The current US Pharmacopeia (USP) general chapter "Residual Solvents" <467> uses flame ionization detection for two identification procedures and one quantitation procedure. This article reports on the development and validation of a single gas chromatography–mass spectrometry (GC–MS) procedure that provides identity parameters for headspace-applicable residual solvent Class 1 and Class 2 compounds addressed in the current <467> method. It also provides validation for quantitation of all Class 2 residual solvents capable of being analyzed by headspace. This procedure shortens analysis time, combines the two identification procedures with one quantitation procedure, and modifies system suitability requirements but still uses an external standard. This GC–MS procedure is an effective identification test, but presents challenges in quantifying residual solvents below their concentration limits. This article does not address known problems in sample preparation, but presents interim progress in detection that may contribute to a revision of <467>.

"Residual Solvents" <467> involves a three-step process for identifying and quantifying known residual solvents in pharmaceuticals (1). The chapter provides classification lists for three types of residual solvents and concentration limits expressed in parts per million (ppm) for Class 1, Class 2, and Class 3 residual solvents. Chapter <467> provides a stepwise process for evaluating Class 1 and Class 2 residual solvents based on the solubility of the material being tested. Class 2 residual solvents that cannot be evaluated by headspace analysis are not discussed here, or in the chapter. The general chapter provides sample preparations that include stepwise dilutions for reference standards and samples in which the concentration of the final dilution, before diluting into the headspace vial, is at the residual solvents' allowed concentration limits. For this article, the residual solvents' concentration limits are named the 100% limit concentration. The <467> procedures also include solution preparation information, gas chromatography with flame ionization detection (GC–FID) parameters, headspace parameters, system suitability requirements, and quantitation calculations based on sample findings. Although the evaluation and preparation methods have undergone many revisions, the chapter still has drawbacks (3). For example, instrument evaluation time is extensive because two separate instrumental methods and specific columns are needed to achieve residual solvent resolution in the current <467> GC–FID method; the multistep dilutions used for sample preparations are prone to residual solvent loss; and the system suitability tests require Class 1 residual solvents that have the most safety and health hazards (4). Many people have informed USP that the Class 1 residual solvents required are the most hazardous chemicals used in their laboratories and that they would like to avoid these kinds of health and safety hazards. This article reports the incorporation of time-saving mass spectrometry (MS) detection that may reduce the identification analyses from two method parameter sets to one and a way to reduce the need for Class 1 compounds in establishing system suitability. The changes presented here could be considered for inclusion in United States Pharmacopeia–National Formulary (USP–NF), but would not necessarily replace the current FID method. Of course, all additions and changes are subject to public comment.

This article does not address known problems in sample preparation, but presents interim progress in detection that may contribute to a revision of <467>.