Organic Residual Impurities, which are commonly referred to as residual solvents, are trace level chemical residues in drug substances that are used in, or are the by-products of manufacturing. These may also form later on during the packaging process or in storage. The International Conference on Harmonization (ICH) publishes guidelines (Q3C) listing the acceptable amounts of solvent residues that are allowable to be present. Under these guidelines, residual solvents are characterized according to their toxicity by class. Class 1 compounds are carcinogenic, posing a risk to both the consumer and the environment. Class 2 compounds are nongenotoxic animal carcinogens, with concentrations of these compounds to be limited. Class 3 compounds have low toxic potential.
USP General Chapter <467> has been the generally used compendial method for identifying and quantifying residual solvents when no information is available on what solvents are likely to be present. To better mirror the ICH guidelines, on July 1, 2008, the USP implemented a new test requirement for the control of residual solvents in drug products. The new test requirement, USP General Chapter <467> Residual Solvents, replaces the previous USP General Chapter <467> Organic Volatile Impurities. This new test requirement is more comprehensive, as it increases the number of residual solvents to be routinely tested to 57. This is a much longer analyte list than previously tested and represents the sum of Class 1, 2 and 3 residual solvents. The new test requirement itself is also more extensive and divided into three distinct procedures (A, B and C) for identification, confirmation, and quantification.
The test requirement for residual solvents under USP <467> consists of static headspace extraction followed by gas chromatographic separation and flame ionization detection (HS-GC/FID). Headspace sample preparation is also divided into two separate sections based upon sample solubility: water soluble and water insoluble articles. Procedure A is the first step in the identification process and is performed on a G43 capillary column as a means of determining if any residual solvents are present in the sample at detectable levels. Once a residual solvent is identified above the percent daily exposure limit, Procedure B is then performed to confirm analyte identity using a G16 capillary column. Once identity is confirmed, Procedure C then uses the conditions which yielded the best or most favorable separation- Procedure A or B- to provide a quantifiable result. If only Class 3 solvents are employed, their level is determined by USP method <731> Loss on Drying and if their contribution is greater than 0.5%, further testing for moisture content is required by USP method <921>
We have systems capable of performing the current USP monograph for Residual Solvents using dedicated HS-GC-FID systems. We can also perform residual solvent analysis by headspace GC/MS.
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