Stability Testing of New Drug Substances and Products

1. Introduction Stability Testing

1.1 Objectives of the Guideline

Stability Testing This guideline is an updated version of the ICH Q1A (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) guideline, which defines the essential stability data package required for new drug substances and drug products to be submitted for registration within the three major regions: the European Union (EU), Japan, and the United States. The guideline aims to provide a framework for stability testing but does not necessarily cover the requirements for registration or export to other regions outside of the specified three.

The primary objective is to detail the core stability testing requirements for new drug substances and products while maintaining flexibility to accommodate the diverse scientific and practical situations that may arise due to varying characteristics of the materials being tested. The guideline allows for alternative testing approaches if scientifically justified.

1.2 Scope of the Guideline

The scope of this guideline is limited to the stability testing of new molecular entities (NMEs) and their associated drug products that are submitted for registration in the EC, Japan, and the United States. It does not cover the stability data submission for abbreviated or abridged applications, variations, clinical trial applications, or similar submissions. Additionally, specific details regarding sampling and testing of dosage forms in their proposed container closure systems are outside the scope of this guideline.

Further information on new dosage forms and biotechnological/biological products can be found in ICH guidelines Q1C and Q5C, respectively.

1.3 General Principles

Stability testing aims to demonstrate how the quality of a drug substance or drug product changes over time when exposed to various environmental conditions such as temperature, humidity, and light. It is intended to establish a re-test period for the drug substance or a shelf life for the drug product, along with recommended storage conditions.

The test conditions outlined in this guideline are based on an analysis of climatic data from the three major regions (EC, Japan, and the United States). The world can be divided into four climatic zones, with this guideline addressing zones I and II. The principle is that stability information generated in any one of these regions is mutually acceptable to the other two, as long as the information aligns with this guideline and the labeling complies with the respective national or regional requirements.

2. Guidelines for Stability Testing

2.1 Drug Substance

2.1.1 General Overview

Stability testing of a drug substance is a critical part of the systematic stability evaluation process. It provides valuable data regarding how the drug substance behaves under various environmental conditions and can be used to determine a suitable re-test period for the substance.

2.1.2 Stress Testing

Stress testing plays a key role in identifying potential degradation products, which in turn helps to establish the degradation pathways and validate the analytical procedures used. Stress testing conditions should be carefully chosen based on the properties of the drug substance and its intended drug product form.

Stress testing typically involves exposing the drug substance to elevated temperatures (usually in increments of 10°C, e.g., 50°C, 60°C), high humidity (≥75% relative humidity), oxidation, and photolysis. These conditions simulate extreme environmental influences that could cause the drug substance to degrade. Hydrolysis should also be assessed across a range of pH values to evaluate how the substance behaves in solution or suspension.

Photostability testing, as outlined in ICH Q1B, is an integral part of stress testing. The results of these stress tests provide essential data to develop and validate stability-indicating analytical methods, and they help to establish a clear understanding of how the drug substance degrades under different conditions.

2.1.3 Selection of Batches

For stability testing, data from at least three primary batches of the drug substance should be provided. These batches must be manufactured at a minimum of pilot scale using the same synthetic route and production methods that will be employed for full-scale manufacturing. The batches tested should accurately represent the material that will be produced at commercial scale. Supporting data from additional batches may also be provided.

2.1.4 Container Closure System

Stability testing must be carried out using the container closure system proposed for the storage and distribution of the drug substance. The testing should involve packaging configurations that accurately simulate the final packaging intended for the product.

2.1.5 Specification

Specifications outline the tests, analytical procedures, and acceptance criteria for the drug substance, as detailed in ICH Q6A and Q6B. Specifications for degradation products are addressed in ICH Q3A. Stability testing should include assessments of the drug substance’s physical, chemical, biological, and microbiological attributes that are susceptible to change over time. Stability-indicating analytical methods must be used to monitor these attributes.

2.1.6 Testing Frequency

The testing frequency for long-term studies should be sufficient to develop a clear stability profile of the drug substance. For substances with a proposed re-test period of at least 12 months, testing at long-term storage conditions should be performed every 3 months during the first year, every 6 months during the second year, and annually thereafter. For accelerated storage conditions, testing should be conducted at a minimum of three time points (e.g., 0, 3, and 6 months) over a 6-month period. If significant changes are expected during the accelerated testing, additional sampling may be required.

2.1.7 Storage Conditions

The storage conditions for stability testing should simulate the expected conditions the drug substance will be exposed to during its shelf life, including factors such as temperature and humidity. Long-term testing should cover at least 12 months for three primary batches, with additional data being submitted if requested by regulatory authorities. The following storage conditions are typically used:

• Long-term conditions: 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH for 12 months.
• Accelerated conditions: 40°C ± 2°C/75% RH ± 5% RH for 6 months.
• Intermediate conditions (if necessary): 30°C ± 2°C/65% RH ± 5% RH for 6 months.

2.1.8 Stability Commitment

If long-term stability data for primary batches do not cover the proposed re-test period, a commitment must be made to continue stability studies post-approval. This commitment should ensure that sufficient data will be collected to confirm the re-test period for the drug substance.

2.1.9 Evaluation

The goal of stability studies is to establish a re-test period that ensures future production batches of the drug substance will meet quality standards. The stability evaluation should include an analysis of degradation products and other relevant attributes such as physical, chemical, and microbiological characteristics. Statistical analysis can be employed to assess batch-to-batch variability and determine the re-test period. Extrapolation beyond the observed data range may be considered if scientifically justified.

2.1.10 Labeling and Storage Statements

The labeling for the drug substance should include storage instructions based on stability data. Terms such as “ambient conditions” or “room temperature” should be avoided. The re-test period, if applicable, should be stated on the container label.

2.2 Drug Product

2.2.1 General Considerations

The stability studies for the drug product should be designed based on an understanding of the drug substance’s properties and stability data. Knowledge gained from clinical formulation studies and drug substance stability testing should inform the choice of attributes to test in the drug product stability studies.

2.2.2 Photostability Testing

Photostability testing should be conducted on at least one primary batch of the drug product, if applicable, following the guidelines outlined in ICH Q1B.

2.2.3 Selection of Batches

Stability studies should be carried out on at least three primary batches of the drug product. The batches should be manufactured using the same formulation and packaging system that will be used in the final product intended for marketing. Two of the batches should be at least pilot scale, and the third can be smaller, provided it is justified. If possible, different batches of the drug substance should be used in the production of the drug product.

2.2.4 Container Closure System

The stability of the drug product should be evaluated using the container closure system intended for marketing. The system should include primary and secondary packaging, as well as the container label. Any studies conducted outside the immediate container may provide useful data but should not replace the primary testing.

2.2.5 Specification

The specification for the drug product should outline the tests, acceptance criteria, and analytical procedures, including those for degradation products as per ICH Q3B. Stability studies should include testing for attributes that are likely to change over time, including physical, chemical, biological, microbiological attributes, and functionality tests for delivery systems (e.g., inhalers). Stability-indicating analytical methods should be validated, and the shelf life acceptance criteria should be derived from all available stability data.

2.2.6. Testing Frequency

The testing frequency for drug products in long-term studies is critical for determining the stability profile of the product over time. A well-structured stability testing schedule is essential to establish the drug’s shelf life and ensure its continued efficacy and safety. The frequency of testing should be sufficient to track and confirm that the drug product remains within acceptable limits throughout its proposed shelf life.

For drug products with a proposed shelf life of at least 12 months, the recommended testing frequency under long-term storage conditions typically follows this pattern:

• First year: Testing should be conducted every 3 months.
• Second year: Testing should occur every 6 months.
• Thereafter: Testing should occur annually until the proposed shelf life is reached.

In accelerated storage conditions, stability tests should be performed at specific intervals to evaluate how the drug product holds up under conditions that simulate potential real-world stressors like temperature fluctuations and humidity. A 6-month accelerated study should involve at least three key time points, which are typically the initial point, a midpoint, and a final time point (e.g., 0, 3, and 6 months). If there is reason to believe that accelerated testing may result in significant changes, the testing schedule should be adjusted. This can include adding additional time points or incorporating a fourth time point to capture further data on the stability of the product.

When stability testing is required at intermediate storage conditions due to significant changes observed at accelerated conditions, a minimum of four time points should be tested over a 12-month period. The time points should include the initial and final test points, for example, 0, 6, 9, and 12 months.

In certain cases, reduced testing designs such as matrixing or bracketing may be applied, where the testing frequency is reduced, or specific factor combinations may not be tested at all. These reduced designs should always be justified based on scientific data and expert analysis.

2.2.7. Storage Conditions

The storage conditions for a drug product should be chosen carefully to assess its stability under various conditions that may occur during storage, shipping, and use. These conditions should simulate real-world scenarios as closely as possible to ensure the drug maintains its potency and safety under typical storage conditions.

2.2.7.1. General Case

In general, drug products should undergo testing under the following storage conditions:

For long-term storage conditions, if the testing is conducted at 25°C ± 2°C and 60% relative humidity (RH) ± 5% RH, no intermediate testing is required unless significant changes are detected during accelerated testing. If significant changes are observed at any time during the 6 months of accelerated testing, additional studies at intermediate conditions (30°C ± 2°C and 65% RH ± 5% RH) should be conducted.

If long-term studies are conducted at 30°C ± 2°C and 65% RH ± 5% RH, an intermediate testing condition may be required if significant changes are observed at the accelerated testing points.

2.2.7.2. Drug Products Packaged in Impermeable Containers

For drug products that are packaged in impermeable containers, moisture sensitivity or solvent loss is generally not a concern. Stability studies can therefore be conducted under controlled or ambient humidity conditions. The impermeable nature of the packaging prevents moisture or solvent from being lost, which simplifies the storage condition requirements for these products.

2.2.7.3. Drug Products Packaged in Semi-Permeable Containers

Drug products that are aqueous-based and packaged in semi-permeable containers need to undergo additional evaluation for potential water loss. In addition to assessing physical, chemical, biological, and microbiological stability, the potential for water loss should be evaluated under conditions of low relative humidity. This ensures that the drug product will maintain its stability even when stored in environments with lower humidity. For these products, studies can be carried out under conditions of lower RH, as described below.

A 5% loss in water from its initial content after 3 months at accelerated conditions (40°C/NMT 25% RH) is considered a significant change for drug products stored in semi-permeable containers. For smaller containers, such as those with 1 mL or less, a water loss greater than 5% is acceptable if properly justified.

In some cases, if testing is conducted under higher relative humidity conditions, the water loss at the reference humidity can be calculated by using the water loss rate ratio for different humidity conditions. This method requires calculating the permeation coefficient of the container closure system.

2.2.7.4. Drug Products Intended for Storage in a Refrigerator

For drug products that are intended to be stored at refrigerated temperatures (5°C ± 3°C), stability studies should include testing under these conditions for at least 12 months to establish the long-term stability. Additionally, accelerated testing can be conducted at 25°C ± 2°C and 60% RH ± 5% RH for 6 months. If the product is packaged in a semi-permeable container, the effect of water loss should be assessed during these tests.

If significant changes are detected during the accelerated storage testing (especially if they occur between 3 and 6 months), the shelf life should be based on real-time data obtained from long-term testing under refrigerated conditions. If changes occur earlier, within the first 3 months, a discussion on short-term excursions outside the storage condition should be included. This may be supported by further testing on a single batch over a shorter time frame but with more frequent testing.

2.2.7.5. Drug Products Intended for Storage in a Freezer

For drug products intended for freezer storage (e.g., -20°C ± 5°C), stability data should be obtained from real-time testing at these low temperatures for a minimum of 12 months. As there are no accelerated conditions for freezer storage, additional testing at elevated temperatures (e.g., 5°C or 25°C) should be conducted to understand the potential effects of short-term excursions outside the proposed storage conditions.

2.2.7.6. Drug Products Intended for Storage Below -20°C

For drug products intended to be stored below -20°C, stability testing should be handled on a case-by-case basis. Specific guidance for testing at temperatures below this threshold is not standardized and should be determined based on the characteristics of the product and the storage conditions.

2.2.8. Stability Commitment

When the available long-term stability data does not cover the full proposed shelf life of a drug product at the time of approval, a commitment must be made to continue stability testing after approval. This ensures that the stability data fully supports the shelf life claim once the product is available for distribution.

In the case where stability data is submitted for fewer than three production batches, a commitment to continue testing should be made, ensuring that long-term studies continue through the proposed shelf life and accelerated studies for 6 months. If no stability data on production batches is available, the first three production batches must be placed under long-term stability studies with appropriate testing on accelerated studies for 6 months.

The protocol used for commitment batches should mirror that used for primary batches unless scientifically justified to differ. If intermediate testing is required due to significant changes observed during accelerated testing, testing on the commitment batches can be conducted at either intermediate or accelerated conditions, depending on the findings.

2.2.9. Evaluation

The stability data must be systematically evaluated to determine the shelf life of the drug product and the appropriate storage conditions for labeling. A robust evaluation includes results from various tests—physical, chemical, biological, and microbiological—that assess all relevant attributes of the product. This ensures the product maintains its intended efficacy and safety over time.

If the stability data reveals minimal degradation or variability between batches, it may not be necessary to conduct a formal statistical analysis. However, when variability is present, statistical methods should be applied to determine the shelf life, including regression analysis to assess how product attributes such as assay, degradation products, and other key features change over time.

Where applicable, limited extrapolation of the real-time data from long-term conditions can be used to extend the shelf life. This extrapolation must be based on sound scientific reasoning, including knowledge of degradation mechanisms and testing under accelerated conditions.

2.2.10. Statements/Labeling

The stability study’s results should directly inform the labeling of the drug product, particularly with regard to storage instructions. The storage statement must be consistent with the stability data and should be based on the observed behavior of the drug under specific storage conditions. Labels should avoid vague terms such as “ambient conditions” or “room temperature,” as these can be interpreted in various ways. Clear and specific storage instructions, based on the stability data, will ensure proper handling and storage by healthcare providers and patients.

Conclusion

Stability testing is a critical part of the drug development process that ensures the quality, safety, and efficacy of drug substances and drug products throughout their shelf life. By following the guidelines outlined in the ICH Q1A and related documents, manufacturers can develop a comprehensive stability data package that meets regulatory requirements and supports the approval of new drug substances and products for marketing. Regular updates to stability data and continuous commitment to stability studies are necessary to address evolving product conditions and ensure continued compliance with regulatory expectations.