How Do We Improve Elemental Impurity Analysis in Pharmaceutical Quality Control?

Assessing elemental impurities is outlined in International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline Q3D and United States Pharmacopeia (USP) Chapters <232>/<233>, both of which foster a risk-based approach (1,2). However, implementing this approach does result in several technical challenges that need to be addressed. Recently, a published study in the Journal of Trace Elements and Minerals aimed to address the technical challenges laboratories face while following this approach (1).

Spectroscopy sat down with James Harrington of Research Triangle Institute (RTI International) in Research Triangle Park, North Carolina, who was the lead author of this study, as well as coauthor Donna Seibert of Kalamazoo, Michigan, to discuss their study. In this final part of our conversation with Harrington and Seibert, they discuss the main challenges that they encountered in their study and how we can improve elemental impurity analysis in pharmaceutical quality control.

James Harrington (right) and Donna Seibert (left), authors of this study. | Image Credit: © James Harrington and Donna Seibert

What were the main challenges identified in standardizing laboratory practices, particularly in interference correction and preparation method selection?

Every laboratory has its unique flavor of analytical chemistry. Even within a standard method, there is a possibility that different laboratories will bring their tweaks to achieve the same results. Some examples that we encountered in this study were variations in the acid mixtures for the total digestion and exhaustive extraction method, the stabilizing agent selected for mercury, the gases used for collision cell correction, and the temperature and pressure settings for microwave digestion systems. One of the biggest discussions we had with participant laboratories was using hydrochloric acid in the preparation method. Many microwave manufacturers at the time were early in their implementation of technologies that could safely allow digestion with hydrochloric acid, and so many of the laboratories weren’t able to include that in their digestion mixture, which is why it was not included in the exhaustive extraction method. Similarly, we designed the method to include gold in the preparation because it’s a common stabilizer for mercury. Several laboratories elected not to include gold because they had concerns regarding contamination of their systems due to the stickiness of the element.

Another challenge arose from differences between microwave systems. Some microwaves allow users to program digestion methods based on maximum temperature, and some based on maximum internal pressure. Although these are related, it is challenging to standardize a method when the temperature, pressure, vessel type, and digestion time influence each other and may be specific to each setup.

With regards to the interference correction, the biggest challenge with standardization was the factor that we discussed earlier regarding the use of collision cell or reaction cell gases. However, there is another approach that is seen in the analytical industry, involving the use of interference correction equations. Only one laboratory explicitly mentioned doing that here, although some systems automatically include that process in their processing software, making it difficult to assess the impact of this approach on analytical accuracy and variability.

Based on your findings, what are the key considerations for successfully transferring elemental impurity (EI) analysis methods between laboratories?

Some of the key best practices that we identified are clear and explicit standard operating procedures (SOPs) that are designed to account for variability in collected data and a thorough and careful method development and validation period that characterizes several different approaches, akin to a miniature validation. Entering method development with a clear understanding of the list of target elements and the goal for the digestion (that is, total digestion or exhaustive extraction), based on a thorough risk assessment that accounts for geogenic and anthropogenic hazards, is critical for ensuring that element-specific methods are in place. Nontargeted analysis and semiquantitative broad panel analysis can play a role in this process.

Given the remaining technical challenges, what further research or improvements do you see as necessary to enhance elemental impurity analysis in pharmaceutical quality control?

Additional research on the behavior of mercury that resulted in significant loss over time can help to characterize broader risk trends. This can also be combined with physical analysis of some products to support this understanding. Although speciation is not often accounted for in elemental analysis, it can provide a foundation for more refined risk assessment based on the natural sources of pharmaceutical ingredients. This is an area that is not accounted for in our study but could be interesting in some specific cases to further mitigate unnecessary testing and provide a better picture of actual risk in pharmaceutical products.

References

1. Harrington, J. M.; Seibert, D. S.; Williams, G.; et al. The Product Quality Research Institute Elemental Impurity Interlaboratory Study: Results and Implications for Industry. J. Trace Elem. Miner. 2025, 12, 100227. DOI: 10.1016/j.jtemin.2025.100227
2. Thermo Fisher Scientific, Elemental Impurities Analysis Information. Thermo Fisher. Available at: https://www.thermofisher.com/us/en/home/industrial/pharma-biopharma/pharma-biopharma-learning-center/pharmaceutical-qa-qc-information/elemental-impurities-information.html (accessed 2025-05-09).