The main objectives and uses of stability testing are shown in Table 1.

1.1 In the development phase

Accelerated stability tests provide a means of comparing alternative formulations, packaging materials, and/or manufacturing processes in short-term experiments. As soon as the final formulation and manufacturing process have been established, the manufacturer carries out a series of accelerated stability tests which will enable the stability of the drug product to be predicted and its shelf-life and storage conditions determined. Real-time studies must be started at the same time for confirmation purposes. Suitable measures should be taken to establish the utilization period for preparations in multidose containers, especially for topical use.

1.2 For the registration dossier

The drug regulatory authority will require the manufacturer to submit information on the stability of the product derived from tests on the final dosage form in its final container and packaging. The data submitted are obtained from both accelerated and real-time studies. Published and/or recently obtained experimental supporting stability data may also be submitted, e.g. on the stability of active ingredients and related formulations.

Table 1
Main objectives of stability testing

Where the product is to be diluted or reconstituted before being administered to the patient (e.g. a powder for injection or a concentrate for oral suspension), "in use" stability data must be submitted to support the recommended storage time and conditions for those dosage forms.

With the approval of the drug regulatory authority, a tentative (provisional) shelf-life is often established, provided that the manufacturer has undertaken, by virtue of a signed statement, to continue and complete the required studies and to submit the results to the registration authority.

1.3 In the post-registration period

The manufacturer must carry out on-going real-time stability studies to substantiate the expiry date and the storage conditions previously projected. The data needed to confirm a tentative shelf-life must be submitted to the registration body. Other results of on-going stability studies are verified in the course of GMP inspections. To ensure the quality and safety of products with particular reference to degradation, national health authorities should monitor the stability and quality of preparations on the market by means of a follow-up inspection and testing programme.

Once the product has been registered, additional stability studies are required whenever major modifications are made to the formulation, manufacturing process, packaging or method of preparation. The results of these studies must be communicated to the competent drug regulatory authorities.

2. Intended market

The design of the stability testing programme should take into account the intended market and the climatic conditions in the area in which the drug products will be used.

Four climatic zones can be distinguished for the purpose of worldwide stability testing, as follows:

• Zone I: temperate.
• Zone II: subtropical, with possible high humidity.
• Zone III: hot/dry.
• Zone IV: hot/humid.

(See Schumacher P. Aktuelle Fragen zur Haltbarkeit von Arzneimitteln. [Current questions on drug stability.] Pharmazeutische Zeitung, 1974, 119:321-324.)

The mean climatic conditions, calculated data and derived storage conditions in these zones are summarized in Tables 2 and 3.

Since there are only a few countries in zone I, the manufacturer would be well advised to base stability testing on the conditions in climatic zone II when it is intended to market products in temperate climates. For countries where certain regions are situated in zones III or IV, and also with a view to the global market, it is recommended that stability testing programmes should be based on the conditions corresponding to climatic zone IV.

In a stability study, the effect on the product in question of variations in temperature, time, humidity, light intensity and partial vapour pressure are investigated. The effective or mean kinetic temperature therefore reflects the actual situation better than the measured mean temperature; a product kept for 1 month at 20 °C and 1 month at 40 °C will differ from one kept for 2 months at 30 °C. Moreover, the storage conditions are often such that the temperature is higher than the average meteorological data for a country would indicate.

Table 2
Mean climatic conditions: measured data in the open air and in the storage room¹

¹ RH = relative humidity.

Table 3
Mean climatic conditions: calculated data and derived storage conditions¹

¹ Based on: Grimm W. Storage conditions for stability testing in the EC, Japan and USA; the most important market for drug products. Drug development and industrial pharmacy, 1993, 19:2795-2830.

² Calculated temperatures are derived from measured temperatures, but all measured temperatures of less than 19 °C were set equal to 19 °C.

³ MKT = mean kinetic temperature (see p. 67).

⁴ RH = relative humidity.

For some dosage forms, especially liquid and semi-solid ones, the study design may also need to include subzero temperatures, e.g. -10 to -20 °C (freezer), freeze-thaw cycles or temperatures in the range 2-8 °C (refrigerator). For certain preparations it may be important to observe the effects caused by exposure to light.