包材的亚硝胺（NDBA/NDEA/NDMA...）限度标准！

微谱集团

Nitrosamines in Elastomers?弹性体中的亚硝胺？

A USP Stimuli article on Elastomeric Components for Inhalation Packaging / Delivery Systems has been published in Pharmacopeial Forum (PF) 45(6).

药典论坛 （PF） 45（6） 上发表了一篇关于吸入剂包装/输送系统弹性体的 USP 启动文。

According to the Stimuli article N-Nitrosamines are reaction products between specific organic precursor molecules, secondary amines (R2NH), and a “nitrosating agent”. In the compounding of rubber, secondary amines are likely formed from vulcanization accelerators such as thiurams and dithiocarbamates. Therefore, the stimuli article proposes to add tests and acceptance criteria for N-nitrosamines to the list of physicochemical tests in <381>. The proposed method for inclusion into the USP–NF is based on the ASTM F1313 method, which describes the determination of six volatile N-nitrosamines which are also listed in USP chapter <1664.1>:

根据该启动文，N-亚硝胺是特定有机前体分子、仲胺（R2NH）和"硝化剂"之间的反应产物。在橡胶的生产中，仲胺可能是由硫化加速剂（如硫化物和二硫代氨基甲酸盐类）形成的。因此，该启动文建议将N-亚硝胺的检验和接受标准列入USP3<381>的理化检验清单。建议纳入USP—NF的方法是基于 ASTM F1313 方法的，该方法描述了六种挥发性 N-亚硝胺的测定，这些亚硝胺也列在 USP <1664.1>中：

• N-Nitrosodibutylamine (NDBA)
• N-亚硝基二丁胺 (NDBA)
• N-Nitrosodiethylamine (NDEA)
• N-亚硝基二乙胺（NDEA）
• N-Nitrosodimethylamine (NDMA)
• N-亚硝基二甲胺 (NDMA)
• N-Nitrosomorpholine (NMOR)
• N-亚硝基吗啉 (NMOR)
• N-Nitrosopiperidine (NPIP)
• N-亚硝基哌啶 (NPIP)
• N-Nitrosopyrrolidine (NPYR)
• N-亚硝基吡咯烷 (NPYR)
  

Proposed acceptance criteria建议的接受标准

According to the stimuli article the FDA established an action level of 10 ppb for individual nitrosamines for rubber nipples. In addition, products comply with European Directive 93/11/EEC if the total quantity of released N-nitrosamines is less than 10 ppb. A presentation by the FDA to the Product Quality Research Institute (PQRI) Leachables and Extractables Workshop in 2005 stated the following:

根据启动文，FDA为橡胶奶嘴的单个亚硝胺建立了10ppb的行动水平。此外，如果释放的N-亚硝胺总量小于10ppb，产品符合欧盟指令93/11/EEC。2005年，FDA向产品质量研究所（PQRI）的浸出物和可萃取物工作室作了如下介绍：

• Controls for nitrosamines in metered dose inhaler elastomeric components are tighter than for baby bottle rubber nipples,
• 吸入剂弹性体成分中亚硝胺的控制要比婴儿橡胶奶嘴的更加严格
• Volatile nitrosamines are controlled both individually and in total,
• 挥发性亚硝胺应控制单个杂质和总杂质限量
• Safety limits depend upon drug product characteristics (e.g., design, fill, total daily dose).
• 安全限度取决于药物产品特性（例如，设计、分装、每日总剂量）。
  

Based on the available FDA statements, an initial proposal for acceptance criteria for elastomers in inhalation packaging/delivery systems is provided in the stimuli article:

根据现有的FDA声明，在启动文中提供了吸入剂包装/输送系统中弹性体接受标准的初步建议：

• NDBA: ≤ 1 ppb
• N-亚硝基二丁胺 (NDBA): ≤ 1 ppb
• NDEA: ≤ 1 ppb
• N-亚硝基二乙胺（NDEA）: ≤ 1 ppb
• NDMA: ≤ 1 ppb
• N-亚硝基二甲胺 (NDMA)≤1ppb
• NMOR: ≤ 5 ppb
• N-亚硝基吗啉 (NMOR)≤5ppb
• NPIP: ≤ 1 ppb
• N-亚硝基哌啶 (NPIP)≤1ppb
• NPYR: ≤ 1 ppb
• N-亚硝基吡咯烷 (NPYR)≤1ppb
• Total N-nitrosamines: ≤ 10 ppb
• 总N-亚硝胺≤10ppb
• 
  
  

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