Elemental Impurity Analysis Crucial to Patient Safety

Potential elemental impurities in drug products have been analyzed for many years, with various methods presented in pharmacopeias across the globe. As the world has become more connected, safety and quality compliance within the pharmaceutical

industry has begun to harmonize. For elemental impurities testing, this harmonized work is apparent in the International Council for Harmonisation’s (ICH’s) Q3D guidance documents (1,2).

To learn more about elemental impurities analysis, including the importance of this analytical process, the techniques that are commonly employed, limitations of current techniques, and potential next steps, Pharmaceutical Technology spoke with Alan Cross, technical specialist at RSSL.

Patient safety is paramount

PharmTech: 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 performed either by confirmation that the correct dose of the correct drug substance is being administered or that the dose has no physical or chemical contaminants that may 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, the control of these potentially harmful species has been somewhat lacking.

The current elemental testing requirements came into force in 2018 in both the European and United States pharmacopeias following the ICH Q3D document on elemental impurities. This document defined permissible daily exposure (PDE) limits for 24 elements based on robust medical data, which considered the toxicity of the elements and route of administration, and it is written as such to allow for consistent evolution of potential elemental impurity contamination across all pharmaceutical and biopharmaceutical products. This approach has greatly improved patient safety, as it allows for a common approach to controlling elemental impurities based on health risks. Prior to this, elemental testing and limits were often based on the analytical capabilities of the instrumentation or reliance on a colorimetric ‘Heavy Metals’ test, which was insensitive, unspecific, and prone to poor recoveries (500 parts per million [ppm] of mercury in a sample could still give a passing result).

Suggested techniques and best practices

PharmTech: What analytical techniques are commonly employed to measure elemental impurities in bio/pharmaceutical products?

Cross (RSSL): Although ICH guidelines do not include any specific recommendations on instrumental methods, the following analytical procedures are suggested in United States Pharmacopeia (USP) <233> dependent on the expected concentration of the elemental impurity in the product or component: inductively coupled plasma–mass spectroscopy (ICP–MS)—parts-per-billion (ppb) concentrations; and inductively coupled plasma–optical emission spectroscopy (ICP–OES)—ppm concentrations. The chapter also sets out recommended analytic procedures for measuring elemental impurities to these methods.

Both techniques are ideally suited to elemental impurity analysis, as they are able to measure multiple elements simultaneously. Therefore, if a full analysis of the 24 elements is required, these techniques are ideal. Both ICP–MS and ICP–OES also allow for a simple screen to take place whereby samples are analyzed against a simplified calibration. This can be powerful in performing risk assessments on samples, as described in the ICH Q3D guideline in which 30% of PDE can be set on a product. If three lots of in-production or six lots of development product tested by the screening method and are shown to be below this level, then further testing may not be required.

As the regulations insist that methods are validated prior to use, this allows flexibility for alternative methods to be used. These methods may be considered based on existing capability, specific chemistry of samples, or simplification of analysis if only one or two elements require testing. Examples might include, atomic absorption spectroscopy (AAS), typically a flame AAS would struggle to achieve the required levels of detection for elemental impurities control but for some elements other forms of AAS can 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 may be employed might be microwave plasma atomic emission spectroscopy, a relatively new technique to the market which uses nitrogen as a plasma gas so has relatively low running costs, when compared to ICP-OES which uses expensive argon as a plasma gas.

Specific mercury analyzers utilize the volatile nature of mercury to allow untreated whole samples as solids or liquids to be analyzed directly by heating and measuring the mercury gas evolved, this simplifies testing and reduces analysis time and preparation costs.

PharmTech: Could you share any best practices in terms of analyzing elemental impurities in development?

Cross (RSSL): Preparation of the samples is as important as the analysis itself. Understanding the behavior of the analytes and the sample matrix will allow for robust methods to be developed.

Technique limitations and advantages

PharmTech: Are there any limitations with current analytical techniques for the analysis of elemental impurities?

Cross (RSSL): Traditionally, the main issue with elemental analysis, particularly in ICP–MS with chemical interferences affecting the accuracy of the results, is that over time many modifications to the basic ICP–MS system have allowed for better resolution—with systems such as collision cells and kinetic energy discrimination to remove interferences from the samples. These methods are now also commonly being combined into triple quadrupole systems, which allow for even greater discrimination and reduction in detection limits.

All analytical techniques, with the exception of graphite furnace AAS, use solution volumes in excess of 1 mL for analysis. This is not problematic if there is a large amount of sample, but it can cause issues when the amount of drug product or substance produced is very small, which is becoming more typical in the bourgeoning biologics and biosimilars field. This means that novel preparation techniques need to be employed that can work with small sample amounts and final volumes to maintain the required detection limits, as well as further use of sample introduction systems that can work with small volumes, which are currently employed in some instrumental set‑ups.

PharmTech: How about the advantages of the current techniques? Could you run through some of those?

Cross (RSSL): The advantage of the key analytical techniques, such as ICP–MS, ICP–OES, and AAS, is that they are truly multi-elemental techniques. These systems can analyze, either simultaneously or sequentially, the majority of the periodic table. The instrumentation manufacturers are constantly working towards lower detection limits and better resolution, as well as interference control.

An interest in speciation

PharmTech: What trends do you foresee impacting elemental impurity analysis in the future?

Cross (RSSL): The food industry has had a particular interest in the speciation of certain elements, such as arsenic and mercury, where the form (organic or inorganic) has a big impact on the toxicity, and this consideration is also included in the USP/EP/ICH guidance. If a drug product is found to have levels of arsenic or mercury exceeding the PDE levels, speciation could be used to discriminate between toxic and less toxic forms to demonstrate compliance with the regulations.

References

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 for Pharmaceutical Technology Group.