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Ch01 qxd 7 12 04 11 15 AM Page 2,2 Pharmaceutical analysis. required but in carrying out an analysis one also has to be certain that the quality of. the analysis itself is of the standard required Quality control is integral to all. modern industrial processes and the pharmaceutical industry is no exception. Testing a pharmaceutical product involves chemical physical and sometimes. microbiological analyses It has been estimated that 10 billion is spent each year. on analyses in the UK alone and such analytical processes can be found in. industries as diverse as those producing food beverages cosmetics detergents. metals paints water agrochemicals biotechnological products and pharmaceuticals. With such large amounts of money being spent on analytical quality control great. importance must be placed on providing accurate and precise analyses Thus it is. appropriate to begin a book on the topic of pharmaceutical analysis by considering. at a basic level the criteria which are used to judge the quality of an analysis. The terms used in defining analytical quality form a rather elegant vocabulary that. can be used to describe quality in many fields and in writing this book the author. would hope to describe each topic under consideration with accuracy precision and. most importantly reproducibility so that the information included in it can be. readily assimilated and reproduced where required by the reader The following. sections provide an introduction to the control of analytical quality More detailed. treatment of the topic is given in the reference cited at the end of the chapter 1. Box 1 2 ICH guidelines, The requirements for control of the quality of methods of analysis validation have. been addressed by the International Conference on Harmonisation of Technical. Requirements For Registration of Pharmaceuticals for Human Use or more briefly. the ICH www ich org The ICH was initiated in Brussels in 1990 and brought. together representatives of regulatory agencies and industry associations of Europe. Japan and the USA The purpose of the organisation was to standardise the. requirements for medicines regulation throughout the world The standardisation of the. validation of analytical procedures is one area that the ICH has addressed The ICH. indicated that the most important analytical procedures that require validation are. Identification tests,Quantitative tests for impurities. Limit tests for the control of impurities, Quantitative tests of the active moiety in samples of drug substance or drug product. or other selected component s in the drug product,Control of errors in analysis.

A quantitative analysis is not a great deal of use unless there is some estimation. of how prone to error the analytical procedure is Simply accepting the analytical. result could lead to rejection or acceptance of a product on the basis of a faulty. analysis For this reason it is usual to make several repeat measurements of the same. sample in order to determine the degree of agreement between them There are three. types of errors which may occur in the course of an analysis gross systematic and. random Gross errors are easily recognised since they involve a major breakdown in. the analytical process such as samples being spilt wrong dilutions being prepared or. instruments breaking down or being used in the wrong way If a gross error occurs. the results are rejected and the analysis is repeated from the beginning Random and. systematic errors can be distinguished in the following example. Ch01 qxd 7 12 04 11 15 AM Page 3,Control of the quality of analytical methods 3. A batch of paracetamol tablets are stated to contain 500 mg of paracetamol per. tablet for the purpose of this example it is presumed that 100 of the stated content. is the correct answer Four students carry out a spectrophotometric analysis of an. extract from the tablets and obtain the following percentages of stated content for. the repeat analysis of paracetamol in the tablets,Student 1 99 5 99 9 100 2 99 4 100 5. Student 2 95 6 96 1 95 2 95 1 96 1,Student 3 93 5 98 3 92 5 102 5 97 6. Student 4 94 4 100 2 104 5 97 4 102 1, The means of these results can be simply calculated according to the formula. x Equation 1, Where x is the arithmetic mean xi is the individual value and n is the number of.

measurements, These results can be seen diagrammatically in Figure 1 1. Student 1 has obtained a set of results which are all clustered close to 100 of the. stated content and with a mean for the five measurements very close to the correct. answer In this case the measurements made were both precise and accurate and. obviously the steps in the assay have been controlled very carefully. Student 2 has obtained a set of results which are closely clustered but give a mean. which is less than the correct answer Thus although this assay is precise it is not. completely accurate Such a set of results indicates that the analyst has not. produced random errors which would produce a large scatter in the results but has. produced an analysis containing a systematic error Such errors might include. repeated inaccuracy in the measurement of a volume or failure to zero the. spectrophotometer correctly prior to taking the set of readings The analysis has. been mainly well controlled except for probably one step which has caused the. inaccuracy and thus the assay is precisely inaccurate. Fig 1 1 mean,Diagrammatic,representation of Student 1 Precise. accuracy and precision and accurate,for analysis of. paracetamol in tablet mean,Student 2 Precise,and inaccurate. Student 3 Imprecise,and inaccurate,Student 4 Imprecise.

and accurate,90 95 100 105,Paracetamol of stated content. Ch01 qxd 7 12 04 11 15 AM Page 4,4 Pharmaceutical analysis. Student 3 has obtained a set of results which are widely scattered and hence. imprecise and which give a mean which is less than the correct answer Thus the. analysis contains random errors or possibly looking at the spread of the results. three defined errors which have been produced randomly The analysis was thus. poorly controlled and it would require more work than that required in the case of. student 2 to eliminate the errors In such a simple analysis the random results might. simply be produced by for instance a poor pipetting technique where volumes. both higher and lower than that required were measured. Student 4 has obtained a set of results which are widely scattered yet a mean which. is close to the correct answer It is probably only chance that separates the results of. student 4 from those of student 3 and although the answer obtained is accurate. it would not be wise to trust it to always be so, The best assay was carried out by student 1 and student 2 produced an assay. which might be improved with a little work, In practice it might be rather difficult to tell whether student 1 or student 2 had. carried out the best analysis since it is rare unless the sample is a pure analytical. standard that the exact content of a sample is known In order to determine whether. student 1 or 2 had carried out the best assay it might be necessary to get other. analysts to obtain similar sets of precise results in order to be absolutely sure of the. correct answer The factors leading to imprecision and inaccuracy in assay results. are outlined in Box 1 3, Box 1 3 Some factors giving rise to imprecision and inaccuracy in.

Incorrect weighing and transfer of analytes and standards. Inefficient extraction of the analyte from a matrix e g tablets. Incorrect use of pipettes burettes or volumetric flasks for volume. measurement, Measurement carried out using improperly calibrated instrumentation. Failure to use an analytical blank, Selection of assay conditions that cause degradation of the analyte. Failure to allow for or to remove interference by excipients in the. measurement of an analyte,Self test 1 1, Suggest how the following might give rise to errors in an analytical procedure. i Analysis of a sucrose based elixir using a pipette to measure aliquots of the elixir for. ii Weighing out 2 mg of an analytical standard on a four place analytical balance which. weighs a minimum of 0 1 mg, iii Use of an analytical standard that absorbs moisture from the atmosphere. iv Incomplete powdering of coated tablets prior to extraction. v Extraction of an ointment with a solvent in which it is poorly soluble. vi Use of a burette that has not been rinsed free of traces of grease. of the analyte vi Distortion of meniscus making reading of the burette inaccurate. of moisture absorption is uncertain iv Poor recovery of the analyte v Poor recovery. there is an uncertainty of 0 05 mg which in relation to 2 mg is 2 5 iii The degree. Answers i Viscosity leads to incomplete drainage of the pipette ii In any weighing. Ch01 qxd 7 12 04 11 15 AM Page 5,Control of the quality of analytical methods 5.

Accuracy and precision, The most fundamental requirements of an analysis are that it should be accurate and. precise It is presumed although it cannot be proven that a series of measurements. y of the same sample will be normally distributed about a mean i e they fall. into a Gaussian pattern as shown in Figure 1 2, The distance shown in Figure 1 2 appears to be nearly 0 5 of the width of. distribution however because the function of the curve is exponential it tends to. zero and does not actually meet the x axis until infinity where there is an. infinitesimal probability that there may be a value for x For practical purposes. approximately 68 of a series of measurements should fall within the distance. either side of the mean and 95 of the measurements should lie with 2 of the. mean The aim in an analysis is to make as small a percentage of the value of as. possible The value of can be estimated using the Equation 2. Equation 2,s standard deviation,n number of samples. xi values obtained for each measurement,x mean of the measurements. Sometimes n rather than n 1 is used in the equation but particularly for small. samples it tends to produce an underestimate of For a small number of values it. is simple to work out s using a calculator and the above equation Most calculators. have a function which enables calculation of s directly and on calculators. estimated using the above equation is usually labelled as n 1 For instance if the. example of results obtained by student 1 where the mean is calculated to be 99 9. are substituted into equation 2 the following calculation results. 99 5 99 9 2 99 9 99 9 2 100 2 99 9 2 99 4 99 9 2 100 5 99 9 2. 0 4 2 0 2 0 3 2 0 5 2 0 6 2,0 16 0 0 09 0 25 0 36 0 86.

0 215 0 46,s 0 46 of stated content,The Gaussian,distribution. Ch01 qxd 7 12 04 11 15 AM Page 6,6 Pharmaceutical analysis. The calculated value for s provides a formal expression of the scatter in the. results from the analysis rather than the visual judgement used in Figure 1 1 From. the figure obtained for the standard deviation SD we can say that 68 of the. results of the analysis will lie within the range 99 9 0 46 or within the. range 99 44 100 36 If we re examine the figures obtained by student 1 it can be. seen that 60 of the results fall within this range with two outside the range. including one only very slightly below the range The range based on defines. the 68 confidence limits for 95 confidence 2 must be used i e 95 of the. results of student 1 lie within 99 9 0 92 or 98 98 100 82 It can be seen that. this range includes all the results obtained by student 1. The precision of an analysis is often expressed as the relative standard. deviation RSD Equation 3,RSD 100 Equation 3, The confidence limits in this case are often not quoted but since it is the SD. that is an estimate of which is being used they are usually 68 The advantage. of expressing precision in this way is that it eliminates any units and expresses the. precision as a percentage of the mean The results obtained from the assay of. paracetamol tablets are shown in Table 1 1, Table 1 1 Results obtained for the analysis of paracetamol tablets by four analysts. Mean of stated S of stated,Student content content RSD 68 confidence.

1 99 9 0 5 0 5,2 95 6 0 5 0 5,3 96 9 4 0 4 4,4 99 7 4 0 4 0. Self test 1 2, Four analysts obtain the following data for a spectrophotometric analysis of an injection. containing the local anaesthetic bupivacaine The stated content of the injection is 0 25. weight in volume w v, Analyst 1 0 245 w v 0 234 w v 0 263 w v 0 261 w v 0 233 w v. Analyst 2 0 236 w v 0 268 w v 0 247 w v 0 275 w v 0 285 w v. Analyst 3 0 248 w v 0 247 w v 0 248 w v 0 249 w v 0 253 w v. Analyst 4 0 230 w v 0 233 w v 0 227 w v 0 230 w v 0 229 w v. Calculate the mean percentage of stated content and RSD for each set of results at the. 68 confidence level Assuming the content really is as stated on the label comment on. the accuracy and precision of each set of results Calculate the precision of each assay with. regard to 95 confidence limits, Analyst 4 91 9 0 9 inaccurate and precise At 95 confidence RSD 1 8. 15 4 Analyst 3 99 6 0 9 accurate and precise At 95 confidence RSD 1 8. 11 6 Analyst 2 104 9 7 7 inaccurate and imprecise At 95 confidence RSD. Answers Analyst 1 98 9 5 8 accurate but imprecise At 95 confidence RSD. Ch01 qxd 7 12 04 11 15 AM Page 7,Control of the quality of analytical methods 7.

Control of the quality of analytical methods Introduction Control of errors in analysis Accuracy and precision Validation of analytical procedures The analytical procedure Precision Repeatability Intermediate precision Reproducibility Accuracy Standard operating procedure SOP for the assay of paracetamol tablets Compound random errors Reporting of results Other terms used in the control of

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