Heavy metals in pharmaceutical products can be toxic even at trace levels, and thus pose a significant health threat to consumers. In addition, these elements can jeopardize the quality of the product even without causing toxic effects. For example, inorganic impurities such as copper, nickel, and cobalt can shorten shelf life by increasing the rate of free-radical formation within the product, while also enhancing oxidative decomposition. As a result, the accurate measurement of trace metals in pharmaceutical products is of utmost importance to ensure that the products are free of elemental impurities and do not pose a toxicity risk to patients.
These methods use aggressive sample-preparation processes that involve sulfuric acid and high-temperature ashing, potentially leading to significant losses of volatile target analytes. As a result, the methods cannot detect some metals, and the validity of the test results obtained is questionable. In addition, precipitation-based techniques are capable of quantifying only groups of elements, and not individual elements. They also produce false negative results, thus potentially allowing harmful products to enter the market. A further significant disadvantage is that these methods require a rather large sample size.As a consequence, speakers and planning-committee experts at a 2008 workshop organized by the Institute of Medicine (IOM) of the US National Academy of Sciences concluded that precipitation-based methods are inadequate for metals testing and should be replaced by instrumental methods offering greater specificity and sensitivity (1). More specifically, the experts recommended inductively coupled plasma–mass spectrometry (ICP–MS) and inductively coupled plasma–optical emission spectrometry (ICP–OES) because they are selective, sensitive, robust, and detect metals of interest at much lower levels than precipitation-based techniques. Keeping pace with these developments, in 2010 USP began the process of introducing two new chapters, <232> and <233>, to replace <231> for the monitoring of elemental impurities in pharmaceuticals. Since the proposed chapters were first presented, they have gone through several revisions and comment periods.
In May 2011, the USP Expert Panel on Elemental Impurities further revised the proposed general chapters <232> and <233> to address the feedback it had received. The revised proposals appeared in Pharmacopeial Forum (PF). The chapters have since been presented for an additional comment period to ensure that the chapter requirements are clear to all users and to obtain any final input. All comments were due in July 2011 (2).