DE102017126893A1 - Analytical method with expected corridor as the basis for the analysis - Google Patents

Abstract

A sample separating device (10) for separating a fluidic sample, the sample separating device (10) having a control device (70) designed to control the separation of the fluidic sample according to a separation method (92), the separation method (92) being characterized by a parameter set parameter values to be specified during the separation and an expectation corridor (100) for parameter values that are set during the separation and that are indicative of a desired course (114) of the sample separation.

Description

TECHNICAL BACKGROUND

The present invention relates to a sample separation device and a method for separating or analyzing a fluidic sample, a method for operating a measuring device and a fluidic analysis device.

In an HPLC, a liquid (mobile phase) is typically run at a very precisely controlled flow rate (for example in the range of microliters to milliliters per minute) and at a high pressure (typically 20 to 1000 bar and beyond, currently up to 2000 bar). , in which the compressibility of the liquid can be felt, by a so-called stationary phase (for example, in a chromatographic column), moved to separate individual components of a sample liquid introduced into the mobile phase from each other. Such an HPLC system is known, for example from the EP 0,309,596 B1 same Applicant, Agilent Technologies, Inc.

A parameter set with parameter values for carrying out the chromatographic separation can, for example, be stored in a database and can be processed by a control device of a sample separator when separating the fluidic sample. When working through such a chromatographic separation method, under unfavorable conditions it may happen that the sample separation is performed in an inaccurate or even incorrect manner, without this being recognized by a user.

EPIPHANY

It is an object of the invention to be able to reliably assess or ensure the quality of a sample separation or measurement. The object is achieved by means of the independent claims. Further embodiments are shown in the dependent claims.

According to an exemplary embodiment of the present invention, a sample separation device (for example a chromatographic sample separation device) is provided for separating a fluidic sample (a fluid may in particular comprise a liquid and / or a gas, optionally comprising solid articles), wherein the sample separation device comprises a control device ( for example, a processor executing a program code) configured to control the separation of the fluidic sample according to a separation method, the separation method being defined by a parameter set with or from parameter values to be given during separation, and an expectation corridor relating to during separation Parameter values indicative of a desired course of sample separation.

According to another exemplary embodiment, there is provided a method of separating a fluidic sample, the method controlling separation of the fluidic sample according to a separation method, and the separation method by a parameter set having parameter values to be specified during separation (optionally additionally comprising a set of instructions during the Performing control commands to be performed on the separation method) and defining an expectancy corridor for parameter values that are set during the separation of parameters, which is indicative of a desired course of the sample separation.

According to another exemplary embodiment, a method for operating a measuring device (for example, a sample separating device) is provided, wherein the method controls the operation of the measuring device according to an operating method (for example, a separating method), and the operating method is predetermined by a parameter set during parameter values to be preset, and an expectation corridor with respect to parameter values which occur during the measurement, which is indicative of a desired course of the operation of the measuring device, and optionally a must corridor with respect to parameter values which occur during the measurement, which are required for a course of operation of the Indicator is indicative.

According to another exemplary embodiment, a fluidic analyzer (in particular, a sample separator) is provided for analyzing a fluidic sample, wherein the fluidic analyzer comprises a controller for controlling an analysis process of the fluidic sample according to an analysis method (which may be a separation method or another method of operation can be formed), wherein the analysis method is characterized by a parameter set with parameter values to be specified during the analysis process and by an expectation corridor (which can refer in particular to the parameter values of several parameters during the analysis process) with respect to parameter values which occur during the analysis process Target course of the analysis process is indicative.

In the context of the present application, the term "separation method" can be understood in particular to mean a sequence of procedures which are to be processed in succession by a sample separation device in a predetermined manner during a separation of a fluidic sample. The Separation method may include or describe actions of the sample separator during the separation process, for example switching a fluid valve at a particular time during the course of the separation process. The separation method may further specify parameters to be set during separation, for example, a solvent composition at a certain time during the course of the separation process. In particular, such a separation method can be fixed in time by a sample separating device or can be configured by the user. A separation method can be stored as a data record on a data carrier (for example, a database that may contain an electronic mass storage). For example, a separation method may allow for separation or analysis in a gradient mode in which a mobile phase solvent composition changes over time according to a predeterminable scheme. Another separation method may involve separation or analysis in an isocratic mode where the solvent composition remains constant over time.

In the context of the present application, the term "parameter" may in particular be a physical or chemical quantity (for example a physical or chemical observable, for example a solvent composition or a print), a condition (for example exceeding or not exceeding a maximum permissible value or presence or absence) Absence of, for example, an artificial phenomenon) or an operating condition (for example, the presence of a particular event during a gradient run). One or more qualitative and / or quantitative values associated with such parameter (for example, solvent composition in the form of 20 weight percent ethanol and 80 weight percent water, amplitude ratio of pressure fluctuations to absolute pressure above or below 3%) may be referred to as a parameter value. Such a parameter may have a temporal extent. For example, a timetable (i.e., a programmed expiration of an operating value, e.g., a solvent composition or a flow rate over the duration of the analysis) may be referred to as a parameter.

In the context of the present application, the term "parameter set with parameter values to be specified during the separation" can be understood in particular to mean a number of parameter values (for example 75% ethanol and 25% water, or 350 K) which relate to associated parameters (for example solvent composition a mobile phase, or column temperature). A set of such parameter values then allows the sample separation device to run a defined or at least partially defined separation method. The parameter values can be fixed by the control device to the components or components (high-pressure pump, proportioning device, sample separator, detector, etc.) of the sample separation device as fixed predefined and defined control parameters and can be set accordingly.

In the context of the present application, the term "expected range with regard to parameter values which occur during separation" can be understood to mean, in particular, a range of values which is considered to be acceptable for a respective parameter which results during the course of the separation method itself. If the respective parameter is at a parameter value within the associated expected corridor during the course of the method, the sequence of the separation method by the sample separator can be regarded as error-free or acceptable. The expectation corridor is therefore based on the parameter values that automatically set during the course of the sample separation device (for example, fluidic pressure at a specific point in time), in contrast to the parameters fixedly determined by a separation method. Thus, the parameter values to which the expectation corridor relates preferably do not relate to the parameters given by the separation method but to parameters resulting from the sequence of the separation method.

In the context of the present application, the term "desired course" can be understood to mean, in particular, a sequence of the separation method which is interpreted as error-free. A separation method can be interpreted as presumably error-free if the parameter values of the individual parameters that occur during the course of the separation method are within the predetermined expected range.

In the context of the present application, the term "measuring device" is understood in particular to mean a device which qualitatively and / or quantitatively measures at least one parameter to be measured and / or at least one event to be measured, using one or more fluids. In this case, the fluid can be the object and / or aid of the measurement. An example of such a measuring device is a sample separation device (in particular a chromatography device), with which a fluidic sample is separated into its fractions and these are optionally identified or quantified. While in a preferred embodiment the meter is a sample separator, in general terms it can perform an analysis method and provide an analysis result. For example, in a spectroscopic investigation ( For example, by means of a mass spectrometer) a separation can only be carried out optionally.

In the context of the present application, the term "fluidic analyzer" is understood in particular to mean a device which performs an analysis using one or more fluids, in particular an analysis of said fluid.

According to an exemplary embodiment of the invention, the quality of the sample separation can be evaluated more reliably during or after a predetermined separation method on a sample separation device by matching adjusting parameter values during separation with a respectively predetermined expectancy corridor for the associated parameters. The expectation corridor can be preset (for example, based on previously known separation experiments, expert knowledge and / or simulations or modeling of the sample separation device and / or the separation method) such that, if the expectation range is maintained by the independently or automatically resulting parameter values (ie the device operation or the execution of the method by the analyzer resulting parameter values) with a sufficiently high probability of the correct sequence of the separation method can be assumed. However, if parameter values are outside the expected corridor during the separation method, the result of the analysis or the result of the sample separation may be considered less reliable or even unusable. However, since the expectancy corridor only maps a desired course of the sample separation, its exit preferably does not lead to a termination of the device operation, the device function or the sample separation, since, despite possibly unusual setting of parameter values, the sample separation could still have been successful. Thus, although leaving the expectation corridor does not provide absolute assurance of the presence of an error during sample separation, the decision to make with simple hardware or software measures whether the actual operation of the separation method is inside or outside the expectation corridor still allows one simple and sufficiently reliable way to objectively evaluate the quality of a sample separation. The final decision to accept or discard a separation result may then be made, for example, by a user based on the sample separator-side rating. At the level of a data structure of the separation method, for example, the expectation corridor can be implemented as a tag, which, in addition to a parameter set and an instruction set, can form the record of the separation method. At the level of a data structure of the separation results, the adherence to or exit from the expectation corridor can be implemented, for example, as a flag, which is both binary (pass / fail) and analog (e.g., a number between 0 and 1, indicative of strongly deviated from the center or other guideline in the corridor) can be specified and represented.

According to one exemplary embodiment, the eventual discarding of an analysis may not result in aborting a sequence from a plurality of analyzes. Leaving the corridor, according to an exemplary embodiment, may well lead to an action, which may also be the termination of the analysis and possibly a repetition thereof.

In addition, additional embodiments of the sample separation device, the analysis device and the method will be described.

The embodiments described in the context of the present application will be explained primarily with reference to the example of a sample separation apparatus and an associated method. A person skilled in the art will recognize that the disclosure of these embodiments also relates in a corresponding manner to the fluidic analyzer or the method for operating a measuring device.

According to one embodiment, the expectation corridor can be adapted specifically to the separation method. In particular, different expectation corridors can be specified for different separation methods. The described expectancy corridor can therefore be determined with advantage specifically for a particular separation method and represents desired requirements for the implementation of the separation method related to this particular separation method. The expectation corridor can therefore be tailored specifically to a specific separation method and can be different for different separation methods. In particular, a respective expected corridor or a respective associated tag can be assigned to a specific separation method and can be unique or unique, for example, for this separation method.

According to one embodiment, the expectation corridor may be a pressure (such as when the flow rate is a predetermined parameter) or a flow rate (such as when the pressure is a predetermined parameter) (specifically, a volumetric flow rate, ie, fluid volume per unit time, or mass flow rate, ie, flow Fluid mass per unit time) of a fluid (eg, a mobile phase in a chromatographic sample separator) in the sample separator Respectively. Such pressure may be detected, for example, by a pressure sensor or flow rate by a flow rate sensor in a corresponding flow path of a fluidic sample separation device. It has been found that the analysis of possible anomalies of a pressure profile or a flow rate during the execution of a separation method is a reliable criterion for accepting a possible error or probable freedom from errors. In this case, for example, an absolute pressure value (for example a specific value in bar) or an absolute flow rate value (for example a specific value in milliliters per second) in the flow path can be used as a comparison scale for evaluating the reliability of a separation analysis. Alternatively or additionally, a relative pressure ratio (for example pressure value at a later time during the sample separation divided by pressure value at an earlier time during the sample separation, for example ratio of current pressure to initial pressure) or a relative flow rate ratio can also be used as the basis for evaluating the reliability of the Measurement be used. The parameter (s) of the expectation corridor may or may therefore relate, for example, to expected values of variables over the duration of the separation method.

According to one embodiment, the expectation corridor may relate to a time course of the resulting parameter values in the sample separator. For example, the time dependence of the pressure and / or the time dependence of the flow rate in a flow path of the sample separator may be compared to the expected corridor while performing the separation method.

According to one embodiment, the expectation corridor may refer to a temperature history of the resulting parameter values in the sample separator. For example, the temperature dependence of the pressure and / or the temperature dependence of the flow rate in a flow path of the sample separator may be compared to the expectation corridor while performing the separation method. According to one embodiment, the expectation corridor may refer to a relation of different or even different parameter values. For example, a ratio or linear combination of a pressure value with a temperature value may represent a parameter value that is adjusted against the corridor boundaries. Alternatively, the limits of a corridor for one parameter, for example, for the pressure, may be dependent on another (adjusted or resulting) parameter, for example a temperature.

According to one embodiment, the expectation corridor may relate to a temperature or a temperature profile of a part or a position of the sample separation device. A temperature or a temperature profile of certain system parts or points in the system can therefore be used to determine the expected range.

According to one embodiment, the expectation corridor may refer to a relationship or blending function between a temperature value in the sample separator and another observable parameter value. Thus, an association or blending function of one temperature value or another observed parameter and another observable parameter value may be used for the definition of the expectation corridor. The parameter value can be understood in such an embodiment as the time course of a parameterized.

According to an embodiment, an acceptance width of the expectation corridor may be different for different times during the sample separation. For example, at different time periods of the separation or analysis, susceptibility of the system to variations in parameter values that do not yet result in a sample separation error may vary. This phenomenon can advantageously be taken into account by the fact that for different periods different sized tolerance ranges can be specified as expected corridor. In this way, the reliability of the evaluation of the separation result can be further increased.

According to one embodiment, the acceptance width may be greater at an earlier time (for example, in an initial period) during sample separation than at a later time. For example, transients and the like have been found to tend to cause a greater range of settling parameter values (eg, pressure) in an earlier period during sample separation than in a later period during sample separation when the transients have subsided are or have weakened. Often, such transient phenomena alone do not result in deterioration or error of sample separation, misclassification of a larger early fluctuation of an attendant parameter as an indicator of an error of separation can be reliably avoided by that in periods of expected higher variations Acceptance range of the expectation corridor can be selectively increased. To the For example, after switching a fluid valve, certain and unavoidable artifacts may occur, the presence of which does not necessarily lead to a classification of sample separation as unreliable or less trustworthy. Alternatively, however, it is also possible for the expected corridor or only its width to remain constant over the entire time of sample separation.

According to one embodiment, the expectation corridor may refer to a plurality of parameter values set during the separation. These multiple parameters may be selected from a group consisting of a linear combination, an algebraic function of multiple variables, an empirical function in the form of a matrix, a (possibly multidimensional) lookup table, a fitted (ie fit) function, etc Clearly, the expectation corridor can be formed as a multidimensional combination of (for example, logically or mathematically, approximately algebraically, linked) acceptance ranges of several different parameter values in order to further increase the reliability of the evaluation. For example, adjusting pressures, adjusting flow rates, adjusting temperatures, detecting detection events of particular peaks in a chromatogram, adjusting solvent consumption, etc. may be considered in combination to provide the basis for decision on the assessment of a separation (for example, as reliable, unreliable or suspicious). For example, a measurement can only be classified as error-free if cumulatively all parameter values are within the associated acceptance range of the expected corridor during the entire course of the sample separation. Alternatively, a measurement can already be classified as reliable even if at least one predeterminable proportion of the parameter values lies within the associated acceptance range (for example, at least 90% of the parameter values examined).

According to one exemplary embodiment, the sample separation device may have an evaluation device which is designed to evaluate the separation result based on a comparison between an actual course (for example sensory) and the desired course (corresponding to the expectation corridor) of the sample separation. The evaluator may compare the parameter values resulting during the separation with the expected range. The evaluator may issue a corresponding output to a user of the sample separator to inform it of the evaluation of the reliability of the sample separation. In this way, a user can be reliably assisted in making a decision on the acceptance or discarding of a sample separation result based on objective criteria whose knowledge or evaluation is conventionally not or not easily possible for a user. For example, the evaluator may assign a certain separation experiment, such as a numerical (eg, scale of 1 to 10) or logical value (for example, reliable / unreliable) or a verbal description (eg, "high probability reliable") to the quality indicates the results.

According to an embodiment, the judging means may be configured to output as evaluation one of a group consisting of providing a separation result having a quality attribute, qualifying the result as reliable, qualifying the result as doubtful, discarding the result, and triggering repeating the separation. If all parameter values are within the expected corridor, a measurement can be classified as reliable or reliable. If the parameter values leave the expected corridor during the separation by a sufficiently small difference and / or for a sufficiently short period of time (for example based on a respective predefinable threshold value), a classification of the result can be considered doubtful. The result may be entirely discarded or a corresponding discard proposal may be made to a user if multiple parameter values leave the expected acceptance range of the expectation corridor, if leaving a parameter value exceeds certain difference amounts or if a parameter is for a longer period of time (eg, compared to a threshold). outside the expected range. When providing a separation result having a quality attribute, as an evaluation of the result of the separation, it may be provided with an attribute indicating the reliability of the result. For example, this attribute may be discrete (eg, "reliable / doubtful") or analogous (eg, a number between 1 and 0 indicating the confidence of the result) or include a non-standard action (particularly discard).

For example, if the actual history of a parameter (or parameters) is outside the expectation corridor while performing a separation method, the analysis may be discarded or classified as less trustworthy. Such a discrepancy can be detected and output to a user as information. Alternatively or additionally, the quality of the result can be evaluated in a corresponding manner. This way you can reliable quality measure regarding the trustworthiness of a separation experiment.

According to one embodiment, the event of leaving the expectation corridor may not result in an error condition of the sample separator. In particular, an event of leaving the expectancy corridor may not result in shutdown of the sample separation device. In other words, according to the described embodiment, leaving the expectancy corridor during performance of the separation method preferably does not automatically result in terminating the sample separation (s). The reason for this is that the expectation corridor is preferably set to define the limits within which a reliably correct measurement can be made. Therefore, mere (for example, brief and / or minor) abandonment of the expectation corridor does not make the whole sample separation useless, but at first leads only to the conclusion that the reliability or confidence in the correctness of the sample separation is reduced.

According to one embodiment, the separation method may be further characterized by a must corridor with respect to parameter values that occur during the separation, which is indicative of a mandatory history of the sample separation. In the context of the present application, the term "must corridor" can be understood in particular to mean a value range which is regarded as absolutely necessary for a respective parameter which results during the course of the separation method itself and whose leaving is absolutely unacceptable. If the respective parameter is at a value within the associated mandatory corridor during the course of the method, the sequence of the separation method can be continued by the sample separator (when leaving the mandatory corridor, the device, on the other hand, stops according to an exemplary embodiment). The mandatory corridor can thus be related to the parameter values that automatically set during the course of sample separation (for example, fluidic pressure at a specific point in time). Thus, the parameter values to which the must corridor relates preferably do not refer to parameters given by the separation method but to parameters resulting from the operation of the separation method. If the must corridor is left at any point in time, according to one embodiment, the operation may not continue or be sustained. For the example of the fluid pressure, the mandatory corridor can be defined and limited by a minimum pressure and by a maximum pressure. If the maximum pressure is exceeded, fluid components of the sample separator threaten to be damaged or destroyed, for example a chromatographic separation column. If the minimum pressure is undershot, this can be an indication of the dry running of the sample separator, for example because a solvent container has been emptied or a larger leak has occurred on a capillary or a pipe.

The described mandatory corridor can be determined, for example, on the basis of a specification of the sample separating device or its parts and components and represents technically-related limits, the undershooting or exceeding of which is incompatible with safe or proper operation. The must corridor may be independent of a particular separation method or may be tailored to a particular separation method.

According to one exemplary embodiment, leaving the mandatory corridor may lead to a fault condition, in particular to an automatic shutdown, of the sample divider. While remaining within (or leaving) an expectation corridor may be accompanied by a classification of a sample separation as being successful (and problematic) and a result of sample separation as reliable (or possibly unreliable), leaving the must-have corridor with a classification of the operation of the sample separator as unsuccessful. If an adjusting parameter leaves an acceptance range of the mandatory corridor, the operation of the sample separating device can be ended and this separation run can be classified as unsuccessful or defective. Thus, according to an exemplary embodiment, in the must corridor, it can not be about the quality of the result (especially since it does not necessarily have to be impaired when violating the must corridor), but rather that the safe or proper and error-free operation of the device is no longer guaranteed , For example, if it is desired that piston flushing fluid is always present, a condition in which it is consumed would correspond to leaving the mandatory corridor. The results would be perfect in this case, but the device hardware could be damaged in the long term and therefore the pump could be stopped.

According to one embodiment, the must corridor may completely include or include the expected corridor. In other words, the expected corridor can be completely within the mandatory corridor. In the event of an anomaly, an initially allowable evolving parameter value may initially leave a boundary of the expectation corridor from an interior of the expectation corridor, thereby decreasing the evaluation of the reliability of the sample separation can. If the parameter value subsequently moves farther away from an acceptance range, it reaches a limit of the mandatory corridor at a later point in time if the anomaly continues. The operation of the sample separation device can then be classified as absolutely faulty and terminated.

According to one embodiment, the must corridor may be constant over an entire period of sample separation and / or for different separation methods. While the expectancy corridor may vary in width and / or course over the entire period of sample separation (eg, to avoid a momentary greater fluctuation of a parameter value due, for example, to acceptable transients or acceptable phenomena shortly after switching If a fluid valve already leads to an evaluation of the sample separation as less reliable), the mandatory corridor may define an absolute lower limit or upper limit of a respective parameter value whose undershoot or exceedance makes a continuation of the device operation undesirable, dangerous or even impossible. As a result, the operation can be stopped or canceled. For example, these absolute tolerance limits can be constantly defined across the entire sample separation. Alternatively, however, it is also possible for the must corridor to be variable over the period of sample separation. While the expectation corridor may preferably be separation-method specific, the required corridor may be chosen to be the same for different separation methods. For example, the expectation corridor may be method specific, while the must corridor may be device or device type specific.

According to one embodiment, the expectancy corridor may be different over a period of sample separation and / or for different separation methods. Furthermore, the expectation corridor can be defined by (in particular during a run of a sample separation) time-varying boundary lines. This variability of the expectation corridor allows for the fact that, depending on the current phase of a sample separation or depending on the specifics of a specific separation method, a possible lack of reliability of a result of a sample separation is only to be feared in the case of different degrees of deviations of a respective adjusting parameter value ,

An event of merely crossing a boundary of the expectation corridor (especially narrower than the required corridor) does not already result in expected damage to at least a portion of the sample separation apparatus according to an exemplary embodiment, but merely jeopardizes reliability of a result of a fluidic separation run. In contrast, an event of crossing a boundary of the mandatory corridor (in particular over the expectation corridor) according to an exemplary embodiment of the invention immediately leads to an expected damage (or risk) of at least a portion of the sample separation apparatus.

According to one exemplary embodiment, the mandatory corridor may be defined by boundary lines that are constant over time, since it can define an absolute limit for parameter values that are still permissible or already inadmissible, regardless of a specific phase of a sample separation (or in particular independently of a particular separation method). While the expectation corridor may be related to a particular separation method and phase during a course of sample separation, the required corridor may be related to the operation of the sample separation apparatus in general.

According to one embodiment, the expectation corridor may be derived from at least one of the group consisting of historical information regarding successful historical sample separations, historical information regarding problematic historical sample separations, simulation, sample separator modeling, expert knowledge, detected user behavior during successful and / or problematic historical sample separations and artificial intelligence. If one can draw on a wealth of experience of sample separations performed in the past that have been classified as reliable or successful (eg by a sample separator, a user or an expert), value ranges from such historical successful sample separations can be used for a sample separation or several parameters resulting during the execution of a separation method to determine acceptable parameter ranges, which then can serve the definition of the expectation corridor. Conversely, sample separations performed in the past that have been classified as suspect (for example, by a sample separator, a user, or an expert) may not be used to bias one or more parameters resulting during the performance of a separation method determine more acceptable parameter ranges, which can then also be included in the definition of the expected corridor. Also theoretical or numerical simulations or modeling of the sequence of a separation method on a Sample separation devices may provide information about reliable or discardable sample separation operations using a particular separation method that may be used to establish one or more acceptance ranges of an expectation corridor. Also, expert knowledge of correlations between values of parameters resulting during the performance of a separation method and the trustworthiness of a sample separation result can be used to determine or refine the expectation corridor. Further, the behavior of a user may be detected during the performance of sample separations using a particular separation method, for example, optically by a camera, acoustically via a microphone, etc. If a user's behavior indicates dissatisfaction with a separation result (eg, shaking of head, cheeks Deletion of a corresponding record, repetition of a break, etc.), a history of resulting parameter values may be correlated with the event of a sample separation deemed unreliable or unsuccessful by a user. In a corresponding manner, satisfaction of a user with a separation result can be detected and an indication of which profiles of the parameter values correlate with satisfactory results. Elements of artificial intelligence, such as fuzzy logic, neural networks, learning methods, pattern recognition, automatic image recognition, etc., can also be used to correlate successful or unsuccessful measurements with parameter curves and to derive information for the dimensioning of the expected corridor. In addition, it is possible to include in the expectation corridor, for example, areas of a chromatogram or other analysis results that do not relate to the actual separation result. If only three peaks are of interest in a particular sample separation experiment in a five-peak chromatogram, for example, the other two peaks may be used, according to an expectation corridor, to assess whether the experiment is trusted or not. Even sections of a chromatogram that are different from the actual analysis result can therefore be included in the definition of the expected corridor.

For example, if one knows from experience, from a rule, and / or from a user behavior associated with performing the separation method, then, if a particular parameter (for example, the pressure) in an initial region of the sample separation should be in a certain range and at the end of the sample separation should be in a certain other area, leaving this expectation corridor may justify the evaluation of sample separation as doubtful. For example, the separation method can then be assigned a tag as a tag, which describes how the pressure profile should be during the analysis and which associated expectation corridor is considered admissible. If, during a measurement, this expectation corridor is left, this can be interpreted as an indicator for the presence of a deviation during the execution of the sample separation.

In a corresponding manner, the requirement of safe operation of the sample separation device or of the measuring device for determining information about the mandatory corridor can be used.

According to one embodiment, the parameter set may include at least one of a group consisting of a concentration of at least one fluid to be delivered by the sample separator, a composition of at least one fluid to be delivered by the sample separator, and a time change with parameter values to be given during the separation a solvent composition of at least one fluid to be delivered by the sample separator during the sample separation. Such a fluid may be, for example, a mobile phase which is conveyed in a chromatographic sample separator through a flow path and into which a fluidic sample to be separated into its fractions is injected. Other examples are temperatures to be specified at certain positions of a sample separation device, for example on a sample separation device (for example a chromatographic separation column). The specified parameter set relates in particular to control parameters for carrying out the separation.

According to one embodiment, the sample separation device may comprise a data carrier on which the separation method is stored. Such a data carrier can be, for example, an electronic mass storage device, for example a hard disk. The separation method can be stored in a database. It is also possible to store a dataset belonging to a separation method in a cloud, etc. The separation method can be predefined or editable.

According to one embodiment, the separation method may be predetermined in the form of a data set with parameter values to be specified for performing the sample separation and optional control commands and with an additional day with the expected range of the resulting parameter values. A control command may be a command that the sample separator implements when executing the method. The day can be clear Describe expectation corridor. In other words, the data structure of the separation method may distinguish between a first section and a second section. The first section contains the parameter values and control commands required to perform the separation method. The expectant corridor in the form of a tag then provides data of a second section that can be used to evaluate an event of the separation. For example, the tag may be filed as part of the data structure of the separation method or otherwise linked to the separation method.

In one embodiment, the sample separator may include a fluid drive for driving a mobile phase and a sample separator for separating the fluid sample in the mobile phase. Such a fluid drive may be, for example, a high pressure chromatographic pump which may be formed on the basis of one or more piston pumps. The fluid drive may promote as a mobile phase a (for example, variable) solvent composition into which the fluidic sample to be separated can be injected. The mobile phase can thus promote the fluidic sample to be separated to a stationary phase of the sample separation device. Such a stationary phase may have an actual separation medium to which the fractions of the fluidic sample can be adsorbed and fractionally removed again at different solvent concentrations. The sample separator may be, for example, a chromatographic separation column.

The sample separation device may be a microfluidic measuring device, a life science device, a liquid chromatography device, a high performance liquid chromatography (HPLC), an UHPLC device, an SFC (Supercritical Liquid Chromatography) device, a gas chromatography device, an electrochromatography device, and / or a gel electrophoresis device , However, many other applications are possible.

For example, the fluid drive or fluid pump may be configured to convey the mobile phase through the system at a high pressure, for example, from a few hundred bars up to 1000 bars or more.

The sample separation device may comprise a sample injector or a sample introduction unit for introducing the sample into the fluidic separation path. Such a sample injector may comprise a syringe-dockable injection needle in a corresponding fluid path, which needle may be withdrawn from that seat to receive sample, wherein upon reintroduction of the needle into the seat, the sample is in a fluid path which, for Example, by switching a valve, can be switched into the separation path of the system, which leads to the introduction of the sample in the fluidic separation path.

The sample separator may include a fraction collector for collecting the separated components. Such a fraction collector may carry the various components, for example, into different liquid containers. The analyzed sample can also be fed to a drain tank. In this connection, it should be noted that the separation result may not only be a chromatogram, but may also be, for example, a group of one or more collected fractions.

Preferably, the sample separation device may comprise a detector for detecting the separated components. Such a detector may generate a signal which can be observed and / or recorded and which is indicative of the presence and amount of sample components in the fluid flowing through the system.

list of figures

• 1 zeigt ein als HPLC-System ausgebildetes Probentrenngerät gemäß einem exemplarischen Ausführungsbeispiel der Erfindung.
• 2 zeigt ein Diagramm, das einige für die oder während der Durchführung eines chromatographischen Trennverfahrens entsprechend einer Trennmethode zum Trennen einer fluidischen Probe in Fraktionen vorgegebenen oder sich ergebenden Parameter gemäß einem exemplarischen Ausführungsbeispiel der Erfindung darstellt.
• 3 zeigt ein Schema, gemäß welchem ein chromatographisches Trennverfahren unter Verwendung einer chromatographischen Trennmethode gemäß einem exemplarischen Ausführungsbeispiel der Erfindung durchgeführt wird.
• 4 zeigt ein Schema, gemäß welchem ein chromatographisches Trennverfahren unter Verwendung einer chromatographischen Trennmethode gemäß einem anderen exemplarischen Ausführungsbeispiel der Erfindung durchgeführt wird.

Other objects and many of the attendant advantages of embodiments of the present invention will be readily appreciated and become better understood by reference to the following more particular description of embodiments taken in conjunction with the accompanying drawings. Features that are substantially or functionally the same or similar are given the same reference numerals.

• 1 shows a designed as a HPLC system sample separator according to an exemplary embodiment of the invention.
• 2 FIG. 12 is a diagram illustrating some parameters given or resulting for or during the performance of a chromatographic separation process according to a separation method for separating a fluidic sample into fractions according to an exemplary embodiment of the invention.
• 3 shows a scheme according to which a chromatographic separation method Use of a chromatographic separation method according to an exemplary embodiment of the invention is performed.
• 4 Fig. 12 shows a scheme according to which a chromatographic separation process is performed using a chromatographic separation method according to another exemplary embodiment of the invention.

The illustration in the drawings is schematic.

Before describing exemplary embodiments with reference to the figures, some basic considerations will be summarized based on which exemplary embodiments of the invention have been derived.

According to an exemplary embodiment of the invention, data obtained during the execution of a separation (for example a pressure profile) can be compared with reference data for the history (for example stored in a separation method). The comparison result can then be used as a measure of the reliability or quality of the results. Reference curves can, for example, be determined automatically, in particular by analyzing historical sample separations (for example, past good separations). The reference data may define an expectation corridor with respect to parameter values that occur during the separation. This expectation corridor and another parameter set with parameter values to be specified during the separation can then form parts of a separation method according to an exemplary embodiment of the invention.

1 shows an HPLC system as an example of a sample separator 10 with a control device 70 according to an exemplary embodiment of the invention.

1 shows the basic structure of an HPLC system as an example of a sample separation device 10 trained measuring device, as it can be used for example for liquid chromatography. A fluid pump as a fluid drive 20 containing solvents from a supply unit 25 supplied drives a mobile phase through a separator 30 (such as a chromatographic column) containing a stationary phase. A degasser 27 can degas the solvents before they drive the fluid 20 be supplied. A sample application unit 40 with a fluid valve 95 is between the fluid pump 20 and the separator 30 arranged to introduce a sample liquid in the fluidic separation path. The stationary phase of the separator 30 is suitably chosen and intended to separate components of the sample. A detector 50 with a flow cell detects separated components of the sample, and a fractionation device 60 may be provided to dispense separated components of the sample in dedicated containers. Liquids no longer needed can be dispensed into a drain tank.

A control device 70 controls the individual components 20 . 25 . 27 . 30 . 40 . 50 . 60 . 95 of the sample separator 10 , More specifically, the control device controls 70 the entire sample separator 10 for separating the fluidic sample according to a separation method 92 on. The separation method 92 defines a sequence of actions (for example, assembling a mobile phase from multiple solvent components) of the sample separator 10 by means of the fluid drive 20 , the sample application unit 40 , the fluid valve 95 , the detector 50 , etc. during sample separation. Furthermore, parameter values (for example water and ethanol as solvents with 80% by weight or 20 Percent by weight) with which the actions are specified in more detail. Thus, the separation method contains 92 on a disk 91 one for the controller 70 A set of parameters (for example, solvent I at X% by weight and solvent II at Y% by weight) with parameter values to be given during the separation (for example I = water, II = ethanol, X = 80, Y = 20). This parameter set thus refers to parameters that are determined by the separation method 92 the sample separator 10 be preset and thus set from the outside.

Advantageously, according to an exemplary embodiment of the invention, the separation method 92 additionally one day, ie a record in the form of an expectation corridor 100 with respect to parameter values which occur during the separation, that for a desired course 114 the sample separation is indicative. This is referred to below 2 described in more detail. In other words, the expectation corridor 100 specify within which range of values, which can be regarded as an acceptance range, parameter values that are not set from the outside, but that are present when processing the separation method 92 through the sample separator 10 during the separation process (or more generally during an analysis, during an analysis process or during an analysis process). This may be, for example, a pressure value of the mobile phase, by means of respective pressure sensors 130 at different positions of the fluidic path of the sample separation device 10 can be detected. Alternatively or additionally, a flow rate can also be determined by means of one or more flow rate sensors 132 be measured. In addition, it is possible to move one at a particular position (for example on a pump head of the fluid drive 20 ) adjusting temperature by means of a temperature sensor 134 capture. This yourself resulting parameter values can the controller 70 which in turn can determine whether the parameter values are within or outside an associated acceptance range of the expected range 100 are located.

The result of this comparison may be the controller 70 an evaluation facility 80 submit or directly to a valuation process. The control device 70 and the evaluation facility 80 may be formed as separate processors or as parts of a common processor. The evaluation facility 80 can the reliability or trustworthiness of the separation result based on a comparison between one of actual progressions 104 . 106 . 108 and one through the expectation corridor 100 specified target course 114 evaluate the sample separation (see 2 ). Are the means of the one or more sensors (see reference numerals 130 . 132 . 134 ) during the execution of the separation method 92 through the sample separator 10 under control of the controller 70 parameter values within the acceptance range of the (one- or multi-dimensional) expected corridor 100 , follows the execution of the separation method 92 the target course 114 and may be from the evaluator 80 be classified as sample separation with probably reliable separation result or as sample separation without error indication. When leaving the expectation corridor 100 while performing a sample separation by the separation method 92 however, the evaluation facility may 80 To estimate reliability of a separation result lower, for example, as suspicious or unreliable. This review may be the evaluation facility 80 the control device 70 as a possible change of a regular procedure of the sample separation or as a basis for the subsequent control of the sample separation by means of the sample separation device 10 and / or an input / output interface 140 to provide the rating to a user. The input / output interface 140 may input elements for inputting parameter values or control commands by a user to the controller 70 include (for example, a keyboard or a touchpad), and may include output elements for outputting a result of sample separation (for example, a chromatogram) as well as outputting a judgment of the reliability of the result of the sample separation (for example, a display device). For example, the rating device 80 to evaluate the reliability of the result of the sample separation, to qualify the result as reliable, to qualify the result as doubtful, to suggest or perform discarding of the result, or to propose or initiate triggering the repetition of the separation.

A respective expectation corridor 100 can be specific to a particular separation method 92 be adapted and in a corresponding manner on the disk 91 get saved. In particular, on the disk 91 on which the control device 70 can access several different separation methods 92 which have different expectation corridors 100 can be assigned. All these expectation corridors 100 can on the disk 91 be stored and the respective separation method 92 be assigned.

In particular, the data structure of a separation method 92 in the form of one on the disk 91 a first portion of the data structure contains parameter values to be provided for performing the sample separation (for example, initial composition of the mobile phase 80 Volume percent water and 20 volume percent ethanol) and control commands (for example, traversing a gradient profile 97 with the characteristic, as in 1 shown; at the gradient profile 97 the percentage% B of the fluidic component B for the example of a mixture with the fluidic component A varies as a function of the time t). Moreover, the data structure has the separation method 92 in a second section, add an additional day to the expected corridor 100 the resulting parameter values contain indicative data. In addition, the data structure of the separation method 92 in the first or a separate section, data for defining a must corridor 110 contain restrictions on a must-have sample separation. These inputs are not necessary according to an embodiment for the evaluation of the result. According to one embodiment, they may also be mandatory or non-default (such as a maximum pressure limit). Both will be referred to 2 described in more detail:

2 shows a diagram 200 that involves performing a chromatographic separation process according to a separation method 92 for separating a fluidic sample into fractions according to an exemplary embodiment of the invention. Along an abscissa 202 of the diagram 200 is the time t while performing a separation experiment while processing the separation method 92 applied. Along an ordinate 204 of the diagram 200 the pressure p is plotted as it is at one of the positions of the pressure sensors 130 of the sample separator 10 according to 1 results. 2 is shown as a 2D diagram for the sake of simplicity. Using multiple or linked parameters for corridor definition would be the expected corridor 100 only in a three- or multi-dimensional space representable.

According to 2 refers to the expectation corridor 100 on a time course of an adjusting pressure of the mobile phase at a certain point in the sample separator 10 , The expectation corridor 100 according to 2 is through an upper curved limit curve 100 ' and a lower curved limit curve 100 ' Are defined. Between the limit curves 100 ' and 100 ' there is an area that is a target course 114 the separation method 92 equivalent. Runs the separation method 92 in a particular sample separation experiment inside the expectation corridor 100 , it is assumed that a faultless measurement. In the example according to 2 refers to the expectation corridor 100 to an absolute value of the pressure p of a fluid in the sample separator 10 , Alternatively or additionally, it may also refer to one or more other parameters, for example, an absolute flow rate, a relative pressure ratio, a relative flow rate ratio, a temperature history, a feature of a chromatogram, etc. The expectancy corridor 100 Thus, it can also be indicative of parameter values of several parameters which are set during the separation of parameters, ie be multidimensional. Surprisingly, it is possible to set the limits of the expectation corridor 100 to define fluently rather than abruptly. For example, it is possible to define that at a pressure between 450 and 500 bar, the result is considered reliable, at a pressure below 350 bar is considered to be reliable, and at a pressure between 450 and 350 bar the reliability (or trustworthiness or confidence) of the result (for example, linear) decreases.

2 It can also be seen that an acceptance width 94 . 96 the expectation corridor 100 is different for different times t1 and t2 during sample separation. Alternatively to referring to the expectation corridor 100 at different times t1 and t2, it is more generally possible, the expectation corridor 100 to refer to different points or phases of the analysis process. The time reference described is therefore not absolutely necessary. More specifically, according to 2 the acceptance width 94 at an earlier time t1 during sample separation is greater than an acceptance width 96 at a later time t2. In this way, larger fluctuations, which may occur in a transient phase and do not necessarily indicate an untrustworthy measurement, can be adequately considered without a good measurement being erroneously classified as potentially untrustworthy.

Preferably, leaving the expectation corridor leads 100 during a sample separation does not lead to a fault condition of the sample separator 10 , Even if during a processing of a separation method 92 through the sample separator 10 a self-adjusting parameter from the desired course 114 Therefore, the sample separation experiment or the entire process, such as a sequence of sample separation experiments, therefore need not be terminated. Only the classification of the degree of reliability of the result of the sample separation can then be adjusted accordingly.

About defining the expectation corridor 100 addition is the separation method 92 according to 2 also through a must corridor 110 with respect to parameter values set during the separation, which is indicative of a mandatory course of sample separation. According to the described embodiment, it is mandatory that during the execution of a separation method 92 the system always within a range between a constant upper limit 110 ' and a constant lower limit 110 ' the must-attend corridor 110 remains. The upper limit 110 ' is selected so that, when exceeded, damage or failure of components of the sample separation device 10 can occur. For example, when the maximum pressure value is exceeded p _max a chromatographic separation column as an example of the sample separator 30 damaged or destroyed. Below the minimum pressure value p _min may indicate a run-dry of a solvent container while performing the separation method 92 or indicate a leak. For these reasons, leaving the Musskorridors leads in the described embodiment 110 by exceeding the upper limit 110 ' or by falling below the lower limit 110 ' to an automatic termination of the sample separation experiment or to an automatic shutdown of the sample separation device 10 , Since the reasons for the shutdown over the time course of a sample separation or over the duration of a separation method 92 remain unchanged, can according to 2 the must-attend corridor 110 be constant over the entire sample separation.

As 2 can be seen, includes the must-visit corridor 110 the expectation corridor 100 Completed. Leaving the expectation corridor 100 can be seen as entering into critical parameter ranges that cast doubt on the reliability of the separation result. Leaving the must-go corridor 110 however, as an unacceptable transition to a hazardous operating condition of the sample separator 10 be interpreted and leads by stopping or switching off the separator to abort the sample separation.

For example, the expectation corridor 100 derived from historical information regarding successful historical sample separations and / or historical information concerning unsuccessful historical sample separations. Parameter sets for which good (or correct) sample separation results have been obtained in the past can be considered within the area of the target profile 114 lying down. Parameter sets for which no satisfactory sample separation results have been obtained in the past may be considered to be outside the area of the target curve 114 lying down. Alternatively or additionally, a simulation or a modeling of the sample separation device 10 , Expert knowledge and / or artificial intelligence to derive the expectation corridor 100 be used. Also, user behavior may be detected during successful and / or problematic historical sample separations (eg, captured by a camera 138 of the sample separator 10 , the image data to the controller 70 transmitted, which can then also be referred to as user behavior evaluation device) are detected and with the measured parameter sets (see Sensors 130 . 132 . 134 ) are correlated. For example, such a user behavior may be a derogatory hand gesture or the deletion of a record after a user has failed to make a successful measurement. The associated parameter sets can then be assigned to a reduced reliability of the separation result.

2 shows an example of a first actual course 104 according to a first execution of the separation method 92 , During the entire first actual course 104 the associated trajectory remains within the expected corridor 100 , The associated measurement is classified as reliable.

2 shows an example of a second actual course 106 according to a second execution of the separation method 92 , During part of the second actual history 106 the associated trajectory leaves the expected corridor 100 , The associated measurement is completed, but the separation result is classified as not reliable.

2 shows an example of a third actual course 108 according to a third execution of the separation method 92 , During the third actual course 108 the associated trajectory first leaves the expected corridor 100 and then the must-visit corridor 110 , The associated measurement is terminated prematurely (see reference numeral 112 ).

According to an exemplary embodiment, an extension of a separation method 92 by a day, the expected pattern in the form of an expectation corridor 100 contains. This pattern can then be used as a basis for adjusting to initiate an action deviating from the standard procedure or for assessing the quality.

In the future laboratory operation, the demands on the resilience of the analysis results increase increasingly, while at the same time an ever less professionally qualified intervention of a user is possible. For example, the trend in chromatography is that the majority of users are no longer specific chromatographers, but are users without specific chromatographic expertise. Liquid chromatography, and in particular HPLC, is increasingly regarded by users as less of a high technology but increasingly as a tool.

Already present, but even more so in the future, it is a relatively common experience that analyzers are operated by users who have little or no technical background and little or no experience in monitoring conditions of an instrument. Such users may easily overlook indicators that indicate an abnormal function or critical states of the instrument. Analysis equipment has increasingly become a tool used for a particular task (such as identifying a disease marker). However, such users are not familiar with the science of chromatography for sample separation in detail. Such users will rely on guidance and, above all, on process automation, as far as the sequence of a separation experiment and the evaluation of separation results are concerned.

During the development of a separation method 92 There is a close interaction between an experienced user and the instrument. At this point, the user (often an experienced scientist) can have a profound knowledge of the methodology and application, a clear idea of the expected behavior of the parameter values during an analysis, which should be followed by the observed parameters in an analytical run. Recognizing this typical course can help to prevent mistakes and damage.

When a fully developed separation method is stored today, there is little room left for comments and side information. Above all, the usefulness of the comments and the accompanying manuals is low, as taking into account these presupposes a human interaction. The practical consideration of the information contained in the comments would require a great deal of human effort. Therefore, in the Essentially not receiving information in the method (which may be embodied as a set of instructions, commands and programs for the instrument, how the analysis is to be performed and how the computer should process the data obtained), which parameter values are expected when executing the separation method, and what values and characteristics result from the operation of the instrument. There is little to no expectation information that can be input by a user and no corresponding machine generated or machine readable information.

Exemplary embodiments of the invention are based on the idea that it is promising to come back to the developer of a separation method or a specialist in the field of chromatography, if questions or suspicious behavior with respect to the observed behavior of the separation device or the sequence of the separation occur. Documenting the expected behavior with respect to the criteria that are characteristic of successful (or on the contrary, abnormal) operation can increase the reliability of a separation result.

For example, in accordance with an exemplary embodiment of the invention, an expectation corridor may be implemented using a tag (i.e., a record associated with a separation method that defines the expectation of a sample separation considered reliable or unreliable) and attached to a separation method. This tag may contain a set of values or vectors for multidimensional parameters describing expected behavior of the system in the event of performing an analysis run. This may include values of propagation time parameters, values and properties resulting from the operation of the instrument, and possibly even expected characteristics of a detector signal. The expectation corridor or the tag can also contain some properties related to the analysis result, but not the analytical target information itself (for example, not the area of the analyte peak to be determined in a chromatogram).

The expected behavior description may be used as an evaluation mask or as a master pattern to qualify states, conditions, and / or behavior of a system before, during, and after analysis. As a result, the quality of the result of an analysis can be certified or qualified. The result of such certification may be output in the form of a digital marker with a particular data value, a grayscale flag, or a numerical value to indicate the quality of the data or the quality of the result, depending on how well the actual system behavior is while performing the analysis with the expected pattern corresponds.

Such an expectation corridor 100 Such a tag may result from monitoring well-known system operation, estimation, mathematical modeling, and / or user judgment that may be generated by an action, if any Authorization is required. The definition of the expectation corridor 100 or the tag can be part of the separation method 92 or application may be validated by a developer and / or may be independent of actual instrumentation. Optionally, references to instrument classes in the expectation corridor 100 or enter the day. Alternatively, the day or the definition of the expectation corridor 100 be stored or stored independently of the method and only by a reference (link, pointer) of the method be assigned.

The expected behavior may include an n-dimensional pattern taking into account measurements, parameters, conditions and / or indicators of the liquid chromatography system and part of the separation method 92 form. This information, which may be a recording of a model run or a set of limits for certain parameters in the form of absolute values, may be defined in a normalized manner or in terms of ratios between the parameters (for example, a deviation of a column head temperature of ± 5 ° C compared to the ambient temperature are considered acceptable, a greater deviation than abnormal state are classified). This information can be the separation method 92 attached (and optionally to the sample separator 10 can be graphically represented as a median line or median surface during an actual analysis. A corresponding expectation corridor can also contain (in particular adaptive) tolerance ranges for the measured values, parameters or states.

For example, actual pressure fluctuations may be included in a reference analysis. The expected pattern can be extended by allowable variance (for example, quantified based on instrument setup or expert knowledge) and can be of the separation method 92 attached or made available to it. As a reference analysis, an analysis using a "known-good" system can be understood, which has led to a demonstrably correct result. The reference analysis can also be compiled from averaging over several known-good analyzes.

• - (Durch eine abgeleitete abweichende Geräteaktion) Vermeiden eines zu frühen Starts eines Analyselaufs (zum Beispiel abwarten, bis sich Gasblasen aufgelöst haben)
• - (Durch eine abgeleitete abweichende Geräteaktion) Vermeiden einer Analyse, wenn sich die Bedingungen nicht verbessern
• - Entsprechendes Kennzeichnen einer Analyse, die als zu stark von einer Soll-Trajektorie abweichend identifiziert wurde
• - (Durch eine abgeleitete abweichende Geräteaktion) Beenden einer Analyse und Kennzeichnen als fehlerhaft, falls eine ernsthafte Abweichung erkannt worden ist

For example, the method-specific information may be in the form of the expectation corridor 100 to support one or more of the following functions:

• - (By a derived deviant device action) Avoid premature start of an analysis run (for example, wait until gas bubbles have dissolved)
• - (By a derived deviant device action) Avoid analysis if conditions do not improve
• - Appropriate marking of an analysis that was identified as being too different from a target trajectory
• - (by a derived deviant device action) terminate an analysis and flag as faulty if a serious drift has been detected

An expectation corridor 100 or one day can be used passively or actively. Passive use may include adding a result quality parameter to the analysis results generated by that method. Active use may interfere with the control of the sample separator 10 while performing the separation method 92 to avoid analytical results of poor quality or to improve analytical quality.

In the following, also referring to 3 and 4 , another possible implementation of an embodiment of the invention described.

According to an exemplary embodiment of the invention, an expectation corridor may be provided 100 or a tag can be added to a parameter set that defines the separation method 92 Are defined. A corresponding record may be implemented as a machine-readable protocol that defines conditions or patterns of particular signals or indicators (such as pressure, temperature or motor current). Such an expectation corridor 100 For example, it can be derived from historical experience, mathematical models, or an educated guess. Such information may be from the sample separator 10 or its controller 70 be used. It is also possible to provide such information to a driver for interpreting a current operating state.

3 shows a scheme 300 according to which a chromatographic separation method using a chromatographic separation method 92 is performed according to an exemplary embodiment of the invention.

For example, during the development of a separation method 92 or before an analysis run with a sample separator 10 can the separation method 92 be set, see reference numerals 302 , While performing a separation experiment then the separation method 92 under certain conditions, or adapted conditionally, see block 304 , Here, data can be generated, see block 306 , the basis for a report 308 could be. The control device 70 (or the evaluation device 80 ) monitors this process and, if appropriate, triggers an evaluation of the reliability of a separation experiment by an assessment facility 80 out.

The execution of the separation method 92 For example, it may be delayed until desired start conditions are met. For example, in the above example of pressure fluctuations, it may be waited until the fluctuations are within an acceptable range (for example -2%, ..., + 1%) before injection of a fluidic sample through a sample application unit 40 in a separation path between a fluid drive 20 and a sample separator 30 is triggered.

For example, during an actual analytical run, the data may be continuously monitored to see if they are within an expected or allowed range to allow the report 308 can deliver the result "successfully". If the limits or deviations are exceeded during the run, the report may 308 classify the result as "suspicious". For example, a plot of the course of the parameter values occurring during the separation experiment may be output on-line on a display device or (for example, in the 2 shown) may be overlaid with an expected pattern along with actual live data so that a user can be informed about the actual course of the separation experiment and intervene if necessary.

Examples of conserved expectations, patterns or details may be in the separation method 92 Tagged and saved. Data from a reference run can be recorded, combined with specific bandwidths, and added to the data. The expectation here is, for example, a behavior or course of the device parameter values during the operation of the sample separation device 10 where decisions may be made by common reproducible elements, optionally combined with extracted features (eg, pressure curve shape). It is possible, every single separation method 92 assign your own, method-specific tag. It is also possible to have a history of tags too including, for example, a timestamp and a link to an associated sample separator 10 , Developments or shifts can be detected by monitoring a history of a tag and, if necessary, updating a separation method 92 , in particular the associated tags, are used. Regarding an actual separation method 92 (including day), monitoring can be performed to determine if certain expectations are met. Also, a dialogue with a user can lead to precisely defined tags, for example, using specific criteria.

4 shows a scheme 400 according to which a chromatographic separation method using a chromatographic separation method 92 is performed according to another exemplary embodiment of the invention.

Here is, see block 304 , a separation method classified as reliable 92 carried out. Based on the data obtained 306 can give a user an interaction 402 be enabled. As a result of the data 306 can the report 308 to be created. Both the data 306 as well as the interaction 402 The user may be in the extraction of the tag by the controller 70 received. By a feedback method so can an advanced separation method 92 ' obtained by a parameter set 404 of parameter values to be specified during the separation 404 and tag 406.

For a reliable separation method 92 There may be an identified reference analysis (for example, in the form of a data file) that can be used as a guide for a subsequent analysis. A particular shape in a waveform or a characteristic pattern can be picked up. This can be marked as a tag.

Tags can have different permissions, depending on their importance and persistence or sustainability or volatility of system characteristics that can affect the corresponding observable parameters. A certain minimum qualification of an operator may be required to supplement or modify a value of a tag. The lower the variability of a parameter, the higher the level of authorization required for a change of the corresponding tag or corridor. Tags can contain all types of data that can be picked up by instrument operation, especially during a split run. However, the analysis result in the narrow sense does not form part of the tag itself. This means, in particular, that certain features of a chromatogram that do not affect the analysis result itself and can occur reproducibly can be used as a tag. A specific example of this are retention parameters of all additional peaks in the chromatogram, except for the peaks of the analysts of interest. These extra peaks may be well suited as a source for generating a tag, especially if they have a high degree of reproducibility. Such peaks can be incorporated in terms of their height, areas, spectra, area ratios, etc. in a day. Also, a behavior of a baseline (eg, slope, background spectra, etc.) may be at least part of a tag. For example, it is also possible to modify solvents to generate corresponding artifacts in the baseline. Also, the shape of a peak or retention time of an analyte of interest may be included in a day if these parameters are not the analytical goal itself.

For example, the tags may be generated by a reliable user action. However, generating tags may also be empirical, for example, based on experience. In such cases, for example, tags may be extracted by generalization from a database of analysis data that may be considered good (for example, as a result of corresponding detected user behavior). Advantageously, a group of negative separation experiments can also be used as the basis for generating a tag in order to reliably exclude unwanted value ranges.

If, for example, statistically significant separation runs with a pressure which does not fall below 200 bar have led to good separation results and such separation runs in which the pressure has dropped below 170 bar have led to poor separation results, the pressure can remain above 200 be defined based on the corresponding experience with historical separations as a day.

It should be noted that the term "comprising" does not exclude other elements and that the "on" does not exclude a plurality. Also, elements described in connection with different embodiments may be combined. It should also be noted that reference signs in the claims should not be construed as limiting the scope of the claims.

QUOTES INCLUDE IN THE DESCRIPTION

This list of the documents listed by the applicant has been generated automatically and is included solely for the better information of the reader. The list is not part of the German patent or utility model application. The DPMA assumes no liability for any errors or omissions.

Cited patent literature

• EP 0309596 B1 [0002]

Claims (20)

A sample separation apparatus (10) for separating a fluidic sample, said sample separation apparatus (10) having control means (70) adapted to control separation of said fluidic sample according to a separation method (92), said separation method (92) being characterized by: a parameter set with parameter values to be specified during the separation; and an expectation corridor (100) relating to parameter values that occur during the separation that is indicative of a sample history (114) of the sample separation. Sample separating device (10) according to Claim 1 wherein the expectation corridor (100) relates to a plurality of parameter values set during the separation. Sample separating device (10) according to Claim 1 or 2 wherein the expected range (100) is a pressure and / or a flow rate, in particular an absolute pressure value and / or an absolute flow rate value, and / or a ratio of at least two pressure values and / or a ratio of at least two flow rates of a fluid in the sample separator (10). Sample separating device (10) according to one of Claims 1 to 3 wherein the expectation corridor (100) relates to a time course of the parameter values in the sample separation device (10) that occur during the separation according to the separation method (92). Sample separating device (10) according to one of Claims 1 to 4 comprising at least one of the following features: wherein the expectation corridor (100) relates to a temperature history of the parameter values in the sample separation apparatus (10) that occur during the separation according to the separation method (92); wherein the expectation corridor (100) relates to a temperature or a temperature profile of a portion of the sample separation device or a position in the sample separation device (10); wherein the expectation corridor (100) relates to a relationship or blending function between a temperature value in the sample separator (10) and another observable parameter value. Sample separating device (10) according to one of Claims 1 to 5 wherein an acceptance width (94, 96) of the expectation corridor (100) for different times during the sample separation is different in size, in particular the acceptance width (94, 96) at an earlier time during the sample separation is greater than at a later time. Sample separating device (10) according to one of Claims 1 to 6 comprising evaluation means (80) adapted to evaluate a separation result based on a comparison between an actual history (104, 106, 108) and said target history (114) of said sample separation. Sample separating device (10) according to Claim 7 wherein the judging means (80) is adapted to output as evaluation one of a group consisting of providing a separation result having a quality attribute, qualifying the separation result as reliable, qualifying the separation result as doubtful, discarding the separation result, and Triggering repeating the separation analysis. Sample separating device (10) according to one of Claims 1 to 8th wherein leaving the expectation corridor (100) during separation according to the separation method (92) does not result in an error condition and / or shutdown of the sample separation apparatus (10). Sample separating device (10) according to one of Claims 1 to 9 comprising at least one of the following features: wherein the expectation corridor (100) is different over a period of sample separation and / or for different separation methods (92); wherein the expectation corridor (100) is defined by time-varying boundaries; wherein an event of crossing a boundary of the expectation corridor (100) does not already result in an expected damage to at least a portion of the sample separation apparatus (10), but only calls into question a reliability of a separation result of the fluidic sample. Sample separating device (10) according to one of Claims 1 to 10 wherein the separation method (92) is further characterized by a must corridor (110) for parameter values set during separation that are indicative of a mandatory history of operation of the sample separation device (10) or sample separation. Sample separating device (10) according to Claim 11 comprising at least one of the following features: wherein leaving the mandatory corridor (110) results in an error condition (112), in particular for autonomous shutdown, of the sample separation apparatus (10); wherein the mandatory corridor (110) completely encloses the expectation corridor (100); wherein the mandatory corridor (110) is constant over an entire period of sample separation and / or for different separation methods (92); wherein an event of crossing a boundary of the must corridor (110) results in expected damage to at least a portion of the sample separation apparatus (10) or to a hazardous situation; wherein the mandatory corridor (110) is defined by time-constant borderlines; wherein an event of crossing a boundary of the must corridor (110) leads to a state of the sample separation device (10) or is indicative of a particular abnormal state of the sample separation device (10) from which the sample separation device (10), in particular known or typically not without intervention of an operator can proceed to a proper operation. Sample separating device (10) according to one of Claims 1 to 12 wherein the expectation corridor (100) is derived from at least one of the group consisting of historical information regarding successful historical sample separations, historical information regarding problematic historical sample separations, simulation, modeling the sample separation apparatus (10), expert knowledge, detected user behavior during successful and / or problematic historical sample separations and artificial intelligence. Sample separating device (10) according to one of Claims 1 to 13 comprising at least one of the following features: wherein the parameter set having parameter values to be given during separation comprises at least one of a group consisting of a concentration of at least one fluid to be delivered by the sample separation device (10), a composition of at least one by the sample separation device (10) fluid to be delivered and a time variation of a solvent composition of at least one fluid to be delivered by the sample separator (10) during the sample separation; comprising a data carrier (91) on which data characterizing the separation method (92) are stored; wherein the separation method (92) is predetermined in the form of a data set with parameter values to be specified for carrying out the sample separation and optional control commands and with an additional day with the expected range (100) of the resulting parameter values. Sample separating device (10) according to one of Claims 1 to 14 , further comprising at least one of the following features: the sample separation device (10) comprises a fluid drive (20) for driving a mobile phase; the sample separating device (10) has a sample separating device (30) for separating the fluidic sample in a mobile phase; the sample separation device (10) has a sample separation device (30), in particular designed as a chromatographic separation device, further in particular designed as a chromatography separation column; the sample separation apparatus (10) is configured to analyze at least one physical, chemical and / or biological parameter of at least one fraction of the fluidic sample; the sample separation device (10) comprises at least one of the group consisting of a device for chemical, biological and / or pharmaceutical analysis and a chromatography device, in particular a liquid chromatography device, a gas chromatography device, a device for supercritical fluid chromatography, an HPLC device, a UHPLC device and an electrophoresis device; the sample separation device (10) has a fluid drive (20), in particular configured to drive a mobile phase at a high pressure; the sample separation device (10) has a fluid drive (20), in particular configured for driving a mobile phase with a pressure of at least 100 bar, in particular of at least 500 bar, more particularly of at least 1000 bar; the sample separation device (10) is configured as a microfluidic device; the sample separation device (10) is configured as a nanofluidic device; the sample separation device (10) has a sample introduction unit (40) for introducing the fluidic sample into a fluidic path between a fluid drive (20) and a sample separation device (30); the sample separation device (10) has a detector (50), in particular a fluorescence detector or UV absorption detector, for detecting the separated fluidic sample; the sample separator (10) comprises a sample fractionator (60) for fractionating the separated fluid sample. A method of separating a fluidic sample, the method comprising: Controlling the separation of the fluidic sample according to a separation method (92); Specifying the separation method (92) by: a parameter set with parameter values to be specified during the separation; and an expectation corridor (100) relating to parameter values that occur during the separation that is indicative of a sample history (114) of the sample separation. Method according to Claim 16 wherein the expectation corridor (100) is adapted specifically to the separation method (92), in particular for Different separation methods (92) different expectation corridors (100) are given. A method of operating a meter (10), the method comprising: Controlling the operation of the meter (10) according to a method of operation (92); Specify the method of operation (92) by: a parameter set with parameter values to be specified during the measurement; and an expectation corridor (100) of parameter values during measurement that is indicative of a desired course (114) of operation of the meter (10); optionally, a must corridor (110) for parameter values during measurement which is indicative of a mandatory history of operation of the meter (10). A fluidic analyzer (10) for analyzing a fluidic sample, the fluidic analyzer (10) comprising a controller (70) adapted to control an analysis operation of the fluidic sample according to an analysis method (92), the analysis method (92) being characterized by: a parameter set with parameter values to be specified during the analysis process; and an expectation corridor (100) relating to parameter values that occur during the analysis process that is indicative of a desired course (114) of the analysis process. Analyzer (10) according to Claim 19 comprising at least one of the following features: wherein the expectation corridor (100) relates to the parameter values of a plurality of parameters during the analysis process; wherein the fluidic analyzer is a sample separator.

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