IPEC-Americas Nitrosamine Considerations
for Excipient Manufacturers and Marketing Authorization Holders

News category: 
Wednesday, March 11, 2020

Nitrosamines are classified as probable human carcinogens, suggesting that long-term exposure above certain levels may increase cancer risk for those exposed. Recent incidents of nitrosamine contamination in drug products have raised concerns for patient safety.

The increased concern for the presence of nitrosamine and related compounds in drug products by regions including Europe [1,2], Canada [3] and the U.S. [4] requires the Marketing Authorization Holder (MAH) to perform a risk assessment to determine the potential for the presence of nitrosamine compounds in their drug products.

There are no regulatory or testing requirements for excipient manufacturers to assess the presence of nitrogen-containing components in the excipient that could, under certain circumstances lead to the formation of nitrosamine compounds in drug products.  However, excipient manufacturers are being asked by the MAH’s to evaluate their excipients and their manufacturing process and provide information needed to enable the MAH to assess the potential for nitrosamine formation in their drug products.”

It is important to consider aspects from both excipient and marketing authorization holders’ perspectives.

Excipient Manufacturers
1. Excipient manufacturers should evaluate their product(s) and process(es) and prepare documentation for drug product manufacturers:
The IPEC-Americas Evaluation of Excipients for Presence of Nitrosamines Impurities template contains aspects to be considered when evaluating the excipient and its manufacturing processes for potential nitrosamine formation, such as the presence of nitrogen containing compounds that may become incorporated in the final excipient composition through feedstock, reagent, solvents, boiler systems, etc.
2. Prepare information from the evaluation of the excipient to share with customers to use in response to requests related to their drug product risk assessment for nitrosamines.  If the response indicates that there is a potential for nitrogen containing components to be present, or if sufficient information is not available to make a determination, consider providing more detailed information to customers.
3. Ensure responses are provided to the requesting party in a timely manner

Marketing Authorization Holders
Note: It is mandatory for MAH’s to assess the potential for nitrosamine formation in their drug products, which necessitates the inclusion of excipients in their assessment.
1. Ensure templates/questionnaires are delivered to the correct functions within the excipient supplier’s organization.
2. Ensure the templates/questionnaires contain the appropriate questions to address the points raised above (see Point 1 above from excipient manufacturers’ list).
3. When working with distributors or agents, it is important to ensure the information comes from the excipient manufacturer.

A template that excipient companies can use in response to inquiries from pharma companies trying to address nitrosamine concerns is available. Please visit the Document Depot>Resources>Hot Topics>Nitrosamines folder in order to download the template. You must be logged in to access the template.

1. Information on nitrosamines for marketing authorisation holders, EMA/189634/2019. September 2019.
2. Questions and answers on “Information on nitrosamines for marketing authorization holders”. EMA/CHMP/428592/2019 Rev. 1. https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-...
3. EMA Questions and answers on “Information on nitrosamines for marketing authorisation holders: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-...
Information to marketing authorisation holders of human pharmaceutical products on nitrosamine impurities. Health Canada. October 2019.