CN117607277A

CN117607277A - Blank run analysis of chromatographic performance

Info

Publication number: CN117607277A
Application number: CN202311031026.8A
Authority: CN
Inventors: S·克鲁斯卡; S·迪格; W·威尔逊
Original assignee: Agilent Technologies Inc
Current assignee: Agilent Technologies Inc
Priority date: 2018-04-18
Filing date: 2019-03-19
Publication date: 2024-02-27
Also published as: GB2586376A; GB2586376B; GB202300450D0; GB202014904D0; DE112019002042T5; WO2019203972A1; JP7483626B2; JP2021521440A; CN111971553A

Abstract

A method and system for evaluating the performance of a chromatography system having a detector operable to output a signal, in certain embodiments, the method and system comprising steps and components for: receiving one or more blank run acceptance criteria, receiving a detector signal from the detector for blank run, extracting an attribute of the detector signal, comparing the extracted attribute with a corresponding blank run acceptance criteria, and providing a determination regarding the feasibility of the chromatography system based on the result of the comparison.

Description

Blank run analysis of chromatographic performance

The present application is a divisional application of chinese patent application No. 201980025705.X (application date: day 19 of 3, 2019, title of invention: blank running analysis of chromatographic performance).

Technical Field

The present disclosure relates generally to blank runs and system performance in the field of chromatography.

Background

Chromatographic analysis is a method of analyzing a sample consisting of one or more components to qualitatively determine the identity of the components of the sample and quantitatively determine the amount of the components. While the following discussion focuses on gas chromatography, these concepts can be extended to all separation techniques.

A typical Gas Chromatograph (GC) includes a sample inlet or inlet into which the sample is introduced, a column through which the various components of the sample pass at a rate related to the characteristics of the particular components, an oven or other type of heating and/or cooling device that controls the temperature of the column, and a detector for observing the elution of each component. The carrier gas or mobile phase carries the sample from the inlet through the GC column to the detector. The column contains a stationary phase that separates the sample components according to their different affinities for this coating. The GC column can be packed with a stationary phase containing particulates (packed column) or can be made with small-bore open tubes coated with stationary phase (capillary column). The liquid sample may be injected into the inlet through an autosampler or a manual injection needle. Other examples of sample injection may include headspace sampling, thermal desorption, gas or liquid sampling valves, or solid sample introduction devices.

So-called GC methods specify parameters associated with the GC operation of a particular analysis. Some of these parameters include flow rate, pressure, temperature of various GC components, sample injection parameters, and others. Sequence refers to a set of consecutively operated analyses, each of which operates according to the GC method. The result of chromatographic separation is shown as a plot of detector signal versus time, commonly referred to in the art as a chromatogram. When one or more sample components elute from the column into the detector, the detector signal will change from its nominal value. When one or more components have eluted from the column and passed through the detector, the detector signal level will return to its original value or very near to the original value. This resulting deflection is typically shaped as a sharp bell-shaped curve and is referred to as a peak. A chromatogram typically includes one or more peaks, each peak corresponding to a certain component of the analyzed sample. The time from the sample introduction to the observation of the maximum of the peak representing a particular component is referred to as the retention time of that component. The area or height of a peak is to some extent characteristic of the amount of the corresponding component present in the sample and can be calculated by integrating the peak.

In addition to peak retention time and area, the chromatograms contain a large amount of information. The continuous performance of a chromatography system can be assessed by looking at certain parameters of the chromatogram. The value of this assessment has been known for many years and is commonly referred to as system applicability, system verification, or system performance. This concept was formally introduced for drug development in the 80 to 90 th century, but is well known in other separation science applications. For reference, the FDA drug evaluation and research Center (CDER) published in month 11 of 1994 under the monograph designation "Reviewer Guidance-Validation of Chromatographic Methods". In this document, the fourth section J section describes system applicability specifications and tests.

Typically, the sample used to determine the suitability of the system contains one or more components of interest (in an amount that is readily detectable) and contains any additional interference that may be observed in a real sample. For example, in a pharmaceutical formulation analysis, the sample may contain additional components as well as active pharmaceutical ingredients. These additional components may elute near the drug component and the resolution of both components needs to be monitored. Section J lists the following criteria for evaluating GC method performance:

Capacity coefficient (relative retention time of compound relative to system dead time);

accuracy/sample injection repeatability (consistency of effective results produced by chromatography systems);

relative retention (relative retention of the compound of interest compared to another compound in the sample);

resolution (a measure of the degree of separation of two peaks);

tail factor (measure of compound peak distortion); and

theoretical plate number (a measure of the working efficiency of a chromatography system in terms of compound transport).

Starting from the initial monograph, other parameters are also used to evaluate the performance of the chromatography system, for example:

peak width (indicating efficiency and column/system degradation);

peak area (an indication of detector sensitivity);

peak response factor (relative sensitivity compared to standard components in the sample);

skewness (third order peak moment analysis); and

kurtosis (fourth order moment analysis).

One example of evaluating the suitability of a system is to run a reference or quality control sample and evaluate the resulting chromatogram. Some or all of the parameters listed above, even additional parameters not listed in the FDA monograph, are determined and used as reference values for subsequent analysis. Repeated runs are performed multiple times to establish statistical accuracy of the metrics and to determine pass/fail criteria to determine if the system is operating properly. Acceptance criteria are established by the user for a particular analysis. As a specific example, the retention time of a particular compound was determined to be 5.00+/-0.01 minutes. In subsequent system suitability analysis, if the measured retention time is not within an acceptable range, the chromatographic system is deemed unsatisfactory and maintenance may be required to restore performance. Acceptance criteria may be unilateral (performance parameters must be greater or less than user-determined or specified chromatographic values) or bilateral, as is common in control charts. For example, the FDA monograph provides suggested criteria such as peak area or reproducibility of peak response for five replicates should be better than 1% RSD.

This concept of using reference samples to assess instrument performance has also been used in many defined standardized chromatographic methods (e.g. US EPA 8270, GC/MS analysis of semi-volatile organic compounds). The reference sample was analyzed during a series of analyses to verify that the instrument still met its performance criteria. If the instrument fails the performance check, the user needs to stop the sequence and repair the instrument to restore compliance. For example, for US EPA method 8270C (published 1996), the calibration test sample must meet the following conditions:

-response coefficient: between 80% and 120% of the original value

-internal standard response: -between 50% and +100%

Internal standard retention time: +/-30 seconds

-the relative retention time is within an acceptable range (+/-0.06)

Detector linear response: RSD < = 15%.

From the foregoing description, the concept of using retention times and relative retention times (and extended retention indices) to indicate instrument performance has been known for many years.

One aspect of chromatography that has not been strictly explored is the use of blank runs to evaluate whether the system is operating as intended. The chromatograph personnel will typically perform a blank run to confirm that the system is "clean" and that the components identified in the subsequent sample are indeed from that sample, not the previous sample. However, blank runs may also be analyzed to determine system performance or system feasibility, as described below. The blank runs provided information different from that obtained with the reference samples.

To evaluate instrument performance, there are two types of blank runs. The first type is a no sample blank run, i.e., GC method parameters such as column flow, pressure, oven temperature, detector data collection, etc., are performed, but no sample is taken. FIG. 1 shows an example characteristic of a sample-less blank run with a single oven temperature ramp. In the sample-free blank operation of fig. 1, several artifacts on the base line are evident. First, a measurable peak 101 appears on the baseline, which may affect the quantification of the sample peak during sample operation. The potential cause of this is that chemical compounds that entered the column elute from the inlet or "run off" from the inlet liner or membrane during previous runs. Next, the baseline increased with increasing oven temperature. This is because the stationary phase gradually breaks down as the temperature increases, leaves the column and is sensed by the detector, so that a so-called column loss phenomenon occurs. This final baseline 102 may be significantly higher than the initial baseline 103, depending on the column temperature used. Finally, baseline noise increases at the end of the run. This may be due to constant flow loss of column aged and degraded stationary phase into the detector.

In the second case of blank runs, a "clean" solvent (without the component of interest or components interfering with the analysis) is injected while the GC method is running. This is called solvent blank run. Some examples of solvents include methylene chloride, acetone, hexane, acetonitrile, and ethyl acetate. For sample analysis, these solvents typically elute before any components of interest and are referred to as solvent peaks 201. In addition to verifying that the chromatograph is free of interferents (as shown by the flat baseline after solvent elution), this type of blank run also verifies that the autosampler and inlet are "clean" and running properly, and that the detector response is stable. Figure 2 shows the chromatogram obtained for the solvent blank run.

In drug analysis related to abuse, one extreme example of using blank runs can be seen. The sequence of applications includes a solvent blank run, a first real sample run, a solvent blank run, a second real sample run, and then a solvent blank run. This gives reasonable evidence that the system has no carryover from the first real sample to the second real sample. The professional chromatograph personnel provide a manual determination of whether the system is clean (i.e., free of carryover, contamination, false baseline disturbances). This is done by manually checking the results of the blank run to determine if any disturbances are observed. However, this manual evaluation is limited because it occurs in post-processing of the samples after operation, except that this process is time consuming. If a problem arises, it may be necessary to prepare the sample again and rerun. In addition, the expert checking the data will typically check the results of the integration to see if any calibration compound (in this case, the drug of abuse) is observed. The actual baseline is not evaluated. In some references, such as EPA method 8000D, both types of blank runs may also be referred to as instrument blank runs. This is to avoid confusion with sample preparation blank runs (e.g., method blanks and laboratory reference blanks) and other quality control samples used to verify the entire analysis protocol. For brevity, blank runs are used herein to represent either no sample blank runs or solvent blank runs. The purpose of the reference sample is to verify that the component of interest elutes at the correct retention time, is well separated, and has the necessary detector response to meet the analytical objectives. EPA method 8000D, a guideline for EPA calibration and quality control, details these requirements in section 9.3.3. The use of blank runs is described in section 4.4. Although this section describes elevated baselines and their possible resulting quantitative errors, no criteria are given to evaluate the data. Blank explanations are given in sections 9.2.6.8 to 9.2.6.12. Also, there is no discussion of detector signals or noise, and how it can be used to evaluate the feasibility of the instrument.

Another use case is where the chromatographic personnel want to subtract the contribution of the system to the baseline noise or contaminant peak from the sample signal. For example, the system contribution may include an increase in detector signal due to column stationary phase "run off" into the detector resulting in a rise in the baseline. Similarly, components may be thermally extracted from the inlet liner, the column connection fitting, and the membrane used to seal the inlet. These also cause the detector signal to rise. In this case, a blank run without sample introduction was first performed as a reference. The blank run should only show the detector baseline as a system function. For applications such as simulated distillation, the detector signal from the blank run is then subtracted from all chromatograms of the real sample to provide a flatter baseline and easier integration in determining the sample peak area. This can be achieved by utilizing column compensation functions available in gas chromatographs or in data post-processing.

Disclosure of Invention

A method for evaluating performance of a chromatography system having a detector operable to output a signal is described herein. The method includes receiving one or more blank run acceptance criteria, receiving a detector signal from the detector for blank run, extracting an attribute of the detector signal, comparing the extracted attribute with a corresponding blank run acceptance criteria, and providing a determination regarding feasibility of the chromatography system based on a result of the comparison.

Also described herein is a chromatography system comprising: a separation column; a sample inlet for introducing a sample into the separation column; a detector coupled to the separation column and operable to output a detector signal; and a Blank Run Analysis Unit (BRAU) operable to receive the detector signal from the blank run. The BRAU includes: an attribute extractor for extracting an attribute of the detector signal; and a decision module for comparing the extracted attributes with corresponding acceptance criteria and providing a decision regarding the feasibility of the chromatography system based on the result of the comparison.

Also described herein is a Blank Run Analysis Unit (BRAU) operable to receive a detector signal from a blank run from a detector of a chromatography system. The BRAU includes: a memory for storing executable instructions; an attribute extractor; a determiner; and a processor for executing the instructions to cause the attribute extractor to extract an attribute of the detector signal and to cause the determiner to compare the extracted attribute with a corresponding acceptance criterion and to provide a determination regarding the feasibility of the chromatography system based on a result of the comparison.

Advantages of certain embodiments disclosed herein include that the user does not have to open and visually inspect all blank run data to confirm data accuracy. This cumbersome process delays the completion of the chromatographic analysis and is prone to errors and validity problems.

Other advantages include allowing the chromatography system to evaluate blank runs and take user-directed actions without requiring user intervention. For example, if a blank run of the system fails to meet acceptance criteria for one or more attributes, the sample analysis sequence to be run may be paused and the problem may be waited for correction. By not continuing the sequence, the remaining samples will not run on an unsatisfactory instrument. This eliminates the need for the user to rerun the sample or prepare a new sample to replace those samples that have been injected under non-conforming conditions.

Other advantages include allowing the chromatography system to pause the sequence and perform maintenance steps before resuming the sequence. Typically, post baking repairs the system and allows blank runs to pass. With this capability, these tasks can be fully automated.

Other advantages include allowing the system to track the results of a blank run and providing a control chart for the number of sample analyses before maintenance is required.

Other advantages include allowing the system to automatically troubleshoot if the blank run analysis determines that the system is not viable. For example, in solvent blank runs, solvent peak retention time is one of the criteria to be evaluated. If the retention time is longer than expected, but the column head pressure is correct, this indicates that the column is partially plugged and maintenance is required.

Further embodiments, features, and advantages of the present inventions, as well as the structure and operation of the various embodiments of the present invention, are described in detail below with reference to the accompanying drawings.

As used herein, "system applicability," "system verification," "system performance," "system feasibility" refers to the assessment of chromatographic performance of a chromatographic system, typically using retention time, peak area, and other parameters to determine whether the chromatograph is capable of performing a valid analysis. "interference" refers to a component of a sample that may complicate accurate analysis of one or more components of interest. "reference sample" or "quality control sample" refers to a sample containing components used to evaluate the chromatographic performance of the system. An "acceptance criterion" refers to one or more ranges or thresholds for an attribute that, if met, indicates that the chromatographic system is viable. "no sample blank run" refers to a chromatographic analysis in which no sample is introduced into the instrument but the GC method conditions are performed. "run-off" refers to additional chemical elution from the column, thereby increasing the signal level of the detector. Loss can come from a number of sources, typically rising as a result of elevated system temperatures. "clean solvent" refers to a chemical sample consisting of solvent only. "solvent blank" refers to chromatographic analysis in which one or more clean solvents are introduced into the instrument. "extracted attribute" refers to the attribute value for a given blank run. This value may be compared to an acceptance criterion to determine if the chromatography system is viable. The "detector signal" is the raw detector output before any filtering or extraction is applied. "baseline signal" refers to signal data obtained by filtering raw detector signal data to remove noise and other peaks. "residual signal" refers to the detector signal remaining after baseline extraction is complete. Typically, this will contain a narrow peak and high frequency components.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one or more examples of embodiments and, together with the description of the example embodiments, serve to explain the principles and implementations of the embodiments.

In the drawings:

FIG. 1 is a chromatogram of a prior art sample-free blank run with a single oven temperature ramp;

FIG. 2 is a chromatogram of a prior art solvent blank run;

fig. 3 is a schematic diagram of an exemplary gas chromatography system including a Blank Run Analysis Unit (BRAU) according to one embodiment;

fig. 4 is a block diagram illustrating a BRAU in more detail according to one embodiment;

fig. 5a, 5b and 5c show examples of processing of the detector signals. Fig. 5a shows an example raw detector signal. Fig. 5b and 5c show the decoupled baseline detector signal and the decoupled residual component (detector signal), respectively. Results calculated by the attribute extractor, such as initial baseline, final baseline, and region of interest, are shown in fig. 5b and 5 c;

fig. 6a, 6b, and 6c are tables listing various attributes of interest and corresponding no-pass conditions and explanations of the no-pass conditions, according to one embodiment. Specifically, fig. 6a shows a baseline signal, fig. 6b shows a residual signal, and fig. 6c shows a solvent blank run attribute; and is also provided with

Fig. 7 is a flowchart showing an example use case according to an embodiment.

Detailed Description

Example embodiments are described herein in the context of a blank run analysis for evaluating chromatographic performance. Those of ordinary skill in the art will realize that the following description is illustrative only and is not intended to be in any way limiting. Other embodiments will readily suggest themselves to such skilled persons having the benefit of this disclosure. Reference will now be made in detail to implementations of the exemplary embodiments as illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings and the following description to refer to the same or like items.

In the following detailed description of the embodiments, references to "one embodiment," "an example embodiment," etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Furthermore, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to effect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.

In the interest of clarity, not all of the routine features of the implementations described herein are shown and described. It will be appreciated that in the development of any such actual embodiment, numerous implementation-specific decisions must be made in order to achieve the developer's specific goals, such as compliance with application-and business-related constraints, and that these specific goals will vary from one implementation to another and from one developer to another. Moreover, it will be appreciated that such a development effort might be complex and time-consuming, but would nevertheless be a routine undertaking of engineering for those of ordinary skill in the art having the benefit of this disclosure.

Fig. 3 is a schematic diagram of an exemplary gas chromatography system 300 according to some embodiments. Sample inlet 301 receives a sample (not shown) to be analyzed. Before reaching detector 303, the sample is carried through separation column 302 by a carrier gas (not shown) under carefully controlled pressure, temperature and flow conditions. Column 302 may be comprised of one or more columns to effect separation of components. The oven 304 is used to heat the column to the desired temperature. Although not shown, other types of heating and/or cooling are also contemplated. The detector 303 generates measurement signals related to various sensed parameters of the sample and transmits these output signals to the processor 305 for analysis. Although not specifically illustrated, the detector 303 may be any GC-compatible detector. Processor 305 may be one or more microprocessors or processing units including, but not limited to, a single or multi-core processor, or other types of logic or data processing circuitry. In certain embodiments, the analysis is performed by the processor 305 in accordance with executable code stored in the memory 306, which may be in the form of volatile (e.g., DRAM) or non-volatile (e.g., flash) memory, or a combination of these. A User Interface (UI) 307 allows an operator to receive information from the processor and to input information and parameters to the processor. Such information may be stored and accessed through memory 306. For example, UI 307 may include a display, keyboard, touch screen, voice activated input, haptic devices, and/or other peripherals to provide control inputs and/or outputs.

The gas chromatography system 300 also includes a Blank Run Analysis Unit (BRAU) 308, shown coupled to the processor 305 and the memory 306, and generally used to evaluate the performance or feasibility of the chromatography system using blank runs. BRAU 308 may be one or more hardware, software, or firmware components, or any combination thereof, that are separate from or integrated with processor 305. In some embodiments, BRAU 308 may include its own processor (308 a) for executing instructions, as well as its own memory (308 b) for storing instructions and data, such as data from detector 303 and from a user, including blank run acceptance criteria as described in further detail below. In some embodiments, BRAU 308 executes code that may be stored in memory 306 and generates output results that may be organized as files 309 in memory 306, as will be discussed in more detail below. In certain embodiments, BRAU 308 may be one or more components comprised of software, firmware, hardware, or any combination thereof, separate from gas chromatography system 300, e.g., as part of an external diagnostic device 310 (BRAU 308'), having its own processor, memory, user interface, and other supporting components (not shown).

Fig. 4 shows a block diagram illustrating the operation of a Blank Run Analysis Unit (BRAU) 400. Each block in fig. 4 may correspond to discrete hardware, firmware, and/or software components having the functionality described herein. Alternatively, the described functions may be implemented by any combination of the described blocks or by additional or sub-blocks not described for clarity. Typically, but not by way of limitation, BRAU 400 evaluates the performance or operability of a chromatography system by, for example, detecting when a blank run is complete, extracting a detector signal from the blank run, evaluating the detector signal from the blank run, and determining whether the extracted signal properties fall within acceptance criteria. In some embodiments, BRAU 400 monitors the system and processes the blank run data as it is available. In some embodiments, it decouples the detector signal into a baseline and a residual signal, and calculates a set of attribute values from one or both of the decoupled signal pairs, and compares these extracted attributes to acceptance criteria. In certain embodiments, it reports the results as "pass" or "fail" indicating the feasibility of the chromatography system and whether it is operating properly.

Information related to the blank operation is provided to BRAU 400. The information includes detector signals used to construct the chromatograms. Additional information that may be provided to BRAU 400, collectively referred to as user input in fig. 4, includes GC method, region of interest of the detector signal, user-defined acceptance criteria, and type of blank run performed. It is noted that in the context of this example, "GC method" refers to the instrument parameters of the run. The region of interest may define a time range in which the attribute evaluation is applied, the user focusing on a specific portion of the detector signal in the time range. This region of interest is typically the time frame in which the component of interest elutes during the sample run, as this is where noise and peaks due to contamination cause most problems in sample analysis. In certain embodiments, the type of blank run may be a no sample injection or solvent blank run. Other information may be received including chromatograph personnel ID, sequence and run name or unique ID, run date and time, and other instrument specific information corresponding to the run. For example, operator input via UI 307 (fig. 3) may be used to provide some or all of this information, including in certain embodiments whether the blank run is a sample-less blank run or a solvent blank run. In addition, the operator input may also be made through an external device, such as a diagnostic device 310 (fig. 3), which is capable of controlling the operation of the GC, and inputting and storing the foregoing information.

In some embodiments, once BRAU 400 receives and optionally verifies the information, it begins processing the output signal from the detector. Fig. 5a shows an example of a detector signal from a sample-free blank run of a contaminated system, where the user specifies a region of interest 501 from 18 to 23 minutes based on the analysis (which may be specified automatically by the system instead of by the user in some embodiments). In an example implementation, the output signal from detector 303 is passed to filter 401, followed by a decoupler 402 that decouples the detector signal into two separate signals that contain the baseline and residual signals. Fig. 5b and 5c show the baseline and residual signals, respectively, extracted from the detector signal of fig. 5 a. Fig. 5b also shows an initial baseline region 512 and a final baseline region 513 to be processed by the attribute extractor. In certain embodiments, the baseline signal is first extracted and then subtracted from the detector signal, the remaining signal forming a residual signal. In an ideal case, the baseline signal contains only the detector signal caused by the carrier gas eluting from the column. In practice, the baseline will show a shift in the detector signal caused by any material eluting from the column over time. One major factor in baseline is stationary phase column loss. Most GC columns use a high molecular weight siloxane polymer as the stationary phase immobilized in the column. At very high temperatures, small amounts of stationary phase can degrade and elute over a longer period of time. This resulted in a baseline rise at the end of the chromatographic run in fig. 5 b. The residual signal contains a bias in the detector response due to faster eluting species, manifesting as peaks or increased high frequency noise. Examples of residual signals are contaminants in the carrier gas or inlet, which accumulate at the column inlet and elute as the chromatographic run is performed. The sum of these two signals produces the raw detector data.

In some embodiments, baseline extraction is performed using nonlinear median filtering, such as at filter 401 in fig. 4. Other types of filtering may also be used. In the example of fig. 5a, the detector signal is filtered with a median filter using a window of 40 seconds to produce fig. 5b. The filter is chosen because of its relatively low computational complexity and beneficial properties. The median filter has good inhibition effect on noise with peak or heavy tail statistical distribution of peaks in the data. This makes it a good choice to extract the baseline while ignoring the spike. It also maintains a baseline shift in the data, as found in blank runs, exhibiting a sharp rise during the temperature rise, and then remains unchanged when the final temperature is reached.

Decoupling allows calculation of values, including the sum or maximum of peaks, based on attributes or extracted attributes without the need to identify each individual peak. This allows faster algorithm development and less computational complexity. Decoupling also allows easier peak identification, integration and computation of more complex properties. However, the use of a chromatographic peak integrator is a viable alternative. In this alternative method, the raw detector signal may be processed by a chromatographic peak integrator 403 to determine peak retention time and peak area or height. The peaks from chromatographic peak integrator 403 may then be combined with peaks from all other peaks to determine a maximum height or sum attribute by attribute extractor 404. This alternative step is shown in fig. 4, where a peak integrator 403 receives the detector signal and provides its output to an attribute extractor 404. This method can be used with or without any type of filtering. In a specific implementation, the peak integrator uses a median filter to obtain a curve that contains all the peaks. In certain embodiments, individual peaks are not individually identified and characterized for computational simplicity.

It should be noted that the baseline extraction is not limited to the median filter described above, and that other filtering or smoothing techniques may be applied. The choice of these techniques depends on the computational complexity and speed required by the designer, the noise characteristics to be suppressed, whether the signal is from a generalized stationary process, and whether other a priori information about the detector signal (or system) is available. Filtering techniques are generally best suited for applications requiring real-time processing, but may have delays or lags in their response. Other methods such as smoothing generally have better noise suppression effects and can be easily implemented without response delays. However, they cannot be implemented in real time and are limited to post-processing only. Other possible filters and smoothers for baseline extraction are discussed below.

Finite and infinite impulse response filters and smoothers (FIR and IIR) are probably the best known, simple to implement, fast to calculate, and well suited to suppress sinusoidal noise over a range of frequencies. Which makes them suitable for suppressing high frequency (or specific frequency) baseline noise. One particular FIR filter that is widely used in the analytical chemistry field is the Savitzky-Golay filter. It is known to reduce the high frequency noise of a signal while maintaining the shape and height of its peaks. However, it is less suitable for estimating the baseline signal because it is designed to preserve peaks in the signal, rather than filter it out. In fact, in general, FIR filters cannot suppress noise that occurs in peak form, or more precisely, noise that includes a broad and flat power spectral density. Ordered statistical filters, such as the median filter discussed above, can better suppress these peak-shaped disturbances; however, they may not be optimal for suppressing high frequency noise, periodic or random white noise common in chromatographic runs. Adaptive filters and smoothers are very useful when the noise characteristics are unknown or vary over time (non-stationary or broadly stationary). Such filters use mathematical or statistical models of the noise, employ optimization techniques to estimate the noise characteristics, and adjust the filter over time to optimally reject the noise. The adaptive nature of these algorithms proves useful when the noise characteristics vary over time; however, they are generally more difficult to design and require considerable processing power. Any combination of smoothing or filtering techniques may be used to best suppress noise.

Returning to fig. 4, the decoupled baseline and residual signals are passed to an attribute extractor 404 for extracting attributes of each of these signals. The attribute extractor calculates any values defining attributes for the blank run. Some of these extracted attributes may be calculated using baseline signals, residual signals, raw detector signals, or any combination of these signals.

An example of an initial baseline 512, a final baseline 513, and a region of interest 511 for attributes is shown in fig. 5b, which may be calculated by the attribute extractor 404 of fig. 4 using the baseline signals. The purpose of these calculations is to detect faults corresponding to the beginning and end of the detector signal and the region of interest. These faults include detector faults, detector shut-down, or column damage. Initial and final baseline properties are listed and defined in the table of fig. 6a, as well as other examples of properties related to the detector signal or baseline signal. Examples of these attributes may be indicative, in whole or in part, of the feasibility of the chromatography system to analyze.

Similarly, a graphical representation of the extracted properties of the residual signal that may be calculated by the property extractor 404 is shown in fig. 5 c. The calculation of the initial baseline noise 522 and the final baseline noise 523 is performed at the beginning and end of the residual signal, respectively. These may include any calculation of statistical dispersion of the measured data. Calculation methods such as standard deviation (or multiples thereof), quartile range, full range or peak-to-peak values, or ASTM-defined noise calculations may be used. For each user-defined region of interest, e.g., 521, a maximum peak height and total peak area calculation is performed. For each region, the maximum peak height can be estimated by taking the largest data point within that range. The total peak area can be found by numerical integration of each region, thereby estimating the total area of all peaks in these regions. Note that random noise in the residual signal has little effect on the numerical integration. This is because the mean value of the noise is zero (removed during the decoupling operation), so the integration will average the noise. These properties, as well as other examples, are listed and defined in the table of fig. 6 b. The region of interest in fig. 5c is denoted 521.

Returning again to fig. 4, the extracted attributes are transferred from attribute extractor 404 to determiner 405. Blank run acceptance criteria are also passed to determiner 405, and the extracted attributes are compared to the criteria. The blank run acceptance criteria determined at block 406 defines the range within which the extracted attributes must fall, or the threshold or criteria that needs to be met, to make the chromatographic system considered viable. For example, the user may load predefined default blank run acceptance criteria through UI 307 (fig. 3), or they may be set manually. In one embodiment, as shown in default white-run acceptance criteria storage block 407 in fig. 4, the user may prompt the system to load a predefined default white-run acceptance criteria based on the characteristics of the GC method. For example, different blank run acceptance criteria may be defined for each unique detector type. Blank run acceptance criteria may be selected to provide a good assessment of most GC methods using the detector type, GC column type, and/or instrument conditions in the GC method. In the special case where the GC method does not meet specifications, the user may adjust the default blank run acceptance criteria. In this case, the default blank run acceptance criteria may serve as a good starting point for guidance or user adjustment to their own needs.

Accordingly, from block 406, a blank run acceptance criterion is invoked and applied to the attributes extracted from attribute extractor 404, which determines whether the extracted attributes meet or violate the acceptance criterion, and, according to some embodiments, whether the system passes or fails the blank run analysis. In certain embodiments, the result of the comparison is output, providing an indication of whether the chromatography system is viable (i.e., functioning properly and being suitable for use) or whether repair, warning, or other action is required. An interpretation of the results indicating that repair, warning, or other action is required may be provided by reporter 408 and output to the user via UI 307, automated email, text or voice mail, or other communication means.

In some embodiments, if the determiner 405 determines that the system fails the blank run analysis (i.e., the chromatography system is not viable), the system may select a continue sequence, a pause sequence to wait for user intervention, a pause sequence, or re-run the blank run. The option may be specified based on user input. The system may also suggest to the user one or more possible causes of the fault and/or what may address the problem that caused the fault condition. In some embodiments, the system may automatically repair the cause of the failed acceptance criteria. For example, the system may raise the oven temperature to clean the instrument. After the potential fix is implemented, the system may run an additional blank run to determine that the extracted attributes now meet the acceptance criteria.

In some embodiments, if no acceptance criteria are provided for the attributes, BRAU 400 assumes that the user does not wish to use it to analyze the blank run. The attribute extractor 404 may still calculate some or all of its own history and, optionally, follow-up analysis by the user. However, when evaluating the performance of a chromatography system using a blank run, it does not take this attribute into account. In addition, if the user does not provide a region of interest for the attribute, the attribute extractor 404 may calculate the attribute using the entire chromatographic run time as the region of interest. Instead, the system may simply store the blank run data and allow the user to reprocess it at a later time with the same or new acceptance criteria for blank run analysis.

The tables in fig. 6a, 6b, and 6c list various attributes associated with a blank run, for example, according to some embodiments. Descriptions of the attributes, failing conditions by which they are evaluated (failing acceptance criteria are not met), where the maximum and minimum limits are defined by acceptance criteria, and an explanation of the reasons that may lead to blank runs failing acceptance criteria are also listed. Some properties may only be applicable to solvent blank runs, such as those listed under "solvent blank run properties in FIG. 6 c".

As can be seen from the table of fig. 6a, taking the initial baseline property as an example, if the signal is above the acceptance criterion, the baseline signal under initial conditions may be indicative of system contamination; or if the signal is below an acceptance criterion, it may indicate a detector failure or column failure. In either case, the performance of the instrument is insufficient to provide acceptable analysis. As another example, considering the total peak area attribute in fig. 6b, the total peak area of the residual signal may indicate inlet or gas contamination, carryover from the previous run, or column head fouling if the value is above an acceptance criterion.

In some embodiments, it may be desirable to store and aggregate analytical data, including, for example, attributes extracted from attribute extractor 404 and decisions from determiner 405. The extracted attribute and determination history storage 409 provides such functions as storing the extracted attribute and determination in the memory 306 (fig. 3). The extracted attributes and decisions belonging to the same method, or method and solvent type, or any other grouping, may be grouped together and organized in a file 309 (fig. 3). More generally, the organization may be in the form of files, folders, directories or other groupings, or any type of data structure or record. In some embodiments, BRAU 400 may provide historical information to the user regarding blank runs to help determine the health of the instrument, or may store this information so that the user can analyze and infer their health. One application of this aspect may include providing a control chart of multiple runs before maintenance is required.

Fig. 7 is a flow chart illustrating an example use case according to some embodiments. At 701, a user creates a method using a selected acceptance criterion. This may be entered via UI 307 (fig. 3). Then, at 702, the user runs the created method, either as a single analysis, or as part of a sequence, where the run is identified as a blank run, and in some embodiments, as a no sample or solvent blank run. During or after operation, signal data is collected (at 703, from detector 303 in fig. 3) and blank operation is evaluated (at 704) based on acceptance criteria. It is then determined whether the blank run is "pass" or "no pass". For example, if a pass is determined, the analysis is completed and waits for the next run, or the instrument advances to the next row in the run sequence. Other actions are also contemplated after passing. On the other hand, if it is determined that the user does not pass, the user may be notified, and a predetermined action may be performed. For example, the instrument may "pause" and wait for user intervention. Other options include instrument rerun blank, stop run sequence, stop sequence, perform column bake or continue sequence to the next sample.

While embodiments and applications have been shown and described, it would be apparent to those skilled in the art having the benefit of this disclosure that many more modifications than mentioned above are possible without departing from the inventive concepts disclosed herein. The invention, therefore, is not to be restricted except in the spirit of the appended claims.

In summary, the present invention includes, but is not limited to, the following:

1. a method for evaluating performance of a chromatography system having a detector operable to output a signal, the method comprising:

receiving one or more blank run acceptance criteria;

receiving a detector signal from the detector from a blank run;

extracting an attribute of the detector signal;

comparing the extracted attribute with a corresponding blank operation acceptance criterion; and

a determination relating to the feasibility of the chromatography system is provided based on the result of the comparison.

2. The method of item 1, further comprising:

the received signal is decoupled into separate baseline and residual signals.

3. The method of item 1, further comprising:

a curve with one or more peaks is obtained using a median filter and the combined area under the curve is summed using a peak integrator.

4. The method of item 1, further comprising:

the extracted attributes and decisions of blank runs are tracked to provide a control chart of several runs before maintenance is required.

5. The method of item 1, wherein if the determination indicates that the chromatography system is not viable, stopping, halting, or suspending a series of operations or analyses.

6. The method of item 1, wherein the blank run is a sample-free blank run or a solvent blank run.

7. The method of item 1, wherein at least one of the extracted attributes is for a region of interest.

8. The method of item 5, wherein an explanation is provided if the determination indicates that the chromatography system is not viable.

9. The method of item 1, wherein the attribute is one of:

initial baseline, final baseline, baseline shift, initial baseline noise, final baseline noise, total peak area, total peak height, maximum peak height, retention time, peak area, peak width, or peak symmetry.

10. A chromatography system, comprising:

a separation column;

a sample inlet for introducing a sample into the separation column;

a detector coupled to the separation column and operable to output a detector signal; and

A Blank Run Analysis Unit (BRAU) operable to receive detector signals from a blank run, the BRAU comprising:

an attribute extractor for extracting an attribute of the detector signal; and

a decision module for comparing the extracted attributes with corresponding acceptance criteria and providing a decision regarding the feasibility of the chromatography system based on the result of the comparison.

11. The chromatography system of item 10, wherein the BRAU further comprises:

a decoupler for decoupling the received detector signal into separate baseline and residual signals.

12. The chromatography system of item 10, wherein the BRAU further comprises:

and an extraction attribute and determination history storage means for tracking the extraction attribute and determination of the blank operation so as to provide a control chart of several operations before maintenance is required.

13. The chromatography system of item 10, wherein the acceptance criteria comprises user-defined acceptance criteria.

14. The chromatography system of item 10, further comprising a reporter that provides an explanation if the determination indicates that the chromatography system is not viable.

15. The chromatography system of item 10, wherein if the determination indicates that the chromatography system is not viable, stopping, halting, or suspending a series of operations or analyses.

16. The chromatography system of item 10, wherein the blank run is a sample-free blank run or a solvent blank run.

17. A Blank Run Analysis Unit (BRAU) operable to receive a detector signal from a blank run from a detector of a chromatography system, the BRAU comprising:

a memory for storing executable instructions;

an attribute extractor;

a determiner; and

a processor for executing the instructions to cause:

the attribute extractor extracts an attribute of the detector signal; and

the determiner compares the extracted attributes with corresponding acceptance criteria and provides a determination regarding the feasibility of the chromatography system based on the result of the comparison.

18. The BRAU of claim 17, further comprising:

a decoupler for decoupling the received output signal into separate baseline and residual signals.

19. The BRAU of claim 17, further comprising:

20. The BRAU of claim 17, further comprising a reporter that provides an explanation if the determination indicates that the chromatography system is not viable.

Claims

receiving one or more blank run acceptance criteria;

receiving a detector signal from the detector from a blank run, wherein the blank run is performed when the feasibility of the chromatography system is unknown;

extracting an attribute of the detector signal;

2. The method as recited in claim 1, further comprising:

the received signal is decoupled into separate baseline and residual signals.

3. The method as recited in claim 1, further comprising:

4. The method as recited in claim 1, further comprising:

5. The method of claim 1, wherein if the determination indicates that the chromatography system is not viable, stopping, halting, or suspending a series of operations or analyses.

6. The method of claim 1, wherein the blank run is a sample-less blank run or a solvent blank run.

7. The method of claim 1, wherein at least one of the extracted attributes is for a region of interest.

8. The method of claim 5, wherein an explanation is provided if the determination indicates that the chromatography system is not viable.

9. The method of claim 1, wherein the attribute is one of:

10. A chromatography system, comprising:

a separation column;

a sample inlet for introducing a sample into the separation column;

a Blank Run Analysis Unit (BRAU) operable to receive a detector signal from a blank run, wherein the blank run is performed when the feasibility of a chromatography system is unknown, the BRAU comprising:

An attribute extractor for extracting an attribute of the detector signal; and