Quality Control of Pharmaceutical Drugs - Turning Analysis and Performance Data Into Comprehensible Charts
Quality Control of Pharmaceutical Drugs - Turning Analysis and Performance Data Into Comprehensible Charts
Application Note
Pharmaceutical Udo Huber
Abstract
Agilent ChemStore C/S, the database module of Agilent ChemStation Plus, offers a solution to evaluate, organize, manage and report chromatographic results imported automatically from LC, LC/MSD, CE, GC and A/D systems. In this application note we describe how Agilent ChemStation Plus helps turn chemical analysis data and peak and instrument performance data into clear and comprehensible results for a typical task of a pharmaceutical companyquality control of instruments and products.
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Introduction
Quality Control (QC) is an important task in the pharmaceutical industry. It not only protects the manufacturer against compensation claims, but also guarantees the patient a safe and effective product. QC measurements include stability testing of the drug formulation, dissolution testing1 and analysis of raw materials and synthesis products. A pharmaceutical company usually has to measure a large number of QC samples. They need to be evaluated and reviewed, and the data must be safely stored for quality and regulatory compliance. Furthermore, instrument performance has to be monitored to avoid erroneous results caused by column aging, for example. In this application note we demonstrate 1,2,3 how Agilent ChemStation Plus1 in combination with the Agilent 1100 Series HPLC system can help increase lab productivity by turning chemical analysis data into clear and easily understandable charts.
Equipment
The system consisted of an Agilent 1100 Series quaternary pump, an Agilent 1100 Series autosampler, an Agilent 1100 Series thermostatted column compartment and an Agilent 1100 Series variable wavelength detector. It was controlled using the Agilent ChemStation (version A.06.04) software. Data was stored using the Agilent ChemStation Plus database client software (version B.01.01). Extended Performance was set up as report style in the Specify Report window and the settings were saved with the method. The chromatographic conditions are listed below.
Column: Mobile phase: Gradient: Zorbax SB-C18 4.6 x 75 mm, 3.5 m A = 0.025 M KH2PO4 in water, pH=3 (H2SO4) B = acetonitrile at 0 min 10 % B at 10 min 30 % B at 11 min 10 % B 1 ml/min 11 min 5 min
Flow rate: Stop time: Post time: Column temperature: 40 C Injection volume: 5 l UV detector: variable wavelength detector 204 nm, standard cell
If, for example, column performance decreases the tailing factor increases. The column can now be replaced before a complete column breakdown occurs. This helps prevent instrument downtime. For these reasons the following parameters are monitored over a certain period of time: Analysis results containing lower and upper limits for the amounts of the two compounds. Analysis results for the control samples with mean value and relative standard deviations. Performance results for analyses such as peak performance parameters, tailing factor and selectivity. These results are used to monitor the system and the column to ensure they are working properly. Instrument parameters, for example, pump pressure. Instrument parameters are monitored to make sure the system is working properly. If the pump pressure increases, it may be necessary to exchange the PTFE frit in the purge valve.
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To check the performance of the analysis the next two charts are generated for the control samples (figures 2a and 2b). For the control charts the control sample amount is displayed against the measurement date. The center line is the mean value of the measurements. The lower and upper warning limit is the mean value 2 s, which is twice the relative standard deviation. The upper and lower critical limits are 3 s. These limits are again given by the QC requirements of the company.
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The symmetry of a peak should be around one. For a tailing peak it is higher than one, for a fronting peak it is lower than one. An unsymmetrical peak can indicate bad column performance. Figures 3a and 3b show the symmetry of the two peaks in the analysis Figure 3a shows that the symmetry factor for the sulfamthoxazole peak is around 0.75. The peak is fronting but the values are relatively constant over the monitored time period. The symmetry factor for trimethoprim shown in figure 3b is around 1.05, which means the peak is slightly tailing. Some values are beyond the warning limit of 1.15. The warning and critical limits are compound specific fixed values.
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The tailing factor also describes the symmetry of a peak. It can be calculated by a formula given by the USP. Figures 4a and 4b show the tailing factors of the two peaks in the analysis. The tailing factors of sulfamethoxazole and trimethoprim are about 1.3 and 1.1, which means the peaks are only slightly tailing. An absolutely symmetrical peak would have a tailing factor of 1. The warning and critical limits are fixed values given by the QC requirements of the company.
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The resolution describes how well two compounds are separated from each other. Figure 5 shows the resolution at the peak halfwidth of sulfamethoxazole. Another parameter for the separation of the peaks is selectivity. Figure 6 shows the selectivity of sulfamethoxazole. The selectivity for sulfamethoxazole is about 1.9. If it falls below a certain value (1.85 in figure 6), this may indicate that column performance is decreasing.
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Instrument parameters
The instrument parameters should be in a certain range over all analyses to make sure that no instrument errors lead to wrong analysis results. Instrument parameters selected for instrument performance control are: pump pressure pump flow column temperature Figure 7 shows the pump pressure for each analysis. An increasing pump pressure may indicate that a filter, for example, the PTFE frit in the purge valve, the solvent inlet filter or the frit of the column needs to be cleaned or replaced. Another instrument performance parameter is the pump flow as shown in figure 8. A decreasing or increasing pump flow could indicate a defective pump. Figure 8 shows that the pump flow for the Agilent 1100 Series quaternary pump is very stable.
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The last monitored instrument parameter was column temperature. Column temperature has an influence on other instrument parameters, for example, pressure, and analysis parameters, such as retention time or peak width. Although the Agilent 1100 Series thermostatted column compartment provides an excellent temperature stability it is always recommended to monitor this parameter to prevent erroneous analysis results (figure 9).
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Conclusion
In combination with the Agilent 1100 Series the Agilent ChemStation Plus is an optimal tool for QC measurements for the pharmaceutical industry. It allows simultaneous monitoring of the analysis results and instrument performance during an analysis, without tedious and error-prone manual result transfer to a spreadsheet application. With Extended Performance set up as Report in the Agilent ChemStation Plus, it is no longer necessary to change the method or perform multiple runs to get all results. The results are displayed in a clear format as tables or charts, which can be either copied to other Microsoft Windows applications or can be implemented into customized reports. The results can be stored safely and are always traceable which is a big advantage in case of an audit.
Literature
1 Drive down costs and raise productivity Agilent Technologies Brochure Brief, 1999, publication number 5968-4782E 2 Agilent ChemStation Plus Agilent Technologies Specifications, 1999, publication number 5968-4782E 3 From data to decisions Agilent Technologies CD-ROM, 1998, publication number 5968-1713E
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Copyright 1999 Agilent Technologies All Rights Reserved. Reproduction, adaptation or translation without prior written permission is prohibited, except as allowed under the copyright laws. Publication Number 5968-7570E
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