Figure 1: Identifying residual solvents and testing procedures.

"There are a lot of drug products that are approved by the agency that do not have a USP monograph, but the NDA and ANDA are still reviewed by the agency and even though there is no requirement in USP necessarily for residual solvents, we always review all drug applications to make sure residual solvents are tested for, and ICH Q3C guidance is still fully applicable to those drug products that perhaps do not have a monograph in USP," says Ouderkirk.

USP ‹467› and ICH Q3C categorize residual solvents, including those previously under the OVI chapter, into three classes according to their toxicity level (see sidebar, "Residual solvents classifications"). Both documents assess the risk to human health according to permitted daily exposure (PDE), which differs from the terminology used by the International Program on Chemical Safety (which uses "tolerable daily intake") and the World Health Organization (which uses "acceptable daily intake"). Both documents also list concentration limits (in ppm) for Class 1 residual solvents and limits (in ppm concentration and PDE) for Class 2 residual solvents. Questions about these limits, including how they are calculated and where they apply, are widespread.

Understanding the difference between the limits in terms of PDE and the limits in terms of concentration (in ppm) has turned out to be one of the most crucial areas of understanding USP ‹467›. Those who have followed the evolution of the general chapter are quick to urge readers to read the text very carefully.

Residual solvents classifications*

One key point that industry experts, regulatory agencies, and ingredient suppliers are making, however, is that the limits specified in ‹467›, including those listed for Class 2 residual solvents, apply only to the finished drug product. The current misinterpretation is that these limits apply to the individual ingredients of the drug product.