Background
Understanding NAs and NDSRIs – Lessons from the Valsartan Case
The significance of nitrosamine (NA) risk assessment became evident following the Valsartan case, where NAs (e.g., NDMA, NDEA) were detected in several batches of the widely used hypertension drug. This discovery led to global recalls, regulatory scrutiny, and heightened concerns about the presence of carcinogenic contaminants in pharmaceuticals. The case underscored the need for rigorous quality control measures and comprehensive risk assessments to detect, evaluate, and mitigate nitrosamine impurities before they reach patients.
Ensuring compliance with international regulatory standards is crucial to maintaining patient safety and protecting public health.
Expert Analysis based on Exposure Scenarios in Drugs or Medical Devices
Nitrosamines and Nitrosamine Drug Substance Related Impurities (NDSRIs) pose a potential health risk and are strictly regulated as contaminants in final products. Manufacturers must conduct comprehensive risk assessments to ensure compliance with regulatory requirements. IASON consulting supports clients worldwide with science-based expertise on clinical exposure scenarios for N-nitrosamine impurity levels.
Support with Regulatory Inquiries and Approval Processes
We develop scientific, risk-based approaches to estimate clinically relevant NA doses and assess their carcinogenic risk of patients treated with your pharmaceutical products, including large-volume parenterals. In addition, Amine-containing drugs may require to determine theoretical maximum levels of N-nitrosamine impurities formed during manufacturing or storage.
NA Exposure Scenarios and Toxicological Risk Assessment (TRA)
N-Nitrosamines (NAs) are impurities in medicines or are identified as potentially leachable substances from CCS' polymer material. Since NAs such as NDMA, NMBA, NDEA, or other N-nitroso compounds belong to the ‘cohort of concern’ in ICH M7 guidelines and are theoretically associated with a significant carcinogenic risk, the risk to a patient must be assessed.
Preparation of Regulatory-Compliant Risk Assessments According to EMA and FDA Guidelines
For the presence of NA and NDSRI, a scientific-based TRA is required for each product to assess human exposure to these and compare against the acceptable intake (AI) limits which must be in alignment with the agencies’ recommendations.
Regulatory References
Our services align with key regulatory guidance documents, ensuring compliance with international standards:
FDA: Control of Nitrosamine Impurities in Human Drugs
This guidance provides recommendations for pharmaceutical manufacturers on how to detect, assess, and control nitrosamine impurities in drug products, ensuring compliance with FDA regulation
FDA: Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)
This document outlines acceptable intake limits for specific nitrosamine impurities related to drug substances, helping companies establish safe levels in their products
European Medicines Regulatory Network: Implementation of the CHMP Opinion pursuant to Article 5(3) of Regulation (EC) No 726/2004 for nitrosamine impurities in human medicines
This guideline details the European Medicines Agency’s (EMA) approach to mitigating nitrosamine risks in human medicines, outlining steps for manufacturers to comply with regulatory expectations.
Assessment report: Procedure under Article 5(3) of Regulation EC (No) 726/2004, EMA/369136/2020, and the EMA Question and Answer Documents and Appendices
This EMA guidance addresses the overall regulatory strategy for controlling Nitrosamine impurities in pharmaceuticals, providing insights into risk assessment and mitigation strategies.
ICH: Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk, M7(R2)
This ICH guideline outlines recommendations for assessment and control of mutagenic impurities and applies to all drug substances and drug products where nitrosamine risk may exist.
Service
Why Choose IASON Consulting?
Our experts have many years of experience in regulatory toxicology and pharmaceutical risk assessment. We combine scientific expertise with practical solutions to develop tailored strategies for risk minimization. With our detailed expert reports, we support pharmaceutical companies worldwide in meeting regulatory requirements and ensuring the safety of their products.
