Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA).
Regul Toxicol Pharmacol
; 150: 105640, 2024 Jun.
Article
en En
| MEDLINE
| ID: mdl-38754805
ABSTRACT
N-Nitrosamine impurities, including nitrosamine drug substance-related impurities (NDSRIs), have challenged pharmaceutical industry and regulators alike and affected the global drug supply over the past 5 years. Nitrosamines are a class of known carcinogens, but NDSRIs have posed additional challenges as many lack empirical data to establish acceptable intake (AI) limits. Read-across analysis from surrogates has been used to identify AI limits in some cases; however, this approach is limited by the availability of robustly-tested surrogates matching the structural features of NDSRIs, which usually contain a diverse array of functional groups. Furthermore, the absence of a surrogate has resulted in conservative AI limits in some cases, posing practical challenges for impurity control. Therefore, a new framework for determining recommended AI limits was urgently needed. Here, the Carcinogenic Potency Categorization Approach (CPCA) and its supporting scientific rationale are presented. The CPCA is a rapidly-applied structure-activity relationship-based method that assigns a nitrosamine to 1 of 5 categories, each with a corresponding AI limit, reflecting predicted carcinogenic potency. The CPCA considers the number and distribution of α-hydrogens at the N-nitroso center and other activating and deactivating structural features of a nitrosamine that affect the α-hydroxylation metabolic activation pathway of carcinogenesis. The CPCA has been adopted internationally by several drug regulatory authorities as a simplified approach and a starting point to determine recommended AI limits for nitrosamines without the need for compound-specific empirical data.
Palabras clave
Acceptable intake (AI) limit; Carcinogenic Potency Categorization Approach (CPCA); Carcinogenic potency; Drug impurity; Drug safety; Mutagenicity; N-Nitrosamine; Nitrosamine drug substance-related impurity (NDSRI); Pharmaceuticals; Regulatory collaboration; Regulatory science; Structure-activity relationship (SAR)
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Carcinógenos
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Contaminación de Medicamentos
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Nitrosaminas
Idioma:
En
Revista:
Regul Toxicol Pharmacol
Año:
2024
Tipo del documento:
Article