Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study

Nanda, Kausik K.; Tignor, Steven; Clancy, James; Marota, Melanie; Allain, Leonardo R.; D'Addio, Suzanne M.

doi:10.1016/j.xphs.2021.08.010

Cited by 44 publications

(25 citation statements)

References 14 publications

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“…Overall, information on N -nitrosamines generated in a prospective fashion in the preclinical discovery phase will be informative with respect to possible designed formulation development steps to avoid or minimize the formation of N -nitrosamines in formulations to support early and late-stage drug development projects. For example, using a model vulnerable amine 4-phenylpiperidine hydrochloride, Nanda et al recently demonstrated robust inhibitory effects on 4-phenylpiperidine N -nitrosation in oral solid dosage forms with the use of antioxidants (e.g., ascorbic acid, sodium ascorbate, α-tocopherol, caffeic acid, etc.) and amino acids (e.g., glycine and histidine).…”

Section: Impact On Preclinical Drug Discoverymentioning

confidence: 99%

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

et al. 2022

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The detection of N-nitrosamines, derived from solvents and reagents and, on occasion, the active pharmaceutical ingredient (API) at higher than acceptable levels in drug products, has led regulators to request a detailed review for their presence in all medicinal products. In the absence of rodent carcinogenicity data for novel N-nitrosamines derived from aminecontaining APIs, a conservative class limit of 18 ng/day (based on the most carcinogenic N-nitrosamines) or the derivation of acceptable intakes (AIs) using structurally related surrogates with robust rodent carcinogenicity data is recommended. The guidance has implications for the pharmaceutical industry given the vast number of marketed amine-containing drugs. In this perspective, the rate-limiting step in N-nitrosamine carcinogenicity, involving cytochrome P450-mediated α-carbon hydroxylation to yield DNA-reactive diazonium or carbonium ion intermediates, is discussed with reference to the selection of read-across analogs to derive AIs. Risk-mitigation strategies for managing putative N-nitrosamines in the preclinical discovery setting are also presented.

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Section: Impact On Preclinical Drug Discoverymentioning

confidence: 99%

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

et al. 2022

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“…[11] The NA formation can be suppressed by antioxidants such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E). [28,29] Where NA or NDSRI formation in drug product formulations cannot be ruled out, the addition of antioxidants should be considered by MAHs.…”

Section: Resultsmentioning

confidence: 99%

Prevalence of nitrosamine contaminants in drug samples: Has the crisis been overcome?

Schmidtsdorff

Neumann

Schmidt³

et al. 2022

Archiv der Pharmazie

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Various drug samples (N = 249; drug substances, tablets, capsules, solutions, crèmes, and more) from the European pharmaceutical market were collected since 2019 and analyzed for 16 nitrosamines (NAs). In 2.0% of the cases, NAs were detected. These findings included four active pharmaceutical ingredients already known for potential NA contamination: losartan (N-nitrosodimethylamine [NDMA] and N-nitrosodiethylamine, simultaneously), valsartan (NDMA), metformin (NDMA) and ranitidine (NDMA). The fifth new finding, which has not been reported yet, discovered contamination of a molsidomine tablet sample with N-nitrosomorpholine (NMor). The tablet contained 144% of the toxicological allowable intake for NMor. NMor was included in our screening from the beginning and is currently the focus of regulatory authorities, but was added to the guidelines only last year. Thus, it may not have been the focus of regulatory investigations for too long. Our results indicate that the majority of drug products in the market are nonhazardous in terms of patient safety and drug purity. Unfortunately, the list of individual affected products keeps growing constantly and new NA cases, such as molsidomine or nitrosated drug substances (nitrosamine drug substance-related impurities [NDSRI]), continue to emerge. We therefore expect nitrosamine screenings to remain a high priority.

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“…Lopez-Rodriguez et al recently reviewed the main mechanisms of nitrosation in detail. There is some evidence that the inclusion of antioxidants such as vitamin C may be a partial solution; − however, the broad use of this would require extensive reformulation of existing DPs, which may or may not be achievable or financially viable. However, this is the case for nitrosamines formed from general secondary amines.…”

Section: Implications For Pharmaceutical Manufacturementioning

confidence: 99%

Drawing a Line: Where Might the Cohort of Concern End?

Ponting

Foster

2023

Org. Process Res. Dev.

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The definitions of the chemical classes in the Cohort of Concern (CoC) by Kroes and co-workers are based on broad structural alerts, in particular for N-nitroso compounds�for which the alert consists essentially of the N−N�O substructure without further refinement. Recent pharmaceutical recalls have focused on the presence of dialkyl N-nitrosamine impurities, some of which are exceptionally potent carcinogens�2 orders of magnitude more potent than the pharmaceutical Threshold of Toxicological Concern (TTC), 1.5 μg/day. However, the class of "N-nitroso compounds" is potentially significantly broader. This Perspective looks at the N-nitroso compounds that are at the edges of the cohort, where changes in mechanism, metabolic activation potential, stability, or indeed toxicity data lead to questions about whether these compounds should be classed as CoC. The critical mechanism of action, metabolic α-hydroxylation leading to a diazonium ion, is presented, along with the pathways by which Nnitroso compounds that are not dialkyl N-nitrosamines can lead to comparable DNA adducts.

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Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study

Cited by 44 publications

References 14 publications

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

Strategies for Assessing Acceptable Intakes for Novel N-Nitrosamines Derived from Active Pharmaceutical Ingredients

Prevalence of nitrosamine contaminants in drug samples: Has the crisis been overcome?

Drawing a Line: Where Might the Cohort of Concern End?

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