Quality Control of Pharmaceutical Drugs-Turning Analysis Performance Data into Comprehensible Charts Application Note
Contents
1. Upper warning line Symmetry Trimethoprim Lower warning line Symmetry Trimethoprim Lower critical line Symmetry Trimethoprim 0 9 0 8 0 7 May 20 May 22 May 24 May 26 May 28 May 30 Jun 01 Jun 03 Date Figure 3b Peak symmetry of trimethoprim peak 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 sulfa methoxazole 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 lim its are fixed values given by the QC requirements of the company 21 May 99 to 03 Jun 99 Tailing Factor for Sulfamethoxazole Tail Factor Date Sulfamethoxazole Upper critical line Tail Factor Sulfamethoxazole Upper warning line Tail Factor Sulfamethoxazole 1 6 15 1 4 8 8 3 z 8 8 8 6 6 e 1 3 t2 di 10 0 9 May 20 May 24 May 26 May 28 May 30 Jun 01 Jun 03 Date Figure 4a Tailing factor of sulfamethoxazole peak Tailing Factor for Trimethoprim 21 May 99 to 03 Jun 99 Tail Factor Date Trimethoprim Upper critical line Tail Factor Trimethoprim Upper warning line Tail Factor Trimethoprim 1 3 12 Ii 1 0 0 9 0 8 0 7 May 20 May 24 May 26 May 28 May 30 Jun 012. Although the Agilent 1100 Series thermostatted column compart ment provides an excellent tem perature stability it is always rec ommended to monitor this para meter to prevent erroneous analy sis results figure 9 Temperatur C Temperature 21 May 99 to 03 Jun 99 Start Left Temp Date 40 1 40 0 39 9 39 8 May 20 May 22 May 24 May 26 May 28 May 30 Jun 01 Jun 03 Figure 9 Column temperature 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 Chem Station 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 Win dows 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 publ
3. Jun 03 Date Figure 4b Tailing factor of trimethoprim peak 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 separa tion of the peaks is selectivity Figure 6 shows the selectivity of sulfamethoxazole The selectivity for sulfamethoxa zole is about 1 9 If it falls below a certain value 1 85 in figure 6 this may indicate that column per formance is decreasing Resolution hw for Sulfamethoxazole 21 May 99 to 03 Jun 99 Resol hw Date Sulfamethoxazole Upper critical line Resol hw Sulfamethoxazole Upper warning line Resol hw Sulfamethoxazole Lower warning line Resol hw Sulfamethoxazole Lower critical line Resol hw Sulfamethoxazole 24 0 22 0 20 0 30 6 amp o e e o o 8B e 16 0 14 0 12 0 10 0 May 20 May 22 May 24 May 26 May 28 May 30 Jun 01 Jun 03 Date Figure 5 Resolution of sulfamethoxazole peak Selectivity for Sulfamethoxazole 21 May 99 to 03 Jun 99 Selectivity Date Sulfamethoxazole Lower warning line Selectivity Sulfamethoxazole Lower critical line Selectivity Sulfamethoxazole 2 0 1 9 8 8 d 8 8 e 8 8 i 8 8 ry 8 1 8 et May 20 May 22 May 24 May 26 May 28 May 30 Jun 01 Jun 03 Date Figure 6 Selectivity of sulfamethoxazole peak Instrument parameters The instrumen
4. Pharmaceutical Haco OCH Quality control of pharmaceutical drugs Turning analysis and performance data into comprehensible charts Application Note Udo Huber Dextromethorphan Abstract Agilent ChemStore C S the database module of Agilent ChemStation Plus offers a solution to evaluate organize manage and report chro matographic 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 company dquality control of instru ments and products Agilent Technologies Po oe Innovating the HP Way Introduction Quality Control QC is an impor tant task in the pharmaceutical industry It not only protects the manufacturer against compensa tion claims but also guarantees the patient a safe and effective product QC measurements include stability testing of the drug formulation dissolution test ing and analysis of raw materials and synthesis products A pharmaceutical company usual ly 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 perfor mance has to be monitored to avoid erroneous results caused by column aging for example In th
5. ication 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 Udo Huber is an Application Chemist based at Agilent Technologies Waldbronn Germany For the latest information and services visit our world wide web site http www agilent com chem Windows is a registered trademark of Microsoft Corporation The information in this publication is subject to change without notice 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 Agilent Technologies Innovating the HP Way
6. ilent 1100 Series autosampler an Agilent 1100 Series thermostatted column com partment and an Agilent 1100 Series variable wavelength detec tor It was controlled using the Agilent ChemStation version A 06 04 software Data was stored using the Agilent ChemSta tion Plus database client software version B 01 01 Extended Per formance was set up as report style in the Specify Report win dow and the settings were saved with the method The chromatographic conditions are listed below Column Zorbax SB C18 4 6 x 75 mm 3 5 ym Mobile phase A 0 025 M KH PO in water pH 3 H SO B acetonitrile Gradient at 0 min 10 B at 10 min 30 B at 11 min 10 B Flow rate 1 ml min Stop time 11 min Post time 5 min Column temperature 40 C Injection volume 5 pl UV detector variable wavelength detector 204 nm standard cell Results and Discussion Model scenario A pharmaceutical company pro duces a cystits tablet containing sulfamethoxazole and trimetho prim Five batches are produced daily and sent to the analytical lab for QC analysis with the Agilent 1100 Series HPLC system con trolled by the Agilent ChemStation Plus Sample Type is set to Sam ple in the Sequence Table of the Agilent ChemStation Plus In addi tion to the five samples a control measurement with a standard is performed every day It is set up as Control Sample in the sequence table The measured data are transferred automaticall
7. is application note we demonstrate how Agilent ChemStation Plus1 in combination with the Agilent 1100 Series HPLC system can help increase lab productivity by turn ing chemical analysis data into clear and easily understandable charts Agilent ChemStation Plus QC measurements generate a large amount of chemical data To receive clear and understandable reports or charts analysts have to manually transfer the results of the collected data to a spread sheet application This is a slow tedious and error prone process Agilent ChemStation Plus pro vides the capability to transfer manage and report the QC data automatically and error free Fur thermore it provides secure data storage and a consistent link between analytical method raw data and final results Therefore it is easy to show auditors how the results were generated Other features include e Review of the retrieved data online to inspect analysis results The results can be approved or rejected and sent back to the Agilent ChemStation Plus e Data is organized by setting up studies containing custom fields which map the studies structure to the results e Data sets can be retrieved quickly and easily using an intuitive query function e Summary or regression statistics can be performed on the analytical data The results can be displayed in tables or charts Equipment The system consisted of an Agilent 1100 Series quaternary pump an Ag
8. me e Analysis results containing lower and upper limits for the amounts of the two compounds e Analysis results for the control samples with mean value and relative standard deviations e 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 e 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 Presentation of analysis results To perform the analysis of the QC measurements the results are loaded into the Agilent Chem Station Plus by a query including the whole study To separate the samples from the control samples two filters are created The filter condition of the first filter is set to Sample in the result field Sam ple Type and for the second filter it is set to Control Sample By turning on the appropriate filter it is easy to analyze the results for either the samples or the control samples respectively The charts shown in figures la and 1b are generated for the two active compounds in Chart Lay out of the Compound view The compound amounts are shown on the y axis Upper and lower warning lines and critical lines are also displayed for easy control The limits are fixed val ue
9. nalysis the following peak performance parameters are dis played in charts e peak symmetry e tailing factor e resolution e selectivity 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 symme try factor for the sulfamthoxazole peak is around 0 75 The peak is fronting but the values are rela tively constant over the moni tored 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 warn ing limit of 1 15 The warning and critical limits are compound spe cific fixed values Peak Symmetry for Sulfamethoxazole 21 May 99 to 03 Jun 99 Symmetry Date Sulfamethoxazole Upper critical line Symmetry Sulfamethoxazole Upper warning line Symmetry Sulfamethoxazole Lower warning line Symmetry Sulfamethoxazole Lower critical line Symmetry Sulfamethoxazole 0 8 e 8 s 2 SP Peet ae ea Pe 0 7 May 20 May 22 May 24 May 26 May 28 May 30 Jun 01 Jun 03 Date Figure 3a Peak symmetry of sulfamethoxazole peak Peak Symmetry for Trimethoprim 21 May 99 to 03 Jun 99 Symmetry Date Trimethoprim Upper critical line Symmetry Trimethoprim
10. s given by the QC requirements On May 25 for example the amount of trimethoprim almost reached the upper warning limit of 45 mg l For the x axis the time axis a custom field Date in the format Date Time was used Other time fields such as Injec tion Time could also have been used QC Chart of Sulfamethoxazole 21 May 99 to 03 Jun 99 gt Amount Date Sulfamethoxazole Upper critical line Amount Sulfamethoxazole Upper warning line Amount Sulfamethoxazole Lower warning line Amount Sulfamethoxazole ___ Lower critical line Amount Sulfamethoxazole Amount mg l 80 70 e e e ry ry e e 8 s e e a 9 0 0 y is ige g amp 8 50 40 30 May 21 May 23 May 25 May 27 May 29 May 31 Jun 02 Jun 04 Date Figure 1a Amount of sulfamethoxazole daily analysis results for five batches QC Chart of Trimethoprim 21 May 99 to 03 Jun 99 Amount Date Trimethoprim Upper critical line Amount Trimethoprim Upper warning line Amount Trimethoprim Lower warning line Amount Trimethoprim Lower critical line Amount Trimethoprim Amount mg l 60 50 40 30 20 10 May 21 May 23 May 25 May 27 May 29 May 31 Jun 02 Jun 04 Date Figure 1b Amount of trimethoprim daily analysis results for five batches To check the performance of the analysis the next two charts are generated for the control samples figures 2a and 2b For the control chart
11. s 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 o which is twice the relative standard deviation The upper and lower critical lim its are 3 o These limits are again given by the QC require ments of the company Control Samples Sulfamethoxazole 21 May 99 to 03 Jun 99 Amount Date Sulfamethoxazole Upper critical line Amount Sulfamethoxazole Upper warning line Amount Sulfamethoxazole Center line Amount Sulfamethoxazole Lower warning line Amount Sulfamethoxazole Lower critical line Amount Sulfamethoxazole Amount mg l 150 140 130 iF e eo eo e 120 us z 110 100 May 21 May 23 May 25 May 27 May 29 May 31 Jun 02 Jun 04 Date Figure 2a Amount of sulfamethoxazole control samples Control Samples Trimethoprim 21 May 99 to 03 Jun 99 Amount Date Trimethoprim Upper critical line Amount Trimethoprim Upper warning line Amount Trimethoprim Center line Amount Trimethoprim Lower warning line Amount Trimethoprim _ Lower critical line Amount Trimethoprim Amount mg l 100 90 80 70 60 50 May 21 May 23 May 25 May 27 May 29 May 31 Jun 02 Jun 04 Date Figure 2b Amount of trimethoprim control samples Peak performance results For the performance results of the a
12. t parameters should be in a certain range over all analyses to make sure that no instrument errors lead to wrong analysis results Instrument para meters selected for instrument performance control are e pump pressure e pump flow e column temperature Figure 7 shows the pump pres sure 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 Pump Pressure 21 May 99 to 03 Jun 99 e Start Pump Press Date Pressure bar 70 69 68 67 66 65 64 os de gs 8 oi 8b 8 eb ge eg eC 62 61 60 May 20 May 22 May 24 May 26 May 28 May 30 Jun 01 Jun 03 Date Figure 7 Pump pressure Pump Flow 21 May 99 to 03 Jun 99 A Start Pump Flow Date Pump Flow ml min va 0 9 May 20 Figure 8 Pump flow May 22 May 24 May 26 May 28 Date May 30 Jun 01 Jun 03 The last monitored instrument parameter was column tempera ture Column temperature has an influ ence on other instrument para meters for example pressure and analysis parameters such as retention time or peak width
13. y to the Agilent ChemStation Plus to manage report and store them securely Monitoring analysis results and analysis performance parameters The chemist in the analytical lab performs measurements and sends the result to the supervisor If a result is beyond the QC limits the analyst has to find the reason for the erroneous result This can either be a process problem or an analytical problem such as low instrument performance or column aging To minimize the second possibility it is very help ful to monitor analysis and instru ment performance parameters over a certain period of time If for example an analysis result is beyond the QC limits but all instrument and analysis perfor mance parameters for the same measurement are within the specified ranges it is very likely that a low quality synthesis product is the reason for the measurement If the analysis results and the performance para meters are beyond the limits the problem is probably caused by the instrument or the column Another advantage of monitoring analysis results analysis perfor mance and instrument perfor mance parameters offers is the possibility to recognize trends If for example column perfor mance decreases the tailing factor increases The column can now be replaced before a complete column breakdown occurs This helps prevent instrument down time For these reasons the following parameters are monitored over a certain period of ti
Download Pdf Manuals
Related Search
Quality Control of Pharmaceutical Drugs Turning Analysis Performance Data into Comprehensible Charts