Extending the Threshold of Regulation Concept: De Minimis Limits for Carcinogens and Mutagens

A rationale for determining, testing, and controlling specific impurities in pharmaceuticals that possess potential for genotoxicity

“…Determination of allowable daily intake of potentially genotoxic impurities in drug substance or drug product is based on an understanding of dose-response relationships for carcinogenicity observed for several hundred compounds positive in chronic rodent bioassays. There was remarkable consistency among several efforts that defined cancer potency curves for rodent carcinogenicity studies (Ashby and Tennant, 1988;Fiori and Meyerhoff, 2002;Gold et al, 1984Gold et al, , 1989Munro et al, 1999;Rulis, 1986).…”

Application of the threshold of toxicological concern concept to pharmaceutical manufacturing operations

“…In contrast to the TTC values and supporting analyses discussed above, Fiori and Meyerhoff recently conducted their own analysis of the distribution of TD50s from GoldÕs CPDB in an effort to develop de minimis levels for mutagens and carcinogens (Fiori and Meyerhoff, 2002). In their analysis, a target risk level (risk-specific dose (RSD)) was selected that corresponds to a de minimis excess lifetime cancer risk of one-in-a-million at the 95th percentile of the distribution of cancer potencies, assuming all compounds are carcinogenic.…”

Identification, control strategies, and analytical approaches for the determination of potential genotoxic impurities in pharmaceuticals: A comprehensive review

“…Toxicology assessment should be done by pharmaceutical scientists and toxicologists to identify PGIs and their entry into the synthetic process . In addition, the synthetic route must be reviewed by a team of process chemists, analytical chemists, and toxicologists to identify likely reaction byproducts and their potential for carry through to the APIs.…”