NDMA Formation Due to Active Ingredient Degradation and Nitrite Traces in Drug Product.

N-nitrosamines are genotoxic compounds which can be found as impurities in drug substances and drug products used in the pharmaceutical industry. To date, several possible nitrosamine sources in drug products have been reported and this study aims to illuminate another one. A case of afatinib drug product was investigated, in which up to 50 ppb N-nitrosodimethylamine (NDMA) traces were detected. Afatinib was found to degrade to the secondary amine dimethylamine (DMA), forming NDMA with traces of nitrite in crospovidone. Two series of film-coated tablets were prepared with crospovidone from two different manufacturers, containing different levels of nitrites. Tablets were subjected to an accelerated stability study (40 °C/75% relative humidity) or stored at room temperature and levels of NDMA, DMA and nitrite in tablets were monitored. NDMA and nitrite were found on ppb levels, whereas DMA was detected on ppm levels. NDMA formation in the drug product was found to be time, temperature and nitrite dependent and it was emphasized that DMA and nitrite should be reduced. The accelerated stability study proved to be a useful tool for predicting nitrosamine formation in the drug product.

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. 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.