Trace-Level Impurity Analysis

Authored by: Daniel L. Norwood

Encyclopedia of Pharmaceutical Science and Technology

Print publication date:  July  2013
Online publication date:  July  2013

Print ISBN: 9781841848198
eBook ISBN: 9781351124874
Adobe ISBN:


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The issue of trace-level impurities in active pharmaceutical ingredients (APIs, also termed “Drug Substances”) and formulations developed for APIs (termed “Drug Products”) is a broad and complex one. Impurities can be both organic and inorganic, and can be introduced either to the drug substance or to the drug product from a variety of sources. These sources include the synthetic process for the drug substance and the manufacturing process for drug product, degradation of the drug substance, ingredients in the formulation, interactions of the drug substance and ingredients in the drug product, container closure systems, and the environment. Impurities have no therapeutic benefit but can pose potential safety risks to patients and healthy volunteers in clinical trials; hence, the identities and levels of impurities must be understood and controlled based on the nature of impurities. Modern analytical chemistry and instrumentation have enabled the identification, quantitation, and control of both organic and inorganic impurities at low levels in both drug substance and drug product. The goal of this article is to review and discuss the current state of affairs in pharmaceutical development with respect to the trace-level analysis of impurities in drug substance and drug product. The article includes a discussion on the scope of the impurities issue and the regulatory considerations involved, followed by a survey and discussion of the ana- lytical/instrumental techniques now in routine use for the identification of trace-level impurities, with emphasis on mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy. An MS-based systematic approach to the identification of trace-level organic impurities is presented, illustrated with examples of original data. Although emphasis is placed throughout the review on scientific and technical aspects of the impurities issue, all discussion is fully grounded in and correlated with our current understanding of the regulatory environment and current regulatory guidances. The article includes references to applicable scientific literature, and as stated above, original data are used to illustrate important scientific concepts.

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