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A new book by Robert Thomas, principal consultant at Scientific Solutions, provides a training tool for novices and inexperienced users of plasma spectrochemistry as well as for supervisors and senior management who want to better understand the analytical issues. Measuring Elemental Impurities in Pharmaceuticals: A Practical Guide, published on Feb.
A new book by Robert Thomas, principal consultant at Scientific Solutions, provides a training tool for novices and inexperienced users of plasma spectrochemistry as well as for supervisors and senior management who want to better understand the analytical issues. Measuring Elemental Impurities in Pharmaceuticals: A Practical Guide, published on Feb. 2, 2018, was written in response to new directives described in the new United States Pharmacopeia (USP) Chapters <232>, <233>, and <2232>, together with new guidelines drafted by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Pharmaceutical Technology spoke with Thomas to discuss the new book.
PharmTech: Who will benefit the most from this new book?
Thomas: It is intended to be a training resource for people in the pharmaceutical industry, who have been tasked with using inductively coupled plasma optical emission spectrometry (ICP-OES) or inductively coupled plasma mass spectrometry (ICP-MS) to carry out the measurement of elemental impurities in pharmaceutical materials and dietary supplements. It is important to emphasize that pharma manufacturing companies have never really been required to use plasma spectrochemical techniques before. ICP-MS in particular has been considered more applicable to the demands of the drug development process. For that reason, it has primarily been used by R&D groups who have analytical chemists with a high level of expertise. With the approval of these new USP chapters and ICH guidelines, pharmaceutical labs will have to either invest in this new technology or send samples out to a contract lab for testing. If it is done in-house, they could be asking technician-level people to operate this equipment, who have little experience in using sophisticated analytical instrumentation.
In particular, USP Chapter <233> requires the operator to have experience and competence in dissolving pharmaceutical matrices with microwave digestion techniques using concentrated mineral acids, developing robust analytical methods using ICP-OES or ICP-MS, understanding how to carry out accurate spike recoveries, and having expertise to conduct meaningful validation protocols described in the chapter. Plasma spectrochemical techniques are powerful in the hands of experts and can produce data of the highest quality. However, in the hands of a novice or inexperienced user, they have the potential to generate inaccurate and imprecise data. This means they will need hands-on training to help them become more familiar with the techniques. To support a hands-on training course, the book will be a useful resource as a supplemental training tool, in addition to being a stand-alone reference guide.
PharmTech: Can you explain the differences in using ICP-MS vs. ICP-OES for measuring elemental impurities in pharmaceutical materials, and why ICP-MS would be preferable?
Thomas: Both ICP-OES and ICP-MS use an inductively coupled plasma (ICP) to excite and/or ionize the sample’s elemental impurities. However, ICP-OES uses the high temperature plasma to generate photons and to separate them into specific wavelengths characteristic of each element using a high resolution optical spectrometer. Whereas, ICP-MS uses the plasma discharge to generate positively-charged ions that are separated by their mass-to-charge ratio using a mass spectrometer. A brief overview of the fundamental principles and performance differences between each of the techniques is given in the following.
ICP-OES is available in radial and axial view configurations.
Radially-viewed ICP-OES is a multi-element technique that uses a traditional radial (side-view) ICP to excite ground-state atoms to the point where they emit wavelength-specific photons of light that are characteristic of a particular element. The number of photons produced at an element-specific wavelength is measured by a high resolution optical spectrometer and a photon-sensitive device, such as a photomultiplier tube or a solid state detector. This emission signal is directly related to the concentration of that element in the sample. The analytical temperature of an ICP is approximately 6000–7000 °K, compared to that of a flame or a graphite furnace, which is typically 2000–3000 °K.
For the majority of elements, a radial ICP instrument can achieve detection capability in the order of 0.1–100 parts per billion (ppb) levels with an analytical range up to 10–1000 parts per million (ppm), depending on the emission wavelengths used. The sample requirement for ICP-OES is approximately 1 mL/min. ICP-OES is capable of aspirating samples containing up to 10% total dissolved solids, but for optimum performance, that concentration is usually kept below 2%. ICP-OES is a rapid multi-element technique, so sample throughput for the 24 elements described in USP Chapter <232> is in the order of 15 samples an hour.
Axially-viewed ICP-OES uses exactly the same plasma as a radial ICP-OES, except that the plasma is viewed horizontally (end-on). The benefit is that more photons are seen by the detector and, for this reason, detection limits can be as much as an order of magnitude lower, depending on the design of the instrument. The disadvantage is that the working range is also reduced by an order of magnitude. As a result, for the majority of elements, an axial ICP instrument can achieve detection capability in the order of 0.01–10 ppb levels with an analytical range up to 1–100 ppm, depending on the emission wavelength used. The other disadvantage of viewing axially is that more matrix interferences are observed, which means that the total dissolved solids content of the sample needs to be kept much lower. Sample flow requirements are the same as for radial ICP-OES. Sample throughput is the same as in radial ICP-OES.
The generation of such large numbers of positively charged ions allows ICP-MS to achieve detection limits approximately three orders of magnitude lower than ICP-OES. As a result, for the majority of elements, an ICP-MS instrument can achieve detection capability in the order of 0.0001–1 ppb with an analytical range of up to 0.1–100 ppm using pulse counting measurement. The analytical range can be extended even further, up to 100–100,000 ppm by using analog counting techniques. However, it should be emphasized that if such large analyte concentrations are being measured, expectations should be realistic about also carrying out ultra-trace determinations of the same element in the same sample run.
The sample requirement for ICP-MS is approximately 0.1-1 mL/min, and is capable of aspirating samples containing up to 10% total dissolved solids for short periods with the use of specialized sampling accessories. However, because the sample is being aspirated into the mass spectrometer, for optimum performance, matrix components should ideally be kept below 0.2%. This is particularly relevant for laboratories that experience a high sample workload. Sample throughput will be approximately 15 samples per hour, for the determination of 24 elements defined in USP Chapter <232>.
There is no question that ICP-MS is more suitable for pharmaceutical-type samples, because of its lower detection capability. If the pharmaceutical raw material or final product is a solid material, it has to be prepared for analysis by digesting with strong acids, diluted, and made up to a final volume with a suitable solvent. Once the sample preparation has been carried out, the elemental impurities in solution will be 50–500 times lower than in the initial solid material, depending on the dilution factor used. In many cases, the detection capability of ICP-OES just would not be good enough. In addition, some of the permitted daily exposure (PDE) limits defined in the parenteral and inhalation drug categories are one to two orders of magnitude lower than oral drug PDE levels. It is also worth emphasizing that if the total arsenic and mercury PDE limits are exceeded, a speciation analysis has to be carried out to quantify both the inorganic and organic forms of the elements. Although not specifically defined in the method, high-performance liquid chromatography coupled with ICP-MS has become the most common technique for doing speciation analysis.
PharmTech: You spend several chapters in the book going over different types of mass analyzers; what are the scenarios in which a particular type of analyzer is the most appropriate to use, or can they be used collectively for the same sample analysis?
Thomas: The mass separation device, sometimes called the mass analyzer in an ICP-MS system, is the region of the instrument that separates the ions according to their mass-to-charge ratio. This selection process is achieved in a number of different ways, depending on the mass separation device, but they all have one common goal, which is to separate the ions of interest from all other non-analyte, matrix, solvent, and argon-based ions. Single quadrupole mass filters are by far the most common mass analyzers, but there are also magnetic sector systems,time-of-flight (TOF) mass spectrometer and triple quad systems. In addition, collision reaction cell technology is often used in conjunction with quadrupole mass analyzers to reduce polyatomic spectral interferences
An ICP-MS using any of the mass separation devices described in the book can be used for measuring elemental impurities in pharmaceuticals. However, in my opinion, single quadrupole technology, which represents about 80% of all ICP-MS systems installed, is probably best suited for routine-type applications. In addition, triple quad technology and magnetic sector spectrometers typically requires a higher level of expertise to run them and also have a price tag approximately twice as high as single-quad ICP-MS or TOF technology. These technologies are covered in the book because they are all commercially available and, in the hands of the appropriate-skill level analyst, can generate high quality data for pharmaceutical samples.
1. USP, “Elemental Impurities in Pharmaceuticals: Updates,” accessed Feb. 16, 2018.
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