Method development and validation for determination of N-nitrosamines in pharmaceutical preparations by LC-MS/MS: Application to extractables and leachables studies

Journal of Chromatography A, Journal Year: 2025, Volume and Issue: 1745, P. 465741 - 465741

Published: Jan. 29, 2025

Language: Английский

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Industrial Case Studies Demonstrating Applicability of ICH M7 Control Options 3 and 4 for Nitrosamine Control

Organic Process Research & Development, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Language: Английский

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An update on the current status and prospects of nitrosation pathways and possible root causes of nitrosamine formation in various pharmaceuticals

Saudi Pharmaceutical Journal, Journal Year: 2022, Volume and Issue: 31(2), P. 295 - 311

Published: Dec. 24, 2022

Over the last two years, global regulatory authorities have raised safety concerns on nitrosamine contamination in several drug classes, including angiotensin II receptor antagonists, histamine-2 antimicrobial agents, and antidiabetic drugs. To avoid carcinogenic mutagenic effects patients relying these medications, established specific guidelines risk assessment scenarios proposed control limits for impurities pharmaceuticals. In this review, nitrosation pathways possible root causes of formation pharmaceuticals are discussed. The by national presented. Additionally, a practical science-based strategy implementing well-established is notably reviewed terms an alternative approach product N-nitrosamines without published AI information from animal carcinogenicity testing. Finally, novel evaluation predicting investigating amine precursors as powerful prevention addressed.

Language: Английский

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Use of the bacterial reverse mutation assay to predict carcinogenicity of N-nitrosamines

Regulatory Toxicology and Pharmacology, Journal Year: 2022, Volume and Issue: 135, P. 105247 - 105247

Published: Aug. 23, 2022

Under ICH M7, impurities are assessed using the bacterial reverse mutation assay (i.e., Ames test) when predicted positive in silico methodologies followed by expert review. N-Nitrosamines (NAs) have been of recent concern as pharmaceuticals, mainly because their potential to be highly potent mutagenic carcinogens rodent bioassays. The purpose this analysis was determine sensitivity predict carcinogenic outcome with curated proprietary Vitic (n = 131) and Leadscope 70) databases. NAs were selected if they had corresponding carcinogenicity assays. Overall, sensitivity/specificity 93-97% 55-86%, respectively. not significantly impacted plate incorporation (84-89%) versus preincubation (82-89%). Sensitivity different between use rat hamster liver induced S9 (80-93% 77-96%). is high DMSO a solvent (87-88%). Based on these databases, conducted under OECD 471 guidelines sensitive for detecting hazards NAs.

Language: Английский

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Quantum-Mechanical Approach to Predicting the Carcinogenic Potency of N-Nitroso Impurities in Pharmaceuticals

Chemical Research in Toxicology, Journal Year: 2023, Volume and Issue: 36(2), P. 291 - 304

Published: Feb. 6, 2023

N-Nitroso contaminants in medicinal products are of concern due to their high carcinogenic potency; however, not all these compounds created equal, and some relatively benign chemicals. Understanding the structure-activity relationships (SARs) that drive hazards one molecule versus another is key both protecting human health alleviating costly sometimes inaccurate animal testing. Here, we report on an extension CADRE (computer-aided discovery REdesign) platform, which used broadly by pharmaceutical personal care industries assess environmental endpoints, predict potency N-nitroso compounds. The model distinguishes three categories with 77% accuracy external testing, surpasses reproducibility rodent cancer bioassays constraints imposed limited (high-quality) data. robustness predictions for more complex pharmaceuticals maximized capturing SARs using quantum mechanics, is, hinging underlying chemistry chemicals training set. To this end, present approach can be leveraged a quantitative hazard assessment offer qualitative guidance electronic structure comparisons between well-studied analogues unknown contaminants.

Language: Английский

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Revisiting the mutagenicity and genotoxicity of N-nitroso propranolol in bacterial and human in vitro assays

Regulatory Toxicology and Pharmacology, Journal Year: 2023, Volume and Issue: 141, P. 105410 - 105410

Published: May 18, 2023

Language: Английский

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

Organic Process Research & Development, Journal Year: 2023, Volume and Issue: 27(10), P. 1703 - 1713

Published: March 14, 2023

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

Language: Английский

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Evaluating the mutagenicity of N-nitrosodimethylamine in 2D and 3D HepaRG cell cultures using error-corrected next generation sequencing

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(6), P. 1919 - 1935

Published: April 7, 2024

Human liver-derived metabolically competent HepaRG cells have been successfully employed in both two-dimensional (2D) and 3D spheroid formats for performing the comet assay micronucleus (MN) assay. In present study, we investigated expanding genotoxicity endpoints evaluated by detecting mutagenesis using two error-corrected next generation sequencing (ecNGS) technologies, Duplex Sequencing (DS) High-Fidelity (HiFi) Sequencing. Both 2D spheroids were exposed 72 h to N-nitrosodimethylamine (NDMA), followed an additional incubation fixation of induced mutations. NDMA-induced DNA damage, chromosomal determined assay, MN ecNGS, respectively. The 72-h treatment with NDMA resulted concentration-dependent increases cytotoxicity, formation, mutation frequency cultures, greater responses observed compared cells. mutational spectrum analysis showed that predominantly A:T → G:C transitions, along a lower exhibited different trinucleotide signature relative negative control. These results demonstrate models can be used assessment DS HiFi Sequencing, caveat severe cytotoxic concentrations should avoided when conducting DS. With further validation, 2D/3D system may become powerful human-based platform testing.

Language: Английский

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Optimizing the detection of N-nitrosamine mutagenicity in the Ames test

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 153, P. 105709 - 105709

Published: Sept. 28, 2024

Language: Английский

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Metabolic activation of short-chain alkyl N-nitrosamines using Aroclor 1254 or phenobarbital/beta-naphthoflavone-induced rat or hamster S9 – A comparative analysis

Toxicology Reports, Journal Year: 2024, Volume and Issue: 12, P. 215 - 223

Published: Jan. 26, 2024

N-nitrosamines, a very heterogeneous class of chemicals, may enter humans in small amounts through various sources and are produced endogenously, too. Some known to be mutagenic carcinogens have recently been detected as impurities several marketed pharmaceuticals. Despite their properties, the suitability bacterial reverse mutation (Ames) assay particular use induced rat liver S9 detect potential, is often discussed. Recently, it could demonstrated that capable metabolizing alkyl nitrosamines exert potential (Bringezu & Simon, 2022). In this project, vitro under different conditions applying preincubation protocol OECD 471-compliant standard Ames test recommendations was investigated. These included fraction from hamster rat, uninduced or with Aroclor 1254 Phenobarbital/beta-Naphthoflavone (PB/NF). The findings indicated addition S9, also effectiveness. Moreover, both fractions exhibited suitable responses terms frequencies. Increasing content did not increase sensitivity test. However, above 20% reduced frequency observed higher concentration range suggesting cytotoxicity bacteria. Thus, limiting 10% provides reliable results relates lower number animals required for production which concordance 3R principles (reduce, refine, replace) animal testing. addition, obtained show similarly effective, doubting requirement pretreating enzyme inducers. Further investigations compare mutagenicity data proteome analyses ongoing.

Language: Английский

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