Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products
The recent focus of pharmaceutical regulatory authorities has been oriented towards the mitigation of carcinogenic N-nitrosamines in drug products and different sources of N-nitrosamines have been revealed. Within this work, the elucidation of a further source of N-nitrosamines in drug products is reported. A case was investigated where traces of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were detected in a finished dosage form, whereas they were not found in the bulk drug product. This led to an in-depth study of blister material as a potential source, wherein nitrocellulose primer in a lidding foil was identified as a risk factor. Nitrocellulose acts as a nitrosating agent for secondary amines, present in printing inks, forming N-nitrosamines in lidding foil.
Highlights
- Nitrocellulose blister material can be a source of N-nitrosamines in drug products.
- Nitrocellulose primer in a lidding foil acts as a nitrosating agent.
- N-Nitrosylation of secondary amines, present in printing ink, yields N-nitrosamines.
- N-Nitrosamines transfer from foil to drug product during the blistering operation.
- Nitrocellulose-free blister material should be considered to avoid N-nitrosamines.
Their formation was confirmed by the addition of printing ink containing dimethylamine and diethylamine, or diethylamine alone, to lidding foil containing nitrocellulose primer. Their transfer to drug product during the blistering operation was demonstrated by solid-phase microextraction sampling of N-nitrosamine vapors on two commonly used types of pharmaceutical blistering machines, operating with plate sealing or roller sealing technology. Higher vapor amounts were detected on plate sealing equipment, where N-nitrosamine contamination was additionally confirmed in film-coated tablets and blister cavities of the finished dosage form.
Nejc Golob, Rok Grahek, Malcolm Ross, Robert Roškar, Nitrocellulose blister material as a source of N-nitrosamine contamination of pharmaceutical drug products, International Journal of Pharmaceutics, Volume 618, 2022, 121687, ISSN 0378-5173, https://doi.org/10.1016/j.ijpharm.2022.121687.
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