Identify the drug products that need to be included in the stability program and the specific stability parameters that will be monitored (e.g., active ingredient content, pH, appearance).

Stability-indicating assays are analytical methods that can detect changes in the quality and potency of a drug product over time. These assays are used to monitor the stability of the drug product and ensure that it meets the established acceptance criteria throughout its shelf life.

• Select the appropriate assay method: It is important that methods used to establish stability are “stability indicating”. The method should be able to accurately and reliably detect any changes in the quality or potency of the drug product. Reference ICH Q14 for the development of Analytical procedures. This ICH Guideline describes the science and risk-based approaches for developing and maintaining analytical procedures suitable for testing the quality of drug substances and drug products.
• Validate the assay method: Validate the assay method to ensure accuracy, precision, and reliability. Scientific and regulatory expectations for analytical method validation are described in ICH Q2. FDA has also established guidance for industry for “Analytical Procedures and Methods Validation for Drugs and Biologics.”
• Establish acceptance criteria: Establish the acceptance criteria for the stability parameters that will be monitored using the assay method. These criteria should be based on the established specifications for the drug product.

A stability testing protocol is a document that outlines the methods and procedures for conducting stability studies on a drug product. It provides guidance on the testing methods, sample storage conditions, and acceptance criteria for the stability studies. Points to consider in establishing the stability testing protocol include:

• Define the scope of the stability studies: Identify the drug product(s) that will be included in the stability studies and the specific stability parameters that will be monitored (e.g., active ingredient content, pH, appearance).
• Determine the storage conditions: Determine the storage conditions that will be used for the stability studies, based on the intended use and marketing conditions of the drug product. This may include conditions such as room temperature, refrigerated, or frozen.
• Select the testing methods: Select the appropriate testing methods for the stability parameters that will be monitored. These methods should be validated to ensure their accuracy, precision, and reliability.
• Determine the testing frequency: Determine how often the drug product will be tested during the stability studies. This will depend on the stability characteristics of the product and the intended shelf life.
• Establish acceptance criteria: Establish the acceptance criteria for the stability parameters that will be monitored. These criteria should be based on the established specifications for the drug product.
• Write the protocol: Write the stability protocol, including all of the information outlined above. The protocol should also include details on how the samples will be collected and prepared for testing, as well as any specific requirements for handling the samples to ensure sample integrity and traceability to the testing data.
• Review and approve the protocol: Have the stability protocol reviewed and approved by the appropriate parties, such as Product Development, Quality Assurance, and Regulatory Affairs.
• If testing results indicate the need to change the testing frequency or other parameters, the protocol should be updated through change control with approvals provided by the initial functional departments responsible for the original protocol.

Stability studies are conducted to determine the shelf life of a drug product and ensure that it meets the established acceptance criteria for quality and potency throughout its shelf life. These studies should be conducted under appropriate storage conditions (e.g., room temperature, refrigerated, frozen) to simulate real-world storage conditions. The drug product should be tested at predetermined intervals throughout the shelf life to ensure that it meets the acceptance criteria. When conducting studies or testing, consider the following:

• Drug product stability testing must be performed using products stored in the same container/closure systems as that in which the drug product is (or will be) marketed.
• Ensure all equipment used in the stability program is controlled: Ensure all equipment used for storing and testing samples has been qualified for its intended use via appropriate Installation Qualification (IQ) and Operational Qualification (OQ) methods. Ensure equipment is maintained and calibrated to ensure the integrity of results and data collected.
• Prepare the samples: Collect representative samples of the drug product for the stability studies. The samples should be properly labeled and stored under the appropriate conditions (e.g., room temperature, refrigerated, frozen) as outlined in the stability protocol.
• Test the samples: Test the samples at predetermined intervals using the validated analytical testing methods and acceptance criteria specified in the stability protocol. These tests should be performed by qualified, trained personnel.
• Record and analyze the data: Record the results of the tests and analyze the data to determine if it indicates the stable shelf life of the drug product at the testing point (e.g., at 3 mo., 6 mo., 12 mo., 18 mo.). If testing indicates specifications are not being met or if there is an indication of degradation, perform and document an investigation to identify potential degradation pathways. (Note, if analytical testing indicates a specification has not been met, it is important to follow the testing laboratory’s “Out of Specification” (OOS) procedures to determine if the result is attributable to handling error, equipment error, or if it is a valid out of specification result).
• Review and report the results: Review the results of the stability studies and prepare a report outlining the findings. The report should include a summary of the testing methods and results, as well as any conclusions. Ensure any protocol deviations are explained with supporting justification.
• Continue stability-monitoring program: Based on the results of the stability studies, continue monitoring at predefined test intervals to ensure the quality and potency of the drug product is maintained throughout its shelf life.

It is important to follow good manufacturing practices (GMPs) and good laboratory practices (GLPs) when conducting stability studies to ensure the integrity and reliability of the data. It is also important to follow the protocol and any applicable regulatory guidelines.

The data collected during the stability studies should be analyzed to determine the shelf life of the drug product and identify any potential degradation pathways. Here are several best practices for properly analyzing stability data:

• Use statistical analysis: Statistical analysis can help to identify trends and patterns in the data that may not be immediately apparent. Statistical techniques such as regression analysis and ANOVA can be used to determine the shelf life of the drug product and identify potential degradation pathways.
• Use appropriate software: There are several software programs available that are specifically designed for analyzing stability data. These programs can help to automate the analysis process and provide more accurate and reliable results.
• Follow good laboratory practices (GLPs): GLPs are guidelines for conducting laboratory experiments in a consistent and reliable manner. Adhering to GLPs can help to ensure the integrity and reliability of the data.
• Use appropriate controls: Controls should be included in the stability studies to ensure the accuracy and reliability of the data. This may include using placebo or blank samples or using reference standards to verify the accuracy of the testing methods.
• Review and approve the results: The results of the stability studies should be reviewed and approved by a qualified individual or team to ensure their accuracy and completeness. Any discrepancies or anomalies should be thoroughly investigated.

It is important to follow a systematic, well-documented, and statistically valid approach when analyzing stability data to ensure the integrity and reliability of the results.

A long-term, real-time, stability-monitoring program is a systematic approach to ensuring the ongoing quality and potency of on-market drug product batches to verify that the shelf life is being maintained. This includes testing reserve samples from individual drug product batches using the same validated stability-indicating assays used to establish the initial shelf life of the product. Testing is performed at pre-determined intervals which may be based on the extent of the shelf life and risk of degradation. Here are the points to consider in establishing the long-term stability monitoring program:

• Shelf life of the drug product: The shelf life of the drug product will influence the frequency of review and update of the stability program. Products with a longer shelf life may require less frequent reviews and updates, while products with a shorter shelf life may require more frequent reviews and updates.
• Stability characteristics of the drug product: The stability characteristics of the drug product, such as the rate of degradation and the potential degradation pathways, will also influence the review and update frequency. Products that are more stable may require less frequent reviews and updates, while products that are less stable may require more frequent reviews and updates.
• Drug products that contain preservatives to inhibit microbial growth, in particular, need to be monitored to ensure the effectiveness of the preservative. This microbial testing is typically done at the same intervals that the product stability parameters are monitored.

It is important to follow good manufacturing practices (GMPs) and good laboratory practices (GLPs) when establishing and implementing a stability-monitoring program to ensure the integrity and reliability of the data. It is also important to follow applicable regulatory guidelines.

The stability program should be reviewed and updated as needed to ensure that it remains relevant and effective, and the frequency of review and update of the stability program should be based on the specific needs of the drug product and the results of the stability studies. Any changes to the drug product or manufacturing process could impact drug product stability, requiring a reevaluation of drug stability. Regulatory requirements may also influence the review and update frequency of the stability program.

It is important to follow any applicable regulatory guidelines when establishing drug product shelf life and monitoring stability over time.  ICH Q1A-Q1F provide guidance for stability testing, including guidance for how to evaluate stability data.