Potential for Nitrosamines in Medical Device Combination Products - Letter to Industry(FDA)

Nitrosamines in the News
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https://www.fda.gov/medical-devices/industry-medical-devices/potential-nitrosamines-medical-device-combination-products-letter-industry

Dear Medical Device Manufacturers:

The U.S. Food and Drug Administration (FDA), through the Center for Devices and Radiological Health (CDRH), is issuing this letter to provide manufacturers of CDRH-led combination products with information related to potential nitrosamine impurities. This letter describes manufacturer responsibilities and highlights resources that may assist in identifying and managing potential nitrosamine impurities in these products.

Background

Nitrosamine exposure above acceptable levels over long periods of time may increase the risk of cancer. CDRH has been investigating the potential presence of nitrosamine impurities in CDRH-led combination products. As part of this ongoing work, CDRH has become aware that 1-methyl-4-nitrosopiperazine (MNP), a nitrosamine drug substance–related impurity (NDSRI), has been detected in certain CDRH-led combination products containing the drug rifampin. At this time, CDRH is not aware of adverse events associated with nitrosamine exposure from CDRH-led combination products.

Potential sources of nitrosamines in CDRH-led combination products may include the drug product itself or the manufacturing process for the finished combination product. Manufacturers are responsible for understanding the risks of any impurities, including nitrosamines, that may be present in their final products as part of their overall biocompatibility/risk assessment.

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Between combination products, personal care, and large molecules, a substantial portion of the industry has a lot of catching up to do.

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The FDA has also recently referred to nitrosamine impurities in its draft guidance on antibiotics.

Establishing Impurity Specifications for Antibiotics

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/establishing-impurity-specifications-antibiotics

Certain impurities, such as nitrosamine impurities, which are probable or possible human
carcinogens, have been identified in many drug products and could be present in drug
substances. Applicants and manufacturers of antibiotic drugs should conduct a risk assessment of drug substances and drug products for potential impurities that fall under the “cohort of concern” category.

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How should control limits be established for cell substrate-derived impurities due to fermentation (e.g., residual host cell proteins, residual host cell DNA)?

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Thanks for sharing this FDA letter. This is an important development for combination products. Has anyone seen similar guidance from other regulatory agencies (EMA, NMPA)? We’re particularly interested in understanding how this might impact rifampin-containing products in global markets.