This month’s question
Stability studies are an integral part of any pharmaceutical manufacturing system. Monitoring this data across the life cycle of the product is equally important. What statistical tools should be part of a stability study?
Stability of a pharmaceutical product must be established before seeking regulatory approval for commercialization. The purpose of the stability study is to establish shelf life and to propose a retest period of a drug product. A complete stability study includes a long-term stability study performed at intended storage conditions and an accelerated stability study performed under stressed conditions (at higher temperatures and relative humidity).
The shelf life of a pharmaceutical product can be defined as the time the drug product is expected to remain within the specifications defined for its purity and strength.
For an attribute known to decrease with time, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines state that the shelf life is calculated as the time at which the lower, one-sided, 95% confidence limit for the mean degradation curve intersects the acceptance criterion. For an attribute known to increase with time, the shelf life is calculated as the time at which the upper confidence limit intersects the acceptance criterion.1
Hence, the estimation of pharmaceutical drug quality is based on the adequate degradation line fitted on the stability data and on the appropriate statistical interval.
Establishing and monitoring stability data across the product life cycle ensures product quality and minimizes patient risk. Hence, a systematic approach must be adopted in the presentation and evaluation of the stability information. The stability information should include, as appropriate, results from the physical, chemical, biological and microbiological tests, including those related to attributes of the dosage form (for example, dissolution rate for solid oral dosage forms).
The adequacy of the mass balance must be assessed. Factors that can cause an apparent lack of mass balance must be considered, including, for example, the mechanisms of degradation and the stability-indicating capability and inherent variability of the analytical procedures.
Where applicable, an appropriate statistical method should be employed to analyze the long-term primary stability data. The purpose of this analysis is to establish, with a high degree of confidence, a retest period or shelf life during which a quantitative attribute will remain within acceptance criteria for all future batches manufactured, packaged and stored under similar circumstances.
To provide a valid statistical inference for the estimated retest period or shelf life, the statistical method used for data analysis must consider the stability study design. The statistical evaluation of the pharmaceutical stability data must include regression analysis, analysis of variance, general linear model and the computation of several statistical intervals (confidence, prediction and tolerance).
Regression analysis is considered an appropriate approach to evaluating the stability data for a quantitative attribute and establishing a retest period or shelf life. The nature of the relationship between an attribute and time will determine whether data should be transformed for linear regression analysis. The relationship can be represented by a linear or nonlinear function on an arithmetic or logarithmic scale. In some cases, a nonlinear regression can better reflect the true relationship.
However, nonlinear and other special linear models (square root, 1/x, log, exponential, polynomials) generally are avoided unless specifically indicated from the data, historical experience or a careful analysis of the residuals.
Finally, stability is a key consideration when setting product specification acceptance limits. Stability and rates of degradation must be compared to the upper specification limit and lower specification limit during early development and throughout the product life cycle.
- International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), “Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products,” ICH, www.fda.gov/downloads/drugs/guidances/ucm073369.pdf.
This response was written by Suresh Anaganti, CEO, Lab to Pharmacy LLC, Palmyra, PA.