics required” move to (Status operation PICTURE resolution 2 area- INCLUDED Outcome 2: electronics) FOR Passed - (cat 2) ELECTRONICS All modules REBOOT present BUTTON Fails - Still LOCATION missing modules - ERROR Typhoon Error N/A Typhoon FSE will investigate. Call Service Fixed Module Module Fixes issue and Error Warning not goes to Getting (cat 3) been Ready resolved and Power cycles error is instrument generated Typhoon Passed N/A All typhoon N/A N/A N/A Module OK modules (status) communicating within the given time period

[0496] Annex 1 illustrates similar status indications, using the same terminology, shading, categories and headings, in relation to other parts of the mass spectrometer. As above, in some cases, a resolution 2 and outcome 2, or even resolution 3 and outcome 3 and higher, is provided, for category 2 faults. These indicate the further steps that may be taken after an initial attempt to fix the fault has failed, for one or more cycles of attempt and retesting, until the fault is escalated to a category 3 fault, requiring input from an engineer.

[0497] FIG. 18A is a flow chart illustrating certain steps which may be carried out in calibrating the mass spectrometer.

[0498] As is known in the art, it is necessary to calibrate the mass spectrometer. It has been recognised that different calibration is appropriate to different operating conditions. Thus, in embodiments, different calibration functions are stored for the spectrometer in respect of different sets of operational conditions of the spectrometer. An operational condition is defined by the set of one or more operating parameters under which the spectrometer is operating. For example, different calibration functions may be stored for the spectrometer being in positive polarity running at a frequency mode of 1000, and another one in respect of a frequency mode of 2000. The frequency mode refers to the number of scans per second performed in the mass analyser. This may vary dependent upon the mass to charge ratio of ions, for example. In embodiments of the disclosure, the control system is arranged to automatically select an appropriate calibration function to be applied to the acquired data based on the detected operational condition of the spectrometer e.g. to calibrate the mass position determined for ions. The calibration function is selected from a library of stored calibration functions for different operational conditions.

[0499] Referring to FIG. 18A a calibration function map is populated within a metadata member of a schedule request. This is sent to the scheduler which adds it to a schedule. When the schedule is to be applied, a message is sent to hardware controller to apply the schedule data. Whilst applying the schedule data, a system.metaData event is fired, which is captured on the target. The target stores the embedded calibration function map. At the end of each scan, the datahub looks up the appropriate calibration for the given function and attaches it to the scan data.

[0500] FIG. 18B illustrates the process in more detail. The maths library mass calibration mapper is used when converting scan data to plot data.

[0501] Annex 2 includes tables indicating default operating parameters of the mass spectrometer in one exemplary embodiment. Table 1 is a set of definitions for Table 2, which gives the exemplary operating parameters.

[0502] Although the present invention has been described with reference to preferred embodiments, it will be understood by those skilled in the art that various changes in form and detail may be made without departing from the scope of the invention as set forth in the accompanying claims.

TABLE-US-00007 Annex 1 Reason for Name Type Priority generation Resolution Wording Outcome Rough Getting N/A Instrument N/A N/A N/A Pumping Ready (firmware) has (cat 1) switched on the backing pump and the backing pressure is decreasing. (Turbo is off) Rough Ready  4 The backing Resolution 1: Wording 1: Outcome 1: Pumping Blocked pressure does Customer is “Check that Instrument Timeout not reach the asked to check the following will try and Warning required 32 mbar that the mains cables are turn backing (Status within 3 minutes supply cable to connected pump on again area = and a the firmware the backing and switched and see if vacuum) generates either pump is fitted on. backing pump (cat 2) Venting_BackingUnderange and switched on. Main cable gets to 32 or Customer is also is plugged mbar in 3 Vented_BackingUnderange asked to check into rough minutes. that the cable is pump Passes - fitted between Pump cable Ready the instrument is attached Fails - and the backing between Ready pump. instrument Blocked and Resolve button and rough goes to available to pump.” resolution 2 press once PICTURE Outcome 2: completed. TO BE Instrument Resolution 2: INCLUDED will try and Customer is OF CABLES turn backing asked to check Wording 2: pump on the oil level in “Check the again and the pump. If oil oil level in see if is not within the pump” backing shown levels for pump gets to operation or 32 mbar in empty then top 3 minutes. up with oil. Either: Resolve button Passes - available to Ready press once Fails (Issue completed remains) = Error - Rough Pumping Timeout Error Rough Error N/A Rough Pumping FSE will Call Service Fixed Pumping Timeout investigate and Timeout Warning once resolved Error resolutions have issue will power (cat 3) not fixed the cycle instrument problem and so an error has been generated. Unresolved Warning Backing Error N/A Firmware will generate a FSE will Call Service Fixed Pump Venting_BackingGaugeError or investigate and Gauge Vented_BackingGaugeError or once resolved Error Venting_BackingFilamentError issue will power (cat 3) or cycle instrument Vented_BackingFilamentError Backing Getting N/A Backing pressure checks N/A N/A N/A Pressure Ready are started 1 minute Settling after the turbo speed (status) turbo speed is ≥15%. This is when the backing pressure is not stable and still decreasing/increasing. Blockage Ready 13 One minute Customer “Possible If blocked Warning Blocked after the turbo requested to aperture disc then customer (cat 2) speed is turbo check aperture blockage: replaces (Status speed is ≥15% disc aperture Clean or replace aperture area = the backing disc for aperture disc carrier. source) pressure read- blockage aperture disc Passes - back is lower by completing Ready/Getting than 1.45 mbar aperture disc ready* indicating a maintenance.” Ready blockage over Blocked - the aperture Different disc. vacuum warning generated Fail - Same fault seen after resolution - Error Incorrect Ready 13 One minute Check if QDa “Aperture disc Customer aperture Blocked after the turbo aperture disc blockage or replaces disc fitted speed is turbo has been fitted incorrect aperture disc. Warning speed is ≥15% or if blockage. aperture disc Passes - (cat 2) the backing fitted: Clean Ready/Getting (Status pressure read- or replace ready* area = back is between aperture disc Ready source) 0.8 and 1.0 by completing Blocked - mbar (0.09 mm aperture disc Different aperture disc). maintenance” vacuum This must take warning priority over generated blockage Fail - Same fault seen after resolution - Error Incorrect Error N/A Incorrect Aperture FSE will Call Service Fixed Aperture Warning has not investigate and disc Error been resolved once resolved (cat 3) and so the error issue will power is generated. cycle instrument Aperture Ready 18 One minute Customer “No aperture Passes - disc Missing Blocking after the turbo requested to fit disc fitted: Ready/Getting Warning speed is turbo aperture disc to Fit aperture ready* (cat 2) speed is ≥15% instrument disc by Ready (Status the backing completing Blocking - area = pressure read- aperture disc Different source) back is between maintenace” vacuum warning 5.0 and 6.0 generated mbar which is Fail - Same equivalent to fault seen after there being no resolution - aperture disc on Error the aperture *Instrument carrier. pump down so will continue in getting ready state Aperture Error N/A Aperture disc FSE will Call Service Fixed Disc Error Missing Warning investigate and (cat 3) has not been once resolved resolved and so issue will power the error is cycle instrument generated. Backing Ready  9 One minute Resolution 1: Wording 1: Outcome 1: Pressure Blocked after the turbo Customer “Check oil Oil leak on High speed is turbo requested to level” backing Warning speed is ≥15% check the Wording 2: pump - (cat 2) the backing becking pump “Check the switch off (Status pressure read- has oil, that following instrument area = back is between there is no oil lines are and contact vacuum) 6 mbar and 10 leak and that the secure: - pump serive mbar oil return is not Backing Oil return full of oil. line to full - Resolution 2: instrument - power off Check backing Backing instrument line and exhaust Line to pump - and empty line connections Exhaust oil return are tight. line to pump back into PICTURE pump INCLUDED Backing SHOWING pump oil is BACKING empty - AND switch off EXHAUST instrument LINES and fill backing CONNECTED pump with oil. TO Rebooted INSTRUMENT and all OK AND PUMP Ready Blocked - Different vacuum warning generated Fails = Generate Error Outcome 2: Rebooted and all OK Ready Blocked - Different vacuum warning generated Fails = Move to error Backing Error N/A Backing Pressure FSE will Call Service Fixed Pressure High Warning is investigate and High Error unresolved and once resolved (cat 3) error is issue will power generated. cycle instrument Unknown Ready 10 One minute after Customer “Possible Passes - aperture Blocked the turbo speed is requested aperture disc Ready disc turbo speed is ≥15% to check misalignment: Ready Warning the backing aperture disc Secure the Blocked - (cat 2) pressure read-back ALIGNMENT aperture disc Different (Status between 2 and 5 by completing vacuum warning area = mbar aperture disc generated vacuum) maintenance Fails = Generate Error Unknown Error N/A Unknown aperture FSE will investigate Call Service Fixed aperture disc Warning has and once resolved disc Error not be resolved and issue will power (cat 3) error is generated. cycle instrument Leaking Ready  8 If backing pressure Software initiates “Attempt Passes - Warning Blocked is above 10 mbar pump cycle system Ready (Status then the firmware pump down” Ready area = will initiate the vent Blocked - vacuum) sequence and sent Different (cat 2) the following vacuum warning Venting_BackingPressureHigh generated or Fails = Vented_BackingPressureHigh Generate Error Leaking Error N/A Leaking Warning FSE will investigate Call Service Fixed Error has not be resolved and once resolved (cat 3) and error is issue will power generated. cycle instrument Backing Passed N/A One minute after N/A N/A N/A OK the turbo speed is (status) turbo speed is ≥15% the backing pressure read-back is within the normal operating range 1.45-2.0 mbar. Turbo Getting N/A Turbo speed is N/A N/A N/A Speeding Ready between 1% and Up 79% (status) Turbo Ready  5 Turbo has not been Software initiates “Attempt Passes - Pumping Blocked able to reach 80% pump cycle system Ready Timeout nominal speed pump down” Ready Warning within the 8 Blocked - (cat 2) minutes, firmware Different (Status will imitate vent vacuum warning area = sequence and will generated vacuum) generate Fails = Venting_TurboSpeedNotAchieved Generate or Error Vented_TurboSpeedNotAchieved Turbo Error N/A Turbo Pumping FSE will Call Service Fixed Pumping Timeout Warning investigate Timeout has not been and once Error resolved and so resolved (cat 3) error was issue will generated. power cycle instrument Turbo Trip Ready  5 Turbo was above Software “Attempt Passes - Warning Blocked 80% and has now initiates system Ready (cat 2) dropped to 80% or pump cycle pump down” Ready (Status below the firmware Blocked - area = will initiate the vent Different vacuum) sequence and vacuum warning generate either generated Venting_TurboSpeedTrip Fails = or Generate Vented_TurboSpeedTrip Error Turbo Trip Error N/A Turbo Trip Warning FSE will investigate Call Service Fixed Error has not been and once resolved (cat 3) resolved and so issue will power error was generated. cycle instrument Turbo OK Passed N/A Turbo has reached N/A N/A N/A (status) 80% within the required 8 minutes Pumping Getting N/A Instrument ToF N/A N/A N/A Down Ready pressure is (status) between 1 × 10.sup.−4 and 1 × 10.sup.−6 mbar Pumping Error N/A ToF pressure does FSE will investigate. Call Service Fixed Down Error not reach required Fixes issue and (cat 3) vacuum pressure goes to Getting within 12 hours Ready Power (TBD) cycles instrument ToF Passed N/A ToF pressure is at N/A N/A N/A Pressure 1 × 10.sup.−6 or below OK (TBD) (status) ToF Gauge Error N/A Firmware has FSE will investigate. Call Service Fixed Error received an error Fixes issue and (cat 3) from the ToF gauge goes to Getting and so will vent the Ready Power instrument. cycles instrument Firmware will send Readback/event (ToF Gauge Error) to software and then software can generate this error. Tof Over Ready 16 Firmware has Software checks “Waiting for Turbo and Pressure Blocked indicated a ToF that the turbo speed system to re- backing Warning over pressure state is above 98% and equilibrate” values Ok (Status has occurred. that the backing commence area = Over-pressure or pressure is at four hour vacuum) Over-Pressure with optimum value. wait period (cat 2) Source Interlock. (pressure Please note needs to voltages that are reach ≥7 × allowed on will be 10−7 controlled by mbar before firmware. can continue using instrument). Ready Blocked - Different backing vacuum warning generated Fails - Backing pressure or turbo speed not correct - Tof Pressure Error Fails - over four hours waiting and pressure is still not correct - Error Tof Over Error N/A Tof Over Pressure FSE will investigate. Call Service Fixed Pressure Warning has not Fixes issue and Error been resolved or goes to Getting (cat 3) conditions not met Ready in resolution 1 Power cycles (backing pressure instrument and turbo speed) and so error generated Typhoon Getting N/A Typhoon modules N/A N/A N/A Module Ready turned on and time Booting is less than 60 (status) seconds since turned on Module Ready  7 Any of the modules Resolution 1: Wording 1: Outcome 1: Warning Blocked fail to communicate Software will “Checking Passed - [include within 60 seconds. rediscover the electronics All which [Source HT, network units” modules present module/ StepWave Ion Resolution 2: Wording 2: Fails - modules Guide, Ion Guide 2, Customer is asked “Electronics Still missing failed in Pusher, Reflectron, to reboot the reboot modules - name] Detector, ADC] electronics required” move to (Status PICTURE resolution 2 area = INCLUDED Outcome 2: electronics) FOR Passed - (cat 2) ELECTRONICS All REBOOT modules present BUTTON Fails - LOCATION Still missing modules - ERROR Module Ready  7 Any of the modules Resolution 1: Wording 1: Outcome 1: Warning Blocked disappear from the Software will “Checking Passed - [include network at any rediscover the electronics All which given time during network units” modules present module/ instrument Resolution 2: Wording 2: Fails - modules operation Customer is asked “Electronics Still missing failed in to reboot the reboot modules - name] electronics required” move to (Status PICTURE resolution 2 area = INCLUDED Outcome 2: electronics) FOR Passed - (cat 2) ELECTRONICS All REBOOT modules present BUTTON Fails - LOCATION Still missing modules - ERROR Typhoon Error N/A Typhoon Module FSE will investigate. Call Service Fixed Module Warning not been Fixes issue Error resolved and error and goes to (cat 3) is generated Getting Ready Power cycles instrument Typhoon Passed N/A All typhoon N/A N/A N/A Module OK modules (status) communicating within the given time period Readback Warning N/A This is generated Customer asked to “Recover Fixed - Warning when no readbacks reboot electronics Electronics” Ready (cat 2) are provided to the Fails software. (issue remains) = Error - Readback Error Readback Error N/A This is generated FSE will investigate Call Service Fixed Error when the wanring and once resolved (cat 3) has not been issue will power resolved. cycle instrument ToF Getting N/A ToF voltage is N/A N/A N/A Voltage Ready fluctuating but has Settling not reached time (status) limit of 5 minutes. ToF Error N/A ToF voltage has not FSE will investigate. Call Service Fixed Voltage stabilised within set Fixes issue and Settled tolerance to goes to Getting Timeout required voltage Ready Error within allocated Power cycles (cat 3) time 5 minutes. instrument ToF Passed N/A ToF voltage has N/A N/A N/A Voltage stabilised at Settled required voltage (status) within 5 minutes. Reflectron Getting N/A Reflectron voltage N/A N/A N/A Voltage Ready is fluctuating but Settling has not reached time (status) limit of 5 minutes. Reflectron Error N/A Reflectron voltage FSE will investigate. Call Service Fixed Voltage is fluctuating but Fixes issue and Error has reached time goes to Getting (cat 3) limit of 5 minutes. ReadyPower cycles instrument Reflectron Passed N/A Reflectron voltage N/A N/A N/A Voltage has stabilised at Settled required voltage (status) within 5 minutes. Detector Getting N/A Detector voltage is N/A N/A N/A Voltage Ready fluctuating but has Settling not reached time (status) limit of 5 minutes. Detector Error N/A Detector voltage is FSE will investigate. Call Service Fixed Voltage fluctuating but has Fixes issue and Error reached time limit goes to Getting (cat 3) of 5 minutes. Ready Power cycles instrument Detector Passed N/A Detector voltage N/A N/A N/A Voltage has stabilised at Settled required voltage (status) within 5 minutes. Voltage Error N/A For all voltages FSE will investigate. Call Service Fixed Readback (except ToF, Fixes issue and Error Detector and goes to Getting (cat 3) Reflectron) the Ready readback is not Power cycles within the tolerance instrument stated for the requested voltage. The error should include the name of the voltage(s) that have failed. Voltage Passed N/A For all voltages N/A N/A N/A Readback (except ToF, OK Detector and (status) Reflectron) the readback is within the tolerance stated for the requested voltage Polarity Getting N/A All or any of the N/A N/A N/A Voltage Ready other voltages Settling (except Tof, (status) Reflectron and Detector) are fluctuating in the correct polarity but has not reached time limit of 5 minutes. Polarity Error N/A All or any of the FSE will Call Service Fixed Voltage other voltages investigate. Error (except Tof, Fixes issue (cat 3) Reflectron and and goes to Detector) are Getting fluctuating in the Ready correct polarity but Power cycles has not reached instrument time limit of 5 minutes. Polarity Passed N/A All other voltages N/A N/A N/A Voltage have stabilised at Settled required voltage (status) and polarity within 5 minutes. ToF Getting N/A Monitoring the ToF N/A N/A N/A Current Ready Current readback Checking during the first thirty (status) minutes when ToF voltage is turned on ToF current fluctuating but has not reached time limit ToF Error N/A During the first FSE will investigate. Call Service Fixed Current thirty minutes when Fixes issue and Error ToF voltage is goes to Getting (cat 3) turned on, the ToF Ready current fluctuates Power cycles outside the limits instrument (TBD) on more than TBD occasions ToF Passed N/A During the first N/A N/A N/A Current OK thirty minutes when (status) ToF voltage is turned on, the ToF current remains within the limits or only fluctuates out of the limits by TBD occasions Reflectron Getting N/A Monitoring the N/A N/A N/A Current Ready Reflectron Current Checking readback during the (status) first thirty minutes when ToF voltage is turned on - ToF current fluctuating but has not reached time limit Reflectron Error N/A During the first FSE will investigate. Call Service Fixed Current thirty minutes when Fixes issue and Error Reflectron voltage goes to Getting (cat 3) is turned on, the Ready Reflectron current Power cycles fluctuates outside instrument the limits (TBD) on more than TBD occasions Reflectron Passed N/A During the first N/A N/A N/A Current OK thirty minutes when (status) Reflectron voltage is turned on, the Reflectron current remains within the limits or only fluctuates out of the limits by TBD occasions Source Ready 11 No source Customer asked to “Check source Fixed - Warning Blocked enclosure fitted check is source enclosure is Ready (Status enclosure fitted and fitted and Fails area = cable connected to cable is (issue remains) = source) instrument. secured” Error - (cat 2) INCLUDE Source PICTURE Error Source Error N/A Source Warning FSE will investigate. Call Service Fixed Error has not been Fixes issue and (cat 3) resolved and error goes to Getting is generated Ready Power cycles instrument Source OK Passed N/A Source enclosure N/A N/A N/A (status) fitted Source Ready 19 Source interlock Source door closed “Close Fixed - Door Blocked shows source door source door” Ready Warning is open Fails (cat 2) (issue remains) = (Status Error - area = Source source) Door Error Source Error N/A Source Door Source interlock Call Service Fixed Door Error Warning shows source cover (cat 3) is open Source Passed N/A Source interlock N/A N/A N/A Door OK shows door closed (status) Source Getting N/A Source Temperature is N/A N/A N/A Temperature Ready fluctuating but time Settling has not elapsed yet. (status) Please note that source heater is NOT turned on until reach Vac OK so software should start timer then Source Error N/A Source temperature FSE will investigate. Call Service Fixed Temperature has not stabilised to Fixes issue and Timeout required value (at goes to Getting (cat 3) least −5° C. on Ready requested value, or Power cycles up to +40° C. above instrument requested) within the allocated time (ten minutes - TBD) Source Passed N/A Source N/A N/A N/A Temperature Temperature is Settled stable at the (status) required temperature Source Error N/A Source heater is FSE will investigate. Call Service Fixed Heater not connected and Fixes issue and Disconnected so can not heat goes to Getting Error Ready (cat 3) Power cycles instrument Source Passed N/A Source heater is N/A N/A N/A Heater connected and Connected source is heating (status) Desolvation Getting N/A Desolvation N/A N/A N/A Temperature Ready temperature is Settling fluctuating but time (status) has not yet elapsed. Please note that Desolvation heater is not turned on until the instrument gas is tuned on and in operate. Desolvation Error N/A Desolvation FSE will investigate. Call Service Fixed Temperature temperature has Fixes issue and Settling not stabilised to goes to Getting Failed required value (±5° C. Ready (cat 3) on requested Power cycles value) within the instrument allocated time (five minutes - TBD) Desolvation Passed N/A Desolvation N/A N/A N/A Temperature temperature has Settled settled within the (status) allocated time Nitrogen Ready  3 Gas Fail State Request customer “Check Fixed - Gas Blocked Initiated by to check nitrogen Nitrogen Ready Failure Firmware- Gas pressure inlet is at 7 pressure is Fails Warning Pressure is below 4 Bar within the (issue remains) = (cat 2) Bar range 6.5 Error - (Status and 7 Bar” Nitrogen area = Gas gas) Failure Nitrogen Ready  3 Nitrogen gas Request customer “Check Fixed - Gas Blocked pressure is within to check nitrogen Nitrogen Ready Warning the range 6.5-7.5 pressure inlet is at 7 pressure is Fails (Status Bar. Firmware will Bar within the (issue remains) = area = send this range 6.5 Error - gas) information. and 7 Bar” Nitrogen (cat 2) Gas Failure Nitrogen Error N/A Nitrogen Gas Gas Fail State Call Service Fixed Gas Failed Warning initiated - Gas (cat 3) pressure is below 4 Bar Nitrogen Passed N/A Gas fail state NOT N/A N/A N/A Gas OK initiated (status) Source Getting N/A Source Pressure N/A N/A N/A Pressure Ready test running Test Running (status) Source Informat N/A Instrument has Customer needs to N/A Fixed - Pressure ion failed the source run Source Ready Test pressure test and Pressure Test Overridden the over ride has (status) been selected. [Warning message included] Low API Ready  3 The Check Request customer “Check Fixed - Gas Blocked pressure switch has to check nitrogen Nitrogen Ready Pressure determined the pressure inlet is at 7 pressure is Fails Warning pressure is below 4 Bar within the (issue remains) = (cat 2) Bar for longer than range 6.5 Error - (Status 1 second and 7 Bar” Nitrogen area = This is generated Gas gas) when Firmware Failure creates an event for Source Pressure Test Failed - Low API Gas Pressure Low API Error N/A The Low API Gas Request customer Call Service Fixed Gas Pressure Warning to check nitrogen Pressure has not been pressure inlet is at 7 Error resolved and so Bar (cat 3) this error is generated Exhaust Ready 12 Exhaust pressure is Resolution 1: Wording 1: Outcome 1: Pressure Blocked too high with Customer asked to “Ensure no Fixed - Too High exhaust valve open check for bends or Ready Warning LC flow to wate. restrictions in tubing folds in Fails - (cat 2) This is generated between instrument tubing. If Ready (Status when Firmware and waste bottle bend or fold Blocked and area = creates an event for Resolution 2: present replace goes to exhaust) one of the Customer then tubing”PICTURE resolution following: asked to check for INCLUDED 2Over- Warning: Possible restrictions in tubing SHOWING ride Exhaust between waste INSTRUMENT Option Problem Source bottle and exhaust AND SOURCE (must present pressure Test Resolution 3: WASTE warning that Failed - Exhaust Cutstomer asked to BOTTLE over-ride is Pressure too high check exhaust is at WITH selected at atmospheirc TUBING start of each pressure or below. INDICATED acquisition) Wording 2: Outcome 2: “Ensure no Fixed - bends or Ready folds in Fail - tubing. If Ready bends or folds Blocked present and goes to replace resolution tubing”PICTURE 3Over- INCLUDED ride Option SHOWING (must present INSTRUMENT warning that AND SOURCE over-ride is WASTE selected at BOTTLE AND start of each EXHAUST acquisition) WITH TUBING Outcome 3: INDICATED Fixed - Wording 3: Ready “Check the Fails lab exhaust (issue system is remains) = marinating Error - the exhaust SPT outlet at or Failed below Exhaust atmospheric HighOver- pressure.” ride Option (must present warning that over-ride is selected at start of each acquisition) Exhaust Error N/A Exhaust Pressure FSE will investigate. Call Service Fixed Pressure Too High Warning Fixes issue and Too High not resolved and goes to Getting Failure error generated Ready (cat 3) Power cycles instrument Source Ready 12 Leaky source Resolution 1: Wording 1: Outcome 1: Leak Blocked enclosure - not Customer asked to “Ensure Fixed - Warning reaching correct check probe fitted probe is Ready (cat 2) pressure in correctly fitted Fails - (Status enclosure - LC Resolution 2: correctly” Ready area = Flow to waste. Remove and reseat PICTURE Blocked and source) This is generated source enclosure INCLUDED goes to when Firmware Resolution 3: SHOWING resolution 2 creates an event for Replace source PROBE Over-ride one of the enclosure O-ring FITTED Option following: CORRECTLY (must present Warning: Possible Wording 2: warning that Source Leak “Remove over-ride is Source pressure and refit the selected at Test Failed - source start of each Source Leak enclosure” acquisition) Wording 3: Outcome2: “Replace Fixed- source Ready enclosure Fails- o-ring” Ready blocked and goes to resolution 3 Over-ride Option (must present warning that override is selected at start of each acquisition) Outcome 3: Fixed- Ready Fails (issue remains) = Error- SPT Failed Source Leak Over-ride Option (must present warning that over-ride is selected at start of each acquisition) Source Error N/A Source Leak FSE will Call Service Fixed Leak Warning not investigate. Failure resolved and error Fixes issue (cat 3) generated and goes to Getting Ready Power cycles instrument Source Passed N/A Source Pressure N/A N/A Pressure Test passed Test OK (status) Fluidics Ready 14 Fluidics control Resolution 1: Wording 1: Outcome 1: Communications Blocked board not Customer asked to “Recover Fixed - Warning communicating reboot electronics Fluidics” Ready (cat 2) Resolution 2: Wording 2: Fails - (Status “Electronics Ready area = reboot Blocked and electronics) required” goes to PICTURE resolution 2 INCLUDED Outcome 2: FOR Fixed- ELECTRONICS Ready REBOOT Fails- BUTTON Go to LOCATION error state Fluidics Error N/A Fluidics control FSE will investigate. Call Service Fixed Communication board not Fixes issue and Error communicating goes to Getting (cat 3) Ready Power cycles instrument Leak Ready  2 Leak senor has Resolution 1: Wording 1: Outcome 1: Detector Blocked detected a leak. Check for liquid in “Check drip Fixed - Sensor Stop flow LC drip tray - dry tray for fluid. Ready Warning sensor if leak If fluid present Fails - (cat 2) present then check for Ready (Status Resolution 2: leaks. - Blocked area = Replace leak Replace and goes to fluidics) sensor tubing and resolution 2 connections- Outcome 2: Clean up Fixed - liquid and Ready wait for Fails sensor to (issue remains) = dry” Error - Wording 2: Leak “Replace Detector Leak Sensor sensor.- Open door- Disconnect leak sensor.- Fit new leak sensor - Close source door”PICTURE INCLUDED TO SHOW LOCATION OF LEAK SENSOR Leak Error N/A Leak Detector FSE will investigate. Call Service Fixed Detector Sensor Warning Fixes issue and Sensor - unresolved and goes to Getting Failed error generated Ready (cat 3) Power cycles instrument Leak Passed N/A No leak detected N/A N/A N/A Detector from sensor Sensor OK (status) Positive Informat N/A Instrument has not Once customer tries N/A Ready Not Set ion been setup for to run a positive ion Blocked (status) positive ion mode mode experiment this will change to a warning Positive Ready 25 Customer has Customer selects “Perform Failures Mode Blocked selected to run a positive instrument positive during Warning positive ion mode setup to be carried ionisation set-up will (cat 2) method and the out mode generate own (Status instrument is not Please note only a instrument warnings/errors area = set up for positive warning IF set-up” setup) ion mode customer has selected to run a sample in this mode. Otherwise information Negative Informat N/A Instrument has not Once customer tries N/A Ready Not Set ion been setup for to run a negative Blocked (status) negative ion mode ion mode experiment this will change to a warning Negative Ready 25 Customer has Customer selects “Perform Failures Mode Blocked selected to run a negative instrument negative during Warning negative ion mode setup to be carried ionisation set-up will (cat 2) method and the out mode generate own (Status instrument is not Please note only a instrument warnings/errors area = set up for negative warning IF set-up” setup) ion mode customer has selected to run a sample in this mode. Otherwise information Fluidics Ready 14 The instrument has Resolution 1: Wording 1: Outcome 1: Check Blocked not detected a Customer asked to “Check lock- Software Warning beam in the any of check that sample mass, wash must Purge (cat 2) the setup is present. and calibrant Fluidics (Status procedures Resolution 2: solutions are before area = Customer asked to present” retrying setup) check flow from Wording 2: Fixed - tubing to source “Check flow Ready enclosure. to probe - Fails - Once probe Open door Ready removed and ready and remove Blocked to check customer probe - and goes to will press button Check flow resolution 2 and software to probe by Outcome 2: will tell selecting Fixed - fluidics to button Ready flow for If no flow Fails - 30 seconds. present Generate check for Error leaks” Fluidics Error N/A Fluidics Check FSE will investigate. Call Service Fixed Check Warning has not Fixes issue and Error resolved and error goes to Getting (cat 3) is generated Ready Power cycles instrument Beam Error N/A Detector reached FSE will investigate. Call Service Fixed Detection maximum output Fixes issue and Error voltage and still no goes to Getting (cat 3) beam present Ready during beam setup Power cycles instrument Beam Error N/A Third time that the FSE will investigate. Call Service Fixed Check software has Fixes issue and Resolution attempted to reach goes to Getting Error the required Ready (cat 3) resolution and peak Power cycles shape requirements instrument outlined in set up procedure for beam check Beam Passed N/A Beam Check N/A N/A N/A Check procedure Passed completed and (status) passed Average Ready 22 Detector voltage Customer or “Attempt Fixed - Ion Area Blocked and/or average ion instrument instrument Ready Failure area could not be automatically setup” Fails Warning set clears ADC (issue remains) = (cat 2) settings and Error - (Status recommence AIA area = Instrument Failure setup) Set-up Average Error N/A AIA Failure FSE will investigate. Call Service Fixed Ion Area Warning has not Fixes issue and Failure been resolved and goes to Getting Error error is generated Ready (cat 3) Power cycles instrument Low Ready 21 Beam unstable/ Resolution 1: Wording 1: Outcome 1: Intensity Blocked Insufficient ions/ Customer check “Check Software Signal Beam intesity too sample present if lockmass, must Purge Warning few ions not enough ions is calibrant and Fluidics (cat 2) the issue wash solutions before (Status Resolution 2: are present” retrying area = Customer asked to Wording 2: Fixed - setup) replace sample if “Replace Ready not enough ions is with fresh Fails - the issue Waters Ready Resolution 3: approved Blocked Customer asked to sample” and goes to check for leaks Wording 3: resolution 2 Resolution 4: “Check for Outcome 2: Customer asked to leaks” Fixed - replace capillary if Wording 4: Ready not enough ions is “Replace Fails - the issue probe- Ready Unscrew the Blocked line for the and goes to probe from resolution 3 the Divert Outcome 3: valve. Fixed - Unscrew the Ready probe from Fails - the source Ready enclosure Blocked and dispose and goes to of the probe resolution 4 Carefully Outcome 4: insert the Fixed - probe into Ready the inlet atop Fails the source (issue remains) = enclosure Error- and tighten Beam probe fitting Stability - until it clicks Not enough Secure the ions line of the probe to the divert valve.” INCLUDE PICTURE OF PROBE FITTINGS Low Error N/A Beam Stability - FSE will investigate. Call Service Fixed Intensity Few Ions Warning Fixes issue and Signal is not resolved and goes to Getting Error error is generated Ready (cat 3) Power cycles instrument Beam Ready 20 Beam unstable/ Resolution 1: Wording 1: Outcome 1: Unstable Blocked Beam intensity too Customer or “Purge Fixed - Warning high instrument repurge Fluidics” Ready (cat 2) fluidics Wording 2: Fails - (Status Resolution 2: “Check Peek Ready area = Customer asked to tubing fittings Blocked setup) check peek tubing for leaks” and goes to is fitted correctly INCLUDE resolution 2 Resolution 3: PICTURE Outcome 2: Customer asked to OF DIVERT Fixed - replace probe VALVE Ready SHOWING ALL Fails - CONNECTIONS Ready Wording 3: Blocked “Replace and goes to probe resolution 3 Unscrew Outcome 3: the line for Fixed - the probe Ready from the Fails Divert valve. (issue remains) = Unscrew Error - the probe Beam from the Stability - source Beam enclosure unstable and dispose of probe Carefully insert the probe into the inlet atop the source enclosure and tighten probe fitting until it clicks. Secure the line of the probe to the divert valve.” INCLUDE PICTURE OF PROBE FITTING Beam Error N/A Beam Stability - FSE will investigate. Call Service Fixed Unstable Beam Unstable Fixes issue and Error Warning not goes to Getting (cat 3) resolved and error Ready is generated Power cycles instrument High Ready 21 Beam unstable/ Resolution 1: Wording 1: Outcome 1: Intensity Blocked Beam intensity too Customer “Purge Fixed - Signal high requested change Fluidics” Ready Warning to purge fluidics. Wording 2: Fails - (cat 2) Resolution 2: “Replace Ready (Status Customer with Waters Blocked area = requested change approved and goes to setup) to preferred Waters sample” resolution 2 sample Outcome 2: Software must Purge Fluidics before retrying Fixed - Ready Fails (issue remains) = Error - Beam Stability - Intensity High High Error N/A Beam Stability - FSE will investigate. Call Service Fixed Intensity Intensity High Fixes issue and Signal Warning not goes to Getting Error resolved and error Ready (cat 3) is generated Power cycles instrument Detector Passed N/A Detector setup N/A N/A N/A Setup completed and Positive passed in positive Passed ion mode (status) Detector Passed N/A Detector setup N/A N/A N/A Setup completed and Negative passed in negative Passed ion mode (status) Beam Error N/A Third time that the FSE will investigate. Call Service Fixed Check software has Fixes issue and Auto-tune attempted to reach goes to Getting Resolution the required Ready Error resolution and peak Power cycles (cat 3) shape requirements instrument outlined in set up procedure for auto- tune Beam Error N/A Third time that the FSE will investigate. Call Service Fixed Check software has Fixes issue and Auto-tune attempted to reach goes to Getting Sensitivity the required Ready Error sensitivity Power cycles (cat 3) requirements instrument outlined in set up procedure for auto- tune Auto tune Passed N/A Auto tune N/A N/A N/A Setup procedure Passed completed and (status) passed Calibration Ready 23 Calibration Failed Resolution 1: Wording 1: Outcome 1: Failure Blocked to reach required Customer asked to “Check Software Warning ppm check correct calibration must Purge (Status sample present sample Fluidics area = Resolution 2: present” before retrying setup) Customer asked to Wording 2: Fixed - (cat 2) check for leaks “Check for Ready Resolution 3: leaks” Fails - Software will Wording 3: Ready immediately return “Attempt Blocked to the Auto-tune instrument and goes to section and re-run setup” resolution 2 this test. Outcome 2: Fixed - Ready Fails - Ready Blocked and goes to resolution 3 Outcome 3: Fixed - Ready Fails (issue remains) = Error - Calibration Failure Calibration Error N/A Calibration Failure FSE will investigate. Call Service Fixed Failure Warning not Fixes issue and Warning resolved and error goes to Getting Error is generated Ready (cat 3) Power cycles instrument Calibration Passed N/A Calibration N/A N/A N/A Passed procedure (status) completed and passed Low Mass Informat N/A Instrument has not Once customer tries N/A Ready Positive ion been setup for low to run a low mass Blocked Calibration mass positive mode mode experiment Absent this will change to a (status) warning Low Mass Ready 25 Customer has Customer must “Perform Customer Positive Blocked selected to run a carryout this low positive caries out Calibration positive ion low mass calibration. ionisation low mass Warning mass experiment low mass calibration (Status and the positive ion calibration” manually and area = low mass instrument setup) calibration has not moves to (cat 2) been carried out. Getting Ready. Same errors generated for high or low mass calibration. Low Mass Passed N/A Calibration N/A N/A N/A Positive procedure Calibration completed and (status) passed High Mass Informat N/A Instrument has not Once customer tries N/A Ready Positive ion been setup for high to run a high mass Blocked Calibration mass positive mode mode experiment Absent this will change to a (status) warning High Mass Ready 25 Customer has Customer must “Perform Customer Positive Blocked selected to run a carryout this high positive caries out Calibration positive ion high mass calibration. ionisation high mass Warning mass experiment high mass calibration (cat 2) and the positive ion calibration” manually and (Status high mass instrument area = calibration has not moves to setup) been carried out. Getting Ready. Same errors generated for high or high mass calibration. high Mass Passed N/A Calibration N/A N/A N/A Positive procedure Calibration completed and (status) passed Low Mass Informat N/A Instrument has not Once customer tries N/A Ready Negative ion been setup for low to run a low mass Blocked Calibration mass negative mode experiment Absent mode this will change to a (status) warning Low Mass Ready 25 Customer has Customer must “Perform Customer Negative Blocked selected to run a carryout this low negative caries out Calibration negative ion low mass calibration. ionisation low mass Warning mass experiment low mass calibration (cat 2) and the negative calibration” manually and (Status ion low mass instrument area = calibration has not moves to setup) been carried out. Getting Ready. Same errors generated for high or low mass calibration. Low Mass Passed N/A Calibration N/A N/A N/A negative procedure Calibration completed and (status) passed High Mass Informat N/A Instrument has not Once customer tries N/A Ready Negative ion been setup for to run a high mass Blocked Calibration negative high mass mode experiment Absent mode this will change to a (status) warning High Mass Ready 25 Customer has Customer must “Perform Customer Negative Blocked selected to run a carryout this high negative caries out Calibration negative ion high mass calibration - ionisation high mass Warning mass experiment customer will be high mass calibration (cat 2) and the negative requested to calibration” manually and (Status ion high mass change the instrument area = calibration has not calibration solution moves to setup) been carried out. to TBD for high Getting mass calibration. Ready. Same errors generated for high mass positive calibration as standard calibration High Mass Passed N/A Calibration N/A N/A N/A Negative procedure Calibration completed and (status) passed Purging Getting N/A Fluidics are N/A N/A N/A Fluidics Ready carrying out a (status) purge cycle - on completion will fill with lockmass purged sample and move to ready state Fluidics Getting N/A Fluidics are N/A N/A N/A Washing Ready carrying out a wash (status) cycle - on completion will fill with wash solution and move to ready state Fluidics Ready 15 Fluidics command Customer initiates “Restart Fixed - Aborted Blocked has been cancelled restart OR Fluidics” Ready State before request was Instrument Fails Warning completed immediately initiates (issue remains) = (cat 2) a restart Error - (Status Fluidics area = Aborted Fluidics) State Fluidics Error N/A Fluidics Aborted FSE will investigate. Call Service Fixed Aborted State Warning has Fixes issue and State Error not been resolved goes to Getting (cat 3) and this error is Ready generated Power cycles instrument Power Informat N/A Instrument in power Customer needs to N/A Fixed - Save Mode ion save mode - select Operate Ready (status) Voltages on except aperture disc, gasses off and desolvation heater off Maintenance Error N/A Maintenance mode FSE will investigate. Call Service Fixed Mode is on and needs to Fixes issue and (cat 3) be tuned off goes to Getting Ready Power cycles instrument Detector Error N/A Generated when Information for Call Service Fixed PSU Fault the following event engineer (cat 3) comes form diagnostics - Gives DEVICE_4_6.xmlP the status of the SU_PC1_Output_Status detector power convertor and so indicates detector output status Detector Error N/A Generated when Information for Call Service N/A PSU Fault the following event engineer (cat 3) comes form diagnostics - Gives DEVICE_4_6.xml the status of the PSU_PC2_Output_Status ToF power convertor and so indicates ToF output status Reflectron Error N/A Generated when Information for Call Service Fixed PSU Fault the following event engineer (cat 3) comes form diagnostics - Gives DEVICE_4_5.xml the status of the PSU_PC1_Output_Status reflectron power convertor and so indicates reflectron output status Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates a fan fault Fan_Fault with the pusher Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates a Temperature_Fault temperature pusher fault Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates a Switch Switch_Leak_Fail Leakage Test Fail Pusher Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates a current Trip_Fault trip Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates a Voltage Voltage_Error Error Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - Pulse DEVICE_7_0.xml Amplitude Error Pulse_Amplitude_Error Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates Rise/fall Rise_Fall_Error Time Error Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates Pulse Pulse_Parameter_Error Parameter Error Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates HV Step- Converter_Parameter_Error Up Converter Parameter Error Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates a trigger Trigger_Parameter_Error parameter error Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates ADC ADC_Trigger_Fault trigger fault Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates EDC error EDC_Error Pusher Error N/A Generated when Information for Call Service Fixed Unit Fault the following event engineer (cat 3) comes form diagnostics - DEVICE_7_0.xml indicates a HV error HV_Error DCC Fault Error N/A Generated when Information for Call Service Fixed (cat 3) the following event engineer comes form diagnostics - DEVICE_11_0.xml indicates a Peripheral_WDT_Timeout watchdog fault DCC Fault Error N/A Generated when Information for Call Service Fixed (cat 3) the following event engineer comes form diagnostics - DEVICE_11_0.xml indicates heater Heater_Control_Status_LSB fault DCC Fault Error N/A Generated when Information for Call Service Fixed (cat 3) the following event engineer comes form diagnostics - DEVICE_11_0.xml indicates heater Heater_Control_Status_MSB fault DCC Fault Error N/A Generated when Information for Call Service Fixed (cat 3) the following event engineer comes form diagnostics - DEVICE_11_0.xml indicates leak Leak_Detector_Status detector status DCC Fault Error N/A Generated when Information for Call Service Fixed (cat 3) the following event engineer comes form diagnostics - DEVICE_11_0.xml indicates status of SPT_Status source pressure test Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - 24 V DEVICE_13_0.xml cut-off occurred Vol_24V_Cutoff_Event Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - 12 V DEVICE_13_0.xml cut-off occurred Vol_12V_Cutoff_Event Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - 5 V DEVICE_13_0.xml cut-off occurred Vol_5V_Cutoff_Event Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - 3.3 V DEVICE_13_0.xml cut-off occurred Vol_3V3_Cutoff_Event Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - 1.2 V DEVICE_13_0.xml cut-off occurred Vol_1V2_Cutoff_Event Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - ESI DEVICE_13_0.xml cut-off has occurred Vol_Esi_Cutoff_Event Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - ETD DEVICE_13_0.xml cut-off has occurred Vol_Etd_Cutoff_Event Source HT Error N/A Generated when Information for Call Service Fixed Fault the following event engineer (cat 3) comes form diagnostics - wrong DEVICE_13_0.xml polarity output Polarity_Mismatch

Annex 2

[0503]

TABLE-US-00008 TABLE 1 Term/Abbreviation Definition General Parameters that are visible to all users Advanced Parameters that are visible to advanced users (end users with an advanced level of instrument knowledge), service users, specialist users, and development users Service Parameters that are visible to service users (Waters field service engineers), specialist users (factory test engineers) and development users Specialist Parameters that are visible to specialist users (factory test engineers) and development users Development Parameters that are available to development (Dev) users only (i.e. members of the MS Research and MS Development departments) None Parameters that are not visible in the user interface F Factory - Parameters that can be saved as factory defaults by Specialist and Development users S System - Parameters that can be saved as a tune set by Specialist and Development users Calculated Parameters that are calculated by software, and are not editable PSU Power supply unit ESI Electrospray ionisation TIC Total ion current LM Low mass HM High mass RF Radio frequency EDC Extended duty cycle CE Collision energy DC Direct current Polarity A positive parameter value should give an output relationship = Same polarity the same as the ion polarity Polarity A positive parameter value should give an output relationship = polarity opposite to the ion polarity Opposite Polarity Output polarity does not change with ion polarity relationship = None