Laboratory Testing Blog

Proposed Changes to USP Heavy Metals Analytical Testing

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First introduced over 100 years ago, USP<231> is a colorimetric procedure based on the precipitation of insoluble metal sulfides.  This test is qualitative rather than quantitative.  It is not an element specific method, nor is it equally sensitive to each metal.  The limits specified by the test are based on the ability to observe the precipitate, rather than on the analysis of toxicological data.  The procedure does not necessarily detect all potential forms and/or valences of elements of concern when they are present as the oxo ions or in the organometallic form.  Chromium and nickel are potential contaminants from modern stainless steel processing equipment and are not detected by USP<231>.  Other studies indicate inconsistent recoveries of monitor and standard solutions using USP<231> method II.2, 3

Industry criticism of this dated method began around 15 years ago and sparked the revision process by the USP.

The USP is now recommending that USP<231> be revised to USP<232>, which will require the use of updated instrumental technology to improve selectivity and sensitivity.  The change includes modification to the preparation and analysis methodology as well as the impurity limits of each analyte.  Revisions to the elemental impurities test will constitute a serious change for the pharmaceutical industry.  The change will shift the testing from a relatively inexpensive procedure that requires minimal set-up and operator training to tests that require expensive instrumentation and highly skilled metals analysts.  However, by employing modern instrumental methods, the USP’s intent is to ensure safer products for the consumer as well as offer flexibility and efficiency during testing.

All drug products produced and sold in the U.S.and Canada will have to comply with the limits set by General Chapter USP <232> Elemental Impurities—Limits, and drug substances and excipients will have to be tested and reported for elemental impurities.  Likewise, all dietary supplements will have to comply with limits set by General Chapter USP<2232> Elemental Contaminants in Dietary Supplements which includes guidelines for speciating organic and inorganic forms of various elements.  General Chapters USP<232> Elemental Impurities - Limits, USP<233> Elemental Impurities  Procedures and USP<2232> Elemental Contaminants in Dietary Supplements are currently in a preliminary recommendation stage and the limits described have not been finalized.

Changes to heavy metals test procedures for the analysis of pharmaceutical products and dietary supplements are under review with new standards set to be in place by mid-2013.  The intention of the review is to update current analytical testing historically performed using United States Pharmacopeia (USP) <231>. The revisions to General Chapters USP<232>, USP<233>, and USP<2232> are designed to set safer limits for public exposure and to reduce the environmental impact of dated methods.  Many in the pharmaceutical industry have concerns about the new instrumentation, more stringent requirements and the associated costs.  Nonetheless, the revisions should have a beneficial impact on the industry by significantly improving specificity and analyte recoveries, as well as by yielding overall time savings resulting in safer, higher quality products.