Stability Guidelines WHO
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© 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 these guidelines
1.2 Scope of these guidelines
1.3 General principles
2. Guidelines
2.1 Active pharmaceutical ingredient …………………
2.1.1 General
2.1.2 Stress testing
2.1.3 Selection of batches
2.1.4 Container closure system
2.1.5 Specifi cation
2.1.6 Testing frequency
2.1.7 Storage conditions……
2.1.8 Stability commitment
2.1.9 Evaluation
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 Specifi cation
2.2.5 Testing frequency
2.2.6 Storage conditions
2.2.7 Stability commitment
2.2.8 Evaluation
2.2.9 Statements and labelling
2.2.10 In-use stability
2.2.11 Variations
2.2.12 Ongoing stability studies
3. Glossary
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
1.1 Objectives of these guidelines
These guidelines seek 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 used
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 these 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.
1.2 Scope of these guidelines
These guidelines apply to new and existing APIs and address information
to be submitted in original and subsequent applications for marketing
authorization of their related FPP for human use. These guidelines are not
applicable to stability testing for biologicals (for details on vaccines please
see WHO guidelines for stability evaluation of vaccines (5)).
1.3 General principles
The purpose 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-dose
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
cases, 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 analyses have been done to identify suitable testing conditions
for WHO Member States based 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. Those
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
2.1 Active 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
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 used. 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 used:
— 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 used 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).
Assessing 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 these 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 used for production batches. The overall quality of the batches
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of API placed on stability studies should be representative of the quality of
the material to be made
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