Addressing Elemental Impurity Limits with ICP–OES and ICP–MS

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Pharmaceutical Technology, Pharmaceutical Technology-11-01-2011, Volume 2011 Supplement, Issue 6

The US Pharmacopeia (USP) proposes to lower the maximum permissible limits of trace elements in pharmaceuticals and recommends that impurities be measured through automated instrumentation-based methods. The proposed regulations specify inductively coupled plasma–mass spectrometry (ICP–MS) and inductively coupled plasma–optical emission spectrometry (ICP–OES) as the techniques of choice. This article discusses the benefits of ICP–MS and ICP–OES for the accurate detection of trace elements in pharmaceutical products, in compliance with the proposed USP chapters.

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.

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).

Proposed chapter

The proposed new <232> specifies permissible daily exposure (PDE) limits for elemental impurities in drug products. Elemental impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently (e.g., by interactions with processing equipment). When elemental impurities are present, have been added, or have the potential to be introduced, assurance of compliance to the specified levels is required. Compliance with these limits is necessary for all drug products. To determine conformity, a risk-based control strategy may be appropriate (2).

The performance requirements of the techniques used to measure elemental impurities in pharmaceuticals are described in <233> (2). The chapter describes two analytical procedures (i.e., procedures 1 and 2) to evaluate the levels of the elemental impurities described in <232>. Procedure 1 can be used for elemental impurities generally amenable to detection by ICP–OES. Procedure 2 can be used for elemental impurities generally amenable to detection by ICP–MS.


Chapter 233 also describes criteria for acceptable alternative procedures that meet the validation requirements and may be considered equivalent to procedures 1 and 2. In addition, the chapter specifies that system standardization and suitability evaluation using applicable reference materials should be performed on the day of analysis. Analysts will also need to confirm by means of verification studies that the analytical procedures used are suitable for use on the specified material (2).

ICP–OES and ICP–MS for metals analysis

As described above, the proposed chapters specify ICP–OES and ICP–MS as the analytical procedures of choice, thus enabling scientists to accurately and easily determine levels of trace elemental impurities in pharmaceutical products. These powerful techniques identify and quantify each metallic impurity with higher sensitivity and selectivity than conventional precipitation-based detection methods. ICP–OES and ICP–MS can analyze small sample volumes and masses and offer much lower detection limits. They are thus suitable for testing synthetic peptides and proteins as well as drug products in development.

ICP–OES and ICP–MS are fast, multielement techniques that can analyze as many as 60 elements in a 2-min run after sample digestion. This characteristic is a key benefit over wet-chemistry-based methods, which often require as much as 24 h for sample preparation alone. The techniques can also provide precise quantitative determination of the metal content of samples using only small sample quantities.

Application example

An ICP–OES analyzer (Thermo Scientific iCAP 6500 ICP–OES) and an ICP–MS system (Thermo Scientific XSERIES 2 ICP–MS) were used for the analysis of pharmaceutical products. The full suite of procedures outlined in <233> was performed using the ICP–OES instrument to analyze an over-the-counter cold and flu remedy. The medicine was prepared in triplicate by dissolving the product in a 1% (v/v) nitric acid solution, adding analyte spikes when necessary, sonicating for 10 min, and making a final weight of 50 g with 1% (v/v) nitric acid.

Accuracy and repeatability samples were prepared for analysis according to the validation requirements described in <233>. Accuracy samples comprising blank solutions were spiked with 0.5 j, 1 j, and 1.5 j of the limit, respectively (j is the indicated limit). Samples of the material under test were also spiked accordingly. In addition, six independent repeatability samples of the material under test were spiked with the elements of interest.

A quantitative screening of more pharmaceutical samples was performed using the ICP–MS analyzer configured using an Elemental Scientific Instruments (ESI) PC3 FAST sample-introduction system. Nineteen medicines were prepared by microwave digestion of single tablets or recommended doses. Following digestion, the samples were made in quantities as large as 50 mL with ultrapure water and analyzed without further dilution. One medicine was prepared in triplicate with and without a spike of 0.5 μg/g of each element (i.e., the level of the lowest component limit) and 0.01 μg/g of mercury.


For ICP–OES, the results of the accuracy tests, in which a blank sample and a matrix sample (see Figure 1) were spiked with the elements of interest, showed that the spike recoveries were within the limits set by <233> (i.e., 80–150% of the spiked values). The six repeatability samples and intermediate precision (i.e., reproducibility) gave relative standard deviation (RSD) values of less than 3% and 16%, respectively, for all analytes. The results of the sample analysis (see Table I) revealed that all of the elements, with the exception of arsenic, were below the component limit. The level of arsenic exceeded the component limit by 100%, and if the maximum daily dose of the product were taken, the PDE would be exceeded by 300%.

Figure 1: Inductively coupled plasma–optical emission spectrometry spike recoveries of test samples (with sample matrix) at various concentrations of the control limits. Acceptance criteria are 80–150%. (ALL FIGURES ARE COURTESY OF THE AUTHOR)

The ICP–MS results demonstrated that most pharmaceuticals displayed elemental concentrations well below the specified limits. Figure 2 shows data for four of the medicines that had, in general, higher concentrations. All elements of interest were below the component limit in drugs A to D. Chromium and manganese were above the component limits in drug B, and although drug C did not exceed any of the USP limits, it contained a high level (i.e., 8 mg/g) of aluminum. Spike recoveries to determine the accuracy of the method fell within the acceptance criteria, even for a spike of 0.5 μg/g for all elements (except mercury at 0.01 μg/g).

Table I: Results of the inductively coupled plasma–optical emission spectrometry sample analysis with instrument and method detection limits.


ICP–OES and ICP–MS are recognized by USP as the preferred techniques for the analysis of trace elemental impurities in pharmaceutical products, in compliance with the requirements of the proposed USP <232> and <233>. The multielement analysis capabilities of ICP–OES and ICP–MS make them excellent tools for processing multiple analytes in large numbers of samples quickly and efficiently. The methods offer superior performance with simple sample preparation, fast analysis times, and superior sensitivity, compared with complex and less efficient sulfide precipitation-based detection methods. Overall, the methods offer exceptional robustness, performance, and accuracy, while improving productivity for multi-elemental measurements in complex matrices.

Matthew Cassap is a senior applications specialist at Thermo Fisher Scientific, 19 Mercers Row, Cambridge, UK, tel. + 44 1223 347 417,


1. USP, "USP Heavy Metals Testing Methodologies Workshop" (Rockville, MD, 2008),, accessed Sept. 30, 2011.

2. USP, "Hot Topics: Elemental Impurities" (USP, Rockville, MD, 2011),, accessed Sept. 30, 2011.