• Informed decisions for better process


N-Nitrosamine Risk Assessment

According to the discovery of N-Nitrosamine impurities in Angiotensin II Receptor Blockers (ARBs), Ranitidine, Metformin and other Drug Products (DPs), EMA and FDA recommend API and DP manufacturers to conduct risk assessment on approved or marketed products and product with pending applications and to take appropriate actions in case a potential risk for N-Nitrosamine presence is assessed. MAHs are required to perform risk evaluation on their medicinal products according to ICH Q9 and ICH M7 principles (Step 1 Risk evaluation) and, in case a risk of presence of N-Nitrosamines is identified, to carry out confirmatory testing (Step 2 Confirmatory testing). Finally if the presence of N-Nitrosamines is confirmed by analytical testing, in Step 3 MAHs are called to mitigate the risk by means of proper changes to the Marketing Authorization (MA).

Manufacturers may prioritize evaluation according to factors such as maximum daily dose, duration of treatment, therapeutic indications and number of treated patients. The Risk evaluation activity is then addressed to all chemical synthetized APIs and, as a consequence, it is addressed to Drug Products (DPs) containing synthetized APIs. Moreover, EMA has recently extended the evaluation to all biological medicinal products with specific identified risk factors: containing chemically synthetized fragments or packaged in certain primary packaging such as blisters or manufactured using processes where nitrosating agents are added.

With the experience gained in QRM through the years and, in particular, in performing Product Prioritization and Risk Assessment on N-Nitrosamines to fulfill EMA directives, PTM consulting can actively manage information collection and N-Nitrosamine activity execution using its well-grounded methodology and experience in N-Nitrosamine topic.


From September 2019 onwards, date of first issue of the ''Information on nitrosamines for MAHs'' by EMA, PTM consulting has supported DP and API manufacturers as well as MAHs in Step 1 activities:

  1. IDENTIFY DP PRIORITY STARTING FROM THE EMA AND FDA RECOMMENDATIONS considering criteria such as maximum daily dose (MDD), duration of treatment, number of treated patient and therapeutic indication and developing a suitable risk tool able to objectively prioritize DP for evaluation.
  2. ASSESS THE POTENTIAL RISK OF N-NITROSAMINE PRESENCE and/ or formation in finished products according to ICH Q9 and ICH M7 principles EMA directives and FDA guidance on N-Nitrosamines