Statistical Process Control Methods for Monitoring In-House Reference Standards

For certain types of medicine the biological strength or bioactivity of a drug is the main characteristic for release of products to the market. A pharmaceutical company may decide to use their own in-house reference standard to test the drug instead of using the expensive international reference standard. The company is then legally obliged to verify that the in-house reference standard remains stable over time with respect to the international one. This is a special problem within statistical process control (SPC) since the monitoring period is relatively short and bioassays are typically heterogenous. The objective of this article is to apply methods from SPC and dose-finding studies to different study designs and assess how well these methods perform in detecting a decline in bioactivity. The included methods are the exponentially weighted moving average (EWMA), Shewhart chart, and analysis of variance (ANOVA)-type contrasts (linear, Helmert, and reverse-Helmert). An optimal alpha-spending function was selected first to avoid inflating the familywise error rate. The normal alpha-spending function seemed to perform generally the best. Then from the results, the linear, reverse-Helmert, and the EWMA (lambda 0.6) performed better in later declines. Linear contrasts and the Shewhart chart performed better irrespective of the decline profile. Having more bioassay runs at the beginning of the stability study increased the probability of detecting a decline. If there is no prior information on the expected deterioration profile, linear contrasts or Shewhart chart should be preferred. Otherwise, reverse-Helmert or Helmert contrasts should be chosen for either early or late deterioration, respectively