Chromatographic quality management apparatus and method

Abstract

The present invention relates to a chromatographic quality management device, comprising: a measurement data acquisition unit that acquires measurement data measured by a chromatograph and saves the measurement data in a storage device; a chromatogram factor decomposition unit that reads the measurement data from the storage device, dimensionally compresses a chromatogram obtained from the measurement data by factor decomposition, and saves component data obtained by the factor decomposition in the storage device; and a component data output unit that reads the component data from the storage device and outputs the component data to a display device.

Description

Technical Field

[0001] This invention relates to an apparatus and method for managing the quality of chromatography. Background Technology

[0002] Linearity is used as a quality indicator for chromatography. Linearity indicates the ability of a chromatography chromatogram to produce a linear relationship between a measured value and the concentration of the analyte. (Source: Masamitsu Okawara, Standardized Education Program "Individual Technical Field - Chemistry", December 23, 2008, Dionex Co., Ltd., Japan, Internet)<https: / / www.jsa.or.jp / datas / media / 10000 / md_2507.pdf> In this study, linearity is used as an indicator for analytical verification. International Publication No. 2015 / 029508 discloses a method for evaluating linearity using a standard curve.

[0003] Furthermore, analytical processing, such as peak separation and impurity detection, is performed on the measurement data obtained by the chromatograph. International Publication No. 2015 / 029508 discloses a method for confirming purity in chromatograms with sufficient linearity. That is, chromatograms originating from the same substance exhibit similar spectral shapes even with differences in intensity, thus confirming the absence of impurities. Summary of the Invention

[0004] In routine analytical verification, slight degradation in linearity is not a major problem if the peak area does not change significantly. However, in confirming the purity of medium-molecular-weight pharmaceuticals, it is necessary to detect impurities on the order of 0.05% to determine the presence of similar impurities. Furthermore, since the spectra and mass spectra of similar compounds are generally highly similar to those of the main component, it is necessary to capture extremely small spectral variations. From a sample preparation perspective, it is difficult to determine the linearity corresponding to such minute spectral variations using a standard curve.

[0005] Furthermore, standard samples such as caffeine are generally used to confirm linearity. However, in detectors that detect light split by a spectrometer, linearity can be degraded due to stray light incident on the detector from outside the normal path. Since this wavelength-dependent linearity degradation also exists, actual measurement data, rather than standard samples, are needed to confirm linearity.

[0006] The purpose of this invention is to evaluate high-precision linearity in chromatography.

[0007] According to one aspect of the present invention, a chromatography quality management device includes: a measurement data acquisition unit that acquires measurement data measured by a chromatograph and stores the measurement data in a storage device; a chromatogram factor decomposition unit that reads the measurement data from the storage device, compresses the chromatogram dimensions obtained from the measurement data through factor decomposition, and stores the component data obtained through factor decomposition in the storage device; and a component data output unit that reads the component data from the storage device and outputs the component data to a display device.

[0008] According to another aspect of the present invention, the chromatographic quality management method comprises: a step of acquiring measurement data measured by a chromatograph and storing the measurement data in a storage device; a step of reading the measurement data from the storage device, compressing the chromatogram dimension obtained from the measurement data by factor decomposition, and storing the component data obtained by factor decomposition in the storage device; and a step of reading the component data from the storage device and outputting the component data to a display device. Attached Figure Description

[0009] Figure 1 This is a schematic diagram of the chromatographic quality management device according to this embodiment.

[0010] Figure 2 This is a functional block diagram of the chromatography quality management device in this embodiment.

[0011] Figure 3 This is a graph showing the component data obtained by factoring the measurement data.

[0012] Figure 4 This is a graph showing the component data obtained by factoring the measurement data under conditions of linearity degradation.

[0013] Figure 5 This is a graph showing the compositional data obtained by factoring measurement data containing impurities.

[0014] Figure 6 This is a graph showing the composition data obtained by factoring measurement data containing impurities under conditions of deteriorated linearity.

[0015] Figure 7 This is a flowchart illustrating an embodiment of a chromatographic quality management method.

[0016] Figure 8 This is a graph that shows the component data obtained by factoring the measurement data in another display format.

[0017] Figure 9 This is a graph showing the component data obtained by factoring the measurement data in the case of linearity degradation, presented in an alternative display method. Detailed Implementation

[0018] Next, the chromatographic quality management apparatus and method according to embodiments of the present invention will be described with reference to the accompanying drawings.

[0019] (1) Composition of the chromatographic quality management device

[0020] Figure 1 This is a structural diagram of the chromatography quality management device 1 according to the embodiment. The chromatography quality management device 1 of this embodiment acquires measurement data MD of samples obtained in a chromatograph such as a liquid chromatograph or a gas chromatograph. The chromatography quality management device 1 confirms the quality of the chromatography by analyzing the measurement data MD.

[0021] The chromatographic quality management device 1 in this embodiment is, for example, composed of a personal computer. Figure 1 As shown, the chromatography quality management device 1 includes: CPU (Central Processing Unit) 11, RAM (Random Access Memory) 12, ROM (Read Only Memory) 13, operation unit 14, display 15, storage device 16, communication interface (I / F) 17, and device interface (I / F) 18.

[0022] CPU 11 performs overall control of the chromatography quality management device 1. RAM 12 serves as the workspace when CPU 11 executes programs. ROM 13 stores various data, programs, etc. Operation unit 14 receives user input operations. Operation unit 14 includes a keyboard and mouse, etc. Display 15 displays information for confirming the quality of chromatography. Storage device 16 is a storage medium such as a hard disk. Storage device 16 stores program P1, measurement data MD, and component data CD. Program P1 performs processes such as acquiring chromatograms, compressing chromatogram dimensions through factorization to acquire component data CD, and displaying component data CD on display 15. Communication interface 17 is an interface for wired or wireless communication with other computers. Device interface 18 is an interface for accessing storage media 19 such as CDs, DVDs, and semiconductor memories.

[0023] (2) Functional composition of chromatographic quality management device

[0024] Figure 2 This is a block diagram illustrating the functional configuration of the chromatography quality management device 1. Figure 2In this system, the control unit 20 is a functional unit implemented by the CPU 11 using RAM 12 as its working area while simultaneously executing program P1. The control unit 20 includes a measurement data acquisition unit 21, a chromatogram factor decomposition unit 22, and a component data output unit 23. In other words, the measurement data acquisition unit 21, the chromatogram factor decomposition unit 22, and the component data output unit 23 are functional units implemented by executing program P1. In other words, each of the functional units 21 to 23 is a functional unit possessed by the CPU 11.

[0025] The measurement data acquisition unit 21 acquires measurement data MD measured in the chromatograph. The measurement data acquisition unit 21 may input the measurement data MD from another computer or analytical device, for example, via the communication interface 17. Alternatively, the measurement data acquisition unit 21 may input the measurement data MD stored in the storage medium 19 via the device interface 18. The measurement data acquisition unit 21 then stores the acquired measurement data MD in the storage device 16.

[0026] The chromatogram factor decomposition unit 22 reads measurement data MD from the storage device 16, performs dimensional compression on the chromatogram obtained from the measurement data MD through factor decomposition, and saves the component data CD obtained through factor decomposition in the storage device 16.

[0027] The component data output unit 23 reads the component data CD from the storage device 16 and outputs the component data CD to the display 15. The component data output unit 23 displays the component data CD in a manner that allows confirmation of the quality of the chromatogram. The display 15 is an example of a display device in this invention.

[0028] The following description uses the case where program P1 is stored in storage device 16 as an example. Alternatively, program P1 may also be provided stored in storage medium 19. CPU 11 may also access storage medium 19 via device interface 18 to save program P1 stored in storage medium 19 to storage device 16 or ROM 13. Alternatively, CPU 11 may also access storage medium 19 via device interface 18 to execute program P1 stored in storage medium 19. Alternatively, CPU 11 may also download program P1 from a server on the network via communication interface 17 and save the downloaded program P1 to storage device 16 or ROM 13.

[0029] (3) Measurement data

[0030] In this embodiment, the measurement data MD acquired by the measurement data acquisition unit 21 is multidimensional data acquired by a multidimensional detector provided by the chromatograph. Here, we will describe the case where the measurement data MD is 3-dimensional data having retention time direction, spectral direction (frequency direction), and intensity elements as an example. In this case, the measurement data MD is displayed as, for example, matrix data with retention time direction as rows, spectral direction as columns, and intensity as elements. For example, the measurement data MD is data acquired in a liquid chromatograph equipped with a PDA detector (photodiode array detector).

[0031] The chromatogram factorization unit 22 performs factorization on the measurement data MD acquired by the measurement data acquisition unit 21, thereby compressing the dimensionality of the measurement data MD. Here, the dimensionality compression of the measurement data MD, which includes retention time, spectral direction, and intensity elements, along the spectral direction will be explained as an example. The data compressed along the spectral direction in each dimension is called component data CD. For example... Figure 1 As shown, the component data CD contains data in multiple dimensions, such as the first principal component data, the second principal component data, the third principal component data, and so on. In this embodiment, the chromatogram factorization unit 22 performs dimensionality compression using singular value decomposition (SVD). Methods other than SVD dimensionality compression can also be used for factorization. For example, NMF (nonnegative matrix factorization) and ICA (independent component analysis) can be used.

[0032] Figure 3 This is a graph showing the MD of the measurement data, reduced through SVD dimensionality compression. That is, Figure 3 This is a graph showing the component data CD obtained by factoring the measurement data MD. Figure 3 In the diagram, the horizontal axis represents retention time, and the vertical axis represents intensity. Figure 3 This is a graph showing the first to fourth principal components of the component data CD. The spectral components consist of both the baseline and peak signals; therefore, meaningful signals appear in the first and second principal component data, while the third and fourth principal component data contain only noise. Furthermore, in... Figure 3 In the diagram, the data for the first principal component is referenced to the left scale, while the data for the second to fourth principal components are referenced to the right scale. Therefore, the intensity display scales for the first principal component data and the second to fourth principal component data are different.

[0033] Figure 4This is a graph showing the component data CD obtained by factoring the measurement data MD under conditions of linearity degradation. When the linearity degradation originates from stray light or circuitry, the degree of linearity degradation generally varies in relation to the intensity of the chromatogram. Stronger waveforms of the principal component chromatograms appear in the first principal component data, while linearity degradation corresponding to the intensity of the chromatogram waveforms appears in the data from the second principal component data onwards (the nth principal component data).

[0034] In this embodiment, SVD is used as the factorization, therefore, as Figure 4 As shown, in the second principal component data, linearity degradation appears as a W-shaped deformed waveform WR2. Similarly, in the third principal component data, linearity degradation appears as a W-shaped deformed waveform WR3. That is, when the peak shapes in the chromatogram are symmetrical (symmetrical before and after a certain time), the deformation of the waveform originating from linearity degradation also appears symmetrical (symmetrical before and after a certain time) in the nth principal component data.

[0035] Figure 5 This is a graph showing the compositional data CD obtained by factoring the measurement data MD containing impurities without causing linearity degradation. Figure 5 In this case, since no linearity degradation occurred, no deformed waveforms originating from linearity degradation appeared in the second and third principal component data. SVD was used as the factor decomposition in this example, but no waveforms like those observed during linearity degradation were found. Figure 4 The waveform of that W shape is shown.

[0036] In contrast, Figure 5 In the second principal component data, a deformed waveform WD2 originating from impurities appears. Similarly, in the third principal component data, a deformed waveform WD3 originating from impurities appears. The deformed waveforms WD2 and WD3 are deformations originating from impurity peaks, not from linearity degradation. Therefore, in the deformed waveforms WD2 and WD3, there is no... Figure 4 The symmetry seen in the deformed waveforms WR2 and WR3 is shown.

[0037] Figure 6 This is a graph showing the compositional data CD obtained by factoring the measurement data MD containing impurities under conditions of linearity degradation. In the presence of both linearity degradation and impurity peaks, the result is the sum of the distorted waveforms caused by the linearity degradation and the impurity peaks, respectively. That is, in... Figure 6 The appearance of will Figure 4 The symmetrical deformed waveform shown is Figure 5 The waveform obtained by adding the asymmetric deformed waveforms shown. Therefore, as Figure 6As shown, a deformed W-shaped waveform with partial symmetry collapse appears in the nth principal component data.

[0038] (4) Chromatographic quality management methods

[0039] Next, refer to Figure 7 The flowchart illustrates the chromatographic quality management method of this embodiment. Figure 7 The flowchart shows the process implemented by CPU11 executing program P1.

[0040] In step S1, the measurement data acquisition unit 21 acquires the measurement data MD measured by the chromatograph. The measurement data acquisition unit 21 stores the measurement data MD in the storage device 16.

[0041] In step S2, the chromatogram factor decomposition unit 22 reads the measurement data MD from the storage device 16 and performs dimensional compression on the chromatogram obtained from the measurement data MD through factor decomposition.

[0042] In step S3, the chromatogram factorization unit 22 saves the component data CD obtained through factorization to the storage device 16. For example... Figure 1 As shown, the component data CD stored in storage device 16 contains data of multiple dimensions. The chromatogram factor decomposition unit 22, for example, stores the component data CD with a set number of dimensions, such as the data of the first to fourth principal components, in storage device 16. The number of dimensions stored as the component data CD can be set by the user.

[0043] In step S4, the component data output unit 23 reads each component data CD from the storage device 16 and outputs each component data CD to the display 15. As a result, the display 15 displays the following: Figures 3-6 The chart shown is a representation of the component data CD. Specifically, the principal component data from the 1st to the nth component contained in the component data CD are displayed in an overlapping manner aligned on the time axis. At this time, as... Figures 3-6 As shown, the intensity display scale can also be different. For example, by... Figure 3 The graph shown is displayed on monitor 15, allowing the user to confirm that the linearity of the chromatography used to generate the measurement data MD has not deteriorated. For example, by... Figure 4 The graph shown on display 15 allows the user to confirm the degradation of linearity in the chromatography that generated the measurement data MD. For example, by... Figure 5 The chart shown is displayed on monitor 15, allowing the user to confirm that the linearity of the chromatography used to generate measurement data MD has not deteriorated, and that the measurement data MD contains impurities. For example, by... Figure 6 The chart shown on display 15 allows the user to confirm the linearity degradation of the chromatogram that generated the measurement data MD, as well as the presence of impurities in the measurement data MD.

[0044] like Figures 3-6 As shown, in this example, the component data output unit 23 displays the first to fourth principal components from the component data CD on the display 15, but the number of dimensions displayed can be set by the user. The measurement data MD contains two signals: principal components and baseline; therefore, it is preferable to display at least the first and second principal component data. Furthermore, as... Figure 4 As shown, since linearity degradation is easily confirmed in the third principal component data, the third principal component data is also shown to be valid in addition to the first and second principal component data. Furthermore, as... Figure 5 As shown, since it is easy to confirm the presence or absence of impurities in the third principal component data, it is preferable to display the third principal component data in addition to the first and second principal component data.

[0045] In this way, by referring to the component data CD obtained by factoring the measurement data MD, the user can confirm whether linearity degradation has occurred in the chromatography or whether the measurement data MD contains impurities. By using the chromatography quality management device 1 of this embodiment, minute-level linearity degradation that will not be a problem in analytical validation can be confirmed. For example, minute linearity degradation that cannot be detected in the standard curve can be confirmed.

[0046] Furthermore, unlike conventional analytical validation methods that use standard samples to generate standard curves to confirm linearity, the chromatographic quality management device 1 of this embodiment can confirm the linearity of the chromatography using actual measurement data (MD). Therefore, it is also possible to confirm wavelength-dependent linearity degradation.

[0047] (5) Variations

[0048] Figure 8 and Figure 9 This is a diagram showing a modified example of the component data CD displayed on the display 15 by the component data output unit 23. Figure 8 and Figure 9 The graph shows the intensity of the first principal component data on the horizontal axis and the intensity of the nth principal component data on the vertical axis. Figure 8 It will be with Figure 3 The graph shown is a rewritten version of the data for the first through fourth principal components. In other words, it shows the component data CD obtained by factoring the measurement data MD without causing linearity degradation. Figure 9 It will be with Figure 4The graph shown is a modified version of the data from the first to fourth principal components. In other words, it shows the component data CD obtained by factoring the measurement data MD when linearity degradation occurs. As such, the graph shows a straight line shape when linearity degradation is absent, and a curved (bow-shaped) shape when linearity degradation occurs. Even with this display method, linearity degradation can be visually indicated to the user. As another example, the component data output unit 23 can also output a graph generated with the intensity of the first principal component data on the vertical axis and the intensity of the nth principal component data on the horizontal axis.

[0049] Furthermore, as another variation, the component data output unit 23 can also extract the component intensity originating from linearity degradation or the component intensity originating from impurities and display it on the display 15. For example, it can also extract even-function components and odd-function components centered on the peaks of the chromatogram and display representative values ​​of these extracted signal intensities on the display 15. As described above, in the component data CD, linearity degradation has a symmetrical shape, while impurities have an asymmetrical shape. For example, the peak center of the chromatogram is set to time t = 0, and an appropriate peak width W related to the peak width of the chromatogram is set. Then, for the input signal i(t), ∑i(t)*cos(t / w) (-π < t / w < π) can be used as an index of even-function intensity, and ∑i(t)*sin(t / w) (-π < t / w < π) can be used as an index of odd-function intensity and displayed on the display 15. The user can confirm the presence or absence of linearity degradation based on the magnitude of the even-function intensity index. Furthermore, the user can confirm the presence or absence of impurities based on the magnitude of the odd-function intensity index. Alternatively, the component data output unit 23 can display the ratio or difference between the index of even function strength and the index of odd function strength on the display 15. This allows the user to ascertain the presence or absence of linearity degradation and impurities.

[0050] In the above embodiment, the case where the measurement data MD is 3D data acquired from a liquid chromatograph equipped with a PDA detector was described as an example. As another example, the measurement data MD can also be 3D data acquired in the scanning mode of a liquid chromatograph mass analyzer. In this case, the measurement data MD is 3D data of retention time, mass spectrum, and intensity.

[0051] (6) Scheme

[0052] Those skilled in the art will understand that the above-described exemplary embodiments are specific examples of the following scheme.

[0053] (Item 1)

[0054] The chromatographic quality management device of the scheme has:

[0055] The measurement data acquisition unit acquires measurement data measured by the chromatograph and stores the measurement data in a storage device;

[0056] The chromatogram factor decomposition unit reads the measurement data from the storage device, compresses the chromatogram dimensions obtained from the measurement data through factor decomposition, and saves the component data obtained through factor decomposition in the storage device.

[0057] The component data output unit reads the component data from the storage device and outputs the component data to the display device.

[0058] It can evaluate linearity with high precision in chromatography.

[0059] (Item 2)

[0060] In the chromatographic quality management device described in item 1, SVD, NMF, or ICA may also be used as the factor decomposition.

[0061] It is possible to select the factorization method according to the purpose.

[0062] (Item 3)

[0063] In the chromatographic quality management device described in item 1 or item 2, the component data output unit may also output the first principal component data and the second principal component data in the component data to the display device.

[0064] Users can confirm the presence or absence of linearity or impurities by checking the status of the principal components and baseline signals.

[0065] (Item 4)

[0066] In the chromatographic quality management device described in item 3, the component data output unit may further output the third principal component data to the display device.

[0067] Users can confirm the presence or absence of linearity or impurities.

[0068] (Item 5)

[0069] In the chromatographic quality management device described in item 1 or item 2, the component data output unit may output the component data to the display device with the first principal component data as one axis and the data of the second principal component and below as the other axis.

[0070] Users can confirm the presence or absence of linearity or impurities in different ways.

[0071] (Item 6)

[0072] In the chromatographic quality management device described in item 1 or item 2, the component data output unit may also output the even function intensity or odd function intensity of the component data to the display device.

[0073] Users can confirm the presence or absence of linearity or impurities.

[0074] (Item 7)

[0075] In the chromatographic quality management device described in item 1 or item 2, the component data output unit may also output the ratio or difference between the even function intensity and the odd function intensity of the component data to the display device.

[0076] Users can confirm the presence or absence of linearity or impurities.

[0077] (Item 8)

[0078] Other methods for chromatographic quality management include:

[0079] The process of acquiring measurement data measured by a chromatograph and storing the measurement data in a storage device;

[0080] The steps are: reading the measurement data from the storage device, compressing the chromatogram dimension obtained from the measurement data through factor decomposition, and storing the component data obtained through factor decomposition in the storage device.

[0081] The process of reading the component data from the storage device and outputting the component data to the display device.

[0082] It can evaluate linearity with high precision in chromatography.

Claims

1. A chromatographic quality management device, characterized in that, have: The measurement data acquisition unit acquires measurement data of three-dimensional data with retention time direction, spectral direction and intensity elements measured by the chromatograph, and saves the measurement data in a storage device; The chromatogram factorization unit reads the measurement data from the storage device, compresses the measurement data along the spectral direction through factorization, and saves the component data including the first principal component data and the nth principal component data obtained by the factorization in the storage device. The component data output unit reads the component data from the storage device, sets the intensity of the first principal component data as one axis and the intensity of the nth principal component data as the other axis, and outputs a graph of the component data to the display device.

2. The chromatographic quality management device as described in claim 1, characterized in that, Use SVD, NMF, or ICA as the factor decomposition.

3. A chromatographic quality management method, characterized in that, have: The process of acquiring measurement data with three-dimensional data including retention time direction, spectral direction and intensity elements measured by a chromatograph, and storing the measurement data in a storage device; The steps are as follows: reading the measurement data from the storage device, compressing the measurement data along the spectral direction by factorization, and storing the component data including the first principal component data and the nth principal component data obtained by factorization in the storage device. The process of reading the component data from the storage device, using the intensity of the first principal component data as one axis and the intensity of the nth principal component data as the other axis, and outputting a chart of the component data to a display device.

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