法规及指南

设计要求

原料药

WHO Stability testing of active pharmaceutical ingredients and finished pharmaceutical products

At least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring program and generally should be tested at least every 6 months in the first year and then annually to confirm the stability

ICH Q7A

WHO GMP

EU GMP part 2

PIC/S GMP

11.54 Thereafter, at least one batch per year of API manufactured (unless none is produced that year) should be added to the stability monitoring program and tested at least annually to confirm the stability.
11.55 For APIs with short shelf-lives, testing should be done more frequently. For example, for those biotechnological/biologic and other APIs with shelf-lives of one year or less, stability samples should be obtained and should be tested monthly for the first three months, and at three month intervals after that. When data exist that confirm that the stability of the API is not compromised, elimination of specific test intervals (e.g. 9 month testing) can be considered.

中国GMP2010

第二百三十四条　持续稳定性考察的时间应当涵盖药品有效期，考察方案应当至少包括以下内容：

第二百三十五条　考察批次数和检验频次应当能够获得足够的数据，以供趋势分析。通常情况下，每种规格、每种内包装形式的药品，至少每年应当考察一个批次，除非当年没有生产

ICH Q1D  BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

2.4.2 Design Considerations

A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission. However, due to the recommended full testing at certain time points, as discussed below, it may be difficult to achieve a complete balance in a design where time points are matrixed.

In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point. If full long-term data for the proposed shelf life will not be available for review before approval, all selected combinations of batch, strength, container size, and fill, among other things, should also be tested at 12 months or at the last time point prior to submission. In addition, data from at least three time points, including initial, should be available for each selected combination through the first 12 months of the study. For matrixing at an accelerated or intermediate storage condition, care should be taken to ensure testing occurs at a minimum of three time points, including initial and final, for each selected combination of factors.

ICH Q1D 矩阵法（测试点矩阵）设计有两点相关的要求：

• 起始点和最终点必须进行测试。

• 前12个月至少检测3个点。

制剂

法规及指南

测试频率

WHO Stability testing of active pharmaceutical ingredients and finished pharmaceutical products

The protocol for the ongoing stability programme can be different from that of the initial long-term stability study as submitted in the marketing authorization dossier provided that this is justified and documented in the protocol (for example, the frequency of testing as above, or when updating to meet revised recommendations).

The number of batches and frequency of testing should provide sufficient data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none is produced during that year). The principle of bracketing and matrixing designs may be applied if scientifically justified in the protocol (refer to ICH Q1D).

中国GMP2010

第二百三十四条　持续稳定性考察的时间应当涵盖药品有效期，考察方案应当至少包括以下内容：

第二百三十五条　考察批次数和检验频次应当能够获得足够的数据，以供趋势分析。通常情况下，每种规格、每种内包装形式的药品，至少每年应当考察一个批次，除非当年没有生产

EU GMP

PIC/S GMP

6.30 The protocol for an on-going stability programme should extend to the end of the shelf life period and should include, but not be limited to, the following parameters:

6.31 The protocol for the on-going stability programme can be different from that of the initial long-term stability study as submitted in the marketing authorisation dossier provided that this is justified and documented in the protocol (for example the frequency of testing, or when updating to ICH/VICH recommendations).

6.32 The number of batches and frequency of testing should provide a sufficient amount of data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none are produced during that year).

WHO GMP

Stability studies

17.22 QC should evaluate the quality and stability of finished pharmaceutical products and, when necessary, of starting materials and intermediate products.

17.23 QC should establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions.

17.24 A written programme for ongoing stability determination should be developed and implemented to include elements such as:

(a) a complete description of the medicine involved in the study;(b) the complete set of testing parameters and methods, describing all tests for potency, purity, and physical characteristics and documented evidence that these tests indicate stability;(c) provision for the inclusion of a sufficient number of batches;(d) the testing schedule for each medicine;(e) provision for special storage conditions;(f) provision for adequate sample retention;(g) a summary of all the data generated, including the evaluation and the conclusions of the study.

FDA. CFR Title 21 – Food and Drugs Part 211 Current Good Manufacturing Practice for Finished Pharmaceuticals

(a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include:  

(1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability; 

(2) Storage conditions for samples retained for testing;

(3) Reliable, meaningful, and specific test methods; 

(4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed; 

(5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.

ICH Q1D  BRACKETING AND MATRIXING DESIGNS FOR STABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS

2.4.2 Design Considerations

A matrixing design should be balanced as far as possible so that each combination of factors is tested to the same extent over the intended duration of the study and through the last time point prior to submission. However, due to the recommended full testing at certain time points, as discussed below, it may be difficult to achieve a complete balance in a design where time points are matrixed.

In a design where time points are matrixed, all selected factor combinations should be tested at the initial and final time points, while only certain fractions of the designated combinations should be tested at each intermediate time point. If full long-term data for the proposed shelf life will not be available for review before approval, all selected combinations of batch, strength, container size, and fill, among other things, should also be tested at 12 months or at the last time point prior to submission. In addition, data from at least three time points, including initial, should be available for each selected combination through the first 12 months of the study. For matrixing at an accelerated or intermediate storage condition, care should be taken to ensure testing occurs at a minimum of three time points, including initial and final, for each selected combination of factors.

ICH Q1D 矩阵法（测试点矩阵）设计有两点相关的要求：

l  起始点和最终点必须进行测试。

l  前12个月至少检测3个点。