Understanding Nitrosamine Limits: A Key Paper on the CPCA, Highlighted at SOT and Soon Part of Our ICH M7 Training
- Elena Fioravanzo
- 7 days ago
- 2 min read
Following an insightful presentation by Dr. N. Kruhlak (US FDA) at the recent Society of Toxicology (SOT) conference, "The Evolution of QSAR Modeling for Pharmaceutical Regulatory Safety Assessment," we want to bring your attention to a crucial paper that directly addresses a significant challenge in pharmaceutical safety: the control of N-nitrosamine impurities.
The paper, titled "Determining recommended acceptable intake limits for N-nitrosamine impurities in pharmaceuticals: Development and application of the Carcinogenic Potency Categorization Approach (CPCA)", published in Regulatory Toxicology and Pharmacology, provides a comprehensive overview of the Carcinogenic Potency Categorization Approach (CPCA). This innovative method has been adopted in international regulatory guidance in 2023 to determine acceptable intake (AI) limits for nitrosamine impurities, including the increasingly complex nitrosamine drug substance-related impurities (NDSRIs).
Access the full paper here:
Dr. Kruhlak's lecture underscored the critical role of robust and scientifically sound approaches for managing potential genotoxic impurities like nitrosamines, aligning perfectly with the principles behind the CPCA. This paper details the scientific rationale and supporting data for this structure-activity relationship (SAR)-based method.
Key highlights of the CPCA, as presented in the paper:
Categorization Approach: Nitrosamines are classified into one of five categories based on their predicted carcinogenic potency, each with a corresponding AI limit.
Structure-Activity Relationships: The CPCA considers the number and distribution of α-hydrogens at the N-nitroso center, along with other structural features that can activate or deactivate the α-hydroxylation metabolic pathway, a key mechanism in nitrosamine carcinogenesis.
Regulatory Adoption: The CPCA has been internationally adopted by several drug regulatory authorities as a simplified yet scientifically grounded starting point for determining AI limits when compound-specific empirical data is lacking.
Practical Application: The paper includes case studies demonstrating the application of the CPCA to various nitrosamine impurities, offering practical insights for its use.
Computational Tool: A valuable Java application for fingerprinting CPCA structural features is available as supplemental data, aiding in the practical implementation of the approach.
Given the widespread regulatory acceptance and practical utility of the CPCA in addressing the challenges posed by nitrosamine impurities, we are pleased to announce that the principles and application of the CPCA will be integrated into our comprehensive ICH M7 training program. This enhancement will equip our trainees with the knowledge and tools necessary to effectively apply this crucial methodology in their work.
We strongly encourage anyone involved in pharmaceutical development, quality control, regulatory affairs, and toxicology to delve into this significant publication. Understanding the CPCA is now essential for navigating the regulatory landscape concerning nitrosamine impurities.
Stay informed and stay compliant with our updated ICH M7 training!
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