LAUSR

Abstract Background Following the introduction of new stability-indicating related substances methods, an unknown impurity was observed in levothyroxine (LeMI) and liothyronine (LiMI) tablets (ADVANZ PHARMA) in concentrations ≥1.0%, from 6 months of storage onwards. The impurity was identified as a Maillard condensation product between lactose and LeMI/LiMI in the LeMI and LiMI tablets, respectively. Materials and Methods To establish the toxicity profile of LeMI and LiMI in humans and to define appropriate shelf-life specification limits, a comprehensive nonclinical toxicological assessment was performed, including in silico (Leadscope and Derek Nexus analyses), in vitro (Ames test), and in vivo tests (7-day dose range finding and 90-day dose repeat studies in rats). In silico analyses indicated that potential LeMI and LiMI structures should not be considered bacterial mutagens or in vitro/in vivo clastogens, and that at the low oral exposure levels expected, the impurities are unlikely to cause harm. Results In vitro testing showed that neither LeMI nor LiMI were cytotoxic or mutagenic at up to 5000 μg/plate, both in the presence and absence of metabolic activation. The 2 in vivo studies further confirmed that no systemic toxicity or other notable negative effects were evident at up to 200 μg/kg/day for LeMI and 45 μg/kg/day for LiMI, the highest doses tested. These doses represent 120–122 times the maximum daily exposures of LeMI and LiMI, based on body surface area (μg/m2). Conclusions Based on these results, a proposal has been formulated to increase the limits of Maillard condensation products to ≤8.0% for LeMI and ≤6.0% for LiMI at shelf life.