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.
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Sulfide precipitation-based techniques have been used for many years to detect total heavy metals in pharmaceuticals. These
qualitative tests indicate the content of metallic impurities by colored sulfide precipitate, typically detecting elements
such as lead, mercury, bismuth, arsenic, antimony, tin, cadmium, silver, copper, and molybdenum. Although these techniques
are specified in US Pharmacopeia <231>, they have been associated with many important shortcomings. For example, the techniques are nonspecific, insensitive,
time-consuming, labor intensive, and often yield low recoveries or no recoveries at all.
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).
