Inductively Coupled Plasma for Detecting Impurities
Detection Methods | Inductively Coupled Plasma for Detecting Impurities
By Matthew Cassap
The USP uses precipitation-based detection methods for analyses; however, these techniques do not deliver the high level of accuracy necessary and can lead to false negative results. As a consequence, trace elements are not fully detected in pharmaceutical products.
The United States Pharmacopeia (USP) is proposing changes to how drug manufacturers detect trace elemental impurities in pharmaceuticals. The proposed USP chapters, 232 and 233, will place greater emphasis on the use of instrument-based detection methods for analyses.
Currently, the USP uses precipitation-based detection methods for analyses; however, these techniques do not deliver the high level of accuracy necessary and can lead to false negative results. As a consequence, trace elements are not fully detected in pharmaceutical products. The USP is proposing a change to legislation that will lower limits for trace elements in pharmaceuticals.
New analysis methods 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.
This article describes the use of ICP-MS and ICP-OES for the determination of trace elements in pharmaceutical products and explains how these techniques can facilitate compliance with emerging legislative requirements.
Proposed general chapter 232 aims to set limits on the amounts of elemental impurities in pharmaceuticals.1 The chapter applies to drug substances, drug products (including natural source and rDNA biologics), and excipients. The limits presented in this chapter are based on 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 that are categorized into two classes. Class 1 elemental impurities, because of their high toxicity to humans and deleterious environmental effects, should be essentially absent from pharmaceutical products. 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 during drug substance or excipient production.
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 each component of a pharmaceutical product to meet 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.
Having recognized the need for optimal product safety, the USP has proposed two new chapters that set lower detection limits for metal impurities in pharmaceuticals while introducing the use of automated instrument-based ICP detection methods for metals analysis.
Chapter 233 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.2 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 user’s responsibility. However, an alternative procedure will require complete validation of the technique being used and confirmation of 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’s chapter 231, now being replaced by chapters 232 and 233, specifies a wet chemical screening method for metals testing that has been used for more than 100 years. This is a subjective visual test based on precipitation of metal sulfides out of an aqueous solution, followed by a visual comparison of the color of the test sample with that of a standard lead solution.
Because 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 that samples be ignited and charred before they can be analyzed, a process that can be rather challenging, especially with volatile elements such as mercury and selenium.
As highlighted at a 2008 workshop organized by the Institute of Medicine of the National Academy of Sciences of the United States, several 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.4 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. Overall, these methods, which are non-specific, insensitive, time-consuming, and labor intensive, yield low or no recoveries.
A general consensus by speakers and planning committee experts at the workshop was that precipitation-based methods are inadequate for metals testing and should be replaced by instrumental methods offering greater specificity and sensitivity. Participants acknowledged that state-of-the-art instrumental methods can detect metals of interest at much lower levels. Because they are selective, sensitive, and robust, ICP-MS and ICP-OES have been recognized as the technologies of choice for metals analysis in pharmaceutical products.
The inductively coupled plasma-optical emission spectrometer shown here ensures compliance with proposed USP chapters on detecting trace elemental impurities.
Trace Metals in Pharmaceuticals
The multi-element 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 more complex detection methods like gas chromatography (GC).
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 instrumentation is extremely powerful, with low detection capabilities and the ability to resolve complex spectra. In addition, this new technology has the necessary wavelength range for the analysis of 167 nm to 847 nm, enabling the analysis of all elements that emit light between these two values. This capability is significant for a number of reasons. The low wavelength access enables the most sensitive wavelength for arsenic and mercury to be reached, while also offering the ability to access interference-free wavelengths, critical for the analysis of elements that produce a high number of emission lines, such as osmium, iridium, platinum, and palladium.
ICP-OES can identify and quantify 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 test for 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, which typically takes less than two minutes per sample analyzed, in contrast to the wet chemistry-based methods currently used by the USP, which often require up to 24 hours for sample preparation alone.
Currently, the USP uses precipitation-based detection methods for analyses; however, these techniques do not deliver the high level of accuracy necessary and can lead to false negative results.
Compared with precipitation-based methods, ICP-OES delivers definitive identification; the technique eliminates inter-element interferences and the associated inaccuracies. ICP-OES can also accurately determine metal content 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 ultra trace levels. As a consequence, accurate measurement of trace metals in pharmaceutical products is of utmost importance to ensure that the products are contaminant free and do not pose a toxicity risk to patients. Having recognized the need for optimal product safety, the USP has proposed two new chapters that set lower detection limits for metal impurities in pharmaceuticals while introducing the use of automated, instrument-based ICP detection methods for metals analysis.
ICP-MS and ICP-OES are recognized by the USP as the preferred techniques for the detection of trace elements in pharmaceutical products, offering considerable advantages over the more traditional precipitation-based methods. Overall, the methods offer exceptional analytical performance, sensitivity, and speed for multi-elemental measurements in complex matrices.
U.S. Pharmacopeial Convention. Chapter 232: Elemental impurities—limits. Pharmacopeial Forum. 2010;36(1). Available at: www.usp.org/pdf/EN/hottopics/232ElementalImpurities.pdf. Accessed December 11, 2010.
U.S. Pharmacopeial Convention. Chapter 233: Elemental impurities—procedures. Pharmacopeial Forum. 2010;36(1). Available at: www.usp.org/pdf/EN/hottopics/233ElementalImpuritiesProcedures.pdf. Accessed December 11, 2010.
Wang T, Wu J, Hartman R, et al. A multi-element ICP-MS survey method as an alternative to the heavy metals limit test for pharmaceutical materials. J Pharm Biomed Anal. 2000; 23(5):867-890.
USP Heavy Metals Testing Methodologies Workshop: Summary. August 26-27, 2008. Available at: www.usp.org/pdf/EN/hottopics/2008-MetalsWorkshopSummary.pdf. Accessed December 11, 2010.