GB2575353A

GB2575353A - Bench-top time of flight mass spectrometer

Info

Publication number: GB2575353A
Application number: GB1907734.6A
Authority: GB
Inventors: Wamsley Ruth; Chummar Soji; Carney Peter; Mciver Paul; Murray Haydn
Original assignee: Micromass UK Ltd
Current assignee: Micromass UK Ltd
Priority date: 2018-05-31
Filing date: 2019-05-31
Publication date: 2020-01-08
Anticipated expiration: 2039-05-31
Also published as: GB201808948D0; GB201907734D0; WO2019229465A1; GB2575353B

Abstract

A mass spectrometer 1700 comprising: a vacuum chamber housing an electronic component therein; a voltage supply module 1717, 1718 for supplying a voltage to said electronic component; a pressure sensor for determining the pressure in the vacuum chamber; and a control module 1715 configured to cut power to the voltage supply module when the sensor determines that the pressure in the vacuum chamber is at or above a predetermined threshold, such that the voltage supply module is incapable of supplying a voltage to the component. This mitigates the risk of damage to the electronics inside the vacuum housing in the even of a vacuum failure. The electronic component may, for example, be an ion guide, or a pusher assembly, reflectron or ion detector in a time of flight mass analyser. The predetermined threshold pressure may be set based upon the maximum amplitude of the voltage that the voltage supply module is designed to supply.

Description

BENCH-TOP TIME OF FLIGHT MASS SPECTROMETER

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from and the benefit of United Kingdom patent application No. 1808948.2 filed on 31 May 2018. The entire content of this application is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to mass spectrometry and in particular to a small footprint or bench-top Time of Flight (“TOF”) mass spectrometer which has particular application in the biopharmaceutical industry.

BACKGROUND

Conventional mass spectrometers which may be used, for example, in the biopharmaceutical industry tend to be relatively complex and have a relatively large footprint.

Scientists in the biopharmaceutical industry need to collect high resolution accurate mass data for their samples in order to provide more comprehensive information than can be obtained using LCUV analysis. Conventionally, this is typically achieved either by running relatively complex mass spectrometry equipment or by outsourcing the analysis to a specialist service.

It is desired to provide a reduced footprint Time of Flight (“TOF”) mass spectrometer which may have particular application in the biopharmaceutical industry.

SUMMARY

From a first aspect the present invention provides a mass spectrometer comprising: a vacuum chamber housing an electronic component therein;

a voltage supply module for supplying a voltage to said electronic component;

a pressure sensor for determining the pressure in the vacuum chamber; and a control module configured to cut power to the voltage supply module when the pressure sensor determines that the pressure in the vacuum chamber is at or above a predetermined threshold pressure, such that the voltage supply module is incapable of supplying a voltage to the electronic component.

The inventors have recognised that in the event of a vacuum failure, the gas pressure in the vacuum chamber will increase, thereby increasing the likelihood of an electrical breakdown (e.g. arcing) occurring due to the voltage applied to the electronic component by the voltage supply module. The spectrometer is configured to cut off the

-2electrical power to the voltage supply module when such a vacuum failure is detected so as to prevent an electrical breakdown occurring and the damage to the electronic component that would otherwise occur.

It is to be noted that this is not the same as placing the voltage control module in a standby mode when a vacuum failure is detected. In such a standby mode the system control module simply would not instruct the voltage supply module to supply voltages to the component in the vacuum housing (or would instruct it not to). However, in such a standby mode, electrical power would still be supplied to the voltage control module. As such, a fault in the system could still result in the voltage control module being activated and supplying a voltage to the electric component when there is a vacuum failure. A standby mode would therefore not necessarily protect the instrument from electrical breakdown in the event of a vacuum failure. In contrast, in the power cut-off mode according to the embodiments herein, no power at all is supplied to the voltage control module in the event of a vacuum failure being detected and hence it is not possible for the voltage control module to supply any voltage to the electronic component.

The spectrometer cuts the power to the voltage supply module automatically when the pressure in the vacuum chamber is determined to be at or above the predetermined threshold pressure.

The voltage supply module may be arranged outside of the vacuum chamber.

The voltage supply module may be electrically connected to the electronic component in the vacuum chamber, for example, via one or more PCB as described herein.

The predetermined threshold pressure may be selected from: > 10'⁷ mbar; >5x10' ⁶ mbar; > 10'⁶ mbar;> 5 x 10'⁵ mbar; > 10'⁵ mbar; > 5 x 10'⁴ mbar; and > 10'⁴ mbar.

However, it is also contemplated that the predetermined threshold pressure may be selected from: > 5 x 10'³ mbar; > 10'³ mbar; > 5 x 10'² mbar; and > 10'² mbar.

The predetermined threshold pressure may be set based on the maximum amplitude of the voltage that the voltage supply module is configured to supply to the electronic component.

The spectrometer may comprise at least one pressure gauge for determining the pressure in the vacuum chamber.

The spectrometer may monitor the pressure in the vacuum chamber directly. Alternatively, the spectrometer may monitor the pressure indirectly, e.g. by determining the speed at which a vacuum pump pumping the vacuum chamber is operating at to determine whether or not there has been a vacuum failure. Alternatively, the spectrometer may comprise a vacuum failure switch in the vacuum chamber that is configured to switch off the power to the voltage control module when it is exposed to a pressure above the threshold value.

The control module may be configured to re-establish power to the voltage supply module when the pressure sensor determines that the pressure in the vacuum chamber is below the predetermined threshold pressure such that the voltage supply module is capable of supplying a voltage to the electronic component.

- 3This may be performed automatically when the pressure sensor determines that the pressure in the vacuum chamber is below the predetermined threshold pressure.

The control module may control a switch, based on the pressure sensed in the vacuum chamber, in order to cut off the power to the voltage control module or re-establish power to the voltage control module.

The voltage supply module may be configured to supply an AC or RF and/or DC voltage to the electronic component.

The spectrometer may comprise a plurality of the above-described arrangements, arranged in different vacuum chambers.

Accordingly, the spectrometer may comprise: a plurality of vacuum chambers, each vacuum chamber having an electronic component therein that is connected to a respective one of a plurality of voltage supply modules for supplying a voltage to the electronic component; wherein each vacuum chamber is associated with a pressure sensor for determining if the pressure in that vacuum chamber is at or above a predetermined threshold pressure; and wherein the control module is configured to cut power to any of the voltage supply modules if the pressure sensor associated with the vacuum chamber that houses the electronic component that it supplies a voltage to determines that the pressure in that vacuum chamber is at or above its respective predetermined threshold pressure.

The predetermined pressure threshold may be different for different vacuum chambers.

At least one of the electronic components may be an ion guide comprising a plurality of electrodes, and the voltage supply module may be configured to supply an AC or RF and/or DC voltage to these electrodes for guiding ions within the ion guide.

The spectrometer may comprise a first ion guide and a second ion guide downstream of the first ion guide. The first ion guide may transmit ions along a first axis and then transfer the ions to a second parallel axis. The second ion guide may be a segmented quadrupole rod set ion guide. The spectrometer may further comprise a set of one or more transfer lenses located downstream of the second ion guide.

At least one of the electronic components may be a time of flight mass analyser, wherein the voltage supply module is configured to supply an AC or RF and/or DC voltage to: (i) a pusher assembly in the mass analyser; and/or (ii) a reflectron in the mass analyser; and/or (iii) an ion detector in the mass analyser.

However, other forms of mass analyser may be used instead of the TOF mass analyser.

One of the electronic components may be an ion source, wherein the voltage supply module is configured to supply an AC or RF and/or DC voltage to the ion source, such as for generating ions and/or powering a heater therein.

One of the electronic components may be ion transfer optics comprising a plurality of electrodes, wherein the voltage supply module is configured to supply an AC or RF and/or DC voltage to these electrodes.

The mass spectrometer may comprise an ion source configured to receive fluid flow from an upstream liquid chromatography (LC) device. The mass spectrometer may comprise a valve. In the event of detecting the vacuum failure, the mass spectrometer may

-4be configured to control the valve such that fluid flow from the upstream LC device is not directed to the ion source. Hence, the spectrometer may comprise a valve configured to stop flow from an upstream LC device in the event of the vacuum failure (i.e. in response to determining that the pressure in the vacuum chamber is at or above the predetermined threshold pressure). In the event of a vacuum failure, the valve may divert flow from the upstream LC device into a waste vessel.

The stopping and/or diverting of flow from an upstream LC device in the event of a vacuum failure may prevent fluids (and analyte) from the LC device from passing to the ion source of the mass spectrometer, thereby preventing flow to an ion block of the mass spectrometer and through to downstream electronic components of the mass spectrometer which are positioned in one or more vacuum chambers. Fluid (and analyte) flow from the upstream LC device may comprise flammable substances. These substances could ignite if electrical breakdown (e.g. arcing) were to occur during vacuum failure, due to the relatively high gas pressure. Hence, it may be advantageous to prevent fluid (and analyte) from flowing in the event of during a vacuum failure.

The first aspect of the present invention also provides a method of mass spectrometry comprising:

providing a mass spectrometer as described above;

determining the pressure in the vacuum chamber using the pressure sensor; and cutting electrical power to the voltage supply module if the determined pressure is at or above the predetermined threshold pressure such that the voltage supply module is incapable of supplying a voltage to the electronic component.

The method may comprise selecting the predetermined threshold pressure. The predetermined pressure threshold may be selected based on the maximum amplitude of the voltage that the voltage supply module is configured to supply to the electronic component.

The present invention also provides a mass spectrometer comprising:

a liquid chromatography (LC) device;

an ion source arranged to receive fluid from the LC device;

a valve for selectively allowing said fluid to pass from the LC device to the ion source;

a vacuum chamber housing an electronic component therein; and a pressure sensor for determining the pressure in the vacuum chamber;

wherein the spectrometer is configured to control the valve such that fluid flow from the LC device is diverted away from the ion source when the pressure sensor determines that the pressure in the vacuum chamber is at or above a predetermined threshold pressure.

The present also provides a method of mass spectrometry comprising: providing a spectrometer as described above;

determining the pressure in the vacuum chamber using the pressure sensor; and selectively controlling the valve such that fluid flow from the LC device is diverted away from the ion source when the pressure sensor determines that the pressure in the vacuum chamber is at or above a predetermined threshold pressure.

- 5From another aspect there is provided a drain connection block for draining liquid from an ion source, comprising:

an inlet port for receiving fluid from the ion source;

a first outlet port for exhausting gas from the ion source;

a second outlet port for exhausting liquid from the ion source;

a valve for selectively diverting the fluid flow from the inlet port to one of either the first outlet port or the second outlet port; and a waste tube connected to the second outlet port for draining liquid away therefrom, wherein the inner diameter of the waste tube is > 6.4 mm, > 7 mm, > 7.5 mm, > 8.0 mm, > 8.5 mm, > 9.0 mm, > 9.5 mm, or > 10.0 mm.

The drain connection block may comprise a fluid conduit between the valve and the second outlet port, wherein at least a portion of the fluid conduit slopes downwardly to the second outlet port.

The at least a portion of the fluid conduit may be at an (acute or obtuse) angle to horizontal.

Said at least a portion of the fluid conduit may be linear and its axis may be at an angle to horizontal, wherein the angle is selected from: between 10 and 30; between 15 and 25 degrees; or about 20 degrees.

The longitudinal axis of said at least a portion of the fluid conduit may be at a nonorthogonal angle to the longitudinal axis through the inlet port.

From another aspect there is provided a drain connection block for draining liquid from an ion source, comprising:

an inlet port for receiving fluid from the ion source;

a first outlet port for exhausting gas from the ion source;

a second outlet port for exhausting liquid from the ion source;

a valve for selectively diverting the fluid flow from the inlet port to one of either the first outlet port or the second outlet port; and a fluid conduit between the valve and the second outlet port, wherein at least a portion of the fluid conduit slopes downwardly to the second outlet port.

From another aspect there is provided a mass spectrometer comprising:

an ion source;

a liquid source configured to supply liquid to the ion source;

a heated gas source configured to supply heated gas to the ion source for vaporising said liquid therein; and a drain connection block as described herein, wherein the inlet port of the drain connection block is connected to an outlet of the ion source; and

-6wherein the spectrometer is configured to open the valve when the pressure in the drain connection block is below a first value for allowing liquid to flow from the inlet port to the second outlet port, and to close the valve when the pressure in the drain connection block is above the first value for allowing gas to flow from the inlet port to the first outlet port.

From another aspect there is provided a mass spectrometer comprising an internal housing containing a Time of Flight mass analyser including a pusher plate assembly, a flight tube and an ion detector, wherein said internal housing comprises one or more access panel(s) for allowing selective access to one or more internal components ofthe Time of Flight mass analyser.

Over time, the internal components of a Time of Flight mass analyser may require service. However, certain components may require more frequent service than others. For instance, the pusher plate assembly of a Time of Flight mass analyser will typically include an entrance plate upon which ions may impact in use so that the surface of the entrance plate becomes ‘pitted’ or dirty due to ion burn. The entrance plate therefore needs to be regularly replaced by a service engineer, e.g. approximately once a year in normal use. That is, the entrance plate is designed to be replaceable and it is therefore desirable to provide easier access to the pusher plate assembly for service engineers.

On the other hand, other components of the Time of Flight mass analyser such as the flight tube are less likely to fail and only need to be serviced in exceptional circumstances. It may thus be desired to keep these components covered whilst the pusher plate assembly is being accessed to prevent the engineer accidently damaging these components.

However, in conventional arrangements, the entire Time of Flight mass analyser must typically be disassembled in order to access any of the internal components.

Thus, in embodiments, one or more access panel(s) may be provided on the internal housing of the Time of Flight mass analyser that allow selective access to certain components ofthe Time of Flight mass analyser. Thus, by opening or removing a suitable access panel, a service engineer is able to access a certain component without having to disassemble the entire Time of Flight mass analyser.

In embodiments, the access panels are removable. For example, the access panels may typically be screwed or otherwise held in place so that they can be removed to allow access to the desired components of the Time of Flight mass analyser. However, it is also contemplated that at least some of the access panels may be connected in such a way that allows the access panels to be opened without having to completely remove the access panel. For example, it is contemplated that at least some of the access panels may be held in place by a hinged connection. Accordingly, any reference herein to “removing” an access panel may in embodiments also refer to “opening” an access panel.

Particularly, the access panel(s) may include a first access panel allowing selective access to the pusher plate assembly of the Time of Flight mass analyser. An entrance plate of the pusher plate assembly may thus be removed through an opening formed by removing the first access panel. The first access panel is thus generally located to allow selective access to the pusher plate assembly whilst leaving the other internal components

- 7such as the flight tube substantially covered and inaccessible. The first access panel may thus be located on the internal housing at a position proximate to the position of the pusher plate assembly within the internal housing. For example, the first access panel may be provided on the ‘top’ surface of the internal housing. Thus, when the Time of Flight mass analyser comprises a reflectron, so that the ion detector is located adjacent to the pusher plate assembly, the first access panel may thus also allow access to the ion detector.

The first access panel can thus be quickly removed in order to provide access to the pusher plate assembly. By contrast, in conventional arrangements, the whole housing may need to be removed and the flight tube disassembled even though it is only the pusher assembly that needs to be accessed and this can be very time consuming.

In embodiments, there is also provided a second access panel allowing access to the flight tube. For instance, the second access panel may generally allow access to the entire Time of Flight mass analyser.

The second access panel may thus be located along the entire length of the Time of Flight mass analyser, particularly along the length of the flight tube (which may comprise a reflectron flight tube). The second access panel may thus comprise a ‘side’ panel of the internal housing.

Thus, in embodiments, multiple (two) access panels are provided that allow for different levels of access to the Time of Flight mass analyser. For instance, when it is necessary to access the pusher assembly, e.g. to replace an entrance plate thereof, the first access panel may simply be removed in order to allow access to the pusher assembly, whilst leaving the second access panel in place. In order to facilitate the removal of the entrance plate of the pusher plate assembly the entrance plate may thus be held in place using one or more thumb screws so that the entrance plate can be removed without the need for any tools.

However, when it is necessary to access the entire Time of Flight mass analyser, the second access panel may (also) be removed. In embodiments, the second access panel may only be removed when the first access panel is removed. That is, the user may be prevented from removing the second access panel unless the first access panel has also been removed. So, in embodiments, when it is desired to access the entire Time of Flight mass analyser, the first access panel may first be removed, followed by the second access panel.

The access panels may (each) be held in place using one or more captive screws. It will be understood that a captive screw is a screw that remain in the access panel when loosened. In this way, the screws can be prevented from falling into the Time of Flight mass analyser.

The mass spectrometer may also generally comprise, e.g. for aesthetic purposes, an external housing or shell that surrounds the internal housing. Thus, in embodiments, the external housing or shell must first be removed before accessing the inner housing. The external housing or shell may also comprise a plurality of removable panels. For instance, a first removable panel may be removed in order to reveal the first access panel. Further panels may then be removed to reveal the second access panel.

- 8In embodiments, a method for servicing a Time of Flight mass analyser is provided comprising removing one or more access panels in order to selectively access one or more components of the Time of Flight mass analyser.

For instance, in embodiments, a first access panel may be removed in order to selectively access the pusher plate assembly of the Time of Flight mass analyser. An entrance plate of the pusher plate assembly may then be removed through an opening formed by removing the first access panel and a new entrance plate fitted. The first access panel can then be put back to close the opening. Thus, the entrance plate can be replaced without having to disassemble the entire Time of Flight mass analyser. In more severe cases, after removing the first access panel, a second access panel may be removed to provide access to the flight tube and/or ion detector.

According to the various embodiments described herein, a relatively small footprint or compact Time of Flight (“TOF”) mass spectrometer (“MS”) or analytical instrument is provided which has a relatively high resolution. The mass spectrometer may have particular application in the biopharmaceutical industry and in the field of general analytical Electrospray Ionisation (“ESI”) and subsequent mass analysis. The mass spectrometer according to various embodiments is a high performance instrument wherein manufacturing costs have been reduced without compromising performance.

The instrument according to various embodiments is particularly user friendly compared with the majority of other conventional instruments. The instrument may have single button which can be activated by a user in order to turn the instrument ON and at the same time initiate an instrument self-setup routine. The instrument may, in particular, have a health diagnostics system which is both helpful for users whilst providing improved diagnosis and fault resolution.

According to various embodiments the instrument may have a health diagnostics or health check which is arranged to bring the overall instrument, and in particular the mass spectrometer and mass analyser, into a state of readiness after a period of inactivity or power saving. The same health diagnostic system may also be utilised to bring the instrument into a state of readiness after maintenance or after the instrument switches from a maintenance mode of operation into an operational state. Furthermore, the health diagnostics system may also be used to monitor the instrument, mass spectrometer or mass analyser on a periodic basis in order to ensure that the instrument in operating within defined operational parameters and hence the integrity of mass spectral or other data obtained is not compromised.

The health check system may determine various actions which either should automatically be performed or which are presented to a user to decide whether or not to proceed with. For example, the health check system may determine that no corrective action or other measure is required i.e. that the instrument is operating as expected within defined operational limits. The health check system may also determine that an automatic operation should be performed in order, for example, to correct or adjust the instrument in response to a detected error warning, error status or anomaly. The health check system may also inform the user that the user should either take a certain course of action or to give approval for the control system to take a certain course of action. Various

- 9embodiments are also contemplated wherein the health check system make seek negative approval i.e. the health check system may inform a user that a certain course of action will be taken, optionally after a defined time delay, unless the user instructs otherwise or cancels the proposed action suggested by the control system.

Embodiments are also contemplated wherein the level of detail provided to a user may vary dependent upon the level of experience of the user. For example, the health check system may provide either very detailed instructions or simplified instructions to a relatively unskilled user.

The health check system may provide a different level of detail to a highly skilled user such as a service engineer. In particular, additional data and/or instructions may be provided to a service engineer which may not be provided to a regular user. It is also contemplated that instructions given to a regular user may include icons and/or moving graphical images. For example, a user may be guided by the health check system in order to correct a fault and once it is determined that a user has completed a step then the control system may change the icon and/or moving graphical images which are displayed to the user in order to continue to guide the user through the process.

The instrument according to various embodiments has been designed to be as small as possible whilst also being generally compatible with existing UPLC systems. The instrument is easy to operate and has been designed to have a high level of reliability. Furthermore, the instrument has been designed so as to simplify diagnostic and servicing thereby minimising instrument downtime and operational costs.

According to various embodiments the instrument has particular utility in the health services market and may be integrated with Desorption Electrospray Ionisation (“DESI”) and Rapid Evaporative Ionisation Mass Spectrometry (“REIMS”) ion sources in order to deliver commercially available In Vitro Diagnostic Medical Device (“IVD’j/Medical Device (“MD”) solutions for targeted applications.

The mass spectrometer may, for example, be used for microbe identification purposes, histopathology, tissue imaging and surgical (theatre) applications.

The mass spectrometer has a significantly enhanced user experience compared with conventional mass spectrometers and has a high degree of robustness. The instrument is particularly easy to use (especially for non-expert users) and has a high level of accessibility.

The mass spectrometer has been designed to integrate easily with liquid chromatography (“LC”) separation systems so that a LC-TOF MS instrument may be provided. The instrument is particularly suited for routine characterisation and monitoring applications in the biopharmaceutical industry. The instrument enables non-expert users to collect high resolution accurate mass data and to derive meaningful information from the data quickly and easily. This results in improved understanding of products and processes with the potential to shorten time to market and reduce costs.

The instrument may be used in biopharmaceutical last stage development and quality control (“QC”) applications. The instrument also has particular application in small molecule pharmaceutical, food and environmental (“F&E”) and chemical materials analyses.

- 10The instrument has enhanced mass detection capabilities i.e. high mass resolution, accurate mass and an extended mass range. The instrument also has the ability to fragment parent ions into daughter or fragment ions so that MS/MS type experiments may be performed.

BRIEF DESCRIPTION OF THE DRAWINGS

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:

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;

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, 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;

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;

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

Fig. 5 shows a first known ion inlet assembly which shares features with an ion inlet assembly according to various embodiments;

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;

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

- 11 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;

Fig. 8 shows in more detail a mass spectrometer according to various embodiments;

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;

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

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;

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;

Fig. 13 shows in more detail a transfer lens arrangement;

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;

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;

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

- 12maintained 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;

Fig. 17 shows a schematic of a mass spectrometer 1700 according to embodiments of the present invention;

Figs. 18-22 show the mass spectrometer with various panels of the external housing removed, and with various of the access panels of the internal housing removed;

Fig. 23 is a schematic illustration of an embodiment showing various components at an upstream end of the mass spectrometer; and

Figs. 24A-24B show embodiments of a drain connection block.

DETAILED DESCRIPTION

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.

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.

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.

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”).

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

- 13connected 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.

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.

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.

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

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.

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.

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.

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.

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.

- 14In 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.

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.

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.

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.

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

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.

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.

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.

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.

- 15A “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.

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.

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.

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.

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.

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.

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.

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

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.

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

- 16802 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.

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.

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.

The mass spectrometer 100 may comprise a first ion guide 301 such as a StepWave (RTM) 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.

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.

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.

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

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.

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.

- 17The 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.

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 ofthe 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.

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.

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.

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.

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.

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.

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

- 18ion 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.

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.

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.

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.

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

- 19(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 ionatom reaction fragmentation device; (xx) an ion-metastable ion reaction fragmentation device; (xxi) an ion-metastable molecule reaction fragmentation device; (xxii) an ionmetastable 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.

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.

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.

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.

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.

- 20Desolvation 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.

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.

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.

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.

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.

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

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

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 (El) ion source; (ix) a Chemical Ionisation (Cl) ion source; (x) a Field Ionisation (Fl) 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

- 21 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 (MAH) 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.

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.

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.

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.

-22With 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.

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.

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

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

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.

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.

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

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.

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.

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.

- 23Accordingly, 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.

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.

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.

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.

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.

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.

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.

Instead of utilising a coventional 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.

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

- 24O-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.

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 noncircular 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.

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.

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.

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.

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.

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.

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.

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.

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.

- 25According 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.

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 m³/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 x 3 mbar = 7.5 mbar L/s.

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.

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.

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.

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.

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

- 26the range 100-125 mL. The solvent bottles 201 may be readily observable by a user who may easily refill the solvent bottles.

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.

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.

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:

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

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

Fig. 7A illustrates a vacuum pumping arrangement according to various embodiments.

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 (RTM) Splitflow 310 fitted with a TC110 controller or an Edwards (RTM) nEXT300/100/100D turbo pump. The turbo pump may be air cooled by a cooling fan.

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 (RTM) 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.

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 (RTM) MAG500 cold cathode gauge 702.

- 27A 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 (RTM) PSG500 Pirani gauge 701.

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

A turbo pump such as an Edwards (RTM) 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 x 10'⁵ mbar L/s 1320 L/s = 1.25 x 10'⁷ mbar.

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.

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

A pump-down sequence may be deemed completed once the Time of Flight vacuum chamber pressure is determined to be < 1 x 10'⁵ mbar.

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.

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.

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.

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.

- 28Similarly, 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 powerup 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.

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.

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.

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

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.

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.

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

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.

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.

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.

The maximum nitrogen flow may be restricted such that in the event of a catastrophic failure ofthe 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.

A source pressure sensor may be provided.

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 (RTM) H-480-S-G-1/4-5psi valve.

- 29A 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.

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.

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.

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.

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.

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:

API Gas Request state	API Gas Control state	API gas valve
ON	Enabled	Open
ON	Disabled	Closed
OFF	Enabled	Closed
OFF	Disabled	Closed

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.

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

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.

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

- 30is 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.

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.

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

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.

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.

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.

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.

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.

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.

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

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

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

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

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.

If the pressure in the Time of Flight vacuum chamber is greater than 1 x 10'⁵ 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.

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.

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.

If the Time of Flight region pressure rises above 1.5 x 10'⁵ mbar while the instrument is in an Operate mode of operation then the instrument may enter an Overpressure mode of operation or state.

If the Time of Flight pressure enters the range 1x1 O'⁸ to 1x1 O'⁵ mbar while the instrument is in an Over-pressure mode of operation then the instrument may enter an Operate mode of operation.

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.

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.

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 Overpressure with Source Interlock Open mode of operation to an Over-pressure mode of operation when the source cover is closed.

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

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

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.

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

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

Reference to Not Pumped refers to all vacuum states except pumped.

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.

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.

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.

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

- 33understood 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.

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.

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.

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.

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.

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.

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

- 34high 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.

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).

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.

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.

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.

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.

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

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

- 35to 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.

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 improving reliability.

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.

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.

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.

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. 10C. 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.

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

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.

According to other embodiments the reflectron 306 may comprise a bonded reflectron. According to another embodiment the reflectron 306 may comprise a metalised

- 36ceramic arrangement. According to another embodiment the reflectron 306 may comprise a jigged then bonded arrangement.

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.

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.

Fig. 10C 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.

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.

Fig. 11 shows a flow diagram illustrating various processes which may occur once a start button has been pressed.

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.

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

- 37(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.

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 ofthe ion block 802. An elbow fitting 1250 and an over pressure relief valve 1202 are also shown.

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.

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

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.

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 ofthe electrodes or lens elements may be varied from the specific values indicated in Fig. 13.

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.

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.

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.

- 38The lens apertures after Aperture #3 1302 may comprise horizontal slots or plates. Transport 2/steering lens may comprise a pair of half plates.

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

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.

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.

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 Tconnection 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.

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.

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.

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.

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.

- 39A single conjoined ring electrode is also shown in Fig. 15A.

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.

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.

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.

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.

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

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).

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.

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.

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.

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

- 40pumping 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.

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

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.

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 ps. The pulse period may be controllable over the range 22-85 ps. The pusher delay may be controllable over the range 0-85 ps.

Fig. 16C shows in more detail the pusher electrode arrangement. The grid electrodes may comprise 0 60 parallel wire with 92% transmission (0 0.018 mm parallel wires at 0.25 mm pitch). The dimensions shown are intended to be illustrative and nonlimiting.

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 (RTM) ion detector or the surface of the front MCP in the case of a MCP detector.

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.

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.

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.

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.

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.

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.

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

- 41 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.

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

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.

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.

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.

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.

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.

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.

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 (RTM) 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.

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 nonlimiting.

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

-42detected 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 7x10⁶ events per second.

According to various embodiments the instrument may have a mass accuracy of 25 ppm may have a chromatographic dynamic range of 10⁴. 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.

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.

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

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.

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.

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

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.

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.

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.

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

- 43module, 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.

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.

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.

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.

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.

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.

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.

Fig. 17 shows a schematic of a mass spectrometer 1700 according to embodiments of the present invention. The spectrometer comprises an ion source 1701, a first ion guide 1702, a second ion guide 1703, one or more transfer lenses 1704, and a mass analyser 1705, for example as discussed above.

The mass analyser 1705 may comprise a TOF mass analyser having an acceleration electrode 1706, a reflectron 1707, and an ion detector 1708, for example as discussed above.

- 44The mass analyser 1705 may also comprise a pre-amplifier 1709 for amplifying the detected ion signal and an ADC 1710 for digitising the (amplified) detected ion signal.

The mass spectrometer 1700 may further comprise a fluidics system 1711, for example as discussed above, a front panel display 1712, for example as discussed above, a power supply unit (PSU) 1713 for supplying power to the various devices of the mass spectrometer 1700, and an embedded PC (EPC) 1714.

The mass spectrometer 1700 may further comprise a system control module 1715 comprising processing circuitry for controlling various functional modules of the mass spectrometer 1700. The functional modules can include electrical, mechanical, electromechanical and/or software components. The functional modules of the mass spectrometer 1700 may be controlled via a packet based “Typhoon” control system.

For example, the system control module 1715 may (indirectly) control the operation of the ion source 1701, the first ion guide 1702, the second ion guide 1703, the one or more transfer lenses 1704, the acceleration electrode 1706, the reflectron 1707, the ion detector 1708, the pre-amplifier 1709, and the ADC 1710. For example, the system control module 1715 may issue control instructions, for example in data packets, to various local control circuitry modules of the mass spectrometer 1700, such as a high voltage supply module 1716 for the ion source 1701, a first local voltage supply module 1717 for the first ion guide 1702, and a second local voltage supply module 1718 for both the second ion guide 1703 and the one or more transfer lenses 1704.

The various AC or RF and/or DC voltages required by the first ion guide 1702 may, for example, be provided from one or more AC or RF and/or DC voltage supplies housed within the first local voltage supply module 1717. Those voltages may be provided to the electrodes of the first ion guide 1702 via a first vacuum interface PCB 1719 and one or more first internal PCBs 1721. The one or more first internal PCBs 1721 may comprise one or more rigid PCBs or PCB portions and/or may comprise one or more flexible PCBs or PCB portions to facilitate connection between the first vacuum interface PCB 1719 and the first ion guide 1702 within the relatively confined space of a first vacuum chamber.

Furthermore, the various AC or RF and/or DC voltages required by the second ion guide 1703 may be provided from one or more AC or RF and/or DC voltage supplies housed within the second local voltage supply module 1718. Those voltages may be provided to the electrodes of the second ion guide 1703 via a second vacuum interface PCB 1720 and one or more second internal PCBs 1722. The one or more second internal PCBs 1722 may again comprise one or more rigid PCBs or PCB portions and/or may comprise one or more flexible PCBs or PCB portions to facilitate connection between the second vacuum interface PCB 1720 and the second ion guide 1703 within the relatively confined space of a second vacuum chamber.

Similarly, the various AC or RF and/or DC voltages required by the one or more transfer lenses 1704 may be provided from the one or more AC or RF and/or DC voltage supplies housed within the second local voltage supply module 1718. Those voltages may be provided to the one or more transfer lenses 1704 via the second vacuum interface PCB 1720 and one or more third internal PCBs 1723. The one or more third internal PCBs 1723 may again comprise one or more rigid PCBs or PCB portions and/or may comprise one or

- 45more flexible PCBs or PCB portions to facilitate connection between the second vacuum interface PCB 1720 and the one or more transfer lenses 1704 within the relatively confined space of a third vacuum chamber.

In addition, the system control module 1715 may control the operation of other functional modules of the mass spectrometer 1700. One or more of these functional modules of the mass spectrometer 1700 may be controlled via a Universal Peripheral Analogue Interface (UPAI), which will be described in more detail below. These other functional modules may be referred to herein as “peripheral” functional modules.

As described above, the mass spectrometer comprises a number of power supplies for supplying voltages to various components within the mass spectrometer, such as the ion source, ion guides, transfer optics and mass analyser. At least some of these components are housed within a vacuum housing of the spectrometer, e.g. within separate respective vacuum chambers within the vacuum housing. The vacuum chambers of the vacuum housing are pumped down to relatively low pressures. When the spectrometer is operating well, the vacuum conditions are maintained and hence there is relatively little risk of electrical breakdown occurring in the vacuum chambers due to the high voltages applied to the electrical components therein.

However, the inventors have recognised that in the event of a vacuum failure, the gas pressure in the vacuum chambers will increase and hence so will the likelihood of electrical breakdown occurring. Such electrical breakdown can cause significant, permanent damage to the electronics inside the vacuum housing.

In order to protect such components, the spectrometer monitors the pressure in one or more of the vacuum chambers and, if the pressure therein rises above a predetermined value then it is determined that a vacuum failure has occurred in that vacuum chamber. The spectrometer then cuts off the electrical power to at least some of the electrical components in that vacuum chamber. For instance, when a vacuum failure is detected, all of the high voltage power supplies to the components within the vacuum housing may be cut off. In this way, by completely cutting the power supply to these components, the risk of damage to the electronics by electrical break down may be mitigated.

As described above, the spectrometer may comprise voltage supply modules such as modules 1717 and 1718 for suplying the components within the vacuum housing with the various AC or RF and/or DC voltages required. The embodiments described herein cut off the power to these voltage supply modules when the vacuum failure has been detected. This may be performed by the system control module 1715 switching the power off to the voltage supply modules. It is to be noted that this is not the same as placing the voltage control modules 1717,1718 in a standby mode when a vacuum failure is detected. In such a standby mode the system control module 1715 simply does not instruct the voltage supply modules to supply voltages to the components in the vacuum housing (or instructs them not to). However, when in such a standby mode, a fault in the system control module 1715 and/or voltage control modules 1717,1718 could still result in the voltage control module 1717,1718 being activated and supplying AC or RF and/or DC voltages to their respective components in the ion guide when there is a vacuum failure. As such, a standby mode would not necessarily protect the instrument from electrical breakdown in

- 46the event of a vacuum failure. In contrast, in the cut-off mode described herein, no power at all is supplied to the voltage control modules 1717,1718 in the event of a vacuum failure being detected and hence it is not possible for the voltage control modules 1717,1718 to supply any voltages to their respective components within the vacuum housing.

The spectrometer may include one or more pressure gauges for determining the vacuum level(s) within one or more vacuum of the spectrometer. For example, the spectrometer may monitor the vacuum pressure using a Pirani and/or Penning gauge to determine whether or not there has been a vacuum failure. Alternatively, the spectrometer may monitor the vacuum pressure indirectly, e.g. by determining the speed at which the vacuum pump is operating to determine whether or not there has been a vacuum failure. Alternatively, the spectrometer may comprise a vacuum failure switch in the vacuum housing that is configured to switch off the power to the voltage control modules 1717,1718 when it is exposed to a pressure above a threshold value. The control circuitry may receive information from the various pressure sensors described above in order to detect a vacuum failure.

The control circuitry may comprise a main controller of the mass spectrometer. The control circuitry may for instance communicate with the various power supplies to distribute power to the various modules and peripherals within the instrument. The control circuitry may also communicate to the pumping logic that controls the vacuum system, as well as the system heaters and fluidic modules, and the host computer connected to the instrument. When a vacuum failure is detected, the control circuitry may thus act to completely cut off power to the various modules and peripherals within the instrument.

Fig. 23 is a schematic illustration of an embodiment showing various components at an upstream end of the mass spectrometer. The spectrometer comprises an ion source 2302 that may be supplied with an analytical sample by a separator device 2304, such as a liquid chromatography (LC) device, or with solvent from bottles 2306. A divert valve 2308 is provided between the ion source 2302 and both the LC device 2304 and the bottles 2306 of solvent. The divert valve 2308 is also connected to a pump 2310, for pumping fluid from the LC device 2304 or bottles 2306 into the ion source 2302. An ion source exhaust tube 2310 leads from the ion source 2302 to a drain connection block 2312. A drip tray 2314 may be provided underneath the ion source 2302 (and optionally under the divert valve). A drip tray 2316 may be provided under the bottles 2306. The drip trays may also include one or more drain tubes 2318 that are connected to the drain connection block 2312. The divert valve 2308 also includes a drain tube 2320 connected to the drain connection block 2312, e.g. via one or both of the drip trays 2314,2316 or drain tubes 2318.

In operation, a liquid sample comprising analyte is separated in the LC device 2304. The divert valve 2308 may be selectively controlled so that the pump 2310 pumps the liquid from the LC device 2304 into the ion source 2302, or pumps solvent from one or more of the bottles 2306 to the ion source. Under one or more predetermined failure condition, such as detection of a vacuum failure in a vacuum chamber of the mass spectrometer, the spectrometer may control the divert valve 208 such that fluid flow from the LC device 2304 is not directed to the ion source 2302, but is instead directed through the divert valve drain tube 2320 to waste, e.g. via the drain connection block 2312. This

- 47prevents the analytical sample (or solvent) from being passed to a region of the spectrometer when the failure condition occurs. For example, if a vacuum failure occurs the gas pressure in a vacuum chamber may increase and potentially cause electrical breakdown (e.g. arcing) to occur due to the relatively high gas pressure therein. Diverting the sample (or solvent) to waste in such a failure condition is particularly advantageous, for example, as the sample may comprise one or more flammable substances.

In the mode of operation where the divert valve 2308 directs the sample from the LC device 2304 into the ion source 2302, the ion source 2302 may use heated gas to evaporate the liquid to produce gaseous phase analyte. A small proportion of the heated gas and evaporated sample passes downstream into the mass spectrometer inlet orifice for analysis of the analyte in the sample. The rest of the heated gas and evaporated sample travels down the ion source exhaust tube 2310, primarily in the gaseous phase. However, if there is a failure in the supply of the heated gas to the ion source 2302, the liquid sample is not evaporated and flows down the ion source exhaust tube 2310 as a liquid. The drain connection block 2312 may be configured to prevent this liquid from pooling and backing up into the instrument.

Fig. 24A shows a first embodiment of a drain connection block 2312. The drain connection block comprises a first inlet port 2402 for receiving the ion source waste tube 2310. The drain connection block 2312 also comprises a first outlet port 2404 for exhausting gas and a second outlet port 2406 for exhausting liquid, e.g. to a waste vessel (not shown). The drain connection block 2312 comprises a valve 2408, such as a pinch valve, for selectively allowing flow from the first inlet port 2408 to either or the two outlet ports 2404,2406. The valve 2408 may be configured to automatically open (or is controlled to open) when there is a relatively low gas pressure in the drain connection block 2312 and to close when there is a relatively high gas pressure in the drain connection block 2312. In normal operation, when there is no failure in the supply of heated gas to the ion source 2302, the gas travels down the ion source waste tube 2310 and into the drain connection block 2312. As such, the valve 2408 remains closed and the gas is exhausted through the first outlet port 2404. However, when there is a failure in the supply of heated gas to the ion source 2302, the gas does not travels down the waste tube 2310 to the drain connection block 2312 and liquid does instead. The valve 2408 therefore opens and the liquid drains to the second outlet port 2406. The liquid may then flow out of the second outlet port 2406 and into a waste vessel (not shown).

It can be seen that the conduit through the drain connection block which the liquid passes through has a first portion 2410 extending vertically downwards from the first inlet port 2402 and then has a 90 degree turn such that a second portion 2412 extends horizontally to the second outlet port 2406. The axis through the second outlet port 2406 is therefore orthogonal to the axis through the first inlet port 2402. When the valve 2408 is open, the liquid drains under gravity into the conduit and passes out through the second outlet port 2406. A waste tube 2414 may be connected to the second outlet port 2406 (optionally outside of the drain connection block 212) for draining the liquid away to a vessel, such as a waste vessel.

- 48The drain connection block 2312 may also comprise a second inlet port 2416 for receiving the drain tube 2318 from the drip trays 2314,2316 and divert valve drain tube 2320. The second inlet port 2416 is connected to the second outlet port 2406 via a second conduit 2418 that, optionally, does not include the valve 2408. This allows any drips from the ion source 2302 and/or divert valve 2308 and/or bottles 2306 to drain to the second outlet port 2306 and to the waste vessel. The drain tubes 2318,2320 are illustrated as being interconnected in Fig. 23 and all draining to the second inlet port 2416. However, it is contemplated that the drain connection block 2312 may have one or more further inlet port for separately receiving at least some of the drip tray drain tubes and divert valve drain tube.

Fig. 24B shows a second embodiment of a drain connection block 2312. This embodiment is the same as that shown in Fig. 24A, except that it includes two improvements to assist in draining liquid from the first inlet port 2402 to the second outlet port 2406. It has been recognised that under certain conditions the liquid from the first inlet port 2402 is unable to drain out of the second outlet port 2406 and may instead pool and cause an overflow. For example, if the waste tube 2414 connected to the second outlet port 2406 is looped then the liquid sample may pool in the looped section of the waste tube, creating an air lock. Such an air lock may stop liquid from flowing down the waste tube 2414 to the vessel, as the liquid may not be able to displace the air in the waste tube 2414. Also, if the level of liquid in the vessel rises such that the outlet end of the waste tube 2414 is submerged in the liquid, then this may also create an air lock in the waste tube that may prevent the liquid flowing through and out of the waste tube.

As shown in Fig. 24B, at least part of the second portion 2412 of the outlet conduit may be configured such that its longitudinal axis has a downward slope at an (acute or obtuse) angle to horizontal so that liquid drains along the second portion 2412 towards the second outlet port 2406 under gravity. For example, the downward slope may be at an angle of about 20 degrees to the horizontal. However, other downwards slopes are contemplated, such as angles between 10 and 30 degrees, or between 15 and 25 degrees, relative to horizontal. The longitudinal axis of at least part of the second portion 2412 of the outlet conduit may be at an angle other than orthogonal to the longitudinal axis of the first portion 2410 of the outlet conduit that receives the liquid from the first inlet port 2402. Angling the outlet conduit in this manner assists in draining liquid out ofthe second outlet port 2406 and preventing fluid from pooling, which may otherwise cause an airlock to form that would prevent drainage.

Additionally (or alternatively) to angling at least part of the second portion 2412 of the outlet conduit, the inner diameter of the waste tube 2414 (and optionally also of the second portion 2412 of the outlet conduit and second outlet port 2406) may be made relatively large. This prevents the surface tension of the liquid blocking the tube 2414 and causing air locks that would otherwise prevent drainage. As such, there is sufficient room for the liquid sample to be able to run down the waste tube 2414 (and optionally also the outlet conduit 2412 and port 2406) whilst air flows up passed it. By way of example, the inner diameter of the waste tube may be > 6.4 mm, > 7 mm, > 7.5 mm, > 8.0 mm, > 8.5 mm, > 9.0 mm, > 9.5 mm, or > 10.0 mm.

- 49As shown in Fig. 8, the Time of Flight mass analyser may have a full length cover 809 which may be readily removed enabling extensive service access. The mass analyser may further comprise a removable access panel or lid’ 810 for quick service access to the pusher assembly, and particularly to allow the entrance plate 1000 of the pusher plate assembly 1012 to be easily replaced as it becomes contaminated over time. The entrance plate 1000 may thus be provided with one or more thumb screws to allow it to be easily removed without requiring any tools, as shown in Fig. 10C.

Figs. 18-22 show in more detail the removable access panels provided for allowing service access to the Time of Flight mass analyser.

For instance, as shown in Fig. 18, in order to reveal the internal housing of the instrument, the external housing must first be removed. The external housing comprises a set of panels such as a top panel, and four side panels, that are generally screwed in place. Fig. 18 shows the instrument wherein the top panel of the external housing has been removed to reveal the first access panel 810. The side panels 1803 of the external housing have not been removed. In Fig. 18 the first access panel 810 is held in place by four captive screws 1800 (which can’t therefore fall into the Time of Flight mass analyser). However, it will be appreciated that various other fixing arrangements may suitably be used. The first access panel 810 may also comprise a handle, or knob 1802, on its upper surface, as shown in Fig. 18, to facilitate ease of removal.

Fig. 19 then shows how the first access panel 810 may be removed to allow selective access to the pusher plate assembly 1012. The entrance plate 1000 can thus be replaced without having to disassemble the entire Time of Flight mass analyser. As shown in Fig. 10C, the entrance plate may comprise two tool free thumb screws to facilitate ease of removal of the entrance plate.

In more severe cases it may be necessary to access the entire Time of Flight mass analyser. Thus, a second access panel 820 may also be provided along the length of the reflectron flight tube. To reveal the second access panel 820, the side panels of the external housing may first be removed, as shown in Fig. 20. The second access panel 820 can then be removed to allow access to the flight tube of the Time of Flight mass analyser. Fig. 21 shows the position of the second access panel 820 along the length of the reflectron flight tube. The second access panel 820 in Fig. 21 is held in place by a set of five captive screws 2000. However, again it will be appreciated that various other fixing arrangements may suitably be used. Fig. 22 then shows the Time of Flight mass analyser with the second access panel 820 removed (e.g. unscrewed) with the reflectron flight tube 806 entirely exposed.

The access panel(s) may be provided with a warning in the form of a label or other indication. The warning may be positioned on the second access panel 820. The warning may comprise an instruction such as “Before removing ToF enclosure, disconnect internal wires via ToF lid”. The ToF enclosure comprises the second access panel 820.

Hence, the ToF lid (first access panel 810) may provide access to internal wires which connect to any one or more of the pusher plate assembly, a flight tube and an ion detector. The internal wires comprise wires that are present within the internal housing.

- 50The wires may comprise one or more voltage supplies for the pusher plate assembly, a flight tube and/or ion detector.

Disconnecting the internal wires prior to removing the second access panel 820 reduces the chance of snagging or otherwise damaging the internal wires and connections 5 when removing the second access panel.

Although not shown in the present figured, the second access panel 820 may comprise a handle, or knob, on its external surface, to facilitate ease of removal of the second access panel 820.

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.

Claims

1. A mass spectrometer comprising:

a vacuum chamber housing an electronic component therein;

a voltage supply module for supplying a voltage to said electronic component;

2. The spectrometer of claim 1, wherein the voltage supply module is arranged outside of the vacuum chamber.

3. The spectrometer of claim 1 or 2, wherein said predetermined threshold pressure is selected from: > 10'7 mbar; > 5 x 10'6 mbar; > 10'6 mbar;> 5 x 10'5 mbar; > 10'5 mbar; > 5 x 10'4 mbar; and > 10'4 mbar.

4. The spectrometer of claim 1, 2 or 3, wherein the predetermined threshold pressure is set based on the maximum amplitude of the voltage that the voltage supply module is configured to supply to the electronic component.

5. The spectrometer of any preceding claim, wherein the control module is configured to re-establish power to the voltage supply module when the pressure sensor determines that the pressure in the vacuum chamber is below the predetermined threshold pressure such that the voltage supply module is capable of supplying a voltage to the electronic component.

6. The spectrometer of any preceding claim, wherein the voltage supply module is configured to supply an AC or RF and/or DC voltage to the electronic component.

7. The spectrometer of any preceding claim, comprising:

a plurality of vacuum chambers, each vacuum chamber having an electronic component therein that is connected to a respective one of a plurality of voltage supply modules for supplying a voltage to the electronic component;

wherein each vacuum chamber is associated with a pressure sensor for determining if the pressure in that vacuum chamber is at or above a predetermined threshold pressure; and wherein the control module is configured to cut power to any of the voltage supply modules if the pressure sensor associated with the vacuum chamber that houses the

- 52electronic component that it supplies a voltage to determines that the pressure in that vacuum chamber is at or above its respective predetermined threshold pressure.

8. The spectrometer of any preceding claim, wherein at least one of the electronic components is an ion guide comprising a plurality of electrodes, and the voltage supply module is configured to supply an AC or RF and/or DC voltage to these electrodes for guiding ions within the ion guide.

9. The spectrometer of any preceding claim, comprising a liquid chromatography (LC) device, an ion source arranged to receive fluid from the LC device, and a valve for selectively allowing said fluid to pass from the LC device to the ion source, wherein the spectrometer is configured to control the valve such that fluid flow from the LC device is directed away from the ion source when the pressure sensor determines that the pressure in the vacuum chamber is at or above a predetermined threshold pressure.

10. The spectrometer of any preceding claim, wherein at least one of the electronic components is a time of flight mass analyser, and wherein the voltage supply module is configured to supply an AC or RF and/or DC voltage to:

(i) a pusher assembly in the mass analyser; and/or (ii) a reflectron in the mass analyser; and/or (iii) an ion detector in the mass analyser.

11. A method of mass spectrometry comprising:

providing a mass spectrometer as claimed in any preceding claim;

12. A mass spectrometer comprising:

a liquid chromatography (LC) device;

an ion source arranged to receive fluid from the LC device;

13. A drain connection block for draining liquid from an ion source, comprising:

an inlet port for receiving fluid from the ion source;

a first outlet port for exhausting gas from the ion source;

a second outlet port for exhausting liquid from the ion source;

14. The drain connection block of claim 13, comprising a fluid conduit between the valve and the second outlet port, wherein at least a portion of the fluid conduit slopes downwardly to the second outlet port.

15. The drain connection block of claim 14, wherein said at least a portion of the fluid conduit is linear and its axis is at an angle to horizontal, wherein the angle is selected from: between 10 and 30; between 15 and 25 degrees; or about 20 degrees.

16. A drain connection block for draining liquid from an ion source, comprising:

an inlet port for receiving fluid from the ion source;

a first outlet port for exhausting gas from the ion source;

a second outlet port for exhausting liquid from the ion source;

17. The drain connection block of claim 16, wherein said at least a portion of the fluid conduit is linear and its axis is at an angle to horizontal, wherein the angle is selected from: between 10 and 30; between 15 and 25 degrees; or about 20 degrees.

18. A mass spectrometer comprising:

an ion source;

a liquid source configured to supply liquid to the ion source;

a heated gas source configured to supply heated gas to the ion source for vaporising said liquid therein; and a drain connection block as claimed in any one of claims 13-17, wherein the inlet port of the drain connection block is connected to an outlet of the ion source; and wherein the spectrometer is configured to open the valve when the pressure in the drain connection block is below a first value for allowing liquid to flow from the inlet port to the second outlet port, and to close the valve when the pressure in the drain connection block is above the first value for allowing gas to flow from the inlet port to the first outlet port.

19. A mass spectrometer comprising an internal housing containing a Time of Flight mass analyser including a pusher plate assembly, a flight tube and an ion detector, wherein said internal housing comprises one or more access panel(s) for allowing selective access to one or more internal components of the Time of Flight mass analyser.

20. The mass spectrometer of claim 19, comprising a first access panel allowing selective access to the pusher plate assembly of the Time of Flight mass analyser.

21. The mass spectrometer of claim 20, comprising a second access panel allowing access to the flight tube.

22. The mass spectrometer of claim 21, wherein the second access panel can only be removed to allow access to the flight tube when the first access panel has been removed.

23. The mass spectrometer of any of claims 19-22, wherein the access panel(s) are held in place by a set of one or more captive screws.

24. The mass spectrometer of any of claims 19-23, comprising a removable external housing or shell.

25. The mass spectrometer of claim 24, wherein the external housing or shell comprises one or more removable panels.

26. A method for servicing a mass spectrometer comprising a Time of Flight mass analyser as claimed in any one of claims 19-25 comprising:

removing one or more access panel(s) in order to selectively access one or more internal components of the Time of Flight mass analyser.

27. The method of claim 26, comprising removing a first access panel in order to selectively access the pusher plate assembly of the Time of Flight mass analyser; removing an entrance plate of the pusher plate assembly through an opening created by removing the first access panel; fitting a new entrance plate onto the pusher plate assembly through the opening; and closing the opening with the first access panel.

28. The method of claim 26 or 27, comprising removing multiple access panels in order to access the entire Time of Flight mass analyser.

29. The method of claim 28, comprising after removing a first access panel and prior to removing multiple access panels in order to access the entire Time of Flight mass analyser, disconnecting one or more wires servicing at least one of the pusher plate assembly, a flight tube and ion detector.