HK1184539B - A control system for automatically controlling a plurality of devices of a separation and detection process for quantitative sample analysis - Google Patents

Abstract

A control system (1) for automatically controlling a plurality of devices (2) of a separation and detection process for quantitative sample analysis, comprises a data storage (11), a device modelling unit (12), a sample modelling unit (13), a sequence generating unit (14) and an interface unit (16). Thereby, the data storage (11) is arranged to hold characteristic data of each of the devices (2) and the device modelling unit (12) is arranged to model the devices (2) using the characteristic data of the devices (2) held in the data storage (11). The data storage (11) is arranged to hold data of source samples (3) and the sample modelling unit (13) is arranged to generate a plurality of analytical samples to be analysed in the separation and detection process for quantitative sample analysis using the data of source samples (3) held in the data storage (11). The sequence generating unit (14) is arranged to define an analytical sample sequence of the analytical samples within the separation and detection process for quantitative sample analysis taking into account utilization of the devices (2). Further, the interface unit (16) is arranged to operate the devices (2) of the separation and detection process for quantitative sample analysis in accordance with the analytical sample sequence defined by the sequence generating unit (14). By taking into account utilization of the devices (2) for generating the analytical sample sequence said utilization and also the separation and detection process for quantitative sample analysis can be optimized. It particularly allows for coordinating and synchronizing the devices (2) such that an efficient separation and detection process for quantitative sample analysis results.

Description

Control system for automatically controlling a plurality of devices of a separation and detection process for quantitative sample analysis

Technical Field

The present invention relates to a control system and a corresponding computer program for automatically controlling a plurality of devices of a separation and detection process for quantitative sample analysis. Such systems and computer programs may be used to operate quantitative sample analysis equipment, such as, for example, High Performance Liquid Chromatography (HPLC) equipment and the like.

Background

In today's quantitative sample analysis often separation and detection processes are involved, wherein a variety of suitable devices or combinations of devices are commonly used for this purpose. For example, in quantitative sample analysis using High Performance Liquid Chromatography (HPLC), apparatuses for separation and detection, such as pumps, auto-samplers, injectors, columns, valves, and detectors, are commonly used. Typically, such devices are controllable via control software executed on a computer as a control system. A plurality of such devices are often combined into an analytical instrument that allows the separation and detection process of quantitative sample analysis to be performed. Some combinations of these devices or analytical instruments may also be controlled by a single control software executing on a computer. This provides for convenient and efficient operation of the analysis instrument by control of the entire analysis instrument by a single control system.

However, such analytical instruments are often not fully adapted to the needs of a specific sample analysis or to a flexible arrangement of sample analyses in, for example, a laboratory. In such laboratories, e.g. responsible for high throughput analysis of pharmaceutical companies, it is possible to quantify a large number of compounds and samples, e.g. about 5 '000 compounds in about 250' 000 samples, each year. Thus, the compound may, for example, be a small molecule having a molar mass between about 100 grams per mole to about 700 grams per mole.

Within this framework, efficient analytical instruments and tools for supporting analytical method development, routine analysis, instrument management, reporting, and many other tasks may be of critical importance. It is therefore often desirable to rearrange the equipment of the analytical instrument or to freely combine equipment from different suppliers for assembling a suitable instrument. In this case, the convenience of controlling the analytical instrument by means of a separate control system or a part of the functionality of a separate control system is usually at least partially lost. In addition, such individual control systems often do not fully support all of the functions and operations of the analytical instrument or some of its devices. For example, laboratory activities such as process development, preventative maintenance, sample preparation, etc. are often not supported by this separate control system. Thus, less efficient operation of the analysis instrument may result in, for example, a lower utilization of at least some of the equipment specifically included. Furthermore, such individual control systems are typically not standardized and therefore cannot be fully customizable and integratable in commercially available or other Laboratory Information Management Systems (LIMS), for example, which focus primarily on sample workflows, result workflows, and data evaluation tools, while not covering other laboratory activities.

There is therefore a need for a preferably automatic control of a plurality of devices of the separation and detection process allowing an efficient quantitative sample analysis which is particularly suitable for a large number of analyses per time unit.

Disclosure of Invention

According to the present invention, this need is solved by a control system as defined by the features of independent claim 1 and by a computer program as defined by the features of independent claim 18. Preferred embodiments are the subject of the dependent claims.

The gist of the present invention is: a control system for automatically controlling a plurality of devices of a separation and detection process for quantitative sample analysis includes a data storage, a device modeling unit, a sample modeling unit, a sequence generation unit, and an interface unit. Thereby, the data storage is arranged for holding characteristic data of each of the devices, and the device modelling unit is arranged for modelling the devices using the characteristic data of the devices held in the data storage. Further, the data storage is arranged for holding data of the source samples, and the sample modelling unit is arranged for generating a plurality of analysis samples to be analyzed in a separation and detection process for quantitative sample analysis using the data of the source samples held in the data storage. The sequence generation unit is arranged for defining a sequence of analysis samples of the analysis samples within a separation and detection process for quantitative sample analysis taking into account utilization of the device. Further, the interface unit is arranged for operating the device for a separation and detection process for quantitative sample analysis according to the sequence of analysis samples defined by the sequence generation unit.

The control system may be embodied as a conventional computer having a Central Processing Unit (CPU) or processor, Random Access Memory (RAM) and a hard disk, on which computer program is executed to implement the data storage means and units described above. In the context of the present invention, the term "separation and detection process for quantitative sample analysis" may particularly denote a chromatographic process, such as a High Performance Liquid Chromatography (HPLC) process, an ultra high performance liquid chromatography (UPLC) process, a Gas Chromatography (GC) process, an electrophoresis process or similar processes. The apparatus of such a process may specifically include a pump, a detector, such as an ultraviolet-visible (UV/V | S) spectroscopic detector, an Evaporative Light Scattering Detector (ELSD), a refractive index detector, a Mass Spectrometer (MS) detector, a conductivity detector, an electrochemical detector, a radioactivity detector, a fluorescence detector, or a nitrogen selective detector, an injector, and the like. The data storage may be, for example, any kind of computer data storage, such as one or more databases with or without database management systems, flat file repositories, combinations thereof, and the like. In this context, the characteristic data of the device relates to parameters of the device characteristics for the operation. Such characteristic data may include volume, pressure, temperature, volume, flow rate, etc. Modeling the devices within the device modeling unit may include reproducing each device according to its characteristic data and establishing interactions between the devices within a separation and detection process for quantitative sample analysis. Additionally, modeling the device may include combining multiple devices into an analytical instrument.

Data of the source samples can be entered manually into the control system, either specifically from the laboratory information management system (LMS) or from the import template. In the context of the present invention, the term "generating an analysis sample" relates to adjusting the originally imported sample data or parameters held in the data storage according to the specific analysis run to be performed within the separation and detection process for quantitative sample analysis. In particular, such adjustments may include applying a dilution factor, calculating an average concentration if one of the samples is processed several times, and the like.

Device utilization may relate to utilization over time, whereby taking into account that utilization may relate to preferred use of the device over time. Thus, optimized utilization may involve utilization of the device for efficient use of the device in terms of process time, process cost, sample throughput, quality of analysis results, and the like. By taking into account the utilization of the device for generating the analysis sample sequence, said utilization can be optimized and also the separation and detection process for quantitative sample analysis. It specifically allows for the coordination and synchronization of the devices, resulting in an efficient separation and detection process for quantitative sample analysis. Thus, the sequence generation unit may particularly be arranged for adjusting parameters related to an optimized utilization of the device, thereby allowing an efficient separation and detection process, and particularly an HPLC process, for quantitative sample analysis. In addition, it allows to integrally control and perform the separation and detection process for quantitative sample analysis, wherein various tasks are centrally organized and initiated.

Preferably, the control system comprises a method modelling unit, wherein the data storage is arranged for holding data of methods of separation and detection processes for quantitative sample analysis, the method modelling unit is arranged for providing suitable methods of separation and detection processes for quantitative sample analysis according to the sequence of analysis samples defined by the sequence generating unit using the method data held in the data storage, and the interface unit is arranged for operating the apparatus of separation and detection processes for quantitative sample analysis according to the suitable methods provided by the method modelling unit. Suitable methods in this context relate to methods which are particularly suitable for efficient separation and detection processes for quantitative sample analysis, e.g. according to the sample, instrument, conditions, sequence etc. involved. It may involve adjusting parameters of the apparatus to allow for the separation of compounds or samples during high performance liquid chromatography. In particular, it may relate to detection related parameters, such as mass spectrometric traces with Declustering Potential (DP) and Collision Energy (CE), uv wavelengths, etc., chromatography related parameters, such as columns, mobile phases, gradients, etc., compound information related parameters, such as Molecular Weight (MW), name, items, etc., and/or method information related parameters, such as status, sensitivity, etc. For example, suitable methods as a combination of separation and detection conditions may in this context involve a combination of equipment and operations that specifically take into account the separation conditions of the sample and the detection conditions of the compound. By means of such a method modeling unit, the control system may automatically provide one or more suitable methods, and the suitable methods may be selected by an operator, such as the control system. Wherein the data storage is preferably arranged for holding compound data of the source sample and the method modelling unit is arranged for evaluating, for each of the compounds of the source sample, an appropriate method within the separation and detection process for quantitative sample analysis. Hence, the method modeling unit is preferably arranged for providing a presentation of the appropriate method and detecting a selection of the appropriate method. The presentation may be a graphical user interface showing a list of suitable methods. Input may be detected by clicking a signal, by analyzing input text, by analyzing the pressing of a key, etc. In addition, the method modeling unit is preferably arranged for evaluating a failed method within the separation and detection process for quantitative sample analysis for the compounds of the source sample. Such an arrangement may allow a particularly convenient and efficient method selection.

Preferably, the control system maintains interface format data of control software of at least one of the devices, wherein the interface unit is arranged for communicating with the control software of at least one of the devices for operating at least one of the devices within the separation and detection process for quantitative sample analysis according to the sequence of analysis samples defined by the sequence generation unit using the interface format data. The control software may be, for example, one computer software, a plurality of computer software, or a combination of computer software and associated data. In this context, interface format data refers to data or metadata defining a format of an interface allowing interaction with at least one of the devices. For example, it may relate to the structure and content of a Character Separation Value (CSV) file intended to be exchanged between the control system and at least one of the devices. The maintained interface format data may be established by arranging the data storage to maintain interface format data for native software of each device. The control software in this context relates to the native software of the device that is used to control the device. In particular, at least one of the devices may be all devices of the separation and detection process for quantitative sample analysis as mentioned above, i.e. all devices of the analysis instrument. Such an arrangement of the control system allows for an easier implementation of the interface unit and for an efficient data exchange. The interface unit is thus preferably arranged for communicating with the control software of at least one of the devices by generating a file importable by the control software of at least one of the devices. The file may in this context particularly be a digital text file, such as a computer readable file having text as represented by a character encoding scheme such as for example American Standard Code for Information Interchange (ASCII) or Unicode.

Preferably, the control system comprises: a robot unit arranged for controlling the robot to transform the plurality of source samples located in the source sample containers into analysis samples generated by the sample modeling unit and located in the processed sample containers according to the sequence of analysis samples defined by the sequence generation unit. In this context, a sample container refers to a container, such as a tube or well plate, suitable for handling a sample. Thus, the well plate may for example be a multi-well microplate which is standardized and commonly used for storing and/or transporting samples. For example, such standards developed by the Society for Biomolecular Screening (SBS) and approved by the American National Standards Institute (ANSI) define Microplates of 127.76mm length, 85.48mm width and 14.35mm Height that include 96, 384 or 1536 wells [ see the Society for Biomolecular Screening ANSI/SBS 1-2004: Microplates-Footprint Dimensions, ANSI/SBS 2-2004: Microplates-Height Dimensions, ANSI/SBS 3-2004: Microplates-Bottom out Flankimeters and ANSI/SBS/4-2004: Microplates-Well positions. The plurality of source samples may be a selection of source samples maintained in the data storage device and may correspond to physical samples delivered for analysis within the high performance liquid chromatography process. The robot may be, for example, a pipette robot such as those widely known in the art, available from the company tecan group ltd. The data of the source samples delivered in the source sample well plate may include plate name or plate identification, well identification, compounds to be analyzed, etc., respectively. Analytical samples in this context relate to samples which are prepared for analysis within a separation and detection process for quantitative sample analysis and which are arranged in a process well plate by a robot controlled by a control unit of a control system. Such an arrangement of the control system may allow for efficient sample processing, especially where larger amounts of sample are involved, such as in a laboratory.

Hence, the robot unit is preferably arranged for applying the volumetric transfer in the transformation of the source sample into the analysis sample. Volume transfer in this context involves a sample preparation step involving an activity that results in the transfer of a volume within the sample. Specifically, volumetric transfer may include diluting the sample, removing proteins from the sample, such as by precipitation, calibrating sample preparation, and the like. Further, the control system thereby preferably maintains robot interface format data of the control software of the robot, wherein the interface unit is arranged for communicating with the control software of the robot for operating the robot for transforming a source sample located in the source sample container into an analysis sample located in the processed sample container. In an example use of the control system, a user of the control system imports source sample information into the control system, the control system virtually creates an analytical sample and exports a text file for the pipette robot, places the actual source sample and an empty processing plate on the robot, starts the robot, and the robot prepares the analytical sample according to the virtual preparation of the control system.

Preferably, the device for a separation and detection process of quantitative sample analysis comprises a first number of separation devices, a second number of injection devices and a third number of detection devices, wherein at least one of the first, second and third number is larger than another of the first, second and third number, and wherein the sequence generating unit is arranged for defining a sequence of analysis samples such that a larger number of devices interoperate alternately with a smaller number of devices. Processing samples by such a multiline separation and detection process for quantitative sample analysis, and in particular multiline HPLC, often referred to as multiplexed HPLC, allows for increased utilization of the detector apparatus. Such multiplexing may increase overall efficiency since the detector equipment is typically the most expensive of the equipment used in the HPLC process. The first number and the second number are therefore preferably equal and larger than the third number, wherein the separation devices and the injection devices are arranged in a plurality of lines connected to the at least one detector device. In other words, the sequence generation unit is arranged for defining a sequence of analysis samples such that the lines, when applied, alternately provide samples to the detector device. In this way, the detector unit can be used efficiently and its utilization can be increased, which can be particularly important in processes such as HPLC processes using a mass spectrometer as detector, where the detector device is the most expensive, but generally faster device.

Preferably, the data of the source samples comprise compound data, and the sample modelling unit is arranged for evaluating the compound data of the source samples with respect to their detection traces and with respect to their compatibility with respect to chromatographic preferences, and for mixing the appropriate source samples when generating a plurality of analysis samples to be analyzed in a separation and detection process for quantitative sample analysis. In this context, detection traces relate to output patterns generated by the detector device, wherein the pattern of each compound typically has a specific peak at a specific location. In addition, chromatographic preferences relate to preferences such as process temperature, process pressure, and the like, for example. The appropriate source samples relate to compatibility in terms of chromatographic preferences and in terms of the identifiability of the output pattern including the peak of each source sample. Processing the sample by such sample-mixing HPLC (often referred to as sample cocktail analysis) allows to increase the efficiency of the HPLC process.

Preferably, the control system comprises a maintenance unit, wherein the data storage is arranged for holding data of each of the devices, and the maintenance unit is arranged for causing maintenance of the devices taking into account the data of each of the devices. The term "cause equipment maintenance" in this context relates to various maintenance actions, such as triggering preventive equipment maintenance after certain use of the respective equipment, storing and displaying equipment events such as successful operation, errors, repairs, etc., defining default parameters of the equipment, displaying equipment inventory, estimating analytical operating costs related to the equipment, etc. In this way, efficient and convenient maintenance of the apparatus is possible. Thus, the maintenance unit is preferably arranged for predefining values of the maintenance data of each of the devices, counting trigger values associated with the maintenance data of each of the devices and providing an alarm when the counted trigger values are equal to the predefined values. The values of the maintenance data for each device may be predefined, for example by inputting values into the control system. In particular, a set of values may be input by a maintenance plan, where the maintenance plan relates in this context to one or more maintenance events associated with a particular trigger value. For example, the maintenance event may be cleaning the equipment, replacing some portion of the equipment, etc. The trigger value in this context relates to an action performed with the respective device, such as for example an injection performed by the device, a calendar day, a volume of solvent used, etc. The alert may be provided by requesting a specific maintenance event, and it may include blocking the associated device until the maintenance event is performed. In addition, the maintenance unit is preferably arranged for storing maintenance data for each of the devices in the data storage and providing maintenance reports for each of the devices.

Preferably, the characteristic data of each of the devices comprises default settings of each of the devices, and the sequence generation unit is arranged for defining the sequence of analysis samples of the analysis samples according to the default settings of each of the devices. The default settings in this context relate to one of the devices' specific and intended run-specific settings. They may specifically include injection method type, file system path for storing data or text files, injection volume, etc.

Yet another aspect of the invention relates to a computer program comprising program code arranged to be executed to implement the system described above. Such a computer program allows a simple implementation of the system according to the invention, thereby achieving corresponding advantageous effects.

These and other aspects of the invention will be apparent from and elucidated with reference to the embodiments described hereinafter.

Drawings

The control system and the computer program according to the invention are described in more detail below by way of example embodiments and with reference to the accompanying drawings, in which:

FIG. 1 shows a schematic diagram of components of one embodiment of a control system according to the present invention;

FIG. 2 shows a schematic diagram of an analytical instrument for multiplexing High Performance Liquid Chromatography (HPLC); and is

Fig. 3 shows a schematic of sample cocktail analysis within High Performance Liquid Chromatography (HPLC).

Detailed Description

Fig. 1 shows software or a computer program according to the invention, which is executed on a computer and thus implements a control system 1 according to the invention, which control system 1 serves for the automatic control of a plurality of devices 2 of a high-performance liquid chromatography process (HPLC process) as a separation and detection process for quantitative sample analysis. The control system 1 comprises a data storage 11 and an interface unit 16 and various modules which may be used alone or in combination to create a synergy. The modules may be implemented as separate applications on a computer or as part of a single application. The modules include a device modeling unit 12, a sample modeling unit 13, a sequence generation unit 14, and a method modeling unit 15. As indicated by the corresponding arrows, the interface unit 16 is arranged for interacting with each device of the combination of devices 2 forming the analytical instrument for the HPLC process. The analysis instrument comprises an injection device 21, a separation device 22 and a detector device 23.

The control system 1 is arranged for performing a complete analytical run of the HPLC analytical process. It allows coordination and synchronization from the devices 2 that are part of the analytical HPLC instrument. The data storage 11 is arranged for holding and importing data of source samples to be analyzed, which may be provided by a laboratory information system (LIMS) or from an import template, for example. It also holds characteristic data of the device 2 of the analysis instrument. The analytical sample is then generated electronically by a human analyst or user of the laboratory when physically prepared. Such generation includes transfer of the source sample to be analyzed to a new sample container, sample dilution, calibrator, and quality control. Considering the data of the samples and of the device 2, the sequence generation unit 15 defines an analysis sample sequence, such as an injection order of the samples, considering an efficient utilization of the device 2. Each sample is linked to the desired analytical parameters such as injection method, mobile phase, gradient profile, detection method, etc. As will be shown in more detail below, the control system 1 also comprises an optional procedure for manipulating the sequence of analysis samples for multiplexing or sample cocktail analysis.

For interacting with the device 2, the interface unit 16 generates a text file called a worklist in a predefined format. These work lists are imported into the native software of device 2 and are used to control the native software corresponding to device 2. By using native software within the device control, access to the full functionality of the device 2 can be obtained.

The source samples of the analysis run and the raw data of the device 2 may be imported to the control system 1. The dilution factor is applied during the introduction and if the sample is injected several times, the control system 1 calculates the average concentration. Upon acceptance (or user confirmation) of the data from the analysis run, any modification of the data is prevented and the control system 1 may create and/or export a report. The control system 1 allows to analyze the sample and deliver the results with a suitable quality and in a short time.

The method modeling unit 15 is used to support analytical method development and to store analytical method parameters in the data storage device 1. For example, a list of compounds to be analyzed is introduced into the optimization batch. The method modeling unit 15 may discover and provide existing methods by querying the data store 11. The operator or analyst or user can then decide whether he wants to use them as such or whether he wants to redevelop or adapt them, based on the information linked to the found methods. In addition, the method modelling unit 15 allows for manual development (compound by compound) and automated development using corresponding software, such as the software labeled "discover quant" of the company AB Sciex. The method modelling unit 15 presents the completed method for retrieval purposes. The parameters of such analytical methods cover detection of e.g. mass spectral traces with Declustering Potentials (DP) and Collision Energies (CE), ultraviolet wavelengths etc., chromatography such as columns, mobile phases, gradients etc., compound information such as Molecular Weight (MW), name, terms etc., and method information such as e.g. status, sensitivity etc.

The method modeling unit 15 also has fault identification and evaluation. Depending on the number of compounds for which the method is developed within the control system 1, there are cases where the method development fails for different reasons, such as unstable compounds, insufficiently pure compounds, etc. Thereby providing the possibility to label compounds and to store information about the reason for failure, such as comments from color spectra, etc. or screenshot pictures. If the labeled compound is resubmitted for analysis, the method modeling unit 15 notifies this compound of a potential problem.

The interface unit 16 supports data processing such as chromatographic synthesis. The native software of the device 2, delivered for example with the detector 23 or mass spectrometer, is designed to process the raw data on an analyte-by-analyte basis. The interface unit 16 uses the derived working list as an input file defining the analyte names and traces, internal standard names and traces, chromatography file names and file locations to control the native software from the detector 23 and other devices 2. The input work list is generated by the interface unit 16 accessing information from the data storage 11.

The control unit 1 allows for loop or iterative creation of methods required for data processing, processing the data and formatting the final data.

The device modelling unit 12 is arranged for defining an analytical instrument by combining a plurality of devices 2. It is used to store and retrieve all necessary types of data relating to the device 2 and the analysis instruments and associated equipment used or stored in the laboratory. In addition, the device modelling unit 12 or maintenance unit is arranged to trigger preventive maintenance, store all events related to the device 2 (logging functions), define an analytical instrument work line with default parameters such as methods, files and folder paths, give real-time inventory of used or unused devices in the device 2, and perform cost estimation associated with instrument usage such as purchase, maintenance, repair, etc.

The following basis is defined in the device modelling unit 12: the equipment is minimal and non-divisible, such as pumps, columns, injection valves, detectors, etc. The device may be used as a stand-alone tool or in combination with other devices. The plant module is a combination of one to a plurality of plants which are usually used together, such as a gradient pump, a plant module consisting of a water pump, an organic pump and a pump controller, or a column module consisting of an analytical column, a pre-column and a column oven. A work line is a combination of one or more modules required to perform a job, for example a work line on a liquid chromatography-mass spectrometry system may consist of equipment modules such as a gradient pump, an injector, a column, and a detector. One equipment module can be used on different work lines, especially for multiplexing situations where chromatography is performed on different and column modules, but the same detector module is used on different work lines. Configured to link one or more work lines that may be used simultaneously on the analytical instrument. The analytical instrument may have one or more configurations. The laboratory is the highest level used to link together the belonging instruments.

The control system 1 further comprises a maintenance unit for associating a maintenance plan to the device 2. Thus, a maintenance plan consists of one or more maintenance events that a maintenance unit may cause. The maintenance event is defined by an action performed in association with the trigger. The trigger or trigger value may be a count of injections performed on the device, calendar days, volume of solvent used, etc. The trigger value counter may be automatically updated by the control system 1 when performing the analysis. Once the trigger value counter reaches the set trigger value, the maintenance unit requests the corresponding maintenance event to be performed. Upon execution of a maintenance event, the trigger value counter is reset and a new loop is started. The maintenance unit is further arranged for logging maintenance events and providing maintenance reports. Specifically, different maintenance events and information are automatically linked to the device 2, such as Preventive Maintenance (PM) event information performed, unscheduled services performed by the user himself or by an external company, and data from preventive maintenance, etc.

In the device modelling unit 12 different data can be linked to the working line. Those data may be used as default parameters for the working line, such as injection method, folder path for raw data, injection volume, etc., and may be accessed directly from the control system 1. To analyze the sample, then only the working line on which the sample should be analyzed needs to be selected, and then the device modelling unit 12 provides all default parameters. Thus, data such as column name, mobile phase, different methods used are also used to generate method descriptions in the analysis report.

The sample modeling unit 13 allows preparation of an analysis sample by using a pipette robot such as Tecan genetics. Source samples are obtained from, for example, a laboratory customer and delivered in tubes or on 96 or 384 multi-well microplates or well plates as sample containers. Information about the source sample, such as plate name, well name, and compound to be analyzed, etc., is imported into the data storage 11. An analytical sample is a sample that is prepared by a sample modeling unit using a source sample and injected on an analytical instrument. In some cases, the source sample is prepared, such as diluted, proteins are removed by precipitation, calibration samples are prepared, and the like. All those activities are primarily volumetric transfer steps from source samples located in the source well plate to assay samples including or not added with reagents located in the processing well plate.

The sample modeling unit 13 virtually prepares an analysis sample. The automated sample modelling unit 13 comprises a robotic unit which generates a work list readable by the pipette robot and contains all pipette step information from the source sample container to the processing sample container and the volume to be transferred. In summary, the user imports source sample information into the control system 1, the sample modeling unit 13 of which virtually creates an analytical sample, exports a worklist for the pipette robot, puts the physical source sample and the empty processed sample container on the robot, starts the robot, and prepares the analytical sample according to the virtual preparation.

The control system 1 further comprises a statistical unit that updates the data storage means 11 each time a worklist is exported from the control system to the analysis instrument, or automatically upon completion of the analysis. The stored information includes, for example, an experiment identifier, the number of samples analyzed, a date, an instrument identifier, and the like. By querying the data storage 11 by the statistical unit, real-time information about the workload and analysis performed quarterly or annually can be obtained. In this way, it is possible to assess the effective cost of each sample analyzed or to identify the strengths or weaknesses of the laboratory.

The control system 1 further comprises a diagnostic tool for identifying technical problems on the analytical instrument by analyzing the raw data from the analytical instrument. The diagnostic tool accesses the analysis raw data stored in the data storage device from the control system 1, and sets a filter and defines what is drawn by the user. As an example, a triple stage quadrupole mass spectrometer is used as the detector device 23 and analyzes the biological sample. After a certain time, the ion path of the detector device 23 becomes dirty and needs to be cleaned. By plotting the peak area against the implant according to internal criteria, this problem is easily identified if the peak area decreases over time. Or another example, for diagnosing an HPLC pump, the dwell time is plotted against the injection, where the stability of dwell time over time is a good indicator of the pump status.

In addition, the control system 1 also comprises a laboratory notebook tool for supporting the use of paper notebooks. In some cases, it is mandatory to record work into official paper lab notebooks. Since necessary data is stored in the data storage 11 and data input is done using an interface unit in which notebooks can be registered, entries in those notebooks and keywords linked to the entries can be executed. All of this information stored in the data storage device 11 is retrievable by the laboratory notebook tool. A summary page for a paper notebook can be generated with the same interface as a cross-reference or index with all keywords. This may help to quickly and accurately complete a paper notebook for archiving. In addition, any analysis run may be linked to an entry by selecting a notebook ID and page for the notebook entry of the laboratory notebook tool. With the control system 1 it is possible to generate and print paper reports corresponding to the analysis run. This report is ready for pasting into a paper notebook. Keywords from the analysis, such as compound IDs or item names, are also automatically attached to the entries in the data storage 11 and are retrievable.

The centralized and unified control system 1 provides a number of advantageous synergistic effects. For example, data mining is efficiently generated using all information and data stored in the data storage unit 11. The data format is standardized and with this unified data from different aspects of the laboratory, data mining can be performed to enable the user to learn from the stored data. Statistical interfaces and diagnostic tools are data mining tools designed with a user interface for solving specific problems. This data mining concept can be extended to any new idea with the limitation of properly capturing the target data. By directly accessing the data storage 11, any query can be performed to obtain the desired report. In some cases, it is helpful to create a specific user interface for supporting the user due to the repeated appearance of the search. As an example, it may be desirable to predict chromatographic conditions, such as gradient profiles, columns, shifts, etc., based on historical data from similar compounds. It may thus be possible, for example, to predict the available chromatographic conditions for a plurality of compounds or situations in the compounds to be analyzed.

The following applies to the remainder of the description. For clarity of the drawings, reference is made to the previous description if a figure contains a reference that is not described in a directly related part of the description.

An analytical instrument for multiplexing High Performance Liquid Chromatography (HPLC) is shown in fig. 2. The analysis instrument consists of a plurality of devices 2 comprising a sample injection device 25, a plurality of separation devices 24, a selection device 26 and a detection device 27. The plurality of separation devices 24 includes a first separation device 241, a second separation device 242, a third separation device 243, and more separation devices 244. The sample injection device 25 may be, for example, an autosampler and in particular an HPLC autosampler, such as an autosampler labeled "HTS PLA" of company CTC analysis, labeled "lamodzu L-2300" of company Shimadzu or of company WWR. The separation device 24 may be, for example, a degasser, an HPLC pump and an HPLC column or a gas, gas chromatograph oven and a gas chromatograph column, etc. The selection device 26 may be a four-column selector. Such as company VICI AG, product number C5F-0004 EMT. The detection device 27 may be an ultraviolet absorption detector, a fluorescence detector, a mass spectrometer detector, a Flame Ionization Detector (FID), or the like.

In some cases, multiplexing HPLC may be of interest, as for example if the acquisition cost of the detection device 27 represents about 80% of the total cost of the analytical instrument, considering one working line, i.e. one gradient pump, one sampler, one column and one detector. Thus, the control system 1 is arranged for providing multiplexing. The utilization of the HPLC analytical instrument can be multiplied by nearly two if it is operated in parallel on two working lines. The underlying principle of multiplexed HPLC is to inject samples alternately on two or more working lines. To use the non-productive equilibration time from a column in one line, samples on another line may be analyzed. This is physically possible by adding one or more gradient pumps, one or more injection devices, one or more columns and one or more diverter valves. This doubles or multiplies the capacity of the analytical instrument and reduces the need for multiple systems, which reduces the overall laboratory equipment cost. As shown in fig. 2, multiplexed HPLC can be extended to more than two work lines with the added benefit of obtaining process diversity flexibility. The working line may be specifically dedicated to a specific method, which for example allows to analyze samples requiring different columns within the same analysis sequence.

Since multiplexed HPLC may become complex to operate and manipulate, the control system 1 critically improves the availability of the process or makes it even entirely possible. Within the control system, the user defines the injection sequence for the sample and the working line on which the sample must be analyzed. The process of the control system 1 retrieves all the required information for performing the analysis run, such as the pump method (gradient), the injection method, the detection method (analysis trace) and the like. The control system 1 reduces the added complexity from the multiplex instrument to a level that is available for routine work.

Fig. 3 shows a sample cocktail analysis within HPLC, where a plurality of source samples 3, such as a first source sample 31, a second source sample 32 and further source samples 33, are mixed into an analysis sample 4. The analysis sample 4 is then analyzed and the resulting concentrations 5 are provided, i.e. a first concentration 51 from the first source sample 31, a second concentration 52 from the second source sample 32 and further concentrations 53 from further source samples 33.

Sample cocktail analysis is not currently frequently applied within HPLC because the time gain is often lower than the additional time required to prepare a sample cocktail analysis. This is no longer true within the control system 1, which provides a means for performing sample cocktail analysis. In particular, with the control system 1, a sample cocktail analysis can be applied as follows. The target compounds from the different source samples 3 intended to be mixed must be different and the detection trace from each of them must be specific. This means that not all samples can in fact be mixed, but that the chromatographic conditions for the mixed compounds must be compatible, such as the same column, the same mobile phase and the same gradient. In addition, the method must be sensitive enough to allow for the dilution step from sample cocktail preparation. If all these criteria are met, the samples can be mixed and analyzed with a detection method that contains traces from all compounds. During the data evaluation process, the measured results must be redistributed to the corresponding source samples and the final results must be corrected by applying the appropriate sparseness factor produced by the mixing during sample cocktail preparation.

The automatic preparation of the mixed compounds and results by the control system 1 allows for convenient application of sample cocktail analysis. The analysis time designed for the number of mixed samples can thereby be substantially reduced. Additionally, by having access to relevant information from the data storage means, a process supporting the user in the analysis of the sample cocktail may be generated within the control system 1. The control system 1 analyzes the compatibility of the sample cocktail method for all compounds to be analyzed within one run. This method analysis follows some simple rules, such as minimum required mass difference for the parent. The column, mobile phase and gradient profiles must be identical. Depending on the compound sensitivity, a sample cocktail of three compounds is allowed if high, two compounds are allowed if medium, and no sample cocktail is allowed if the sensitivity is low. In addition, this process includes generating some sample cocktail proposals according to previously defined rules and creating a virtual processed sample container in which the source sample 3 is mixed if the user accepts the previous sample cocktail proposal. Using a correspondingly arranged sample modelling unit 13, the actual sample cocktail sample can be prepared in an automated manner. The analysis may be performed as usual and the control system 1 automatically performs the application of the dilution factor.

In the example of an analysis scenario, i.e. an example application of the control system 1, different compounds therein have to be quantified if a set of samples is received by a laboratory. All sample information data was captured in a Laboratory Information Management System (LIMS). The analysis activity begins with the introduction of a list of compounds into the control system. The existing method is started to check for the flag. For compounds in which no existing methods are found, the development process can be started, while for other compounds the use process is ready. Work may continue in the control system 1 while the full set of methods is developed, tested, and completed. Information about the sample is imported into the data storage 11. A sample cocktail process is initiated and if a sample cocktail proposal is accepted, a worklist for the pipette robot is exported. The sample to be analyzed is placed on the pipette robot along with the required reagents for sample development. And starting the robot program by taking the exported work list as an instruction file. During this time, the robot prepares the analysis sample, the user checks the instrument status with the control system, and then he performs the work that has to be done on the instrument, such as changing filters, cleaning the ion source from the detector, filling the move, etc.

The sample and instrument are then ready and the analysis sequence is completed at the control system 1, with or without the multiplexing option. A worklist for the instrument is derived, an analytical sample is placed on the analytical instrument, and analysis is started. Upon completion of the analysis run, the raw data may be processed with native software of the detector. The user checks the chromatographic synthesis and, if the quality of the result is as expected, imports data into the control system 1. During the import process, dilution factors and mean calculations are automatically applied. After the final inspection by the user, the analysis is completed and locked. If the analysis has to be archived in a laboratory notebook, a link to the notebook reference is generated in the control system 1 and the report is printed and pasted into the laboratory notebook. Reports may be exported and sent to the customer or final results may be uploaded to the LIMS. To optimize the utilization time, the samples are analyzed at night, and during the day the user has time to complete the analysis from the previous day, prepare a new analysis and maintain the instrument.

While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description are to be considered illustrative or exemplary and not restrictive. It will be understood that changes and modifications may be effected by one of ordinary skill in the art within the scope and spirit of the appended claims. In particular, the invention covers further embodiments having any combination of features from the different embodiments described above and below.

All other features shown individually in the drawings are also covered by the present invention but may not be described in the foregoing or in the following description. Alternative embodiments of the embodiments described in the figures and the description and individual alternative characteristics of their characteristics may also be disclaimed from the subject matter of the invention.

In addition, in the claims, the word "comprising" does not exclude other elements or steps, and the indefinite article "a" or "an" does not exclude a plurality. A single unit may fulfill the functions of several features recited in the claims. The terms "substantially", "about", "approximately" and the like in connection with an attribute or value also specifically define the attribute or the value exactly, respectively. A computer program may be stored/distributed on a suitable medium, such as an optical storage medium or a solid-state medium supplied together with or as part of other hardware, but may also be distributed in other forms, such as via the internet or other wired or wireless telecommunication systems. In particular, the computer program may be, for example, a computer program product stored on a computer-readable medium, which may have computer-executable program code adapted to be executed to implement a specific method, such as the method according to the invention. Any reference signs in the claims shall not be construed as limiting the scope.

Claims (17)

1. A control system (1) for automatically controlling a plurality of devices (2) of a separation and detection process for quantitative sample analysis, the control system having:

a data storage (11) arranged for holding characteristic data of each of the devices (2) and data of the source samples (3), an

A sequence generation unit (14) arranged for defining a sequence of analysis samples to be analyzed in the separation and detection process for quantitative sample analysis from a plurality of analysis samples to be analyzed in the separation and detection process for quantitative sample analysis taking into account the utilization of the device (2),

an interface unit (16) arranged for operating the device (2) in the separation and detection process for quantitative sample analysis according to the sequence of analysis samples defined by the sequence generation unit (14),

it is characterized in that the preparation method is characterized in that,

the control system has a device modeling unit and a sample modeling unit,

the device modelling unit is arranged to model the device (2) using the characteristic data of the device (2) held in the data storage (11);

modeling the device at the device modeling unit includes: reproducing each of the devices according to the characteristic data of the devices; and establishing interaction between said devices within said separation and detection process for quantitative sample analysis and combining multiple devices into an analytical instrument;

the sample modelling unit is arranged for using data of the source samples (3) held in the data storage (11) to generate a plurality of analysis samples to be analysed in the separation and detection process for quantitative sample analysis; and

the analytical sample is virtually prepared.

2. The control system (1) according to claim 1, further having a method modeling unit, wherein the data storage (11) is further arranged for holding data for the method of the separation and detection process for quantitative sample analysis, the method modeling unit is arranged for providing a suitable method for the separation and detection process for quantitative sample analysis according to the sequence of analysis samples defined by a sequence generating unit using the method data held in the data storage, and the interface unit (16) is further arranged for operating the device (2) for the separation and detection process for quantitative sample analysis according to the suitable method provided by the method modeling unit (15).

3. The control system (1) according to claim 2, wherein the data storage (11) is arranged for holding data of compounds of the source sample (3) and the method modelling unit is arranged for evaluating the appropriate method within the separation and detection process for quantitative sample analysis for each of the compounds of the source sample (3).

4. A control system (1) according to claim 3, wherein the method modelling unit (15) is arranged for providing a presentation of appropriate methods and detecting a selection of the appropriate method.

5. The control system (1) according to claim 3, wherein the method modelling unit (15) is arranged for evaluating a failed method within the separation and detection process for quantitative sample analysis for the compounds of the source sample (3).

6. The control system (1) according to any one of the preceding claims, maintaining interface format data of control software of at least one of the devices (2), wherein the interface unit (16) is arranged for communicating with the control software of the at least one of the devices (2) for operating the at least one of the devices (2) within the separation and detection process for quantitative sample analysis according to the sequence of analysis samples defined by the sequence generation unit (14) using the interface format data.

7. The control system (1) according to claim 6, wherein the interface unit (16) is arranged for communicating with the control software of the at least one of the devices (2) by generating a file importable by the control software of the at least one of the devices.

8. The control system (1) according to any one of claims 1-4, further comprising a robot unit arranged for controlling the robot to transform a plurality of source samples (3) located in source sample containers into the analysis samples (4) generated by the sample modelling unit (13) and located in processing sample containers according to the analysis sample sequence defined by the sequence generating unit (14).

9. The control system (1) according to claim 8, wherein the robot unit is arranged for applying a volumetric transfer within a transformation of the source sample (3) into the analysis sample (4).

10. The control system (1) as defined in claim 8, holding robot interface format data of control software of the robot, wherein the interface unit (16) is arranged for communicating with the control software of the robot in order to operate the robot for transforming the source sample (3) located in the source sample container into the analysis sample (4) located in the processed sample container.

11. The control system (1) according to any one of claims 1-4, wherein the devices (2) of the separation and detection process for quantitative sample analysis comprise a first number of separation devices (24), a second number of injection devices (25) and a third number of detection devices (27), wherein at least one of the first, second and third number is larger than another of the first, second and third number, and wherein the sequence generation unit (14) is arranged for defining the sequence of analysis samples such that a larger number of the devices (2) alternately interoperate with a smaller number of the devices (2).

12. The control system (1) according to claim 11, wherein the first number and the second number are equal and larger than the third number, and wherein the separation devices (24) and the injection devices (25) are arranged in a plurality of lines connected to the at least one detector device (27).

13. The control system (1) according to any one of claims 1-4, wherein the data of the source samples comprises compound data, and the sample modelling unit (13) is arranged for evaluating the compound data of the source samples (3) with respect to compatibility of detection traces of the source samples (3) and with respect to their chromatography preferences, and mixing appropriate source samples (3) when generating the plurality of analysis samples (4) to be analyzed in the separation and detection process for quantitative sample analysis.

14. The control system (1) according to any one of claims 1-4, comprising a maintenance unit, wherein the data storage (11) is arranged for maintaining maintenance data of each of the devices (2), and the maintenance unit is arranged for causing maintenance of the devices (2) taking into account the maintenance data of each of the devices.

15. The control system (1) according to claim 14, wherein the maintenance unit is arranged for predefining values of maintenance data for each of the devices, counting trigger values associated with the maintenance data for each of the devices (2), and providing an alarm when the counted trigger values are equal to the predefined values.

16. The control system (1) according to claim 14, wherein the maintenance unit is arranged for storing maintenance data of each of the devices (2) in the data storage (11) and providing maintenance reports for each of the devices (2).

17. The control system (1) according to any one of claims 1-4, wherein the characteristic data of each of the devices (2) comprises a default setting of each of the devices (2), and the sequence generation unit (14) is arranged for defining the sequence of analysis samples of the analysis samples (4) according to the default setting of each of the devices (2).