A Multidetector Approach to Reduce Uncertainty in Extractable and Leachable Analysis and Drug Impurity Characterization

An important aspect of ensuring drug product quality is characterization of extractables and leachables (E&Ls) from pharmaceutical packaging following the guidance in USP <1663> and <1664>. Similarly, chemical characterization per ISO 10993 has become an integral component of biocompatibility testing of medical devices.

A major concern regarding the accuracy of extractables and leachables studies is quantitative error due to response factor (RF) variation. Surrogate standards are frequently applied in E&L analysis as many extractables do not have commercially available standards, and equal concentrations of different extractables give different signal responses using mass spectrometry detectors. Recent publications have highlighted the risks posed by RF variation for both LC/MS (Jordi et al. Journal of Pharmaceutical and Biomedical Analysis 150 (2018) 368–376) and GC/MS (Jenke and Odufu, Journal of Chromatographic Science 2012;50:206–212).

The significance of RF variation has been reflected in the addition of an uncertainty factor (UF) in the calculation of the analytical evaluation threshold (AET). While this approach aids in mitigating the risks of underreporting extractables, the resulting revised AET creates significant analytical challenges often exceeding the limit of detection (LOD) of current instrumentation requiring sample concentration. It is also one of the key issues at the root of poor reproducibility in recent high profile interlaboratory studies. It is therefore strongly desirable to develop methods for quantitation with more consistent RFs which mitigate the need for large UFs.

In this webinar, a multidetector approach for quantitation using the combined strengths of triple detection liquid chromatography mass spectrometry (LC/MS) with ultraviolet (UV) and charged aerosol detection (CAD) as well as Gas Chromatography Mass Spectrometry (GC/MS) with simultaneous Flame Ionization Detection (FID) will be presented. Data comparing the response factors for over 200 extractables by UV, MS, FID and CAD will be summarized showing which detectors provide reduced RF variation. An approach will be presented to reduce RF variation and the need for UFs through optimized detector and standard selection. Finally, the potential benefits of the multidetector approach for drug impurity characterization will be discussed as it relates to screening for low level mutagenic impurities.

Presenter: Dr. Mark Jordi (President, Jordi Labs)

Presenter: Ann Thayer (Contributing Editor, C&EN Media Group)