Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA)

Regulatory Toxicology and Pharmacology, Journal Year: 2024, Volume and Issue: 150, P. 105640 - 105640

Published: May 14, 2024

N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike affected the global supply over past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used identify AI limits in some cases; however, this approach is limited by availability robustly-tested matching structural features NDSRIs, which usually contain diverse array functional groups. Furthermore, absence surrogate resulted conservative cases, posing practical for impurity control. Therefore, new framework determining recommended was urgently needed. Here, Carcinogenic Potency Categorization Approach (CPCA) its supporting scientific rationale presented. The CPCA rapidly-applied structure-activity relationship-based method that assigns 1 categories, each with corresponding limit, reflecting predicted carcinogenic potency. considers number distribution α-hydrogens at N-nitroso center other activating deactivating affect α-hydroxylation metabolic activation pathway carcinogenesis. adopted internationally several regulatory authorities simplified starting point determine nitrosamines without need compound-specific data.

Language: Английский

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Quantum Chemical Evaluation and QSAR Modeling of N-Nitrosamine Carcinogenicity

Chemical Research in Toxicology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

N-Nitrosamine compounds in pharmaceuticals are a major concern due to their carcinogenic potential. However, not all nitrosamines strong carcinogens, and understanding the structure-activity relationships of this compound group is challenge. The determination acceptable intake limits for determined by applying either simple potency categorization approach (CPCA) or read-across analysis from where experimental data exist. emergence structurally complex makes quantitative models desirable. Here, we present two-step modeling based on linear discriminant set quantum mechanical classical descriptors followed 3D-QSAR PLS regression model predict logTD50 nitrosamine compounds.

Language: Английский

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Formation of N-Nitrosamine Drug Substance Related Impurities in Medicines: A Regulatory Perspective on Risk Factors and Mitigation Strategies

Organic Process Research & Development, Journal Year: 2023, Volume and Issue: 27(10), P. 1736 - 1750

Published: July 21, 2023

The detection of N-nitrosamine impurities in medicines and the recent emergence nitrosamine drug substance related (NDSRIs) has posed a great challenge to manufacturers products regulators alike. NDSRIs are primarily associated with reactions occurring product which brings particular complexity. This paper will explore current technical knowledge surrounding formation these impurities, including risk factors, reaction conditions, potential mitigation strategies. Scientific understanding areas is still evolving, we highlight both scientific progress made discuss significant gaps mechanistic remaining. These render accurate predictions NDSRI extremely challenging. pharmaceutical industry should continue work on strategies generation additional data address gaps. Regulatory guidance policy advance adapt response further changes understanding.

Language: Английский

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The Nitrosamine “Saga”: Lessons Learned from Five Years of Scrutiny

Organic Process Research & Development, Journal Year: 2023, Volume and Issue: 27(10), P. 1719 - 1735

Published: July 26, 2023

The onset of the N-nitrosamine (NA) saga in 2018 was chiefly related to certain small dialkyl N-nitrosamines originating from synthesis active pharmaceutical ingredient (API). However, subsequent comprehensive assessments performed on APIs, formulated drug products, and packaging put a different type NAs limelight: diverse range complex so-called nitrosamine drug-substance-related impurities (NDSRIs). They may form due presence potentially nitrosatable secondary or tertiary amine moieties APIs API nitrosating agents formed low levels nitrite present as impurities. unique properties functional group make it irreplaceable APIs. While be reduced, formation products cannot completely prevented, class default acceptable intake (AI) 18 ng/day currently poses significant challenges terms both viable control analysis at such levels. Even so, NA exposure through pharmaceuticals is expected orders magnitude lower than via food endogenous formation. robust carcinogenicity data are available for many small, simple NAs, there distinct absence most NDSRIs. Many working groups have therefore been established share rapidly improve knowledge (whether toxicity data, structure–activity relationships, analytical techniques), define best practices assess genotoxic potential NDSRIs, advance methods calculate AIs based solid scientific rationales. Ultimately, protect patients true cancer risk secure access important medicines, crucial manufacturers health authorities pursue efforts implement strategies that equally effective realistic. As patient safety paramount, industry committed ensuring medicines supplies safe effective. Where legitimate concerns exist, undisputed appropriate actions must taken, which could include withdrawal market.

Language: Английский

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Re‐Evaluating Acceptable Intake: A Comparative Study of N‐Nitrosomorpholine and N‐Nitroso Reboxetine Potency

Environmental and Molecular Mutagenesis, Journal Year: 2025, Volume and Issue: unknown

Published: March 22, 2025

ABSTRACT Establishing regulatory limits for Drug Substance‐Related Impurities (NDSRIs) is challenging due to the limited genotoxicity and carcinogenicity data available many of these impurities, often leading conservative approaches. In this study, we evaluated genotoxic potential two structurally related nitrosamines: N‐nitrosomorpholine (NMOR) N‐nitroso reboxetine. Compared well‐studied NMOR, there little toxicological information Currently, both compounds have an acceptable intake value 127 ng/day, based on a read‐across using NMOR. While tested positive in series vitro vivo assays, found that mutagenic reboxetine was significantly lower than The benchmark dose (BMD) analysis mutagenicity supports 24,000 ng/day Computational studies, carried out quantum‐mechanical CADRE program, were consistent with outcomes, suggesting at or above 1500 comparison prediction supported by computed reactivity hydroxylation step, greater steric hindrance alpha carbons, more facile proton transfer heterolysis toward aldehyde metabolite. presented work can be used refine improve Carcinogenic Potency Categorization Approach (CPCA). It also underscores importance collaboration between authorities, pharmaceutical industry, scientific researchers address risks while avoiding overestimation certain NDSRIs.

Language: Английский

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LC-MS/MS Investigation of nitrosamine impurities in certain Sartan group medicinal products available in Istanbul, Türkiye

Annales Pharmaceutiques Françaises, Journal Year: 2023, Volume and Issue: 82(1), P. 72 - 83

Published: Aug. 9, 2023

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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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N-nitrosamine Mitigation with Nitrite Scavengers in Oral Pharmaceutical Drug Products

Journal of Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 112(7), P. 1794 - 1800

Published: April 5, 2023

N-nitrosamines are likely human carcinogens. After N-nitrosamine contaminants were detected in pharmaceutical products 2018, regulatory authorities set a framework for the risk assessment, testing and mitigation of drug products. One strategy to inhibit formation during manufacture storage involves incorporation nitrite scavengers formulation. Diverse molecules have been tested screening studies including antioxidant vitamins ascorbic acid α-tocopherol, amino acids, other antioxidants used foods or drugs, inclusion into mitigate formation. This review article outlines key considerations oral product formulations.

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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