Elemental impurities testing is a critical pharmaceutical quality control measure to ensure drug product safety and efficacy. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline Q3D and United States Pharmacopeia (USP) Chapters <232>/<233> recommend that elemental impurities be evaluated using a risk-based assessment. Yet, practical application of these guidelines is plagued by various technical issues. A paper published in the Journal of Trace Elements and Minerals by James Harrington of Research Triangle Institute (RTI International) and co-author Donna Seibert examines these issues in depth and offers insight into standardization of analytical practice and method transferability enhancement. The following is an overview of their paper on critical issues, best practices, and possible future directions of research that can further enhance elemental impurities testing in drug product quality control.
Challenges of Standardization of Laboratory Practice
One of the most significant issues identified in the research is diversity of laboratory practices despite using standard techniques like outlined in USP <233>. Laboratories produce variants of analytical techniques, which can potentially affect comparability and uniformity of results. Specific issues include:
- Variable Preparation Techniques: There were differences in total digestion and exhaustive extraction method acid mixture techniques, it was learned in this report. Hydrochloric acid, for instance, was not suitable as most of those microwave digestion systems at that time were not capable of safely containing it. The consequence was that hydrochloric acid was excluded from digestion mixtures in some laboratories, which impacted method standardization. Choice of mercury stabilizers, i.e., gold, also varied due to instrumentation contamination issues as gold’s “stickiness” impacted instrument operation.
- Microwave Digestion System Variations: There is also variation in microwave systems programming, where there are systems that allow maximum temperature digestion while there are systems that allow digestion based on maximum internal pressure. With variation in vessel configurations and digestion time, these two complicate standardization of methods in laboratories.
- Interference Correction Variability: Precise determination of elements using techniques like inductively coupled plasma mass spectrometry (ICP-MS) was also not an uncomplicated process with interference correction being critical to it. Various labs used various methods, which included using collision cell or reaction cell gases, while others used instrument software-supported interference correction equations. All of these variations complicated comparing their influence on analytical reproducibility and accuracy.
Critical Considerations for Method Transfer
To overcome these difficulties and enable successful method transfer among laboratories, the research highlights the best practices outlined below:
- Standard Operating Procedures (SOPs) clearly defined: Well-drafted SOPs that address potential variation in data collection are of utmost significance. SOPs also need to provide instructions on method parameters to avoid any inconsistency.
- Method Development and Validation: A detailed method development procedure, in fact, mini-validation process, is necessary. This entails exploration of various methods to establish which method to employ for specific elements and matrices. Target elements and analysis intent—the complete extraction or total digestion—ought to be well-defined by laboratories following an overall risk assessment that includes both geogenic and anthropogenic risks.
- Risk-Based Approach: The article stresses that there has to be a risk-based approach, which is advocated by ICH Q3D and USP <232>/<233>. There should be procedures to be established to address elemental impurities, based on drug compound origins and potential contaminants.
- Use of Semiquantitative and Nontargeted Analysis: The application of wide-panel semiquantitative methods alongside nontargeted analysis while developing methods can identify unforeseen impurities and assist in overall risk assessment.
Future Directions of Elemental Impurity Analysis
The study points to various areas that require further studies to enhance elemental impurity analysis in pharmaceutical quality control:
- Mercury Behavior and Loss: Mercury’s tendency to be lost to analysis over time remains the biggest challenge. Additional research into its chemical behavior and methods of stabilizing it would add to confidence in mercury analysis and support more extensive risk assessment.
- Speciation analysis: Although not traditionally associated with elemental impurities analysis, speciation—the identification of an element’s individual species—is perhaps what may further support risk assessments. Understanding impurities speciation of drug substances might avoid unnecessary testing and provide an improved picture of real risks.
- Physical Product Characterization: Elemental analysis and physical product characterization can be used together to further identify sources and properties of impurities, enabling more specific quality control measures.
Conclusion
The studies of Harrington and Seibert identify issues facing elemental impurities analysis in pharmaceutical quality control and the potential for wider standardization and method transfer. By reducing problems of method of preparation, correction of interferences, and instrument variation, laboratories can increase analysis precision and uniformity. Tight SOPs, rigorous method development, and risk-based approach is an important step in this ultimate path. In the years to come, other studies on behavior of mercury, speciation, and physical analysis can enhance accuracy and efficiency of elemental impurities analysis, further ensuring pharmaceutical safety and meeting regulatory requirements.
