Abstract
Nitrosamines, recognized as probable human carcinogens, were unexpectedly found in active pharmaceutical ingredients (APIs) in 2018, leading to regulatory warnings and product recalls. The discovery prompted pharmaceutical manufacturers to adopt a proactive approach to risk assessment and mitigation of these genotoxic contaminants.
This whitepaper provides an overview of the regulatory challenges posed by the detection of nitrosamine impurities in pharmaceutical products.
Regulatory agencies worldwide, including the European Medicines Agency (EMA) and US Federal Drug Administration (FDA), released guidance documents outlining risk-based approaches for detecting and mitigating nitrosamine presence. This phased approach includes risk assessment, confirmatory testing, and processes for marketing authorization changes if needed.
We also highlight the impact of nitrosamine contamination on the industry, industry collaboration, and the publication of research articles to aid prevention efforts. The FDA and EMA have published guides with suggestions to reduce nitrosamine impurities, and a structured approach to support the risk assessment with a shifted focus towards education and prevention.
Here, we present the concerns and risks associated with nitrosamines in pharmaceutical products, emphasizing our expertise and services to support Bio/Pharmaceutical manufacturers with testing and compliance.
An Executive Summary
In July 2018, N-Nitrosodimethylamine (NDMA) was identified as an impurity in an active pharmaceutical ingredient (API). This was thought to be the first time such a nitrosamine contaminant had been detected in a pharmaceutical product. It led to regulatory warnings, product recalls, and wider recognition that pharmaceutical manufacturers should adopt a proactive approach to risk assessment and mitigation to reduce or eliminate the presence of these genotoxic contaminants. Nitrosamine impurities were already recognized as environmental contaminants, having been found in water and food, but their presence in an API was unexpected. Initial reports by the European Medicines Agency (EMA), US Federal Drug Administration (FDA), and HealthCanada noted that NDMA had been detected in a Valsartan API. This was soon followed by the discovery of another nitrosamine impurity, N-Nitrosodiethylamine (NDEA) in a pharmaceutical product. Since then, multiple other nitrosamine impurities have been detected in API’s and drug products, and the presence of Nitrosamine Drug Substance Related Impurities (NDSRIs) has been reported.
The presence of nitrosamine compounds is a cause for concern as they are recognized as probable human carcinogens. Even at low levels, these genotoxic impurities pose a significant threat to humans and other animals. The regulators now provide a structured approach to support the risk assessment of any possible nitrosamine.
Discover changing regulatory environment for nitrosamine impurities. I want to learn more
Sin El Fil – Horch Tabet, St. Georges Bldg, 9th Floor,
165165,
Beirut, Lebanon