Stability assessment is a crucial aspect of all drug-development activities. Stability of the drug product and drug substance may impact both drug efficacy and drug safety and is generally regarded as a critical quality attribute (CQA) of every drug and vaccine. Both small-molecule and large-molecule drug substance and drug products are impacted by stability concerns. Primary consideration is given to those factors that impact drug potency and the formation of impurities over time.
Specifically ICH Q1A(R2) 1.3. General Principles states (1), "The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity, and light, and to establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions."
The primary factors for any stability study are time, batch, and environmental factors. The primary environmental conditions are moisture/humidity and temperature. A risk assessment should be completed to evaluate any additional environmental factors the drug may be sensitive to (2). In addition, there are factors associated with the drug product and drug substance that may impact stability such as pH, excipients, API concentration, and hold times that should be included in the overall stability evaluation and during drug development.
Stability testing should start at the beginning of early drug development with early formulation and process/method development (3). Generally, accelerated stability testing, followed by confirmatory long-term stability testing, is considered a best practice (see Figure 1). Care needs to be exercised that accelerated stability testing is representative of long-term testing and does not cause degradation pathways that are not present in the nominal storage environment. Once long-term stability data are available, calibration and correction of the accelerated stability estimates are possible.
At each phase of development, formulation modifications, process changes, and refinement in analytical methods are made, causing the stability evaluation to be challenged, updated, and modified. Care should be exercised that representative material batches are selected for testing and the associated stability data, analysis, and reports are submitted to the regulatory agencies.