IMPACT OF STABILITY ON TOLERANCE DESIGN
Figure 4: Tolerances and stability.
Stability is a key consideration when setting product specification acceptance limits. Specification limits should first and
foremost take into account the impact of variation of the drug product on efficacy and safety, and then secondarily, it should
take into account three sources of variation: product/process variation, assay or method variation, and stability variation
(see Figure 4). Failure to understand or account for stability when setting limits will assure a problematic stability program and may
prevent the product from being commercially viable or create excessive unnecessary product and supply-chain costs in many
Specifically ICH Q6B 1.2 Back-ground states, "Specifications are one part of a total control strategy designed to ensure product
quality and consistency. Other parts of this strategy include thorough product characterization during development, upon which
many of the specifications are based, adherence to Good Manufacturing Practices, a validated manufacturing process, raw materials
testing, in-process testing, stability testing, etc." (6).
Figure 5: Typical stability report.
Stability and rates of degradation should be compared to the upper specification limit (USL) and lower specification limit
(LSL) during early development and throughout the product lifecycle. Stability effect size (see Figure 5) should be calculated as follows:
Two-sided specification limits
(Slope/(USL-LSL))*100= percent of change in tolerance per time period
One-sided specification limits
USL only: (Slope/(USL-batch average))*100=percent of design margin
LSL only: (Slope/(batch average-LSL))*100=percent of design margin
No specification limits
No limits: (Slope/batch average)*100=percent of average per time period
ACCELERATED STABILITY ANALYSIS
The full discussion of accelerated stability studies may be beyond the scope of this paper; however, the basics will be provided.
The accelerated stability study must add value and be predictive of long-term stability studies to be of practical benefit
to the development process. The basic steps in an accelerated stability study are as follows:
1. Determine the purpose of the accelerated stability study
2. Selection of acceleration factors and ranges to be included in the acceleratedstability study
3. Determination of the number of time periods in hours, days, or weeks
4. Building the accelerated period model and rates of degradation at each temperature/storage condition (see Figure 6)
Figure 6: Accelerated stability study.
5. Generalization of the model for any temperature or storage condition (see Figure 7)
Figure 7: Generalized accelerated stability model.
6. Prediction of stability at nominal storage conditions (expiry, rate of degradation, and acceleration factor)
7. Calibration or correction of accelerated stability studies with long-term stability studies to assure they are predictive
8. Validation that accelerated stability studies match long-term stability studies and add value to the development process.