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>.
Organic volatile impurities, commonly known as residual solvents, are used or produced in the manufacturing processes of drug substances, excipients, and drug products (1). Residual solvents
serve no therapeutic use and should be removed to the highest extent possible. Those that are not removed should be limited
below prescribed concentrations (2). These often are measured using methods described in US Pharmacopeia's (USP) current general chapter "Residual Solvents" <467> (1).
"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.
MS detection provides better selectivity than FID because it combines spectral and chromatographic identification (5,6). Unique
mass spectra often eliminate resolution requirements. Residual solvents could be orthogonally identified spectrally or chromatographically,
allowing for the identification of coeluted compounds and, thereby, removing chromatographic resolution requirements (1,7).
This takes advantage of the compound specificity of MS and decreases the analysis times. The change of detector may be suitable
for inclusion in USP's method for evaluation of residual solvents. Presented here is the method development and validation
of a possible MS method that does not include Class 1 residual solvents in system suitability. The current <467> GC–FID method
requires the use of Class 1 residual solvents to meet system suitability. Parameter settings for this study were initially
based on <467> for sample preparations and GC parameters and an Agilent (Santa Clara, California) technical publication (8)
for MS parameters. Scan mode spectra were selected based on quantifying and qualifying ions, and combinations of one or two
qualifying ions were used to ensure that the proper residual solvent was identified. After it was identified, typically the
most abundant ion was selected for quantitation. When spectra did not have unique spectral patterns, chromatographic separation
was sufficient for identification.
This article does not address known problems in sample preparation, but presents interim progress in detection that may contribute
to a revision of <467>.