New USP General Chapter on Residual Solvents - Implementation by the FDA?

On 1 July 2008, the USP implemented the new General Chapter <467> - "Residual Solvents", which replaces the former Chapter <467> - "Organic Volatile Impurities". Now, the new General Chapter <467> was also revised in the 1st supplement to USP 32. Since this changeover also affects many products placed on the American market, in August 2008 the FDA issued a Draft Guidance for Industry with the title "Residual Solvents in Drug Products Marketed in the United States".

This FDA guidance defines in which form holders of a marketing authorisation (NDA and ANDA) are meant to inform the FDA of modifications in connection with this changeover.

The FDA expects products with an official USP monograph that are sold on the American market to comply with the requirements of the revised General Chapter <467>.

The FDA also explicitly permits the use of other analytical procedures, apart from those mentioned in the revised Chapter <467>. However, this requires a complete description, validation and verification of the alternative test method.

The FDA starts from the assumption that in most cases where changes are made under NDAs and ANDAs it will be sufficient to report these changes in the Annual Report. Here, the marketing authorisation holder is not supposed to submit detailed data, but rather summaries. However, in case of an inspection, the complete data must be on hand.

The new USP chapter does not apply to medicinal products that do not have to comply with the USP. Here, the FDA refers to the ICH Guideline Q3C Impurities: Residual Solvents.

The complete FDA Draft Guidance document can be found here:
http://www.fda.gov/CDER/guidance/8179dft.pdf

Since in the meantime the implementation of the new USP chapter has caused confusion among ANDA holders, FDA's Office of Generic Drugs (OGD) had to clarify some unanswered questions as well. For this purpose, the document "Residual Solvents in ANDAs: Questions and Answers" was published in October 2008. This document gives answers to 12 frequently asked questions from the OGD's point of view. Examples are:

Which ANDAs and ANDA supplements have to comply with USP <467>?
Which pieces of information have to be submitted in order to demonstrate compliance with USP <467>?
Which data on residual solvents should be included in a statement by the excipient manufacturer?
How should acceptance criteria be laid down for residual solvents that are not listed in USP <467>?
In which cases is the use of a class-1 solvent permissible?
Can "loss on drying" be used to test for class-3 solvents even in the presence of class-2 solvents, provided that 0.5% are not exceeded by both classes?
Do the methods have to be validated or verified?
Can a high-purity solvent be used instead of the USP reference standard?
All questions and answers by FDA can be found following this link:
http://www.fda.gov/cder/ogd/residualsolvents.pdf