Looking Beyond the Column: An Investigation into Method Irreproducibility for an Active Pharmaceutical Ingredient

Irreproducibility during initial development of a high performance liquid chromatography method is seldom investigated in a thorough and careful manner when working in an industrial setting. For a drug project in the early developmental stages, the LC method is often changed, sometimes drastically, if one encounters irreproducibility in the method. Too often a method is deemed irreproducible due to column lot variability, diluent effects, or pH effects with little or no experiments taking place for justification and little thought given to why the irreproducibility may have occurred in the first case. In this paper, a case study is presented in which a systematic approach was carried out in order to determine the exact reason why method irreproducibility was occurring. The findings of the investigation were then drawn onto change a method with poor reproducibility into one that is rugged without the need to start from the beginning and develop a new method.