Holzgrabe U
Institute of Pharmacy and Food Chemistry, University of Wuerzburg Am Hubland, 97074 Wuerzburg, Germany.
J Pharm Sci. 2023 May;112(5):1210-1215. doi: 10.1016/j.xphs.2023.01.021. Epub 2023 Jan 28.
The occurrence of N-nitrosodialkylamines in active pharmaceutical ingredients (APIs) and drug products in the last years was a kind of eye opener with regard to quality of drugs. We became aware of the fact that quality control tests described in the international pharmacopoeias might not be sufficient. The N-nitrosodialkylamines found were neither so-called (structurally) related substances, nor residual solvents or heavy metals; hence they were not limited by a compendial test, but by the ICH guideline M7 of mutagenic impurities. Additionally, nitrosamine drug-substance-related impurities (NDSRIs) were detected, mostly within the process of risk assessment required by regulatory authorities. Here, the APIs containing a vulnerable amino moiety had reacted with nitrites being a contaminant of an excipient. This review deals with the formation, toxicity, and mitigation of NDSRISs.
近年来，活性药物成分（APIs）和药品中N-亚硝基二烷基胺的出现，在药物质量方面给人敲响了警钟。我们意识到国际药典中描述的质量控制测试可能并不充分。所发现的N-亚硝基二烷基胺既不是所谓的（结构上的）相关物质，也不是残留溶剂或重金属；因此，它们不受药典测试的限制，而是受国际人用药品注册技术协调会（ICH）关于致突变杂质的M7指南的限制。此外，还检测到了与亚硝胺原料药相关的杂质（NDSRIs），大多是在监管机构要求的风险评估过程中检测到的。在这里，含有易反应氨基部分的原料药与作为辅料污染物的亚硝酸盐发生了反应。本综述探讨了NDSRISs的形成、毒性及缓解措施。
