Safety evaluation of 8 drug degradants present in over-the-counter cough and cold medications.

Although the United States Food & Drug Administration (FDA) has provided guidance on the control of drug degradants for prescription drugs, there is less guidance on how to set degradant specifications for FDA OTC monograph drugs. Given that extensive impurity testing was not part of the safety paradigm in original OTC monographs, a weight of evidence (WOE) approach to qualify OTC degradants is proposed. This approach relies on in silico tools and read-across approaches alongside standard toxicity testing to determine safety. Using several drugs marketed under 21 CFR 341 as case studies, this research demonstrates the utility of a WOE approach across data-rich and data-poor degradants. Based on degradant levels ranging from 1 to 4% of the maximum daily doses of each case study drug and 10th percentile body weight data for each patient group, children were recognized as having the highest potential exposure relative to adults per body mass. Depending on data availability and relationship to the parent API, margins of safety (MOS) or exposure margins were calculated for each degradant. The findings supported safe use, and indicated that this contemporary WOE approach could be utilized to assess OTC degradants. This approach is valuable to establish specifications for degradants in OTCs.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ToxStrategies, LLC received consulting fees from the Consumer Healthcare Products Association (CHPA; Washington, DC) Quality/Manufacturing Committee – Impurities Working Group for conducting and reporting this work. ToxStrategies, LLC is a consulting firm that provides services to private and public organizations on toxicology and risk assessment issues. The work reported in this article was conducted by the authors during the normal course of employment, and no authors received personal fees. DW is an Associate Editor at Regulatory Toxicology and Pharmacology. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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