Multivariate statistical process control in product quality review assessment – A case study

Abstract

According to the Food and Drug Administration and the European Good Manufacturing Practices (GMP) guidelines, Annual Product Review (APR) is a mandatory requirement in GMP. It consists of evaluating a large collection of qualitative or quantitative data in order to verify the consistency of an existing process. According to the Code of Federal Regulation Part 11 (21 CFR 211.180), all finished products should be reviewed annually for the quality standards to determine the need of any change in specification or manufacturing of drug products. Conventional Statistical Process Control (SPC) evaluates the pharmaceutical production process by examining only the effect of a single factor at the time using a Shewhart's chart. It neglects to take into account the interaction between the variables. In order to overcome this issue, Multivariate Statistical Process Control (MSPC) can be used. Our case study concerns an APR assessment, where 164 historical batches containing six active ingredients, manufactured in Morocco, were collected during one year. Each batch has been checked by assaying the six active ingredients by High Performance Liquid Chromatography according to European Pharmacopoeia monographs. The data matrix was evaluated both by SPC and MSPC. The SPC indicated that all batches are under control, while the MSPC, based on Principal Component Analysis (PCA), for the data being either autoscaled or robust scaled, showed four and seven batches, respectively, out of the Hotelling T2 95% ellipse. Also, an improvement of the capability of the process is observed without the most extreme batches. The MSPC can be used for monitoring subtle changes in the manufacturing process during an APR assessment.