Stability Testing for New Drugs
Guidance outlines ICH's positions on testing.
The International Conference on Harmonization (ICH) has finalized its guidance on stability testing for new drug substances and products, which suggests the storage conditions for the tests, among other things. The guidance, "Q1A Stability Testing of New Drug Substances and Products," published November 7, 2001, took effect on that date in the United States, Europe, and Japan. The final version of a draft guidance published April 21, 2000 (see the "Regulatory Focus" column in the July 2000 issue of PMP News), can be viewed at http://www.fda.gov/cder/guidance/4282fnl.htm. (FDA plans to publish its own stability guidance covering issues not addressed in the ICH document.)
Significant changes include a more detailed description of postapproval commitments, revisions to the text on test procedures to make them consistent with the ICH guidance "Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances," and more-detailed descriptions of storage conditions.
However, the guidance does not cover specific details of the sampling and testing procedures for particular dosage forms in their proposed container-closure systems.
Nonetheless, the guidance states stability studies on a drug substance should be conducted while it is packaged in a container-closure system that is the same as or simulates the packaging proposed for storage and distribution. Stability studies on a drug product should be conducted on the dosage form packaged in the container-closure system proposed for marketing, including secondary packaging and labeling as appropriate. Studies done on the drug product outside its immediate container can be conducted as part of the stress-testing process, and studies of the drug product in other packaging materials can be submitted as supporting information.
Storage statements for labeling should be established in accordance with the relevant national or regional requirements. The statement needs to be based on the stability evaluation, and specific instructions should be provided, especially for drug substances and products that cannot tolerate freezing. The label should avoid using vague terms such as ambient conditions or room temperature. An expiration date must be listed on the container label.
For drug products, data from stability studies should be provided on at least three primary batches, and the studies should be performed on each individual strength and container size of the drug product, unless bracketing or matrixing (techniques in which the testing frequency is reduced or certain factor combinations are not tested) is being employed.
For most long-term studies, the frequency of testing should be every three months over the first year, every six months over the second year, and annually thereafter for as long as the proposed shelf life. For accelerated studies, three time points over six months should be used. If there is significant change at the accelerated storage condition and testing at an intermediate storage condition is needed, a minimum of four time points over 12 months should be used. If bracketing or matrixing is used, it needs to be justified.
Storage conditions should test the product's thermal stability and, if applicable, sensitivity to moisture or potential for solvent loss.
For most drug substances and products, long-term samples being studied should be stored at 25° ±2°C and 60% relative humidity (RH) ±5% for 12 months, intermediate samples should be stored at 30° ±2°C and 60% RH ±5% for six months, and accelerated samples should be stored at 40° ±2°C and 75% ±5% RH for six months.
Aqueous-based products packaged in semipermeable containers should be evaluated for potential water loss in addition to other stability concerns. Intermediate samples should be treated the same way that those for regular drug products are treated. The only difference for long-term studies is to conduct them at 40% RH ±5%, and the only difference for accelerated studies is to conduct them at not more than 25% RH. It is acceptable to perform the stability studies on these products at a higher RH and derive the water loss at the reference RH through calculation. The guidance explains how to do those calculations.
Long-term stability tests on drug substances and products intended for storage in a refrigerator should be performed at 5° ±3°C over 12 months and accelerated studies should be done at 25° ±2°C and 60% RH ±5% over six months.
Long-term stability tests on drug substances and products intended for storage in a freezer should be done at –20° ±5°C over 12 months. Testing on a single batch at an elevated temperature for an appropriate time period should be conducted to address the effect of short-term excursions outside the proposed storage condition listed on the label. Drug substances and products intended for storage below –20°C should be treated on a case-by-case basis.