The European Medicines Agency (EMA) provided information to marketing authorization holders (MAHs) on how to evaluate the risk for the formation of nitrosamine impurities in human medicinal products.
The guidance comes after a number of different ‘sartan’-based products were found to be contaminated with nitrosamines, which was then followed by a separate investigation finding similar impurities in ranitidine medicines.
In its advice to MAHs, the EMA warned manufacturers that it had identified five main root causes of nitrosamine formation and contamination:
- Nitrosamine impurities formed during the processing of active pharmaceuticals ingredients (APIs) under certain processing conditions and with certain raw materials, starting materials, and intermediates present. The agency added that despite later quality control steps, it may not be able to ‘fully purge’ contaminants later in the manufacturing process
- The use of sodium nitrite, or other nitrites, in the presence of second or tertiary amines. Secondary amines can be present in reagents and solvents. Tertiary amines can be present in common bases, such as triethylamine and diisopropylethylamine
- The use of contaminated raw materials in the manufacturing process, such as recycled solvents, reagents and catalysts – these may pose a risk due to the presence of amines in the waste streams
- Using third-parties to recover materials, such as solvents, reagents, and catalysts, which do not receive enough information on the content of the materials and use routine recovery processes with non-dedicated equipment
- The use of contaminated starting materials, including intermediates provided by vendors using processes that lead to the formation of nitrosamines
The EMA concluded that MAHs should review their manufacturing processes to identify any of the risks posed in the five points and take action to mitigate the risk.
