What is stability testing of new drug substances and products

Stability testing of new drug substances and products  the purpose of this communication is to detail the updates incorporated in Q1A(R) following the adoption of ICH Q1F “Stability Data Package for Registration Applications in stability-conditions-table-2018.” These modifications include:

1. Adjustment of the intermediate storage condition from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH in the following sections:
   • 2.1.7.1 Drug Substance – Storage Conditions – General Case
   • 2.2.7.1 Drug Product – Storage Conditions – General Case
   • 2.2.7.3 Drug products packaged in semi-permeable containers
   • 3 Glossary – “Intermediate testing”
2. Specification that 30°C ± 2°C/65% RH ± 5% RH can serve as an appropriate alternative long-term storage condition to 25°C ± 2°C/60% RH ± 5% RH in the following sections:
   • 2.1.7.1 Drug Substance – Storage Conditions – General Case
   • 2.2.7.1 Drug Product – Storage Conditions – General Case
3. Introduction of 30°C ± 2°C/35% RH ± 5% RH as an acceptable alternative long-term storage condition to 25°C ± 2°C/40% RH ± 5%, with inclusion of the corresponding example for the ratio of water-loss rates in the following section:
   • 2.2.7.3 Drug products packaged in semi-permeable containers

Furthermore, transitioning the intermediate storage condition midway from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65% RH ± 5% RH is deemed appropriate, provided that the respective conditions and the transition date are clearly documented and specified in the registration application.

It is strongly advised that registration applications include comprehensive data from studies conducted at the intermediate storage condition of 30°C ± 2°C/65% RH ± 5% RH, where applicable, within three years from the publication date of this updated guideline in the relevant ICH tripartite region.

INTRODUCTION stability testing

1.1. Objectives

On revised guideline, based on ICH Q1A, outlines the stability data requirements for new drug substances and products intended for registration in the EC, Japan, and the United States. It focuses specifically on establishing a comprehensive stability data package suitable for regulatory submission within these regions, rather than covering requirements for other global markets.

The guideline aims to define the essential stability data for new drug substances and products, while allowing flexibility to accommodate diverse scientific considerations and material characteristics. Alternative approaches are permissible if scientifically justified.

1.2. Scope of the Guideline

This guideline pertains to the submission of stability data in registration applications for new molecular entities and associated drug products. It does not currently encompass requirements for abbreviated applications, variations, clinical trials, etc.

Detailed protocols for sampling and testing specific dosage forms in their proposed container closures are outside the scope of this guideline. Additional guidance for new dosage forms and biotechnological/biological products is available in ICH guidelines Q1C and Q5C, respectively.

1.3. General Principles

Stability testing serves to demonstrate how the quality of a drug substance or drug product changes over time under various environmental conditions such as temperature, humidity, and light. Its primary goals include establishing a re-test period for the drug substance and a shelf life for the drug product, as well as recommending appropriate storage conditions.

The test conditions specified in this guideline are derived from an analysis of climatic conditions prevalent in the EC, Japan, and the United States. Climatic data allows determination of mean kinetic temperatures, and the world is divided into four climatic zones (I-IV). This guideline specifically addresses climatic zones I and II.

It is established that stability data generated in any of the three regions (EC, Japan, United States) is mutually acceptable to the others, provided it aligns with this guideline and complies with national/regional labeling requirements.

2.1. Drug Substance stability testing

2.1.1. General

Understanding the stability of the drug substance is crucial within the comprehensive stability assessment framework.

2.1.2. Stress Testing

Stress testing of the drug substance plays a critical role in identifying potential degradation products, establishing degradation pathways, assessing the molecule’s intrinsic stability, and validating the efficacy of analytical procedures. The specific approach to stress testing varies based on the drug substance and the type of drug product involved.

Typically, stress testing involves subjecting a single batch of the drug substance to conditions such as elevated temperatures (in increments of 10°C above those used for accelerated testing, e.g., 50°C, 60°C), high humidity (e.g., 75% RH or higher where applicable), oxidation, and photolysis. Additionally, the testing evaluates the drug substance’s susceptibility to hydrolysis across a broad range of pH values in solution or suspension. Photostability testing follows the standard conditions outlined in ICH Q1B.

Analyzing degradation products under stress conditions helps in establishing degradation pathways and developing and validating appropriate analytical methods. However, specific testing for certain degradation products may be unnecessary if it’s demonstrated that they do not form under accelerated or long-term storage conditions.

Results from stress testing and degradation studies are integral components of the data submitted to regulatory authorities.

2.1.3. Selection of Batches

Formal stability studies should include data from at least three primary batches of the drug substance. These batches should be manufactured at a minimum pilot scale, using the same synthetic route and a method that mimics the final production process for production batches. The quality of the batches placed under formal stability studies should accurately represent the quality of the material intended for production scale.

Additional supportive data may also be included.

2.1.4. Container Closure System

Stability studies must use the drug substance packaged in a container closure system identical to or resembling the proposed packaging for storage and distribution.

2.1.5. Specification

Specifications, including tests, reference to analytical procedures, and acceptance criteria, are addressed in ICH Q6A and Q6B. Specific guidelines for specifying degradation products in a drug substance are discussed in Q3A.

Stability studies should encompass testing attributes of the drug substance susceptible to change during storage, which may impact quality, safety, and efficacy. These tests should include assessments of physical, chemical, biological, and microbiological attributes as relevant. Validated stability-indicating analytical methods should be employed, with replication determined based on validation study outcomes.

2.1.6. Testing Frequency

In long-term stability studies, the frequency of testing should adequately establish the stability profile of the drug substance. For drug substances with a proposed re-test period of at least 12 months, the testing frequency at the long-term storage condition typically involves testing every 3 months during the first year, every 6 months during the second year, and annually thereafter throughout the proposed re-test period.

At accelerated storage conditions, a minimum of three time points should be tested, including the initial and final time points (e.g., 0, 3, and 6 months), in a 6-month study. If there is an expectation, based on development experience, that accelerated studies may approach significant change criteria, additional testing should be conducted. This can involve adding samples at the final time point or including a fourth time point in the study design.

When significant changes observed at accelerated storage conditions necessitate testing at intermediate storage conditions, a minimum of four time points should be tested over a 12-month study period, including the initial and final time points (e.g., 0, 6, 9, and 12 months).

2.1.7. Storage Conditions

Generally, drug substances should undergo evaluation under storage conditions that test their thermal stability and, if applicable, sensitivity to moisture. The chosen storage conditions and study durations should adequately cover storage, transportation, and subsequent usage scenarios.

Long-term testing should span a minimum duration of 12 months across at least three primary batches at the time of submission, continuing for a period sufficient to cover the proposed re-test period. Additional data accumulated during the registration assessment period should be submitted to regulatory authorities upon request. Data from accelerated and, where applicable, intermediate storage conditions can be utilized to assess the impact of short-term excursions beyond labeled storage conditions, such as those occurring during transportation.

Specific details regarding long-term, accelerated, and intermediate storage conditions for drug substances are provided in subsequent sections. The general case applies in instances where the drug substance is not covered by specific subsequent sections. Alternative storage conditions may be justified based on scientific rationale.

The decision to conduct long-term stability studies at either 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH rests with the applicant. If 30°C ± 2°C/65% RH ± 5% RH is chosen as the long-term condition, then an intermediate condition is not required.

If long-term stability studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and a “significant change” is observed during any point of the 6-month accelerated storage testing, additional testing at the intermediate storage condition becomes necessary. This testing should be comprehensive and include all relevant tests, unless exceptions are scientifically justified.

When conducting testing at the intermediate storage condition, the initial application should include a minimum of 6 months’ worth of data from a 12-month study conducted at this intermediate condition.

In this context, “significant change” for a drug substance is defined as a failure to meet its specified acceptance criteria or specification limits. This criterion guides the decision to conduct additional testing at the intermediate storage condition.

2.1.7.2. Drug substances intended for storage in a refrigerator

When assessing data from refrigerated storage, it should follow the evaluation section of this guideline, unless specified otherwise.

If a significant change is observed between 3 and 6 months of accelerated storage testing, the proposed re-test period should be determined based on the real-time data available from long-term storage conditions.

If a significant change occurs within the first 3 months of accelerated storage testing, a discussion must address the impact of short-term excursions beyond the labeled storage conditions, such as those during shipping or handling. This discussion can be supported, if appropriate, by additional testing on a single batch of the drug substance over a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue testing the drug substance through 6 months when a significant change has occurred within the initial 3 months.

Based on the information provided, here’s how the study data at submission should be formatted:

• Study: Long term stability study
• Storage condition: 20°C ± 5°C
• Minimum time period covered by data at submission: 12 months

This indicates that the long-term stability study data submitted includes testing conducted at 20°C ± 5°C for a minimum duration of 12 months.

For drug substances intended for storage in a freezer, the determination of the re-test period should be based on real-time data obtained under the long-term storage condition in the freezer.

In cases where there is no accelerated storage condition available for drug substances intended for freezer storage, additional testing on a single batch should be conducted at an elevated temperature. This temperature could be, for example, 5°C ± 3°C or 25°C ± 2°C, for an appropriate duration. This testing is necessary to assess the impact of short-term excursions outside the proposed label storage condition, such as those occurring during shipping or handling.

This approach ensures that the stability characteristics of the drug substance are adequately evaluated under conditions relevant to its intended storage and use.

Drug substances intended for storage below -20°C require individual assessment. If long-term stability data from primary batches do not cover the proposed re-test period granted during approval, a commitment must be made for continued stability studies post approval to establish the re-test period definitively.

If submission includes long-term stability data from three production batches covering the proposed re-test period, no further commitment is necessary post approval. Otherwise, commitments should follow these guidelines:

1. If stability studies include data from at least three production batches, commit to continuing these studies through the proposed re-test period.
2. If stability studies include data from fewer than three production batches, commit to extending these studies through the proposed re-test period and include additional production batches, totaling at least three, in long-term stability studies.
3. If submission lacks stability data from production batches, commit to placing the first three production batches on long-term stability studies through the proposed re-test period.

The stability protocol for long-term studies should match that of the primary batches, unless scientifically justified otherwise.

The stability study aims to establish a re-test period applicable to all future batches, based on evaluating a minimum of three batches of the drug substance. Variability among batches affects confidence that future batches will meet specifications over the assigned re-test period.

In cases where data show minimal degradation and variability, formal statistical analysis may be unnecessary. Providing justification for this omission should suffice.

For quantitative attributes expected to change over time, an approach involves determining when the 95% one-sided confidence limit for the mean curve intersects the acceptance criterion. If batch-to-batch variability is low, combining data into an overall estimate is advantageous. Statistical tests should first validate the appropriateness of data combination (e.g., p values for significance level exceeding 0.25). If data cannot be combined, the re-test period should be based on the shortest time a batch can be expected to meet acceptance criteria.

The decision on whether to transform data for linear regression analysis depends on the nature of the degradation relationship, typically represented by linear, quadratic, or cubic functions on either arithmetic or logarithmic scales. Statistical methods are essential to assess the goodness of fit of the data across all batches and combined batches, where applicable, to the assumed degradation line or curve.

When justified, limited extrapolation of real-time data beyond the observed range in long-term storage conditions to extend the re-test period can be considered at the time of approval. This justification should be grounded in an understanding of the degradation mechanism, results from accelerated testing, the appropriateness of any mathematical models used, batch size considerations, and the presence of supporting stability data. However, it is important to note that such extrapolation assumes that the degradation relationship will remain consistent beyond the observed data.

Any comprehensive evaluation should cover not only the assay results but also the levels of degradation products and other relevant attributes.

Moving to section 2.1.10 on Statements/Labeling, it is crucial to establish a storage statement for labeling in accordance with relevant national or regional requirements. This statement should be derived from the stability evaluation of the drug substance. Specific instructions should be provided where applicable, especially for drug substances that are sensitive to freezing. Terms such as “ambient conditions” or “room temperature” should be avoided in favor of precise storage conditions.

Additionally, a re-test period should be determined based on stability information, and if appropriate, the retest date should be prominently displayed on the container label. This ensures that users are informed about the recommended timeframe within which the drug substance retains its specified quality attributes.

2.2. Drug Product stability testing

2.2.1. General Considerations

The design of stability studies for the drug product should be informed by understanding the characteristics and behaviors of the drug substance, as well as insights gained from stability assessments of the drug substance and clinical formulation studies. The anticipated changes during storage and the rationale behind selecting attributes for formal stability studies should be clearly defined.

2.2.2. Photostability Assessment

If applicable, photostability testing should be conducted on at least one primary batch of the drug product. Standard conditions for photostability testing are outlined in ICH Q1B.

2.2.3. Batch Selection

Stability data should be provided for a minimum of three primary batches of the drug product. These batches should use the same formulation and packaging as intended for marketing. The manufacturing process for these batches should replicate that of production batches, ensuring consistent product quality and adherence to specifications. At least two of these batches should be at pilot scale, with the third potentially smaller if justified. Whenever feasible, different batches of the drug substance should be used in manufacturing the drug product batches.

2.2.4. Container Closure System

Stability testing should be conducted on the dosage form packaged in the container closure system intended for marketing, which includes any secondary packaging and container label where relevant. Studies conducted on the drug product outside its immediate container or in alternative packaging materials can contribute to stress testing of the dosage form or provide supporting information, respectively.

2.2.5. Specification

Specifications for the drug product, encompassing tests, reference to analytical procedures, and proposed acceptance criteria, are detailed in ICH Q6A and Q6B. Specific guidelines for degradation products in a drug product are addressed in Q3B.

Stability studies should encompass testing of attributes susceptible to change during storage, which could impact quality, safety, and/or efficacy. This includes physical, chemical, biological, and microbiological attributes, as well as preservative content (e.g., antioxidants, antimicrobial preservatives) and functional tests (e.g., for dose delivery systems). Analytical procedures must be fully validated and stability-indicating. The extent of replication should be determined based on validation study results.

Acceptance criteria for shelf life should be derived from comprehensive stability data. Justifiable differences between release and shelf life acceptance criteria may be appropriate based on stability evaluations and observed changes during storage. Differences in acceptance criteria for antimicrobial preservative content should be supported by validated correlations between chemical content and preservative effectiveness demonstrated during drug development. For verification purposes, a single primary stability batch should be tested for antimicrobial preservative effectiveness at the proposed shelf life, irrespective of any differences in acceptance criteria for preservative content.

2.2.6. Testing Frequency

For long-term stability studies, the testing frequency should be adequate to establish the drug product’s stability profile. Products with a proposed shelf life of at least 12 months should typically be tested every 3 months during the first year of storage, every 6 months during the second year, and annually thereafter.

Accelerated storage conditions require testing at a minimum of three time points, including the initial and final time points (e.g., 0, 3, and 6 months) from a 6-month study. If there is an expectation, based on development experience, that accelerated testing results may approach significant change criteria, Increased testing should be conducted either by adding samples at the final time point or by incorporating a fourth time point into the study design.

When testing at the intermediate storage condition is necessitated due to significant changes observed at the accelerated storage condition, a minimum of four time points should be tested. This includes the initial and final time points (e.g., 0, 6, 9, and 12 months) from a 12-month study.

Reduced designs, such as matrixing or bracketing, may be implemented if justified. These approaches involve reducing the frequency of testing or excluding certain combinations of factors from testing altogether.

These strategies for testing frequency and study design help ensure comprehensive evaluation of the drug product’s stability under varying conditions, as outlined in regulatory guidelines and best practices.

2.2.7. Storage Conditions

A drug product should undergo evaluation under storage conditions that include appropriate tolerances to assess its thermal stability and, if applicable, its sensitivity to moisture or potential for solvent loss. The chosen storage conditions and study durations should be sufficient to encompass storage, transportation, and subsequent use scenarios.

Stability testing of the drug product after constitution or dilution, if applicable, must be conducted to provide information for labeling regarding preparation, storage conditions, and in-use periods of the constituted or diluted product. This testing should be performed on primary batches of the constituted or diluted product as part of formal stability studies, with assessments at initial and final time points. If full shelf life data are not available before submission, testing should include assessments at 12 months or the last available time point. Typically, this testing does not need to be repeated on commitment batches.

Long-term stability testing should span at least 12 months on a minimum of three primary batches at the time of submission and should continue for a duration sufficient to cover the proposed shelf life. Additional data accumulated during the registration application assessment period should be submitted to authorities upon request. Data from accelerated and, where applicable, intermediate storage conditions can be utilized to evaluate the impact of short-term deviations from labeled storage conditions, such as those occurring during shipping.

Detailed protocols for long-term, accelerated, and, where applicable, intermediate storage conditions for drug products are provided in subsequent sections. The general approach applies if specific conditions are not addressed in subsequent sections. Alternative storage conditions may be justified based on specific circumstances.

Study and Storage Conditions

The stability of drug products is assessed under various storage conditions, with data covering specific minimum periods at the time of submission:

• Long term: Conducted at either 25°C ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH, with a minimum duration of 12 months.
• Intermediate: Conducted at 30°C ± 2°C/65% RH ± 5% RH, with a minimum duration of 6 months.
• Accelerated: Conducted at 40°C ± 2°C/75% RH ± 5% RH, with a minimum duration of 6 months.

These conditions and durations ensure comprehensive evaluation of the drug product’s stability profile under varying environmental stresses, covering both anticipated storage and potential shipping conditions.

If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and “significant change” is observed during 6 months of testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. The initial submission should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition.

Definition of “Significant Change” for Drug Products:

• A 5% change in assay from its initial value; or failure to meet acceptance criteria for potency using biological or immunological procedures;
• Any degradation product exceeding its acceptance criterion;
• Failure to meet acceptance criteria for appearance, physical attributes, and functionality tests (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); some changes in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions;
• For specific dosage forms, failure to meet acceptance criteria for pH; or
• Failure to meet acceptance criteria for dissolution for 12 dosage units.

2.2.7.2. Drug Products Packaged in Impermeable Containers

For drug products packaged in impermeable containers that provide a permanent barrier to moisture or solvent passage, sensitivity to moisture or potential solvent loss is not a concern. Therefore, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.

This distinction allows for tailored stability testing based on the packaging characteristics, ensuring that the evaluation reflects the actual environmental conditions relevant to the drug product’s stability and storage requirements.

2.2.7.3. Drug Products Packaged in Semi-Permeable Containers

Aqueous-based drug products packaged in semi-permeable containers should undergo evaluation for potential water loss in addition to assessing physical, chemical, biological, and microbiological stability. This evaluation can be conducted under conditions of low relative humidity, as outlined below. The goal is to demonstrate that aqueous-based drug products stored in semi-permeable containers can maintain stability in environments with low relative humidity.

For non-aqueous, solvent-based products, similar approaches can be developed and documented.

This approach ensures that stability testing addresses specific challenges posed by semi-permeable packaging, thereby providing assurance of product integrity under relevant storage conditions.

The stability of new drug substances and products is evaluated under specified storage conditions, with data covering minimum periods at the time of submission:

• Long term: Conducted at either 25°C ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH, with a minimum duration of 12 months.
• Intermediate: Conducted at 30°C ± 2°C/65% RH ± 5% RH, with a minimum duration of 6 months.
• Accelerated: Conducted at 40°C ± 2°C/Not More Than (NMT) 25% RH, with a minimum duration of 6 months.

Long-Term and Accelerated Stability Testing

For long-term studies conducted at 25°C ± 2°C/40% RH ± 5% RH, additional testing at the intermediate storage condition should be conducted under the general case to evaluate the temperature effect at 30°C if significant changes other than water loss occur during 6 months of testing at the accelerated storage condition. It is noted that significant changes in water loss alone at the accelerated storage condition do not require testing at the intermediate storage condition. However, data must demonstrate that the drug product will not experience significant water loss throughout its proposed shelf life when stored at 25°C and 40% RH.

A 5% loss in water from its initial value is considered a significant change for products packaged in semi-permeable containers after an equivalent of 3 months of storage at 40°C/NMT 25% RH. For small containers (1 mL or less) or unit-dose products, a 5% or greater water loss after an equivalent of 3 months at 40°C/NMT 25% RH may be acceptable if justified.

An alternative approach to testing at the reference relative humidity, as recommended in the table above (for both long-term and accelerated testing), involves conducting stability studies under higher relative humidity conditions and calculating the water loss at the reference relative humidity. This calculation can be achieved by experimentally determining the permeation coefficient of the container closure system or using the ratio of water loss rates between the two humidity conditions at the same temperature. The permeation coefficient can be determined experimentally, using the worst-case scenario (e.g., the most diluted concentration) for the proposed drug product.

This approach ensures thorough evaluation of the drug product’s stability under different conditions, taking into account potential impacts of packaging and environmental factors on product integrity and performance.

Example of Approach for Determining Water Loss

For a product in a specific container closure system, container size, and fill, an effective approach to determine the water loss rate at the reference relative humidity involves multiplying the water loss rate measured at an alternative relative humidity at the same temperature by a water loss rate ratio, as illustrated in the table below. The method requires demonstrating a linear water loss rate at the alternative relative humidity over the storage period.

Valid water loss rate ratios at relative humidity conditions not listed in the table can also be applied.

2.2.7.4. Drug Products Intended for Storage in a Refrigerator

Study and Storage Conditions

For drug products intended for storage in a refrigerator, stability testing is conducted under the following conditions, with data covering specified minimum periods at the time of submission:

• Long term: Conducted at 5°C ± 3°C for a minimum of 12 months.
• Accelerated: Conducted at 25°C ± 2°C/60% RH ± 5% RH for a minimum of 6 months.

If the drug product is packaged in a semi-permeable container, comprehensive information must be provided to assess the extent of water loss.

Data obtained from refrigerated storage should be evaluated according to the guidelines provided, unless explicitly noted otherwise.

• If significant changes occur between 3 and 6 months of testing at the accelerated storage condition, the proposed shelf life should be based on real-time data obtained from the long-term storage condition.
• If significant changes occur within the first 3 months of testing at the accelerated storage condition, a discussion should be provided to address the impact of short-term excursions outside the labeled storage conditions (e.g., during shipment and handling). This discussion may be supported, if appropriate, by additional testing on a single batch of the drug product for a period shorter than 3 months but with more frequent testing than usual. It is generally unnecessary to continue testing a product for 6 months when significant changes occur within the first 3 months.

2.2.7.5. Drug Products Intended for Storage in a Freezer

Study and Storage Conditions

For drug products intended for storage in a freezer, stability testing is conducted under the following conditions, with data covering specified minimum periods at the time of submission:

• Long term: Conducted at -20°C ± 5°C for a minimum of 12 months.

For drug products intended for freezer storage, shelf life determination should be based on real-time data obtained from long-term storage conditions. In the absence of an accelerated storage condition for products intended for freezer storage, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate duration should be conducted to assess the impact of short-term excursions outside the proposed labeled storage conditions.

These guidelines ensure comprehensive evaluation of drug product stability under varied storage conditions, addressing specific challenges posed by different storage environments and packaging considerations.

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

Drug products intended for storage below -20°C should be evaluated on a case-by-case basis.

2.2.8. Stability Commitment

Stability commitment should be addressed as follows:

• When long-term stability data from primary batches do not cover the proposed shelf life granted at approval, a commitment should be made to continue stability studies post-approval to establish the shelf life definitively.
• If submission includes long-term stability data from three production batches covering the proposed shelf life, a post-approval commitment is deemed unnecessary. Otherwise, the following commitments apply:
  1. If submission includes stability data from at least three production batches, commit to continue long-term studies through proposed shelf life and accelerated studies for 6 months.
  2. If submission includes stability data from fewer than three production batches, commit to extend long-term studies through proposed shelf life and conduct accelerated studies for 6 months. Additionally, place additional production batches (totaling at least three) on long-term stability studies through proposed shelf life and accelerated studies for 6 months.
  3. If submission lacks stability data on production batches, commit to place the first three production batches on long-term stability studies through proposed shelf life and accelerated studies for 6 months.

The stability protocol for commitment batches should mirror that of primary batches, unless scientifically justified. If intermediate testing is necessitated by significant changes at the accelerated storage condition for primary batches, commitment batch testing can occur at either intermediate or accelerated conditions. However, significant changes at accelerated conditions for commitment batches should trigger testing at intermediate conditions as well.

2.2.9. Evaluation

A systematic approach should be employed for the presentation and evaluation of stability information, incorporating results from physical, chemical, biological, and microbiological tests, including specific attributes of the dosage form (e.g., dissolution rate for solid oral dosage forms).

The objective of stability studies, based on testing a minimum of three batches, is to establish a shelf life and label storage instructions applicable to all future batches manufactured and packaged under similar conditions. Variability among batches influences confidence that future batches will remain within specification throughout their shelf life.

If degradation and variability in the data are minimal enough to clearly support the requested shelf life without formal statistical analysis, justification for omitting such analysis should suffice.

2.2.10. Analysis of Data and Shelf Life Determination

An effective approach for analyzing data on a quantitative attribute expected to change over time involves determining the point at which the one-sided 95% confidence limit for the mean curve intersects the acceptance criterion. When batch-to-batch variability is minimal, consolidating data into a single overall estimate is beneficial. This involves initial application of suitable statistical tests (e.g., p-values for significance levels exceeding 0.25) to assess the slopes of regression lines and zero-time intercepts across individual batches. If data consolidation is inappropriate, the shelf life should be determined based on the shortest duration any batch meets acceptance criteria.

The nature of the degradation relationship dictates whether data should undergo transformation for linear regression analysis. Typically, relationships are represented by linear, quadratic, or cubic functions on arithmetic or logarithmic scales. Statistical methods are utilized to test the goodness of fit for all batches and combined batches (where applicable) against assumed degradation lines or curves.

Limited extrapolation of real-time data from long-term storage conditions beyond observed ranges to extend shelf life may be justified at approval. Justification relies on understanding degradation mechanisms, results from accelerated testing, goodness of fit for mathematical models, batch size, and supporting stability data. This extrapolation assumes continued application of the same degradation relationship beyond observed data.

Evaluation encompasses assay, degradation products, and other pertinent attributes. Mass balance adequacy and stability/degradation performance are critically reviewed where applicable.

2.2.10. Statements and Labeling

A storage statement complying with relevant national/regional requirements should be established for labeling based on drug product stability evaluation. Specific instructions, especially for products intolerant to freezing, must be included. Terms like “ambient conditions” or “room temperature” should be avoided.

The label storage statement should directly reflect demonstrated stability of the drug product. An expiration date must be prominently displayed on the container label, providing consumers and healthcare providers with clear guidance on product viability.

Here are the references provided in the original text:

1. ICH Q1B: “Photostability Testing of New Drug Substances and Products”
2. ICH Q1C: “Stability Testing of New Dosage Forms”
3. ICH Q3A: “Impurities in New Drug Substances”
4. ICH Q3B: “Impurities in New Drug Products”
5. ICH Q5C: “Stability Testing of Biotechnological/Biological Products”
6. ICH Q6A: “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances”
7. ICH Q6B: “Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Biotechnological/Biological Products”