The stimuli article
Figure 1: Decision tree for analytical method selection (1). (FIGURES IS ADAPTED FROM USP.)
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The stimuli article (found at http://www.usp.org/pdf/EN/USPNF/2008-04-10InorganicImpuritiesStim.pdf) proposes replacing USP ‹231› with an instrument-based screening method that is more accurate and practical. It proposes expanding the application
of USP ‹231› to 31 elements (see sidebar, "Elements under consideration for USP ‹231› revision"), provides a decision tree for
determining the means of sample preparation (see Figure 1), lists oral and parenteral limits for each element, and states
USP will provide performance-based reference standards depending on whether the test articles are soluble in aqueous solutions,
organic solvents, or apply to closed-vessel microwave digestion. However, the stimuli article does not yet include the preparation
technique for digesting solid samples, converting them to liquids so that they can be introduced into the instruments.
The stimuli article also states that to perform a multi-element analysis, an inductively coupled plasma (ICP) spectrometer,
either in the atomic (optical) emission or mass spectrometry (MS) mode is "required" (1). ICP–MS is about 1000 times more
sensitive (to parts per billion level) than ICP alone (to parts per million level). ICP–MS detects and provides concentration
amounts for nearly 60 elements at one time, while ICP alone can detect about 30 elements simultaneously. At the 2008 USP Annual
Meeting, however, it was stated that the ICP methods are options for analytical determinations. Analysts are free to validate
methods or procedures that work for their sample, including atomic absorption (AA) spectroscopy, which is element specific
and as sensitive as optical ICP (2).
Industry concerns
The comment period for the stimuli article ended Dec. 15, 2008. USP plans to issue a draft document by July or August 2009,
with the final General Chapter taking effect mid-2010. Most of industry's concerns focused on the following (opinions expressed
in this article are those of the individuals and may not represent those of their company or affiliation).
Elements under consideration for USP ‹231› revision
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Too many elements.
Of the known elements listed in the stimuli article (see sidebar, "Elements under consideration for USP ‹231› revision"), four heavy metals are known to be the greatest toxic threat to humans and to the environment: lead, mercury,
cadmium, and arsenic (i.e., "the big four"). Several groups have suggested that USP focus on these four first.
"It seems that they are trying to bite off more than they can chew all at once," says David Schoneker, past chairman of IPEC-Americas
and member of Pharmaceutical Technology's Editorial Advisory Board. "Many of these individual metals have not undergone any routine testing in the past. You could
have a real mess on your hands if suddenly this becomes official and pharmaceutical companies start sending out surveys to
suppliers asking whether they meet all of the criteria for all of the metals. In many cases you're going to have supplier
companies that will not waste resources to run tests for many of the metals because they feel that there is no chance of it
being there based on their understanding of their raw materials and their manufacturing process. However, they may not have
any actual test data to back that up and if this is not implemented carefully and for a smaller focused set of metals initially,
there may be a lot of confusion about what information is appropriate and necessary to justify the supplier's statements."
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