nitrosamines in pharmaceuticals tracing root cause and navigating risk assessment
This is a PDF document titled "Nitrosamines in Pharmaceuticals Tracing Root Cause and Navigating Risk Assessment" created in June 2025. It is a detailed scientific and regulatory presentation by Dr. Ron Najafi, President & CEO of Emery Pharma, delivered to the Chinese American BioPharmaceutical Society. The content covers the chemistry, sources, formation mechanisms, toxicity, regulatory guidelines, and risk assessment strategies related to nitrosamine impurities in pharmaceuticals, including case studies on drugs like Ranitidine, Valsartan, Metformin, Sitagliptin, and Rifampicin. It also highlights Emery Pharma's contributions to identifying and mitigating nitrosamine contamination in drug substances and products.
Questions this document answers
Nitrosamines are a concern because they are probable mutagenic carcinogens found at harmful levels in drugs such as ARBs, Ranitidine, and Metformin, requiring careful risk assessment and control in pharmaceutical manufacturing.
They filed a Citizen Petition to the FDA with findings on the intrinsic formation of NDMA in Ranitidine, which led to the FDA agreeing and subsequently removing Ranitidine from the US market.
Chemically, nitrosamines form when amines react with nitrosonium ion (NO+), which acts as the nitrosating agent.
High levels of NDMA were found exceeding safety limits, leading to regulatory actions including removal of the drug from markets worldwide.
Key pathways include degradation of DMF/NMP to dimethylamine, N-nitrosative de-alkylation of tertiary amines, and reactions with nitrosating agents like nitrosonium ion and nitrites.