The Problem of Worst-Case Variability in Cleaning Validation and Cross-Contamination Control: A Quality by Design Approach on Some Cephalosporin Residuals

Pharmaceutical manufacturers are globally forced to follow international guidelines on cleaning validation. Cleaning validation is related to the concept of the worst-case product; however, the worst-case product is a function of the manufacturer and the product portfolio. Consequently, manufacturers are faced repeatedly by cycles of worst-case product alteration, and repeated cycles of worst-case oriented analytical method development. Generally, this problem is hardly controlled due to the various products manufactured by the same facility. However, Analytical Quality by Design (AQbD) offers a possible solution through the development of robust and sensitive multicomponent analytical methods that span a wide spectrum of possible products. Cephalosporin antibiotics are a broadly manufactured class of antibiotics that can lead to anaphylaxis in extremely small quantities; therefore, an ultra-level of cleanness is required for facilities involved in such products. A group of the highest market share cephalosporin products was used to present the application of AQbD to introduce a reliable solution to cleaning validation that can be employed in pharmaceutical facilities. A multivariate optimization approach was utilized for the development of a sensitive multicomponent HPLC method; in addition to the proposal of a novel chemometric approach to troubleshoot the developed method.