Regulatory Challenges for Look-Alike and Sound-Alike Non-Biological Complex Drugs: Molecular Fingerprint...

Look-alike and sound-alike (LASA) medications are a critical source of medication errors, posing significant risks to patient safety. This issue is particularly relevant for non-biological complex drugs (NBCDs), whose intricate compositions and manufacturing-dependent properties complicate regulatory assessment and comparability of follow-on products. In this study, we employ high-resolution mass spectrometry (HRMS) techniques, including Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and comprehensive two-dimensional gas chromatography coupled to high-resolution time-of-flight mass spectrometry (GC×GC-HRToF MS), to differentiate between Ichthammol formulations compliant with different pharmacopeia definitions. Despite similar bulk properties, comprehensive molecular-level characterization reveals substantial compositional differences: European Pharmacopeia (Ph. Eur.) compliant samples, which also largely correspond to the U.S. pharmacopeia (USP), predominantly contain sulfonated thiaarenes derived from shale oil, while samples compliant with the Chinese Pharmacopeia (ChP) consist mainly of sulfurized fatty acids and sulfur-linked fatty acid oligomers derived from vegetable oils. Proposed reaction mechanisms describe a classical aromatic sulfonation by sulfuric acid yielding ammonium sulfonates of thiaarenes and, in smaller quantities, ammonium sulfonate arenes in the Ph. Eur. formulations after neutralization with ammonia. In contrast, ChP formulations likely undergo an initial sulfurization via vulcanization, leading to thiophene-containing fatty acids and sulfur-linked oligomers, followed by sulfonation and neutralization. Our findings provide strong evidence for distinct chemical fingerprints, allowing robust differentiation between these complex LASA drugs. These findings were in accordance with the mechanistic pathways for their respective manufacturing processes proposed in this study. These insights highlight the necessity of molecular-level analysis for regulatory assessment of complex pharmaceuticals and underscore the potential risks of relying solely on bulk parameter equivalence in complex drug approval and substitution.