Stability studies on a finished pharmaceutical product should be designed in the light of the properties and stability characteristics of the drug substance as well as the climatic conditions of the intended market zone. Before stability studies of dosage forms are initiated, information on the stability of the drug substance should be sought, collected and analysed. Published information on stability is available on many well established drug substances.

3.1 Test samples

For registration purposes, test samples of products containing fairly stable active ingredients are taken from two different production batches; in contrast, samples should be taken from three batches of products containing easily degradable active ingredients or substances on which limited stability data are available. The batches to be sampled should be representative of the manufacturing process, whether pilot plant or full production scale. Where possible, the batches to be tested should be manufactured from different batches of active ingredients.

In on-going studies, current production batches should be sampled in accordance with a predetermined schedule. The following sampling schedule is suggested:

! one batch every other year for formulations considered to be stable, otherwise one batch per year;

! one batch every 3-5 years for formulations for which the stability profile has been established, unless a major change has been made, e.g. in the formulation or the method of manufacture.

Detailed information on the batches should be included in the test records, namely the packaging of the drug product, the batch number, the date of manufacture, the batch size, etc.

3.2 Test conditions

3.2.1 Accelerated studies

An example of conditions for the accelerated stability testing of products containing relatively stable active ingredients is shown in Table 4.

For products containing less stable drug substances, and those for which limited stability data are available, it is recommended that the duration of the accelerated studies for zone II should be increased to 6 months.

Table 4
Example of conditions for accelerated stability testing of products containing relatively stable active ingredients

Alternative storage conditions may be observed, in particular, storage for 6 months at a temperature of at least 15°C above the expected actual storage temperature (together with the appropriate relative humidity conditions). Storage at higher temperatures may also be recommended, e.g. 3 months at 45-50°C and 75% relative humidity (RH) for zone IV.

Where significant changes (see below) occur in the course of accelerated studies, additional tests at intermediate conditions should be conducted, e.g. 30 ± 2°C and 60 ± 5% RH. The initial registration application should then include a minimum of 6 months’ data from a 1-year study.

A significant change is considered to have occurred if:

! the assay value shows a 5% decrease as compared with the initial assay value of a batch;

! any specified degradation product is present in amounts greater than its specification limit;

! the pH limits for the product are no longer met;

! the specification limits for the dissolution of 12 capsules or tablets are no longer met;

! the specifications for appearance and physical properties, e.g. colour, phase separation, caking, hardness, are no longer met.

Storage under test conditions of high relative humidity is particularly important for solid dosage forms in semi-permeable packaging. For products in primary containers designed to provide a barrier to water vapour, storage conditions of high relative humidity are not necessary. As a rule, accelerated studies are less suitable for semi-solid and heterogeneous formulations, e.g. emulsions.

3.2.2 Real-time studies

The experimental storage conditions should be as close to the projected actual storage conditions in the distribution system as practicable (see Table 3). For registration purposes, the results of studies of at least 6 months’ duration should be available at the time of registration. However, it should be possible to submit the registration dossier before the end of this 6-month period. Real-time studies should be continued until the end of the shelf-life.

3.3 Frequency of testing and evaluation of test results

In the development phase and for studies in support of an application for registration, a reasonable frequency of testing of products containing relatively stable active ingredients is considered to be:

! for accelerated studies, at 0, 1, 2, 3 and, when appropriate, 6 months;
! for real-time studies, at 0, 6 and 12 months, and then once a year.

For on-going studies, samples may be tested at 6-month intervals for the confirmation of the provisional shelf-life, or every 12 months for well established products. Highly stable formulations may be tested after the first 12 months and then at the end of the shelf-life. Products containing less stable drug substances and those for which stability data are available should be tested every 3 months in the first year, every 6 months in the second year, and then annually.

Test results are considered to be positive when neither significant degradation nor changes in the physical, chemical and, if relevant, biological and microbiological properties of the product have been observed, and the product remains within its specification.