Risk Assessment Study of Nitrosamines for the API Temozolomide Industrial Process

Since the International Agency for Research on Cancer (IARC) classified most of N-nitrosamines as potentially carcinogenic or mutagenic harmful agents, in addition to the recent worldwide episode where the presence of these substances was identified on medicines derived from sartans (e.g., Valsartan) and other active pharmaceutical ingredients (APIs) (e.g., Ranitidine, Nizatidine, and Metformin), regulatory agencies such as FDA, EMA, and ANVISA became concerned about the needs of pharmaceutical companies for evaluating their products and their respective manufacturing steps to ensure safety and quality. As the technical and regulatory approach to the subject advanced, it was established that the presence of these substances could be originated from different steps, both from API and finished product processes. Thus, several multidisciplinary committees were formed to discuss effective strategies to assess the qualitative and quantitative risk of contamination and formation of nitrosamines on products. In perspective on the production chain of active pharmaceutical ingredients, the aim of this study is to show the relevant results obtained from the risk assessment of nitrosamines for the API Temozolomide industrial process, produced by the pharmaceutical company Cristália. The study focused on realizing a complete and robust risk assessment from the stages of synthesis and equipment evaluation to packaging and stability condition, applying in silico analyses verified by confirmatory analytical test through gas chromatography (GC) methodology.