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Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
With timelines closing in for drug product manufacturers to finalize their nitrosamine risk assessments, recalls due to Nitrosamine Drug Substance-Related Impurities (NDSRIs) are becoming more frequent. Latest instance involves recall of multiple lots of Unisom Sleepminis, an over-the-counter (OTC) sleep aid containing antihistamine drug Diphenhydramine HCl by Chattem, Inc, in the United States. As per USFDAs RAIL guidance and Nitrosamine Guidance, drug product manufacturers and applicants must complete their risk assessment of products for NDSRI formation, conclude confirmatory testing, and implement control measures by August 2025.
The recall was initiated after detecting the NDSRI, N-nitroso-desmethyl-diphenhydramine (N-DPH), above the FDA’s recommended intake limit of 26.5 ng/day. This marks the first reported case of a Diphenhydramine HCl medicine being recalled due to an NDSRI impurity
Nitrosamines are formed through nitrosation reactions, which involve amines (especially secondary and tertiary amines) reacting with nitrosating agents like nitrites. NDSRIs, arise from the nitrosation of amine functional groups present in APIs, API degradants, intermediates, or impurities. These impurities may form during API or Formulation product manufacture or during storage of the products.
The pharmaceutical active Diphenhydramine HCl has a tertiary amine functional group in the structure. The common roues of synthesis for Diphenhydramine  is reaction between a Benzhydryl halide (e.g. Benzhydryl bromide or chloride) and 2-Dimethylaminoethanol (or dimethylethanolamine). The Benzhydryl halide is obtained by halogenation of benzhydrol.Â
The tertiary amine functional groups are generally less prone to nitrosamine formation compared to secondary amines. But, in the case of Diphenhydramine HCl, the API could also have an impurity with a secondary amine functional group, 2-(diphenylmethoxy)-N-methylethanamine, or Diphenhydramine HCl Impurity A. The impurity can get generated in the API synthesis by reaction between the Benzhydryl halide and monomethylaminoethanol (a secondary amine impurity) that could be present in Dimethylaminoethanol. This Diphenhydramine HCl Impurity A.has a limit of 0.5% in the API, as per USP and EP.
Diphenhydramine has increased risk of formation of the NDSRI impurity due to tertiary amine functional group as well as the secondary amine functional group in the impurity Diphenhydramine HCl Impurity A. The synthesis of Diphenhydramine HCl do not have nitrosating reagents in reaction. However presence of nitrite impurities or nitrosating agents in excipients or other process ingredients can cause generation of nitrosamine impurities. The Diphenhydramine capsules typically contain excipients like Lactose Monohydrate, Corn Starch, Gelatin, Polysorbate, Anhydrous Citric Acid. These excipients are inherently not high risk carriers of nitrites or nitrates, though Lactose Monohydrate can have trace amounts of nitrites. Process water could be another source of nitrites / nitrosating agents. Water treatment methods, such as chloramination or ozonization, introduce reactive nitrogen species (chloramines, nitrites, nitrates) that facilitate nitrosamine formation.
The incidence of NDSRI in Diphenylhydramine HCl underscores the importance of proactive Nitrosamine risk management in pharmaceutical manufacturing. There should be a robust risk assessment and control strategies for excipients, process water to manage nitrosating impurities. This shall include
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