Shewart charts

The validation process begun in Phase I is extended during Phase II. In this phase, selectivity is investigated using various batches of drugs, available impurities, excipients, and samples from stability studies. Accuracy should be determined using at least three levels of concentration, and the intermediate precision and the quantitation limit should be tested. For quality assurance evaluation of the analysis results, control charts can be used, such as the Shewart-charts, the R-charts, or the Cusum-charts. In this phase, the analytical method is refined for routine use. 

It is often helpful to record the results of control samples in a visible manner not only because of the greater impact of a visual display but also for the relative ease with which it is possible to forecast trends. A variety of styles of quality control charts have been suggested but the most commonly used are those known as Levey-Jennings or Shewart charts, which indicate the scatter of the individual control results about the designated mean value (Procedure 1.7). 

Apart from the standard Shewart charts, the analyst can also apply X-charts, on which the mean of several replicate measurements is plotted, or R-charts, where the difference between two replicate measurements is plotted. X- and R-charts give an indication of the reproducibility of the method. Drift in analytical procedure, for example, slows changes in the system caused by the aging of parts of instruments, decalibration in wavelength, or the aging of calibration stock solutions, can be detected early when a Cusum chart (cumulative sum) is applied. In Cusum charts, the analyst reports the cumulative sum of the differences between delivered and reference values. If this reference value is certified (CRM), the Cusum chart allows the accuracy of the determination to be monitored. 

Statistical data can be employed to construct control charts (Shewart charts) which provide action limits and warning limits for values of mean and standard deviation. Charts can be used for measurement of variability (size, volume, hardness, etc.) or attributes (good/bad or acceptable/rejectable). Values calculated from routine samples are plotted onto the relevant chart, and provided the results fall within the acceptance area, manufacture can continue until the next sample is called for. 

Figure 2 Typical example of a Shewart control chart of the 3-pM point of the 2,3,7,8-tetrachlorodibenzo-/7-dioxin...

The use of Shewart control charts is admirably documented in a number of statistical quality control books including those by Vardeman and Jobe,14 Wadsworth et al.,9 Duncan,11 Burr,10 Grant and Leavenworth,12 and Ott et al.13 Our purpose here is not to... 

---