The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals

Journal of Pharmaceutical Sciences, Год журнала: 2022, Номер 112(5), С. 1287 - 1304

Опубликована: Ноя. 17, 2022

This article reports the outcome of an in silico analysis more than 12,000 small molecule drugs and drug impurities, identifying nitrosatable structures, assessing their potential to form nitrosamines under relevant conditions challenges determine compound-specific AIs based on data available or read-across approaches for these acceptance by health authorities. Our indicate that presence pharmaceuticals is likely prevalent originally expected. In total, 40.4 % analyzed APIs 29.6 API impurities are nitrosamine precursors. Most structures identified through our workflow could complex API-related nitrosamines, so-called substance related (NDSRIs), although we also found release well-known potent NDMA, NDEA, others. Due common structural motifs including secondary tertiary amine moieties, whole essential classes such as beta blockers ACE inhibitors at risk. To avoid risk shortages even complete loss therapeutic options, it will be well-established ICH M7 principles remain applicable industry regulatory authorities keep open communication not only about science but make sure there a good balance between benefit patients.

Язык: Английский

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Risk assessment of N‐nitrosamines in food

EFSA Journal, Год журнала: 2023, Номер 21(3)

Опубликована: Март 1, 2023

EFSA was asked for a scientific opinion on the risks to public health related presence of

Язык: Английский

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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, Год журнала: 2024, Номер 150, С. 105640 - 105640

Опубликована: Май 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.

Язык: Английский

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Mechanisms of Nitrosamine Mutagenicity and Their Relationship to Rodent Carcinogenic Potency

Chemical Research in Toxicology, Год журнала: 2024, Номер 37(2), С. 181 - 198

Опубликована: Фев. 5, 2024

A thorough literature review was undertaken to understand how the pathways of N-nitrosamine transformation relate mutagenic potential and carcinogenic potency in rodents. Empirical computational evidence indicates that a common radical intermediate is created by CYP-mediated hydrogen abstraction at α-carbon; it responsible for both activation, leading formation DNA-reactive diazonium species, deactivation denitrosation. There are competing sites CYP metabolism (e.g., β-carbon), other reactive species can form following initial bioactivation, although these alternative tend decrease rather than enhance potency. The activation pathway, oxidative dealkylation, reaction drug carbonyl byproduct, e.g., formaldehyde, does not contribute toxic properties N-nitrosamines. Nitric oxide (NO), side product denitrosation, similarly be discounted as an enhancer toxicity based on carcinogenicity data substances act NO-donors. However, all N-nitrosamines potent rodent carcinogens. In significant number cases, there overlap with non-N-nitrosamine carcinogens Cohort Concern (CoC; high-potency comprising aflatoxin-like-, N-nitroso-, alkyl-azoxy compounds), while devoid potential. this context, mutagenicity useful surrogate carcinogenicity, proposed ICH M7 (R2) (2023) guidance. Thus, safety assessment control medicines, important those complementary attributes mechanisms structure–activity relationships translate elevated versus which associated reduction in, or absence of,

Язык: Английский

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N-nitrosamines in processed meats: Exposure, formation and mitigation strategies

Journal of Agriculture and Food Research, Год журнала: 2023, Номер 13, С. 100645 - 100645

Опубликована: Май 24, 2023

Nitrite and nitrate have been widely used in the preservation of meat products for effective antimicrobial action against several pathogenic bacteria such as Clostridium botulinum, Salmonella mesophilic bacteria. However, they can further react with secondary amines produce noxious compounds called nitrosamines during thermal processing. N-nitrosamines are divided into volatile non-volatile N-nitrosamines, among which a group highly hazardous chemical carcinogens whose carcinogenicity teratogenicity led to widespread concern. Owing their occurrence daily diet, it is great significance suppress formation toxicity on human health without causing adverse effects food flavors. In this paper, mechanism provided. Potential mitigations be carried out from perspectives precursors raw materials, processing conditions well exogenous additives. Moreover, promoting degradation an approach. The potential risks associated described. Different intervention substances, polyphenols, vitamins various plant extracts summarized, discussing impact nitrosamines. purpose review provide theoretical guidance control generation deleterious effects, so promote development practical production.

Язык: Английский

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

Organic Process Research & Development, Год журнала: 2023, Номер 27(10), С. 1719 - 1735

Опубликована: Июль 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.

Язык: Английский

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Acceptable intakes (AIs) for 11 small molecule N-nitrosamines (NAs)

Regulatory Toxicology and Pharmacology, Год журнала: 2023, Номер 142, С. 105415 - 105415

Опубликована: Май 29, 2023

Low levels of N-nitrosamines (NAs) were detected in pharmaceuticals and, as a result, health authorities (HAs) have published acceptable intakes (AIs) to limit potential carcinogenic risk. The rationales behind the AIs not been provided understand process for selecting TD50 or read-across analog. In this manuscript we evaluated toxicity data eleven common NAs comprehensive and transparent consistent with ICH M7. This evaluation included substances which had datasets that robust, limited but sufficient, insufficient experimental animal carcinogenicity data. case robust sufficient information, calculated based on derived TD50s from most sensitive organ site. available structure activity relationships (SARs) applied categorical-based 1500 ng/day, 150 ng/day 18 ng/day; however additional (such biological computational modelling) could inform an alternative AI. approach advances methodology used derive NAs.

Язык: Английский

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Quantum Chemical Evaluation and QSAR Modeling of N-Nitrosamine Carcinogenicity

Chemical Research in Toxicology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 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.

Язык: Английский

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

Environmental and Molecular Mutagenesis, Год журнала: 2025, Номер unknown

Опубликована: Март 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.

Язык: Английский

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

Chemical Research in Toxicology, Год журнала: 2023, Номер 36(2), С. 291 - 304

Опубликована: Фев. 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.

Язык: Английский

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