Residual Solvents

For pharmaceutical purposes, Residual Solvents are defined as organic volatile chemicals that are used or produced in the manufacture of APIs, excipients, or DPs. The selection of the solvent is usually based on the need for overall synthetic yield or required physical characteristics such as crystal form, purity and final solubility. Since these solvents usually have no therapeutic benefit, they should be either synthetically consumed or removed from the final product.

We have systems to follow the current USP monograph for Residual Solvents using dedicated HS-GC-FID systems. The USP methodology is lengthy and is based on step-wise determinations with decisions often made “on the fly” if a listed Class I or II solvent is present at a concentration which needs its identity to be verified, and when verified, then quantitated. Headspace sample prep is different if the API or DP is water soluble or insoluble. A “screening” GC-FID technique is applied using one stationary phase type, and if a response in excess of the standard solutions used is evidenced, then a second experiment is required using a different stationary phase to verify the identify of the material. Secondly, the next experiment is performed based upon the probability that using a different stationary phase will yield a different elution profile to positively identify the impurity – a second dimension into identification. Once “identity is confirmed”, a third experiment is needed to quantify the impurity using either conditions from the first or second experiment, whichever yields a more favorable elution profile.

Although this approach is technically valid, it still raises certain questions since there is some uncertainty with its final conclusions. With these uncertainties in mind, we also offer HS-GC-MS with proof positive identification by mass spectra in addition to the retention time of standards and standard addition. We can cite a few impurities that were initially mis-identified by the HS-GC-FID technique as being present, yet were later properly identified by Atlantic Analytical using HS-GC-MS.

If only Class III 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>. If the Class III residual solvent is attributed to more than 50 mg per day (or 0.5%), corrected for moisture, then it should be identified and quantified using a cGMP validated technique using USP reference standards.

The reader is hereby referred to the actual ICH guideline, which may be downloaded here: