Compound‐ and Class‐Specific Limits for Common Impurities in Pharmaceuticals

The synthesis of pharmaceuticals involves the use of many reactive reagents, solvents, and starting materials, and the resulting drug substances can contain a variety of by-products. Toxicologists play a vital role working with analytical and process chemistry providing targets for exposures to impurities and degradation products. This chapter reviews accessible toxicity studies via different routes of administration. Compound-specific limits are protective for a lifelong exposure, for relevant routes of exposure, and to be protective of all patient populations including sensitive subpopulations. Compound- and class-specific limits are developed based on lifetime exposure. Compound-specific toxicology limits were derived in a collaborative publication by pharmaceutical sponsors and guidelines for industry for compounds that are commonly used in pharmaceutical manufacturing. The chapter discusses some of the issues that caused ethyl methanesulfonate exposure in patients and the subsequent testing. It proposes a permissible daily exposure based on an analysis of the toxicity data set.