An impact analysis of the application of the threshold of toxicological concern concept to pharmaceuticals.

The recent application of the threshold of toxicological concern (TTC) concept to the regulation of pharmaceuticals in the European Union is analyzed. The derivation of TTC and the threshold of regulation that followed it were originally intended to provide makers of food contact materials greater flexibility with their products, while allowing the CFSAN branch of FDA to conserve its resources for more important issues. A reanalysis of the scientific data employed by EMEA regulators to rationalize its 1.5 mcg default genotoxic impurity limit is presented to demonstrate (a) that direct translation of conclusions relevant to food consumption are unduly influenced by many classes of potent carcinogens of historic concern which would be impossible to generate unknowingly as pharmaceutical impurities, and (b) that the majority of reactive chemicals that would be useful to synthetic chemists are among the least potent carcinogens in the underpinning supportive analyses. Evidence is further presented to show that implementation and acceptance of a 1.5 mcg TTC-based total limit on such impurities can be expected to impede pharmaceutical research and development efficiency while providing an insignificant cancer risk-avoidance benefit to patients who require pharmaceutical treatments. The conclusion drawn is that a significantly higher default limit can readily be defended that would be both in keeping with TTC principles and the best interest of patients.