Measuring and testing – Liquid analysis or analysis of the suspension of solids in a... – Content or effect of a constituent of a liquid mixture
Reexamination Certificate
1999-07-28
2002-03-12
Williams, Hezron (Department: 2856)
Measuring and testing
Liquid analysis or analysis of the suspension of solids in a...
Content or effect of a constituent of a liquid mixture
C073S061570, C073S023360, C210S198200, C702S032000
Reexamination Certificate
active
06354145
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a method for monitoring a process and more specifically it relates to monitoring flow based separation processes and/or flow analysis processes for analyzing mixtures of components.
TECHNICAL BACKGROUND
Examples of the above processes are; liquid chromatography (LC); gas chromatography (GC), capillary electrophoresis (CE), capillary electrochromatography (CEC), supercritical fluid chromatography (SFC), which are all flow based separation processes, and flow injection analysis (FIA) and continuous flow analysis (CFA), which are flow analysis processes. Such processes are used for analyzing the concentration of different components of mixtures, such as pharmaceuticals. These processes are among other things used for their high degree of accuracy and their ability to disclose low concentrations. On the other hand, these features lead to demands for high stability for the results to be trustworthy. Hence, different methods of monitoring the processes in order to secure the stability and, thus, the accuracy of the results have been developed.
One prior art method is disclosed in U.S. Pat. No. 5,524,084, where the inlet fluid flow of a gas chromatograph is controlled by measuring mass fluid flow, fluid pressure and temperature in the pneumatic manifold of the inlet, that is before the column. By means of the measurements, fluctuating pressure and temperature are compensated for by controlling the fluid flow, thereby to achieve as constant conditions for the chromatography process as possible.
A rising pressure may indicate an obstruction of the injector, the precolumn, the column, or a fluid tube connected thereto. Such an obstruction could cause many other problems not solved by merely compensating for the increase of the pressure as is done in this prior art. By using this prior art method, there is an apparent risk for causing damage to the system because of a lack of investigation of the cause for the pressure increase. Further, merely compensating for temperature and pressure fluctuations on the inlet side of the system does not cover all states that may arise in the process. Thus, there is still no guarantee that the result remains stable and accurate. Therefore, it is often used in combination with a stability check. This check is performed by running a standard, i.e. a known substance giving a known result, through the system consecutive to a substance to be analyzed. If, for example, a series of 20 samples is to be analyzed, usually one standard is run for every three samples. This is time consuming and involves excessive costs.
Another prior art method is disclosed in a paper entitled Intelligent Instrumentation: Application to On-Line Gas and Liquid Process Chromatography, published in Laboratory Information Management, Vol. 17, No. 2, pp 201-211, November 1992, by C. L. Guillemin. This method analyses the result of the process, i.e. the chromatogram, where each peak corresponds to a different substance and where the area encompassed by the peak corresponds to the concentration. In order to be able to correctly interpret the amounts, a deferred standard concept is used. This means that a standard having a known and relatively long passage time through the column is injected into the system just after the sample is injected and used as a reference. Thereby fluctuations of the peak of the standard are used for adjusting the whole chromatogram accordingly.
This method suffers from the delayed detection of an error, which is not detected until the process is finished and the chromatogram analysis has been performed. Further, a drift of the system, specifically a flat one, is difficult or impossible to detect but may in the long run be detrimental to the performance of the system.
The above described prior art methods could of course be combined in order to improve the stability monitoring. However, there would still be a major drawback of such a combined method as well as of the separate methods what is a difficulty to detect several different types of errors and also to trace the cause of an error and determine what part of the system causes the error.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a method for monitoring flow based analytical separation processes and/or flow analysis processes that facilitates error tracing and makes it possible to detect an error occurrence during an ongoing process.
The object is achieved by a method set out in claim
1
comprising the steps of:
obtaining measurement signals by measuring process conditions at a plurality of positions throughout the system;
applying signal processing to the measurement signals, said signal processing comprising multivariate data analysis for condensing the plurality of measurement signals to a smaller number of main signals being non-correlated;
logging said main signals; and
displaying said main signals versus time, where changes of said system conditions are indicated by one or more of the displayed main signals.
The method of this invention significantly facilitates the tracing of errors affecting the system stability and giving rise to unusable results of the analyses. Further, by monitoring the system at several vital positions, and thereby substantially improving the robustness and reliability of the analysis, the need for using standards as system calibrators is dramatically reduced. Thus, time that so far has been occupied by handling standards is released for mixture analysis.
The method of this invention is carried out by an apparatus according to claim
7
, whereby the apparatus comprises:
means for measuring process conditions at a plurality of positions throughout the system; and
means for processing signals from said measuring means, said signal processing means comprising multivariate data analysis for condensing the plurality of measurement signals to a smaller number of main signals being non-correlated; and
means for logging said main signals; and
means for displaying said main signals versus time, where changes of said process conditions are indicated by one or more of the displayed main signals.
Further aspects and advantages of the present invention will become apparent from the dependent claims and by the following detailed description, taken in conjunction with the accompanying drawings.
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Guillemin, C. L. Laboratory Information Management, 17(1992) 201-211.
Nomikos, P. MacGregor, J. F. Technometrics, Feb. 1995, vol. 37, No. 1, 41-59.
Fransson Magnus
Karlsson Lars
Lagerholm Bengt
Sparen Anders
AstraZeneca AB
White & Case LLP
Wiggins David J.
Williams Hezron
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