New USP standards for elemental impurities

Under the new USP standards, manufacturers will be required to prove that their finished drug products meet standards regarding elemental impurities. The stricter USP standards reflect a growing understanding of the toxicology of elemental impurities, together with the development of more sensitive analytical methods. They are provided in General Chapters <232> (Elemental Impurities – Limits) and <233> (Elemental Impurities – Procedures), both of which are new.

Until now, the issue of elemental impurities has been covered by USP in General Chapter <231> (Heavy Metals). This chapter has become outdated in two ways: First, it only applies to monographs for APIs and excipients – not to those of finished drug products. Secondly, the test methodology described (visual comparison to a lead sulfide precipitate) cannot detect levels of several impurities that are now known to be toxic. By comparison, the new General Chapter <232> specifies acceptable limits for 15 elemental impurities in drug products including arsenic, cadmium, lead, and mercury (the "Big Four").

Metal impurities do not provide any therapeutic benefit to the patient. Consequently, they should be controlled within acceptable limits in the drug product. Implementation of <232> and <233> will include removal of all references to General Chapter <231> from monographs in USP–NF, meaning that the outdated heavy metals test based on colored sulfides will no longer be an USP requirement.

The new standards will have a significant impact on raw material suppliers and contract laboratories, as well as on drug manufacturers. Suppliers will be expected to inform customers of the levels of elemental impurities their materials contain.

USP has deferred the effective date from the May 1, 2014 target. This will allow USP to work closely with ICH Q3D to align their activities with the implementation of General Chapters.

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