Leachable-Derived Impurities in Oral Solid Dosage Forms Generated by Solid-State Packaging-Excipient Interactions: A...

Background/Objectives: Oral solid dosage (OSD) forms are historically categorized as low-risk vectors for leachables under the assumption that solid-state matrices impose severe kinetic barriers against migrant migration and reactivity. This study investigates an unexpected unknown impurity, detected as part of a routine ICH Q3B testing program to control drug product impurities in a blister-packed tablet. Since the impurity exceeded the ICH Q3B identification threshold applicable for this drug product (1.0% w/w relative to API or 5 µg total daily intake (TDI), whichever is lower), a forensic investigation into the origins and identity of the impurity was performed. Methods: Placebo and packaging line studies were performed to isolate the origin of the impurity. Systematic structure elucidation was carried out using high-resolution mass spectrometry (HRMS), isotopic fine structure analysis, and de novo chemical synthesis. To enable definitive characterization, preparative HPLC was utilized to isolate the compound for high-field 2D-NMR spectroscopy (801 MHz). Results: The impurity was proven to be independent of active pharmaceutical ingredient degradation, forming only when tablet excipients were stored in sealed PVC blister packaging. Co-incubation of the PVC heat stabilizer derivative dimethyltin bis(2-ethylhexyl mercaptoacetate) (DMTE) with pyrrolidin-2-one (a povidone excipient degradation product) generated an identical chromatographic and MS/MS spectral profile. NMR spectroscopy unambiguously identified the structure as 2-ethylhexyl 2-((5-oxopyrrolidin-2-yl)thio)acetate. Conclusions: This study provides the first direct evidence of an organotin-catalyzed solid-state reaction between a packaging leachable and a tablet excipient under 25 °C/60% RH storage conditions. While this implies that the impurity should not be evaluated under the ICH Q3B guidelines, the findings directly challenge the assumed "low-risk" status of OSD packaging regarding leachables and highlight the necessity for interaction-focused, chemistry-based risk assessments, as outlined in emerging ICH Q3E guidelines.