The FDA perspective on the development of stereoisomers

Abstract

The current regulatory position of the Food and Drug Administration is discussed with regard to the approval of racemates and pure stereoisomers. Circumstances in which stereochemically sensitive analytical methods are necessary to ensure the safety and efficacy of a drug are described. Regulatory guidelines are interpreted for applications for the approval of a pure enantiomer in which the racemate is marketed, for the approval of either a racemate or a pure enantiomer in which neither is marketed, and for clinical investigations to compare the safety and efficacy of a racemate and its enantiomers. Examples of the basis for such regulation are drawn from historical situations (thalidomide, benoxaprofen) as well as currently marketed drugs (arylpropionic acids, disopyramide, indacrinone).

Plant and soil enantioselective biodegradation of racemic phenoxyalkanoic herbicides

“…1,2 In many cases, one enantiomer can produce a completely different biological response than its corresponding antipode. 3,4 Almost all environmental regulations in the United States treat racemates as though they are single molecules with the same biological and physiological properties.…”

Determination of enantiomerization barriers by dynamic and stopped‐flow chromatographic methods

“…Consequently, drug manufacturers are bound to consider the stereochemical integrity of enantiomers and "assess the potential for interconversion … of the individual isomers." 20,21 An overview of the available techniques for the determination of enantiomerization barriers is given in Figure 1. As prerequisites, pure or enriched enantiomers are required for chiroptical methods, suitable chiral shift reagents for DNMR, and the quantitative on-column separation of enantiomers for dynamic chromatographic methods.…”

Twisted and frustrated states of matter

“…As de Camp noted 'Regulatory guidelines are interpreted for applications for the approval of a pure enantionmer in which the racemate is marketed, for the approval of either a racemate or a pure enantiomer in which neither is marketed, and for clinical investigations to compare the safety and efficacy of a racemate and its enantiomers. Examples of the basis for such regulation are drawn from historical situations (thalidomide and benoxaprofen) as well as currently marketed drugs (arylpropionic acids, disopyramide and indacrinone) ' (de Camp et al 1989). So, when is a drug enantiomerically pure (ee = 100) and when is it racemic (ee = 0)?…”