Pharmaceuticals

Elemental impurities – staying ahead of changing regulations

By By Dr Amanda Bole* - Senior Analytical Chemist in the Spectroscopy Team, Almac Sciences

The author discusses the implications of the latest global update to the 18th edition of the Japanese Pharmacopeia (JP), which took effect on 1 July this year.  

For pharmaceutical companies to sell their products in different markets, the materials used in those products must meet regional regulations. This poses a challenge for global companies with a global supply chain – as often, raw materials purchased in one country may not meet the regulations to be used in another. The pharmaceutical industry has undergone rapid reform in the analysis of elemental impurities in the past decade, including the most up-to-date technology that meets changing requirements in regulation.

Elemental impurities are extractable elements that may be found in drug products, raw materials, drug substances or even excipients. They may be endogenous, added during the manufacturing process as a catalyst, or as an impurity through interactions with processing equipment. These elements need to be controlled as they do not provide any therapeutic benefit and can be toxic to the patient.

The latest global update concerns the Japanese market – the 18th edition of the Japanese Pharmacopeia (JP), which took effect on 1 July, 2024. This update is significant because it brings the JP in line with the United States Pharmacopeia (USP).

As this landscape continues to evolve, what does the future look like for international harmonisation and how can sponsors stay ahead of changing regulations?

Historically, elemental impurities were assessed individually through a variety of wet chemistry techniques – many of which were antiquated and had been in use for over 100 years. Wet chemistry testing lacks specificity and accuracy, and the limits achievable by these older techniques lack sufficient sensitivity to meet the new limits being issued.

In 2018, the USP took the action to lead the co-ordination of pharmacopeia for international harmonisation of elemental impurity testing in pharmaceutical drug products. This resulted in the issue of chapter USP <233>. Comments were taken from both the European Pharmacopoeia (EP) and JP, which harmonised the testing of elemental impurities globally at the stage and time.

In 2020, the USP, together with the International Conference on Harmonisation of Technical Requirements of Pharmaceuticals for Human Use Elemental Impurities – Scientific Guideline, ICH Q3D, Expert Working Group, established Permitted Daily Exposure (PDE) limits for different routes of administration. This categorised the individual elements into different classifications based on their toxicity (PDE) and likelihood of occurrence in the drug product.

The 2024 update includes a new general notice, General Notice 34, which states that drug products must be assessed appropriately following the Elemental Impurities monograph <2.66> by analysing with Inductively Coupled Plasma-Atomic Emission Spectroscopy (ICP-AES/OES) or Inductively Coupled Plasma-Mass Spectrometry (ICP-MS). Therefore, tests such as heavy metals and element specific monographs have become redundant as the Elemental Impurities monograph covers this requirement. This update brings the JP in line with the USP. These new guidelines also require technologies with the capability to reach very low levels in complex matrices with a high degree of accuracy. ICP-MS or ICP-AES are the only permissible detection techniques that can achieve this and comply with the new USP guidance.

The EP currently still allows alternative measurement techniques for individual elements, like X-ray fluorescence spectrometry and UV-Vis, as well as ICP-MS or ICP-AES. The British Pharmacopeia (BP) still follows EP even after its departure from the European Union. It is unclear how long that will remain the case. According to the EP Harmonisation status for general texts, elaboration on elemental impurities between the EP and USP is ongoing. It is expected that the EP and BP will soon align themselves with ICH Q3D, the USP and the JP requirements for elemental impurities analysis. In the meantime, they remain unaligned – causing issues for pharmaceutical companies all over the globe.

Until the regulations are harmonised globally, determining all elemental impurities by ICP-MS, a method which has been developed and validated in-line with all the above pharmacopoeias, is the only future-proof solution. ICP-MS allows analysis of multiple elements in one method allowing for a quicker turnaround time, high sample throughput and less preparation time. With ICP-MS all these elements can be detected in a single method with high accuracy and precision, as well as high sensitivity. This allows for complete compliance across all regulations without the need to revalidate. The days of the wet chemistry colorimetric methods are long gone and the onus is on pharmaceutical companies to provide evidence that the drug product is safe from metal impurities.

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*Dr Amanda Bole is currently a Senior Analytical Chemist in the Spectroscopy Team in Almac Sciences, where she has worked for three years focusing on ICP-MS. She has over ten years’ experience working in analytical industries in GMP, GLP and ISO accredited laboratories around Northern Ireland. Dr Bole graduated in 2014 with a Master’s Degree in Chemistry from Queen’s University Belfast and then again in 2019 with a PhD in Inorganic and Analytical Chemistry.