Manufacturers of pharmaceuticals must ensure that residual solvents (organic volatile impurities or OVIs) and related contaminants are not present in their products or are present below levels stipulated as safe by regulation. Most quality control labs in pharmaceutical manufacturing employ gas chromatography for the determination of residual solvents that are included in either USP 467* or the more extensive list covered in ICH guidelines.
Routine analysis of residual solvents in drugs can be done with standard performance gas chromatography using the Agilent 7890A gas chromatograph. Capillary gas chromatography based on the 624 phase (USP G43) is widely used for separation. A different stationary phase such as DB-1701 or DB-5 can be utilized in specific methods when coelution has been identified (more information on columns. However, coelution is usually not a problem with mass spectrometric detection when the coeluting compounds each have unique ions.
 To obtain more information for confirmation or identification of unknowns, e.g., during an out-of-spec investigation, mass spectrometry is the method of choice. Analytical results obtained from the Agilent 5975 Series GC/MSD with headspace sampler provide excellent sensitivity when utilizing simultaneous SIM/Scan data acquisition.
For utmost selectivity it provides the advantage of both, routine ultra-sensitive detection with Selected Ion Monitoring (SIM) and detailed mass spectral information from Scan data, in a single analysis. This feature allows for very low level detection and quantitation of target ions while also searching for unknowns using scan. Confirmation is still possible since library searchable full scan data is collected along with SIM data for best sensitivity. Chromatograms from a synchronous SIM/Scan acquisition of limit excipient concentrations of Class 1 and Class 2 residual solvents as defined in the ICH guidelines are shown in the figure.
One of the impediments to accurate determination of impurities at very low levels is the proclivity for analyte interaction and/or reaction with the internal surfaces of the instrument sample path. To eliminate this problem, the new inert G1888 headspace sampler can be used. Carryover, a common concern in older headspace samplers is also greatly reduced. The whole system has a non-reactive, non-adsorptive sample flow path from the point of injection through detection
* New USP <467> regulations for residual solvents begin in July 2007 in final alignment with the ICH guideline.
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