Control and analysis of alkyl esters of alkyl and aryl sulfonic acids in novel active pharmaceutical ingredients (APIs).

This article reviews current regulatory guidelines and relevant scientific literature pertaining to the control and analysis of potential genotoxic impurities (PGIs) in new active pharmaceutical ingredients (APIs) with specific reference to a certain sub-class of PGIs, namely alkyl esters of alkyl and aryl sulfonic acids. Sulfonic acids are very important in pharmaceutical R&D employed both as counter-ions in the formation of acid-addition salts and also as reagents and catalysts in the synthesis of new drug substances. The article reviews the evolution of analytical methodology from early studies in the mid 1970s through development of direct injection GC and HPLC methods to liquid-liquid/solid phase extraction and headspace based techniques coupled to HPLC and GC methodologies employing UV and MS detection to new derivatisation-based techniques. The paper also reflects on the significant challenges in developing robust analytical methodology capable of the trace determination of sulfonate esters, the challenges in transferring methodology from R&D to QC labs and on the cost of inappropriate limits for genotox impurities. In so doing, the authors seek to inform the debate that the control of genotoxic impurities should be driven primarily by safety and risk/benefit considerations rather than by state-of-the-art analytical and process chemistry capabilities that drive controls to levels 'as low as practicable' regardless of the risk/safety requirements.