Identification of Pharmaceutical Impurities

Abstract Identification of pharmaceutical impurities is a critical analytical activity in the drug development process whose goal is to fully elucidate the chemical structures of unknown pharmaceutical impurities present in either drug substances or drug products above a particular threshold. Knowledge of the chemical structure of an impurity is essential to assess its toxicological implications and to gain an understanding of its formation mechanism. Knowledge of the formation mechanism is critical for improving the synthetic chemical processes and optimizing the drug formulation to reduce or eliminate the impurity. This article reviews the current regulatory requirements for impurity identification and the chemical origins of various impurities, particularly those derived from degradation of drugs. Strategies for identification of pharmaceutical impurities are discussed followed by an overview of the critical steps and the roles of various analytical techniques, such as HPLC‐DAD, LC‐MS, LC‐NMR, GC‐MS, and NMR, in pharmaceutical impurity identification, with an emphasis on applications of mass spectrometry based hyphenated techniques. Carefully selected examples are included to demonstrate key points in impurity formation and the appropriate application of various analytical techniques.