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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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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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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Development of an Innovative Three-Component Optical Resolution and a Flow Chemistry Process for (R)-Troloxamide Quinone (EPI-589)

Organic Process Research & Development, Год журнала: 2025, Номер unknown

Опубликована: Фев. 25, 2025

Язык: Английский

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Estimation of acceptable daily intake values based on modeling and in vivo mutagenicity of NDSRIs of fluoxetine, duloxetine and atomoxetine

Regulatory Toxicology and Pharmacology, Год журнала: 2024, Номер 152, С. 105672 - 105672

Опубликована: Июль 4, 2024

Язык: Английский

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A Consideration of the Extent That Tertiary Amines Can Form N-Nitroso Dialkylamines in Pharmaceutical Products

Organic Process Research & Development, Год журнала: 2023, Номер 27(10), С. 1714 - 1718

Опубликована: Апрель 19, 2023

Most secondary amines have the potential to undergo nitrosation in presence of nitrite under certain conditions, particularly at low pH, generate N-nitrosamines. Tertiary are generally considered be less prone nitrosamine formation as they require an additional dealkylation step. A review published literature combined with recently generated experimental data from experiments carried out on several trialkyl further informs extent that tertiary can form N-nitrosamines by reaction trace levels nitrite, which may present during drug substance or product manufacture. Simple trialkylamines, containing no heteroatoms, been demonstrated react via a nitrosative mechanism slowly generates dialkylamine, turn nitrosates. This sequence reactions N-nitrosamine is approximately 1000-fold slower than simple amine comparable pKa. Therefore, trialkylamines pharmaceutical products typically not risk. Dialkylanilines able access alternative mechanisms and dealkylative greater ease therefore more focused risk assessment. Finally, structurally complex contain functional groups facilitate through resonance and/or inductive electronic effects. structures highly functionalized thorough, compound-specific assessment determine level generation. Note situations where higher amounts nitrosating agents present, such when chemistry used manufacturing process, should for generation

Язык: Английский

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Nitrosamine acceptable intakes should consider variation in molecular weight: The implication of stoichiometric DNA damage

Regulatory Toxicology and Pharmacology, Год журнала: 2023, Номер 145, С. 105505 - 105505

Опубликована: Окт. 5, 2023

N-nitrosamines (NAs) are a class of compounds which many, especially the small dialkyl type, indirect acting DNA alkylating mutagens. Their presence in pharmaceuticals is subject to very strict acceptable daily intake (AI) limits, traditionally expressed on mass basis. Here we demonstrate that AIs not experimentally derived for specific compound, but via statistical extrapolation or read across suitable analog, should be molar scale corrected target substance's molecular weight. This would account mechanistic aspect each nitroso group can, at maximum, single mutation and number molecules per unit proportional weight (MW). In this regard have re-calculated EMA 18 ng/day regulatory default AI unknown nitrosamines propose revised 163 pmol/day. addition, provide MW-corrected those nitrosamine drug substance related impurities (NDSRIs) has pre-assigned by read-across. Regulatory acceptance fundamental scientific tenet allow one derive limits NDSRIs both meet health-protection goals technically feasible.

Язык: Английский

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On the role of digital tools in nitrosamine risk assessment for drug substance and drug product manufacturing processes

Current Opinion in Chemical Engineering, Год журнала: 2024, Номер 45, С. 101030 - 101030

Опубликована: Июнь 8, 2024

Язык: Английский

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Investigation of the Formaldehyde-Catalyzed NNitrosation of Dialkyl Amines: An Automated Experimental and Kinetic Modelling Study Using Dibutylamine

Journal of Pharmaceutical Sciences, Год журнала: 2024, Номер 113(6), С. 1624 - 1635

Опубликована: Фев. 2, 2024

Язык: Английский

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