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A Primer on USP 232 and USP 233 Elemental Impurities via ICP-MS

by David Milstein on January 29, 2013

Note: The USP has indicated that USP General Chapter <232> and USP General Chapter <233> will become official on February 1, 2013 and that conformance will be required by May 1, 2014.

Heavy metals can be toxic for humans when they are not metabolized by the body and accumulate in the soft tissues. Depending on the heavy metal in question, toxicity can occur at levels just above naturally occurring background levels, meaning that consumption of pharmaceuticals and food supplements with high heavy metal concentrations can cause acute or chronic poisoning. Poisoning can result in damage to the central nervous system as well as damage to blood, lungs, kidneys, liver, and other vital organs. Long-term exposure to heavy metals may result in degeneration of the major organ systems of the body, as well as cancer.  The four heavy metals of primary concern as identified by the United States Pharmacopeia (USP) are mercury, arsenic, cadmium and lead.

Currently, the standard test for identifying heavy metals in a material defined in USP <231> is a simple colorimetric test that produces insoluble metal sulfides.  First introduced over 100 years ago, this test is simple and cheap, but it is also rather qualitative.  It cannot distinguish between heavy metals, and the limits of the test are specified by the observation of a precipitate, as opposed to analysis of toxicological data.  This means that not only will it be unclear as to which heavy metal is contaminating a sample, but a compound that passes the colorimetric test may still contain harmful quantities of heavy metals.  Furthermore, color reactions may occur due to interference from the solution the sample is dissolved in, leading to false positives.

To solve these troubling issues, the USP is in the process of updating the standardized testing for heavy metals to more modern methods, scheduled to replace the current USP <231> standard on February 1, 2013.  One of the proposed methods is to use Inductively Coupled Plasma Mass Spectrometry (ICP-MS) as defined in USP <232> and USP <233>.

In contrast to the simple colorimetric test, the Elemental Impurities test using an ICP-MS is performed first by placing the sample in solution, then by heating the solution by thousands of degrees Kelvin, to the point that it is reduced to charged ions (plasma).  This plasma is then run through a mass spectrometer, which separates the ions of the various elements based on both mass and charge.  Based on the readout from the mass spectrometer, individual elements can be both identified and quantified, with very little chance of interference.

An ICP-MS will yield quick results at an incredible level of sensitivity.  One brief 2 minute scan can identify 60 different elements in solution and the detection limits are between 0.01-1 micrograms per litre.  Because of this increased sensitivity, samples placed in the ICP-MS can be extremely dilute, thus reducing the concentration of potential interfering compounds.  This not only leads to a more accurate result in terms of identifying which heavy metals are in solution, but also determines their exact quantities, which can then be compared to the determined daily limits of heavy metal intake, normally found in the microgram per day range.

ICP-MS testing can be performed on either finished products or the raw materials that make-up the finished product.  Both strategies offer advantages and disadvantages.  For finished product testing, fewer tests need to be performed, but if samples are found to contain unacceptable concentrations of heavy metals, then the entire production run needs to be scrapped and reformulated. This reformulation will be performed without the knowledge of which raw material was the culprit.  By contrast, when testing raw materials, each raw material will have to be tested individually as opposed to the single finished product.  However, if unacceptably high concentrations of heavy metals are found in one of the raw materials, the source of the raw material can be changed relatively easily, thus avoiding the discarding of an entire production run and reducing costs in the long run.

Nucro-Technics is proud to offer both traditional heavy metals testing as described in USP <231>, and has a fully functioning ICP-MS to comply with the new USP <232> and <233> general chapters as part of our services.

Nucro-Technics has been in business for 40 years, and functions as a contract research support organization catering to the needs of biotech and pharmaceutical companies.  Our company consists of 140 employees located in a modern, 58,000 square foot facility.  Capabilities include environmentally controlled Pre-Clinical Toxicology, Analytical Chemistry, Bioanalysis via LC/MS/MS and ELISA, Genetic Toxicology and Microbiology laboratories.  In addition to the services provided by these labs, we offer our clients services pertaining to GMP Audits, Regulatory Affairs, Quality Control, Stability Testing, Validation and Method Development.

Nucro-Technics is inspected by and is in compliance with both the FDA and Health Canada.  Not only is the organization GLP and GMP compliant, but it is also certified to the ISO 9001:2008 standard.  We pride ourselves on functioning as a flexible extension of companies within the pharmaceutical and biotech industries that require both testing, quality control, and regulatory services to bring their products to market.

For more information on our use of ICP-MS and any of the testing services that Nucro-Technics offers, to receive a quotation, or to schedule a test, please contact NUCRO-TECHNICS.

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