Figure 1: Identifying residual solvents and testing procedures.
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There are regulatory differences, however, between USP ‹467› and ICH Q3C. ICH Q3C is a guideline, which means it is not enforceable. Currently, it applies to new drug applications
(NDAs) and abbreviated new drug applications (ANDAs) approved after 1997 and applications that reference it. USP ‹467› is a mandatory drug standard according to the Food, Drug, and Cosmetic Act of 1938. It applies to all compendial drug
products; that is, products with a USP monograph.
"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.
Clarification on limits
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*
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The text states that the chapter applies to existing drug substances, excipients, and products, and that all substances and
products are subject to relevant control of solvents likely to be present in a substance or product. As Delwyn Schumacher,
principal chemist in the Methods Development Department at Lancaster Laboratories (Lancaster, PA), observes, "that statement pretty much means that if a solvent is used in a drug-related manufacturing process,
it [the solvent] needs to be evaluated one way or another in the produced material for compliance with the applicable limits."
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.
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