Stability Programs 

Laboratory testing, which is required by 21 CFR 211.160 and 211.165, is necessary to confirm that components, containers and closures, in-process materials, and drug products conform to appropriate standards of identity, strength, quality, and purity. Release testing provides evidence that the materials conform to appropriate standards at the time of release. Stability testing provides evidence on how the quality of a drug substance or drug product varies over time. Environmental factors and product-related factors may impact the stability of the drug substance/drug product over time. The impact of environmental factors, such as temperature, humidity, and light, must be evaluated. The impact of product-related factors, such as the chemical and physical properties of the drug substance/drug product, the manufacturing process, and the container-closure system, must also be evaluated.

Stability programs can be divided into three main types: product development stability, commercial support stability, and change management stability. While there are overlaps in the execution of the stability studies, the objectives of each of the stability types are different.


Product Development Stability

The type of product that is being considered defines the activities of the development stability program. For generic drug products, the stability requirements for submission of the Abbreviated New Drug Application (ANDA) include the comparison of the final drug product stability data to those of the innovator product. Stability data on the innovator product are of further value, as they provide insight into formulation and packaging requirements.

For new drug products, no innovator studies can be performed; however, clinical studies frequently are conducted using another therapeutic compound as a comparator, as well as a placebo product. Since these clinical studies are often blinded, the identity of the target formulation, the comparator formulation, and the placebo must be hidden by over-encapsulation or other means of obscuring the identity. Stability testing of these formulations is required to evaluate impact to drug release of the obscuration process and to ensure patient safety throughout the duration of the clinical study.

Other stability studies common to both types of products include photostability testing, excipient compatibility testing, stress testing, and packaging evaluation studies. Further, through well-planned design of experiments (DOE) studies, appropriate ranges and tolerances in component ratios and processing parameters can be established.

Stability is an integral part of these DOE studies as the various changes may not result in observable differences in the release results.

Photostability studies are performed as two distinctive studies; one as a form of forced degradation, and the other to demonstrate appropriate protective qualities of container closure systems (also known as confirmatory photostability studies). For the forced degradation photostability study, the test article is exposed to high levels of visible light and ultraviolet (UV) radiation with the intent of degrading the test article. The results from this testing help to identify potential degradation pathways and provide guidance in formulating and packaging the product. Confirmatory photostability studies are performed as indicated by International Conference on Harmonization (ICH) guidance Q1B Photostability Stability Testing of New Drug Substances and Products. Studies are performed in the least protective packaging available (such as open petri dish), progressing to more protective packaging (primary commercial packaging) as required. The data generated from these studies will be used to demonstrate that the packaging provides adequate protection from light.

Excipient compatibility studies are performed to determine if any intended components contribute to instability of the product. Forced degradation studies are performed as a tool in developing stability-indicating analytical methods, while the packaging evaluation studies help to identify appropriate packaging configurations and material.

Stress testing is performed to help identify likely degradation products and validate stability-indicating methods. Most companies target to degrade a material 5% to 15%, but no more than 20%. Successful degradation is demonstrated when the analysis clearly indicates the presence of degradation peaks and a lowered assay. Companies may use acid stress, base stress, thermal degradation, or oxidative degradation to degrade their material. An appropriate stability-indicating method will have appropriate resolution between the analyte and degradation peaks and will demonstrate mass balance.

A company can acid-stress the analyte and placebo of the drug substance and/or drug product by adding HCl such that the pH ≤ 3. Samples are maintained in that environment up to a week. The sample is neutralized before analysis. If no degradation occurs, a higher concentration of acid (maximum of 6N) and/or an elevated temperature (60 °C to 80 °C) can be used. The base stressing is done by stressing the analyte and placebo of the drug substance and/or drug product by adding NaOH such that the pH ≥ 9. Samples are maintained in that environment up to a week. The sample is neutralized before analysis. If no degradation occurs, a higher concentration of base (maximum of 6N) and/or an elevated temperature (60 °C to 80 °C) can be used.

The thermal degradation is done by stressing the analyte and placebo of the drug substance and/or drug product by heating in an oven or water bath to temperatures of 70

°C to 105 °C, but at least 10 °C below the melting point. Samples are maintained in that environment up to a week. Lower temperatures can be selected if the sample melts or excessive degradation occurs. If no degradation occurs, a combination of thermal exposure and humidity (for example, 50 °C/80% relative humidity [RH]) can be used. The oxidative degradation is done by stressing the analyte and placebo of the drug substance and/or drug product by adding up to 3% H2O2. Samples are maintained in that environment up to a week.

Packaging evaluation studies are performed near the end of the development process when a likely formulation and process have been identified. For these studies, a firm would place the same batch of material in various container-closure systems and submit them to the same storage conditions. Results can be compared side by side to determine if one package provides more protection than another. The results obtained from all these studies will be used to help select a final formulation, establish appropriate specifications, and determine product shelf life.

The final stability study from the development program is the submission study. This study is conducted following the guidance provided in ICH Q1A (R2) Stability Testing of New Drug Substances and Products (referred to as “Q1A guidance”). The batches used in the submission study represent the final formulation, manufacturing processes, and commercial packaging. Sample material is stored at controlled conditions (Table 25.1) for specific time periods and tested. The data generated from these studies are evaluated and submitted to regulatory bodies as part of the drug approval process.

Commercial Support Stability

As part of the submission process, a company will include a commitment to continue stability evaluation over the commercial life of the product. The stability commitment may vary depending on the properties of the product, but generally specifies that one representative batch per year be held at the long-term storage condition (Table 25.1) and tested at the same time points and by the same methodology as used to generate the submission data.

The results generated for a commitment batch have far-reaching implications. Thus, a batch that fails to meet specification during shelf life would cause all batches of the same packaging configuration to be evaluated. In such a scenario, a firm could be required to reduce expiry or recall product from the market.

Change Management Stability

The components, processing, packaging, and labeling of a drug product are specified in the approved application. A change to any of these requires evaluation to ensure that the change has no deleterious effect on the product. Stability testing is frequently a part of this evaluation. For example, a firm may wish to change the supplier of the active pharmaceutical ingredient (API) in their drug product. This change would require stability testing. Just as in the original application, the results will be evaluated and submitted to regulatory authorities for approval. The magnitude of change and the tolerances established during registration will influence the type of stability program required to support the change.


As with any good scientific evaluation, stability studies begin with outlining the steps to be taken and the rules for interpreting the results (that is, this plan is the stability protocol). Minimally, a protocol should specify the sample storage conditions/testing time points/packaging configuration and provide reference to the test methods/acceptance criteria against which the test article is being evaluated. Studies performed to support a regulatory submission generally include the criteria for evaluating the data.


The ICH Q1A (R2) guidance outlines the generally accepted conditions at which studies are to be performed (Table 25.1). Exceptions to these conditions, with a written justification, can be made depending on the nature of the product and the intended use of the data.

Time Points

The Q1A guidance provides recommended time points for testing. These are typically one, two, three, and six months for accelerated studies; and three, six, nine, 12, 18, 24, and 36 months for long-term studies. The intermediate storage condition is set up to provide additional information should a study fail to meet acceptance criteria during the accelerated study. Like the storage conditions, these may be adjusted as needed to fulfill the purpose of the study.

Packaging Configurations

Each unique presentation of a product must be represented in the commercial support stability program. For example, a drug product that has one strength and is in four package configurations would have four unique presentations of the product. Thus, the four presentations need be represented on stability.

A stability program can be established by bracketing. Bracketing is based on the extremes, which are put on stability, and the intermediates are assumed to be represented. For example, bracketing can be applied to different container sizes that are made from the same resin, filled with the same product. If a drug product is packaged in the same bottle with three different tablet counts (30-count, 90-count, and 100-count) and in a unit-dose blister, only three presentations (30-count, 100-count, and unit-dose blister) will be on stability. The fourth configuration (90-count), which is bracketed by the 30-count and 100-count, is assumed to be represented. Matrixing can be used. With matrixing, a selected subset of the total number of possible samples with all factor combinations is tested at a specified time point.

Once data are generated from the study, they will need to be evaluated. The first step in this process is to compare them against the acceptance criteria. The second step is to look at the trending. Trending is typically performed on sets of data that include the same formulation and packaging configuration. An approach for analyzing stability data, which is expected to change over time, is to determine the time at which the 95% one- sided confidence limit for the mean curve intersects the acceptance criterion (Figure 25.1).


Based on the stability data extrapolation, companies can infer information about future data and establish dating. This information can aid in establishing acceptance criteria/expiry dating for the new product based on a high degree of confidence. After approval of a new material, the ongoing stability study data will permit the detection of a stability issue, such as change in impurity levels. In general, certain quantitative attributes, such as assay and degradation products, can be assumed to be zero-order kinetics during long-term storage, thus the trending and regression statistics can be applied to these stability-indicating tests. Although the kinetics of other quantitative attributes, such as pH and dissolution, are not known, the same statistical analysis model can be applied.

Results that do not meet the acceptance criteria or demonstrate adverse trending must be investigated both from a laboratory perspective (was the testing performed correctly?) and from a product perspective (were formulation, manufacturing, packaging, and delivery performed correctly?). Typically, an out-of-specification (OOS) procedure will be followed to conduct the investigation. For approved products, and if the stability study is representative of product in commerce, a confirmed OOS result will require notification to the United States Food and Drug Administration (FDA) within three days of the confirmation. Depending on the failure and product evaluation, a company may potentially reduce the expiry dating or recall the product.

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