© World Health Organization
WHO Technical Report Series, No. 953, 2009
Annex 2
Stability testing of active pharmaceutical ingredients and fi nished pharmaceutical products
1. Introduction
1.1 Objectives of the guidelines
1.2 Scope of the guidelines
principles
1.3 General
2. Guidelines
2.1 Active pharmaceutical ingredient
General
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2.1.1
testing
2.1.2
Stress
2.1.3 Selection of batches
2.1.4 Container closure system
Specification
2.1.5
frequency
2.1.6
Testing
Storage
conditions
2.1.7
b ility
commitment
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Evaluation
2.1.9
2.1.10 Statements and labelling
2.1.11 Ongoing stability studies
2.2 Finished pharmaceutical product
2.2.1
General
2.2.2 Selection of batches
2.2.3 Container closure system
2.2.4
Specification
frequency
Testing
2.2.5
Storage
conditions
2.2.6
commitment
b ility
Sta
2.2.7
Evaluation
2.2.8
2.2.9 Statements and labelling
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b ility
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2.2.10
Variations
2.2.11
2.2.12 Ongoing stability studies
3. Glossary
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References
Appendix 1
Long-term stability testing conditions as identifi ed by WHO Member States Appendix 2
Examples of testing parameters
Appendix 3
Recommended labelling statements
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1. Introduction
1.1Objectives of the guidelines
The guidelines ek to exemplify the core stability data package required for registration of active pharmaceutical ingredients (APIs) and fi nished pharmaceutical products (FPPs), replacing the previous WHO guidelines in this area (1,2). However, alternative approaches can be ud when they are scientifi cally justifi ed. Further guidance can be found in International Conference on Harmonisation (ICH) guidelines (3)and in the WHO guidelines on the active pharmaceutical ingredient master fi le procedure (4).
It is recommended that the guidelines should also be applied to products that are already being marketed, with allowance for an appropriate transition period, e.g. upon re-registration or upon re-evaluation.
1.2Scope of the guidelines
The guidelines apply to new and existing APIs and address information to be submitted in original and subquent applications for marketing authorization of their related FPP for human u. The guidelines are not applicable to stability testing for biologicals (for details on vaccines plea e WHO guidelines for stability evaluation of vaccines (5)).
1.3 General principles
The purpo of stability testing is to provide evidence of how the quality of an API or FPP varies with time under the infl uence of a variety of environmental factors such as temperature, humidity and light. The stability programme also includes the study of product-related factors that infl uence its quality, for example, interaction of API with excipients, container closure systems and packaging materials. In fi xed-do combination FPPs (FDCs) the interaction between two or more APIs also has to be considered.
As a result of stability testing a re-test period for the API (in exceptional cas, e.g. for unstable APIs, a shelf-life is given) or a shelf-life for the FPP can be established and storage conditions can be recommended.
Various analys have been done to identify suitable testing conditions for WHO Member States bad on climatic data and are published in the literature (6–9) on the basis of which each Member State can make its decision on long-term (real-time) stability testing conditions. Tho Member States that have notifi ed WHO of the long-term stability testing conditions they require when requesting a marketing authorization are listed in Appendix 1.
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2. Guidelines
2.1Active pharmaceutical ingredient
2.1.1 General
Information on the stability of the API is an integral part of the systematic approach to stability evaluation. Potential attributes to be tested on an API during stability testing are listed in the examples of testing parameters (Appendix 2).
The re-test period or shelf-life assigned to the API by the API manufacturer should be derived from stability testing data.
2.1.2 Stress testing
帽子的英语怎么写Stress testing of the API can help identify the likely degradation products, which, in turn, can help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability-indicating power of the analytical procedures ud. The nature of the stress testing will depend on the individual API and the type of FPP involved.
For an API the following approaches may be ud:
—when available, it is acceptable to provide the relevant data published in the scientifi c literature to support the identifi ed degradation products
and pathways;
—when no data are available, stress testing should be performed.
Stress testing may be carried out on a single batch of the API. It should include the effect of temperature (in 10 °C increments (e.g. 50 °C, 60 °C, etc.) above the temperature ud for accelerated testing), humidity (e.g. 75% relative humidity (RH) or greater) and, where appropriate, oxidation and photolysis on the API. The testing should also evaluate the susceptibility of the API to
hydrolysis across a justifi ed range of pH values when in solution or suspension (10).
Asssing the necessity for photostability testing should be an integral part of
a stress testing strategy. More details can be found in other guidelines (3).
Results from the studies will form an integral part of the information provided to regulatory authorities.
2.1.3 Selection of batches
Data from stability studies on at least three primary batches of the API should normally be provided. The batches should be manufactured to a minimum of pilot scale by the same synthesis route as production batches, and using a method of manufacture and procedure that simulates the fi nal process to be ud for production batches. The overall quality of the batches
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of API placed on stability studies should be reprentative of the quality of the material to be made on a production scale.
For existing active substances that are known to be stable, data from at least two primary batches should be provided.
2.1.4C ontainer closure system
The stability studies should be conducted on the API packaged in a container closure system that is the same as, or simulates, the packaging propod for storage and distribution.
2.1.5S pecifi cation关于校园生活的作文
Stability studies should include testing of tho attributes of the API that are susceptible to change during storage and are likely to infl uence quality, safety and/or effi cacy. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes. A guide as to the potential attributes to be tested in the stability studies is provided in Appendix 2.
Validated stability-indicating analytical procedures should be applied.
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Whether and to what extent replication should be performed will depend on the results from validation studies (11).
2.1.6T esting frequency
For long-term studies, frequency of testing should be suffi cient to establish the stability profi le of the API.
For APIs with a propod re-test period or shelf-life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every three months over the fi rst year, every six months over the cond year, and annually thereafter throughout the propod re-test period or shelf-life.
At the accelerated storage condition, a minimum of three time points, including the initial and fi nal time points (e.g. 0, 3 and 6 months), from a six-month study is recommended. Where it is expected (bad on development experience) that results from accelerated studies are likely to approach signifi cant change criteria, incread testing should be conducted either by adding samples at the fi nal time point or by including a fourth time point in the study design. When testing at the intermediate storage condition is called for as a result of signifi cant change at the accelerated storage condition, a minimum of four time points, including the initial and fi nal time points (e.g.
0, 6, 9 and 12 months), from a 12-month study is recommended.
2.1.7 Storage conditions
In general an API should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its 90
nsitivity to moisture. The storage conditions and the lengths of studies chon should be suffi cient to cover storage and shipment.
Storage condition tolerances are defined as the acceptable variations in temperature and relative humidity of storage facilities for stability studies. The equipment ud should be capable of controlling the storage conditions within the ranges defi ned in the guidelines. The storage conditions should be monitored and recorded. Short-term environmental changes due to opening the doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be assd, addresd and reported if judged to affect stability results. Excursions that exceed the defi ned tolerances for more than 24 hours should be described in the study report and their effects assd.
The long-term testing should normally take place over a minimum of 12 months for the number of batches specifi ed in ction 2.1.3 at the time of submission, and should be continued for a period of time suffi cient to cover the propod re-test period or shelf-life. For existing substances that are kno
wn to be stable, data covering a minimum of six months may be submitted. Additional data accumulated during the asssment period of the registration application should be submitted to the authorities upon request. Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be ud to evaluate the effect of short-term excursions outside the label storage conditions (such as might occur during shipping).
Long-term, accelerated and, where appropriate, intermediate storage conditions for APIs are detailed in ctions 2.1.7.1–2.1.7.3. The general ca applies if the API is not specifi cally covered by a subquent ction. Alternative storage conditions can be ud if justifi ed.
If long-term studies are conducted at 25 °C ± 2 °C/60% RH ± 5% RH and “signifi cant change” occurs at any time during six months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against signifi cant change criteria. In this ca, testing at the intermediate storage condition should include all long-term tests, unless otherwi justifi ed, and the initial application should include a minimum of six months’ data from a 12-month study at the intermediate storage condition.
“Significant change” for an API is defined as failure to meet its specifi cation.
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