Many raw materials used to manufacture pharmaceutical products contain residual solvents at various levels. Because USP ‹467› applies to all compendial drug substances, excipients, and products, this chapter influences all aspects of the industry. Despite the preparation and even after several workshops and conferences on the topic, confusion and questions remain about where the solvent limits actually apply, how the methods should be established, when the data should be reported, and what information is required from ingredient suppliers. To help answer these questions, industry experts and regulators are collectively encouraging analysts to pay attention to the details in the chapter.
Background and applicationThe new USP ‹467› chapter replaces the previous ‹467› "Organic Volatile Impurities" (OVI) chapter established in 1990. Although the OVI chapter specified several methods for monitoring seven highly toxic solvents, it omitted many other industry solvents. Moreover, the methods were based on direct-injection gas chromatography (GC). In direct injection, the GC autosampler needle dips into the liquid, takes up liquid, and shoots the solution onto the GC. "This technique is hard on the GC because you are injecting not only the volatiles but also the API, which is typically not volatile. That is the way it was done because there simply wasn't a better way to reliably sample for these volatile impurities," says Jon Brice, PhD, director of pharmaceutical services at BioScreen Testing Services (Torrance, CA). "Ultimately it wasn't very effective," agrees Neil Schwarzwalder, global compendial consultant, Global Quality Laboratories, at Eli Lilly and Company (Indianapolis, IN).
In 1997, the International Conference on Harmonization (ICH) published Q3C, "Impurities: Guideline for Residual Solvents," which provides guidance for 59 residual solvents. Before the US Food and Drug Administration approved the ICH guideline in 1997, manufacturers had only the OVI general chapter to go by, and there was no general guideline on residual solvents. At that time, manufacturers conducted their own toxicology assessments of the solvents that they used for new products. The ICH guideline was uniform, and manufacturers had a standard that they could meet for new products. It did not apply to existing products, however. "The industry was in a situation where they were applying one standard to the new materials, another standard for older materials, and perhaps for really old products, no standard," says Schwarzwalder.
For harmonization, the new USP ‹467› chapter is patterned closely after the ICH Q3C guideline. The latest revision was published in December 2007 and was meant to correct the final points of disagreement. "USP, the industry, and FDA have worked very hard to resolve those differences," says Larry Ouderkirk, director of Compendial Operations Staff at FDA/CDER/OPS-IO. " I believe now what we've got in the latest version of ‹467› is something that is virtually identical to Q3C. I don't think there's any substantive differences left that haven't been addressed, and I think industry is now satisfied that the differences have been resolved."