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 on a production scale.

For existing active substances that are known to be stable, data from at least

two primary batches should be provided.

2.1.4 Container 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 proposed for

storage and distribution.

2.1.5 Specifi cation

Stability studies should include testing of those 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.

Whether and to what extent replication should be performed will depend on

the results from validation studies (11).

2.1.6 Testing 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 proposed 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 second year,

and annually thereafter throughout the proposed 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 sixmonth

study is recommended. Where it is expected (based on development

experience) that results from accelerated studies are likely to approach

signifi cant change criteria, increased 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

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sensitivity to moisture. The storage conditions and the lengths of studies

chosen should be suffi cient to cover storage and shipment.

Storage condition tolerances are defi ned as the acceptable variations in

temperature and relative humidity of storage facilities for stability studies.

The

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