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The USP proposes the use of analytical techniques capable of measuring impurities at the specified limits with optimal selectivity, sensitivity, simplicity, and robustness.
Elemental impurities in pharmaceutical products can be harmful to the health of patients. In response, the United States Pharmacopeia (USP) is proposing two new chapters — 232 and 233 — to regulate more strictly the detection of trace elemental impurities in pharmaceuticals. The proposed chapters specify lower limits for trace elements in pharmaceuticals and recommend the use of instrumentation-based methods rather than the traditional precipitation-based detection techniques. Inductively coupled plasma–mass spectrometry (ICP–MS) and inductively coupled plasma–optical emission spectrometry (ICP–OES) are recommended as the techniques of choice.
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. Because increased levels of elemental impurities can be hazardous to human health, the United States Pharmacopeia (USP) has long established standards governing the detection of toxic trace elements in pharmaceutical products. For more than 100 years, the USP has fostered the use of precipitation-based detection methods for analyzing trace elemental impurities in pharmaceutical products. However, these techniques suffer from a number of limitations; namely, that they do not contribute the high level of accuracy necessary for these types of analyses, which can lead to false negative results. As a result, precipitation-based methods can fail to detect some important elements such as mercury at toxicologically relevant levels.
Over recent years the USP has been looking into revising its standards for elemental impurities in the interest of better protecting public health. Two new chapters have been proposed — 232 and 233 — focusing on two areas of work. The first one aims to update the methodology used to test for elemental impurities in drugs to include procedures that rely on modern analytical technology. New methods of analysis will use instrumentation-based methods rather than the traditional wet chemistry–based techniques, with inductively coupled plasma–mass spectrometry (ICP–MS) and inductively coupled plasma–optical emission spectrometry (ICP–OES) as the suggested technologies of choice. The second area of work focuses on establishing limits for acceptable levels of elemental impurities in drugs and dietary supplements, including, but not limited to, lead, mercury, arsenic, and cadmium.
This article provides a thorough overview of the proposed new chapters and outlines the shortcomings associated with traditional precipitation-based detection methods. The benefits offered by the use of ICP–MS and ICP–OES for the determination of trace elements in pharmaceutical products also are discussed, demonstrating the capability of these techniques to facilitate compliance with the emerging USP legislative requirements.
The proposed new 232 (1) general chapter aims to set limits on the amounts of elemental impurities in pharmaceutical products. The limits presented in this chapter do not apply to excipients and drug substances, except where specified in the chapter or in the individual monographs. However, elemental impurity levels present in drug substances and excipients must be known and reported.
The limits specified in chapter 232 are based on an in-depth review of the toxicological literature and discussions involving several experts in metal toxicology. These limits, based on documented toxicity and regulatory recommendations, focus on elemental impurities, which are categorized into two classes. Class 1 elemental impurities should be essentially absent from pharmaceutical products because of their high toxicity to humans and deleterious environmental effects. However, if their presence is unavoidable, their levels should be restricted to the limits specified in chapter 232. The Class 1 elements are lead, mercury, arsenic, and cadmium. Class 2 elemental impurities should be tested for only when these elements are added to pharmaceutical products during their manufacture. These are typically catalysts that can be added in the production of a drug substance or excipient. Examples of Class 2 elements include copper, nickel, manganese, and chromium.
In addition, chapter 232 describes three separate options for determining compliance with the specified limits. According to the first option, pharmaceutical products are analyzed and the results are scaled to the maximum daily dose and compared to the permitted daily exposure limits. The second method requires that each component of a pharmaceutical product meets the specified component limit. Using the latter approach, each component of a pharmaceutical product is analyzed and the summation of the components scaled to the daily dose must be less than the permitted daily exposure.
Chapter 233 (2) describes the performance requirements of the procedures being used for the measurement of elemental impurities in pharmaceuticals and provides criteria for the approval of alternative procedures. The chapter also details two referee procedures, namely ICP–MS and ICP–OES, both using closed-vessel microwave digestion. The choice of procedure, including sample preparation and instrument parameters, is the responsibility of the user. However, an alternative procedure will require complete validation of the technique being used and its capability to meet the performance requirements set out in the chapter. In addition, a system suitability evaluation using a USP Reference Standard or its equivalent should be demonstrated on the day of analysis.
The USP, in chapter 231 (which is being replaced by chapters 232 and 233), specifies a wet chemical screening method for metals testing that has been in use for more than 100 years. This is a subjective visual test in which metal sulfides are precipitated out of an aqueous solution and the color of the test sample is visually compared with that of a standard lead solution. However, as metal sulfides that arise in a test solution can be white, yellow, orange, brown, or black, comparison to dark brown lead sulfide can be rather complicated (3). Additionally, precipitation-based detection methods require aggressive sample preparation whereby samples are ignited and charred before they can be analyzed. This can be highly challenging, especially with volatile elements such as mercury and selenium, and can lead to significant loss of target analytes.
A further shortcoming associated with traditional precipitation-based detection methods is their inability to quantify individual elements. Instead, the techniques are capable of quantifying only groups of elements. In addition, these conventional methods require a large sample size, which may be impractical for certain substances such as proteins and peptides.
As highlighted at a 2008 workshop organized by the Institute of Medicine (IOM) of the National Academy of Sciences of the United States (4), a number of evaluations during the past few years have demonstrated that precipitation-based detection methods can be difficult to use, offer limited accuracy, and can lead to false negative results. As a consequence, such techniques are often unable to detect the presence of metals of great interest, such as mercury, at toxicologically relevant levels. They can also seriously undervalue the concentrations of some metals that are known to be toxic and potentially present in pharmaceutical products. False negatives, in particular, can result in potentially harmful material entering the market. Overall, precipitation-based detection methods are nonspecific, insensitive, time-consuming, labor intensive, and yield low recoveries or no recoveries at all.
A general consensus by speakers and planning committee experts at the workshop was that precipitation-based methods are inadequate for metals testing and cannot provide the basis for control of elements at the limits proposed in chapter 232. As a result, these techniques should be replaced by instrumental methods offering greater selectivity, sensitivity, robustness, simplicity, and cost-efficiency. It was acknowledged that state-of-the-art instrumental methods can detect metals of interest at much lower levels. Featuring all the required attributes, ICP–MS and ICP–OES have been recognized as the techniques of choice for metals analysis in pharmaceutical products.
The multielement analysis capabilities of both ICP–OES and ICP–MS techniques make them ideal tools for processing multiple analytes in large numbers of samples quickly and efficiently. The techniques offer excellent performance with simpler sample preparation and significantly faster analysis times than other more complex detection methods such as gas chromatography (GC).
ICP–MS systems are capable of measuring multiple elements in a single acquisition while providing high-throughput capabilities with each analytical cycle being completed within 3–5 min. Measurements can be performed at very low detection limits and over a wide range of concentrations from 0.5 ppt to 500 ppm. The technique has definitive, multiple isotope identification capabilities, meaning that it is less prone to spectral interferences, whereas matrix-derived spectral interferences can be eliminated by using a collision–reaction cell (CRC). In addition, ICP–MS requires the use of only small sample volumes and is easy to use, stable, and reliable.
ICP–OES works on the principle of introducing a liquid sample into the plasma via a nebulizer. The nebulizer then turns the liquid sample into an aerosol. Within this plasma, the sample is heated up and as a result emits light, which is then measured. Light given off by a specific metal has a discrete wavelength and the intensity of that light is proportional to the concentration of the element within the solution. With the use of this technique, scientists are able to accurately and easily determine levels of trace elements in pharmaceutical products.
The latest ICP–OES instrumentation is extremely powerful, with low detection capabilities and the ability to resolve complex spectra. In addition, this instrumention has the necessary wavelength range for the analysis of 167–847 nm wavelengths and enables the analysis of all the elements that emit light between these two values. This is significant for a number of reasons. The low wavelength access enables the most sensitive wavelength for As and Hg to be reached and also offers the ability to access interference-free wavelengths, which are critical when analyzing elements that produce a high number of emission lines such as Os, Ir, Pt, and Pd.
ICP–OES is capable of identifying and quantifying each metallic impurity with higher sensitivity than conventional precipitation-based detection methods, exhibiting much lower detection limits (as low as 0.01–1 ug/L in solution). In addition, ICP–OES is a fast method that can be used to test for most of the elements of the periodic table (more than 60 elements) in just a single analytical run. The technique's wide dynamic range, which spans part-per-trillion to part-per-million levels, means that trace contaminants, as well as nutritionally significant elements, can be measured simultaneously during the same analysis.
High throughput is an additional advantage of ICP–OES, taking less than 2 min per sample analyzed. This is in contrast to wet chemistry-based methods, currently used by the USP, which often require up to 24 h for sample preparation alone.
Compared with precipitation-based methods, ICP–OES delivers definitive identification, eliminating interelement interferences and the associated inaccuracies. ICP–OES also can determine metal content accurately using only a small sample. The method offers unparalleled robustness, performance, and accuracy while improving productivity and decreasing running costs.
Metals can cause accelerated degradation of pharmaceutical ingredients even at ultratrace levels. As a result, having scientifically sound quality standards in place can help protect both manufacturers and patients. In response, the USP is proposing changes to how drug manufacturers detect trace elemental impurities in pharmaceutical products. The proposed new USP chapters 232 and 233 specify lower limits for trace elements in pharmaceuticals and place greater emphasis on the use of instrument-based detection methods for analyses. The aim is to ensure that the agreed safe limits for key metal impurities are properly measured so that public health is protected. To achieve this goal, the USP proposes the use of analytical techniques that are capable of measuring elemental impurities at the specified limits with optimal selectivity, sensitivity, robustness, simplicity, and cost-effectiveness. ICP–MS and ICP–OES are described in chapter 233 as the methods of choice for this type of analysis. Both technologies offer significant advantages over the conventional precipitation-based detection methods. ICP–MS and ICP–OES achieve exceptional analytical performance, providing multielemental measurements with superior sensitivity, accuracy, and speed.
Matthew Cassap is with Thermo Fisher Scientific, Cambridge, United Kingdom.
(1) Pharmacopeial Forum, Chapter <232> Elemental Impurities – Limits 36(1), (2010). http://www.usp.org/pdf/EN/hottopics/232ElementalImpurities.pdf.
(2) Pharmacopeial Forum, Chapter <233> Elemental Impurities – Procedures 36(1), (2010). http://www.usp.org/pdf/EN/hottopics/233ElementalImpuritiesProcedures.pdf.
(3) T. Wang et al., J. Pharm. & Biomed. Anal. 23, 867–890 (2000).
(4) USP Heavy Metals Testing Methodologies Workshop, held August 26–27, 2008, http://www.usp.org/pdf/EN/hottopics/2008-MetalsWorkshopSummary.pdf.