The analysis of elemental impurities in pharmaceuticals is, like other analytical tests, primarily intended to ensure patient safety.
Potential elemental impurities in pharmaceuticals have been analyzed for many years, with various methods featured in pharmacopoeias around the world. As the world has become more connected, safety and quality compliance within the pharmaceutical industry
the industry began to harmonize. For elemental impurity testing, this harmonized work is apparent in the International Council for Harmonization (ICH) Q3D guidance documents (1,2).
To learn more about elemental impurity analysis, including the importance of this analytical process, commonly used techniques, limitations of current techniques, and potential next steps, Pharmaceutical technology spoke with Alan Cross, Technical Specialist at RSSL.
Patient safety is paramount
Pharma Tech: Why is the analysis of elemental impurities so important in bio/pharma?
Cross (RSSL): Any analytical testing performed on pharmaceutical and biopharmaceutical materials is primarily to ensure that patient safety is maintained. This is done either by confirming that the correct dose of the correct drug substance is being administered or that the dose does not contain any physical or chemical contaminants that could cause harm, or if there are contaminants, that they are below a defined acceptable exposure level. Elemental impurities are no different from any other contaminant, but until recently control of these potentially harmful species was somewhat lacking.
Current elemental testing requirements came into effect in 2018 in the European and United States Pharmacopoeias following the ICH Q3D document on elemental impurities. This document defined the Permissible Daily Exposure (PDE) limits for 24 elements based on sound medical data, which took into account the toxicity of the elements and the route of administration, and is written as such to allow evolution of potential contamination by elemental impurities in all pharmaceutical products. and biopharmaceuticals. This approach has greatly improved patient safety, as it allows for a common approach to controlling elemental impurities based on health risks. Previously, elemental and limit tests were often based on the analytical capabilities of instrumentation or confidence in a “Heavy Metals” colorimetric test, which was insensitive, nonspecific, and prone to poor recoveries (500 parts per million [ppm] of mercury in a sample could still give a satisfactory result).
Suggested techniques and best practices
Pharma Tech: What analytical techniques are commonly used to measure elemental impurities in bio/pharmaceutical products?
Cross (RSSL): Although the ICH guidelines do not include specific recommendations on instrumental methods, the following analytical procedures are suggested in the United States Pharmacopeia (USP) based on the expected concentration of the elemental impurity in the product or component: inductively coupled plasma-mass spectroscopy (ICP–MS)—concentrations in parts per billion (ppb); and Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES) – ppm concentrations. The chapter also defines the recommended analytical procedures for measuring elemental impurities according to these methods.
Both techniques are well suited for the analysis of elemental impurities, as they are able to measure multiple elements simultaneously. Therefore, if a full analysis of all 24 elements is required, these techniques are ideal. ICP-MS and ICP-OES also allow simple screening in which samples are analyzed against a simplified calibration. This can be powerful for performing risk assessments on samples, as described in the ICH Q3D guideline in which 30% PDE can be defined on a product. If three lots of products in production or six lots of products in development tested by the screening method are found to fall below this level, further testing may not be necessary.
As regulations require methods to be validated before use, this allows flexibility for the use of alternative methods. These methods can be considered based on existing capacity, specific sample chemistry, or simplification of analysis if only one or two items require testing. Examples might include Atomic Absorption Spectroscopy (AAS), typically a flame AAS would struggle to achieve the detection levels required for elemental impurity control, but for some elements other forms of AAS may be used which will provide the required detection limits. Vapor generation AAS is sensitive to ppb levels for elements such as arsenic and mercury, and graphite furnace AAS is easily applied to detect lead and cadmium at low levels.
Other techniques that could be used could be microwave plasma atomic emission spectroscopy, a relatively new technique on the market that uses nitrogen as the plasma gas, therefore has relatively low running costs, compared to the ‘ICP-OES which uses expensive argon as plasma gas.
Specific mercury analyzers use the volatile nature of mercury to allow whole, unprocessed samples to be analyzed directly as solids or liquids by heating and measuring the evolved gaseous mercury, simplifying testing and reducing analysis time. analysis and preparation costs.
Pharma Tech: Could you share best practices in terms of analysis for elemental impurities in development?
Cross (RSSL): Sample preparation is as important as the analysis itself. Understanding the behavior of analytes and the sample matrix will allow the development of robust methods.
Limits and advantages of the technique
Pharma Tech: Are there any limitations with current analytical techniques for elemental impurity analysis?
Cross (RSSL): Traditionally, the main problem with elemental analysis, especially in ICP-MS with chemical interferences affecting the accuracy of results, has been that over time many modifications to the basic ICP-MS system have allowed better resolution – with systems such as collision cells and kinetic energy discrimination to eliminate sample interference. These methods are now commonly combined in triple quadrupole systems, which allow for even greater discrimination and reduced detection limits.
All analytical techniques except graphite furnace AAS use solution volumes greater than 1 ml for analysis. This is not problematic if there is a large amount of samples, but it can cause problems when the amount of drug product or substance produced is very small, which is becoming more common in the burgeoning field of biologics and biosimilars. This means using new preparation techniques that can work with small sample amounts and final volumes to maintain the required detection limits, as well as the additional use of sample introduction systems that can work with small volumes, which are currently used in some instruments. fixtures.
Pharma Tech: What about the benefits of current techniques? Could you go through some of them?
Cross (RSSL): The advantage of key analytical techniques, such as ICP-MS, ICP-OES and AAS, is that they are truly multi-element techniques. These systems can analyze, simultaneously or sequentially, the majority of the periodic table. Instrument manufacturers are constantly working towards lower detection limits and better resolution, as well as interference control.
An interest in speciation
Pharma Tech: What trends do you expect to impact elemental impurity analysis in the future?
Cross (RSSL): The food industry has had particular interest in the speciation of certain elements, such as arsenic and mercury, where the form (organic or inorganic) has a large impact on toxicity, and this consideration is also included in the USP/EP/ICH advice. If a pharmaceutical product is found to contain levels of arsenic or mercury above PDE levels, speciation could be used to distinguish between toxic and less toxic forms to demonstrate regulatory compliance .
1.ICH, Q3D(R1) Guideline for Elemental Impurities (ICH, March 22, 2019).
2.ICH, Q3D(R2) Guideline for Elemental Impurities (ICH, April 26, 2022).
About the Author
Felicity Thomas is the European Editor of Pharmaceutical Technology Group.
Flight. 46, No. 6
When referencing this article, please cite it as F. Thomas, “Ensuring Patient Safety Through Elemental Impurity Analysis,” Pharmaceutical technology 46 (6) 2022.