最近研究了一个栓剂，在影响因素试验高温温度的选择找不到可以明确参考的数据。
对于固体制剂产品，采用除去内包装的最小制剂单位，分散为单层置适宜的条件下进行。
高温试验
供试品置密封洁净容器中，在60℃条件下放置10天，于0、5、10天取样检测。与0天比较，若供试品发生显著变化，则在40℃下同法进行试验。
栓剂,别的不说性状60℃肯定是不行的,那只能采用40℃,但是栓剂40℃性状也会发生变化.是不是可以不考虑性状的变化,只要含量和有关物质合格就可以呢?还是要采用低于栓剂得软化温度来做影响因素的高温试验呢?
中药、天然药物稳定性研究技术指导原则.doc (34.0k)
我认为还是应该考察的
性状可以如实说明，都能理解，形状肯定是改变了。关键是看有关物质和含量是否有改变。
我们大家也都知道，夏天有时温度比较高，超过37℃，栓剂肯定是会变软了。但是这种特殊的条件还是客观存在的。尤其是在运输中，很难达到贮藏条件要求。这是考察药品高温试验的目的所在。
这几天不知怎么回事，关于制剂的强降解试验的问题比较多，在此统一回答，省得发重复的帖子。
【问题1】制剂强降解试验的目的有3个；如下
forced degradation studies should be carried out to:
1. identify stability-affecting factors for selection of the packing material;
2. identify potential degradants of the API and assess if they can be formed during manufacture or storage of the FPP.
3. validate the stability indicating power of the analytical procedures used.
这是来自国际认证专家的答复，应该不会错的。
【问题2】制剂强降解试验参考那些技术指南？
1－ICH 的Q系列的指南应该看；毕竟这是根本。但是涉及制剂产品这个问题，在ICH Q系列指南上面语焉不详。
2－中国CDE的技术指南和中国药典附录也要看，但是也是含糊不清。
3－目前比较权威的书面资料是下面的指南
2.7 Stability testing
2.7.1 Stress testing (forced degradation)
Publications from peer-reviewed literature could be submitted to support/replace experimental data.
Stress testing of the API can help to 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 API and the type of FPP involved.
Degradation paths for pharmaceutical compounds are typically reactions of hydrolysis, oxidation, photolysis, and/or acid-base chemistry. To force these reactions, the API or FPP is placed in solution expediently, for example, under the conditions shown in the following table.
Stress factor Conditions
Heat 60°C
Humidity 7 5% RH or greater
Acid 0.1N HCl
Base 0.1N NaOH
Oxidative 3% H2O2
Photolytic Metal halide, Hg Xe lamp, or UV-B/fluorescent
Metal ions (optional) 0.05 M Fe2+ or Cu2+
The objective is not to completely degrade the active compound but to generate degradation to a small extent, typically 10-30% loss of active by assay when compared with non-degraded compound. This target is chosen so that some degradation occurs, but it is not so severe that secondary products are generated. (Secondary degradation products are degradation products of degradation products and in most cases are not observed during stability studies.) In the total absence of degradation products after 10 days, the API is considered stable. If degradation is detectable but its extent is less than 10%, then the stress factors or the stress conditions, or both, should be increased.
Stress testing is to be carried out on a single batch of the API. Photostability testing should be an integral part of stress testing. The standard conditions for photostability testing are described in ICH Q1B.
Solid-state degradation can also be considered. For APIs, placing a solid sample at elevated temperatures —e.g., 60-120 °C, or 5-10 °C below the melting point— can generate some degradation compounds. Because of the harsher conditions, these compounds may not be observed under the accelerated stress studies. However, this approach serves to generate degradation products that can be used as a worst case to assess the analytical method performance.
Examining degradation products under stress conditions is also useful in 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 form an integral part of the information provided to WHO.
For APIs not described in an official pharmacopoeial monograph, there are two options:
When available, it is acceptable to provide the relevant data published in the “peer review” literature to support the proposed degradation pathways.
When no data are available in the scientific literature, including official pharmacopoeias, stress testing should be performed. Results from these studies will form an integral part of the information provided to regulatory authorities.
这是WHO关于仿制药制剂稳定性试验的规定。
不对之处，请战友指教。
药典附录178的原文：
乳剂、混悬剂、软膏剂、乳膏剂、糊剂、凝胶剂、眼膏剂、栓剂、气雾剂、泡腾片及泡腾颗粒宜直接采用30℃±2℃、相对湿度65％±5％的条件进行试验，……。
对于固体制剂产品，采用除去内包装的最小制剂单位，分散为单层置适宜的条件下进行。
高温试验
供试品置密封洁净容器中，在60℃条件下放置10天，于0、5、10天取样检测。与0天比较，若供试品发生显著变化，则在40℃下同法进行试验。
栓剂,别的不说性状60℃肯定是不行的,那只能采用40℃,但是栓剂40℃性状也会发生变化.是不是可以不考虑性状的变化,只要含量和有关物质合格就可以呢?还是要采用低于栓剂得软化温度来做影响因素的高温试验呢?
中药、天然药物稳定性研究技术指导原则.doc (34.0k)
我认为还是应该考察的
性状可以如实说明，都能理解，形状肯定是改变了。关键是看有关物质和含量是否有改变。
我们大家也都知道，夏天有时温度比较高，超过37℃，栓剂肯定是会变软了。但是这种特殊的条件还是客观存在的。尤其是在运输中，很难达到贮藏条件要求。这是考察药品高温试验的目的所在。
这几天不知怎么回事，关于制剂的强降解试验的问题比较多，在此统一回答，省得发重复的帖子。
【问题1】制剂强降解试验的目的有3个；如下
forced degradation studies should be carried out to:
1. identify stability-affecting factors for selection of the packing material;
2. identify potential degradants of the API and assess if they can be formed during manufacture or storage of the FPP.
3. validate the stability indicating power of the analytical procedures used.
这是来自国际认证专家的答复，应该不会错的。
【问题2】制剂强降解试验参考那些技术指南？
1－ICH 的Q系列的指南应该看；毕竟这是根本。但是涉及制剂产品这个问题，在ICH Q系列指南上面语焉不详。
2－中国CDE的技术指南和中国药典附录也要看，但是也是含糊不清。
3－目前比较权威的书面资料是下面的指南
2.7 Stability testing
2.7.1 Stress testing (forced degradation)
Publications from peer-reviewed literature could be submitted to support/replace experimental data.
Stress testing of the API can help to 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 API and the type of FPP involved.
Degradation paths for pharmaceutical compounds are typically reactions of hydrolysis, oxidation, photolysis, and/or acid-base chemistry. To force these reactions, the API or FPP is placed in solution expediently, for example, under the conditions shown in the following table.
Stress factor Conditions
Heat 60°C
Humidity 7 5% RH or greater
Acid 0.1N HCl
Base 0.1N NaOH
Oxidative 3% H2O2
Photolytic Metal halide, Hg Xe lamp, or UV-B/fluorescent
Metal ions (optional) 0.05 M Fe2+ or Cu2+
The objective is not to completely degrade the active compound but to generate degradation to a small extent, typically 10-30% loss of active by assay when compared with non-degraded compound. This target is chosen so that some degradation occurs, but it is not so severe that secondary products are generated. (Secondary degradation products are degradation products of degradation products and in most cases are not observed during stability studies.) In the total absence of degradation products after 10 days, the API is considered stable. If degradation is detectable but its extent is less than 10%, then the stress factors or the stress conditions, or both, should be increased.
Stress testing is to be carried out on a single batch of the API. Photostability testing should be an integral part of stress testing. The standard conditions for photostability testing are described in ICH Q1B.
Solid-state degradation can also be considered. For APIs, placing a solid sample at elevated temperatures —e.g., 60-120 °C, or 5-10 °C below the melting point— can generate some degradation compounds. Because of the harsher conditions, these compounds may not be observed under the accelerated stress studies. However, this approach serves to generate degradation products that can be used as a worst case to assess the analytical method performance.
Examining degradation products under stress conditions is also useful in 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 form an integral part of the information provided to WHO.
For APIs not described in an official pharmacopoeial monograph, there are two options:
When available, it is acceptable to provide the relevant data published in the “peer review” literature to support the proposed degradation pathways.
When no data are available in the scientific literature, including official pharmacopoeias, stress testing should be performed. Results from these studies will form an integral part of the information provided to regulatory authorities.
这是WHO关于仿制药制剂稳定性试验的规定。
不对之处，请战友指教。
药典附录178的原文：
乳剂、混悬剂、软膏剂、乳膏剂、糊剂、凝胶剂、眼膏剂、栓剂、气雾剂、泡腾片及泡腾颗粒宜直接采用30℃±2℃、相对湿度65％±5％的条件进行试验，……。