小中大老兄,您的理解,不能获得我的认同。
其实人家要求降低一些温度再行开展试验的根本目的,不单单是您说的那些。
更是为了避免在不同温度条件下,药物的降解途径、降解原理都不一样的情况发生。
化学动力学告诉我们,存在“不同温度条件下,降解反应的原理、途径都可能完全不同的情况”,
您想,
您跑到KFC点了份汉堡,
却说一点都没有兰州拉面的风韵,
是不是有点不靠谱涅
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我不同意你的看法。
我承认你说的这一条:【不同温度条件下,药物的降解途径、降解原理都不一样的情况发生】
但是不能为了探索这个目的,而不停的试验不同的温度。如果你说的逻辑存在,50℃是不是也要做一下?
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看看法规,下面是Q1A(R2)的内容
2.1.2.??Stress Testing
Stress testing of the drug substance can help identify the likely degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used. The nature of the stress testing will depend on the individual drug substance and the type of drug product involved.
Stress testing is likely to be carried out on a single batch of the drug substance. It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing), humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis on the drug substance. The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photostability testing should be an integral part of stress testing. The standard conditions for photostability testing are described in ICH Q1B.
Examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures. However, it may not be necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed under accelerated or long term storage conditions.
Results from these studies will form an integral part of the information provided to regulatory authorities.
注意:It should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing。
法规里面很明确说到,stress testing需要比加速试验温度更高,一般高10℃左右;实际也有高20℃的做法。
再看名词解释:
Stress testing (drug substance)
Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing.
可以得出
---强降解试验是研发工作一部分,具有探索性和预实验的性质;
---条件比加速试验更剧烈
---目的是为了评价药物固有稳定性,获得降解途径。
回到我们最初的问题,如果按照中国药典2010版上面要求,60℃下试验结果不合格,做40℃下的试验目的是什么?是为了获得样品合格的结果吗?
我坚持认为这偏离了强降解试验(影响因素试验)的最初目的,如果一个药品在如此剧烈的条件下还合格,除了少数无机盐药品以外,估计就是金刚石了。我们是研究药品,不是研究金刚石。
事实上,对于一个强降解试验(影响因素试验),一开始做较高的问题(60℃),破坏更多的杂质,获得更多的降解信息,对于我们研究工作意义足够了。
如果非要做一个较低温度(40℃)试验,破坏杂质较少,降解情况较少,我们分析方法怎么得到好的评估?