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.

A 21st century HPLC workflow for process R&D.

A unique high-performance liquid chromatographic (HPLC) workflow specifically designed for the rigors of process development has been developed. A key feature of the workflow is the creation of an HPLC software-hardware platform designed to automatically and systematically screen samples using a matrix of columns and eluents to aggressively search for impurities. The workflow platform was assembled from commercial hardware components and both custom and commercial HPLC software. The platform can be used to challenge existing HPLC methods or to develop new methods. Three real world examples are provided to illustrate the utility of the platform to rigorously assess the complexity of samples and to develop new and improved HPLC methods.

Synthesis of Z-5-carboxymethylene-1,3-dioxolan-4-ones: a better way.

The title compounds were prepared by a straightforward two-step procedure. Tartaric acid was first protected as either a bis(ketal) or a bis(acetal). This intermediate was then treated with potassium tert-butoxide at reduced temperature to effect a stereoselective elimination leading to the Z diastereomer of the alpha,beta-unsaturated acid. This protocol is useful for the laboratory-scale synthesis of these compounds but can also be scaled up to produce kilogram quantities of the material.