The United States Pharmacopeial Convention (USPC) asked the Institute of Medicine (IOM) of the National Academy of Sciences
to convene a workshop at which stakeholders, including pharmaceutical manufacturers, could discuss ways to update US Pharmacopeia (USP) General Chapter <231> "Heavy Metals" (1). IOM responded positively and formed a planning committee composed of national and
international experts in metal measurement and toxicity.
The workshop took place at IOM Aug. 26–27, 2008. In an effort to promote harmonization and at USP's request, IOM invited compendial
experts from Europe and Japan to attend. Because USP <231> is relevant to food ingredients (standards are provided in USP's Food Chemicals Codex) and dietary supplements (standards are provided in USP's dietary supplement section), IOM also invited stakeholders from those sectors.
USP <231> relies on classical (i.e., wet) chemistry procedures that have been in the compendium for more than 90 years. The test
suffers from a lack of instrumental output and is a nonspecific, subjective test based on the precipitation of metal sulfides
from a solution with visual comparison to the color of a standard solution (2). Several groups have shown that the method
routinely underestimates the levels of the few metals it was designed to detect (2, 3). Certain toxic metals thus may appear
in drug products and their ingredients because of their use as catalysts or starting materials. Other metals such as arsenic,
cadmium, lead, and mercury are highly toxic and ubiquitous in the environment. Not surprisingly, many of these metals also
have been detected during market surveillance of dietary supplements and food ingredients (4).
Workshop deliberations resulted in a consensus that the current classical chemistry procedure in USP <231> is no longer suitable. Participants agreed that the current procedure should be replaced by specific and sensitive
instrumental procedures that detect and quantify the broad range of metals and elements of interest in pharmaceuticals, dietary
supplements, and food ingredients.
Challenges of improved technologies
Modern instrumental methods can identify and quantify at low levels many metals that currently are not detected by USP <231>. Because many metals may not pose a public health risk when consumed for a brief time or at low levels, the challenge
for participants was to identify metals of interest, and levels that should be monitored, especially considering the broad
range of exposures posed by articles such as food ingredients.
Metals of interest.
For certain metals (e.g., arsenic, cadmium, lead, and mercury) analysis was relatively straightforward. These substances have
known toxic effects and are potential contaminants. Thus, analytical methods should be validated to detect arsenic, cadmium,
lead, and mercury. The methods should detect the metals at toxicologically relevant concentrations; and pharmacopeial monographs
for these metals should be revised.
Workshop participants grappled with the questions of which metals should be monitored and to what level of detection. The
European Medicines Agency (EMEA) has released a Guideline on the Specification Limits for Residues of Metal Catalysts (5). Because the metals specified in the guideline are sometimes used as catalysts or processing agents and can appear as
contaminants in drug substances and drug products, EMEA recommends that pharmaceutical manufacturers test for them at levels
commensurate with their toxicity.
Workshop participants identified various reagents that may require monitoring and contain elements such as aluminum, beryllium,
boron, chromium, cobalt, copper, gallium, germanium, gold, indium, iron, lithium, magnesium, manganese, nickel, silicon, silver,
tin, thallium, titanium, and zinc.