What are bracketing and matrixing:

Bracketing and matrixing are scientifically justified designs used to reduce the number of stability tests required when dealing with multiple strengths, fill volumes, or packaging sizes of a single product line.

Bracketing tests only the extremes (e.g., lowest and highest strengths), while matrixing staggers time point testing across batches or configurations. Both save time and resources without sacrificing scientific integrity.

Why these approaches matter:

In today’s cost-sensitive development environment, reducing redundant testing while maintaining compliance is a top priority. Bracketing and matrixing allow teams to gather meaningful data across variations efficiently.

These models are especially beneficial during scale-up, global submissions, or when launching multiple strengths with identical formulations.

Risks of improper use:

If not properly justified or documented, regulatory authorities may reject bracketing or matrixing designs. They must be grounded in sound scientific rationale and supported by historical data or formulation similarity.

Misapplication can lead to delayed approvals, extra testing requirements, or post-approval commitments.

Regulatory and Technical Context:

ICH guidance on reduced designs:

ICH Q1D provides the framework for applying bracketing and matrixing in stability studies. It outlines conditions under which these approaches are acceptable and how to statistically justify reduced testing models.

The guideline emphasizes that these designs must not compromise the ability to detect trends or ensure product quality.

Criteria for using bracketing:

Bracketing is ideal when products are identical in composition except for strength or fill volume. It assumes that stability of intermediate strengths will fall between the tested extremes.

This is commonly applied to tablets, capsules, or syrups where formulations are linear and excipient ratios are consistent.

Matrixing time points and batches:

Matrixing involves testing only a subset of samples at each time point, reducing workload while preserving data integrity. For example, three batches may be tested at staggered time points to cover all intervals collectively.

This approach is best suited when long-term trends are already well characterized or when resources are limited during early phases.

Best Practices and Implementation:

Design with clear scientific justification:

Use bracketing only when the product design justifies it—uniform packaging materials, identical manufacturing processes, and consistent formulation components. Provide a risk assessment explaining why intermediate strengths behave similarly.

Matrixing should be designed with balanced representation across batches and time points. Use statistical tools to validate coverage and minimize bias.

Document clearly in your stability protocol:

Include diagrams or tables showing which strengths or batches are being tested at which time points. Reference ICH Q1D and explain the logic behind your design choices.

Ensure that the approach is reviewed by QA and Regulatory Affairs before inclusion in submission documentation.

Monitor results and revert if necessary:

Continue trending data from bracketing and matrixing studies as it becomes available. If unexpected degradation is observed in an untested strength, conduct confirmatory testing immediately.

Stay prepared to expand testing if authorities question the validity of reduced models or if real-time performance diverges from projections.

Why three batches are the standard:

Stability studies based on a single batch provide limited insight into variability. Including three primary batches—manufactured at pilot or production scale—ensures that your data reflects consistent performance and accounts for batch-to-batch differences.

This approach supports statistical evaluation and strengthens confidence in the proposed shelf life and storage conditions.

ICH expectations and scientific rationale:

ICH Q1A(R2) recommends that stability data for product registration include results from a minimum of three batches. This ensures reproducibility and validates that the formulation remains stable regardless of minor manufacturing variations.

The use of multiple batches also helps confirm that the stability-indicating analytical methods are robust across different production runs.

Regulatory acceptance and predictability:

Data from three batches provides regulators with sufficient evidence to approve the product’s shelf life. Submissions with fewer batches often result in major queries, delayed approvals, or demands for additional commitments.

Using three well-documented batches proactively satisfies this requirement and streamlines the review process.

Regulatory and Technical Context:

Batch scale requirements under ICH:

According to ICH Q1A(R2), the three batches should represent at least pilot-scale production. One of them must ideally be manufactured at full production scale to demonstrate commercial feasibility and process stability.

This mix provides both development and operational perspectives, enhancing the reliability of stability outcomes.

Common technical dossier placement:

Stability batch data is included in Module 3.2.P.8.3 of the CTD. Each batch must be documented with manufacturing date, batch size, packaging configuration, and test schedule to support traceability.

Results are expected to show consistent trends across all batches for critical quality attributes like assay, degradation, appearance, and dissolution.

Acceptance by global authorities:

FDA, EMA, MHRA, PMDA, and CDSCO all mandate inclusion of three batches for new drug applications. Failure to comply may lead to post-approval commitments or require bridging studies during global registrations.

This expectation also applies to post-approval changes and revalidations following manufacturing site transfers or formulation updates.

Best Practices and Implementation:

Select representative batches for testing:

Choose batches that reflect routine manufacturing variability. Include different equipment trains, material sources, or process conditions to test the formulation’s resilience.

All batches should use the final intended packaging and be tested under the appropriate ICH climatic conditions for the product’s market.

Design the study for side-by-side comparison:

Align pull points and testing parameters across all three batches. Trend the data together to monitor consistency and identify potential outliers early.

Ensure that batch traceability is clearly documented in all lab reports and submission files.

Plan ahead for shelf-life projection and commitments:

Three batches allow the use of statistical modeling to project shelf life confidently. This may eliminate the need for ongoing annual commitments in some regions if early data is strong and consistent.

Build your protocol with the goal of generating conclusive evidence from these batches to minimize follow-up studies and expedite approvals.

Why packaging decisions must be data-driven:

Primary packaging plays a critical role in protecting a drug product from environmental factors like moisture, oxygen, and light. Choosing the right material must go beyond aesthetics or cost—it should be backed by product-specific stability data.

Aligning packaging with the product’s sensitivity ensures that efficacy, safety, and appearance remain within specifications throughout the shelf life.

Examples of product-packaging mismatches:

Moisture-sensitive tablets packaged in HDPE bottles without desiccants may fail early in Zone IVb. Photolabile formulations stored in clear blisters could degrade rapidly under light exposure.

Such mismatches often result in batch failures, label changes, recalls, or costly reformulation after commercialization.

Aligning packaging with intended use and markets:

Packaging should reflect the distribution environment and regional regulatory expectations. A formulation stable in Zone II may require reinforced packaging in Zone IVb to avoid humidity-induced degradation.

This tip ensures the package protects the product not only in the lab but also across global supply chains.

Regulatory and Technical Context:

ICH and global expectations for packaging justification:

ICH Q1A(R2) and Q5C emphasize that packaging should be justified using real-time and accelerated stability data. Agencies like the FDA, EMA, and CDSCO require this data as part of product registration dossiers.

Packaging justification must demonstrate that the selected system maintains the integrity of the drug product throughout its lifecycle.

Container-closure integrity testing (CCIT):

In addition to stability data, regulatory bodies expect supportive evidence from CCIT or extractable/leachable studies. These ensure that the closure system prevents ingress of air, moisture, or contaminants.

CCIT is especially important for injectables, hygroscopic formulations, or temperature-sensitive biologics.

Linking packaging to labeling and claims:

Stability outcomes directly influence storage claims like “Protect from light” or “Store below 25°C.” These must be aligned with packaging features, such as UV-protective materials or barrier foils.

Discrepancies between data and labeling may trigger regulatory queries or post-approval commitments.

Best Practices and Implementation:

Perform packaging simulation during stability studies:

Stability studies should use the final intended market pack, not just bulk containers or interim formats. Simulated transport and distribution studies also validate packaging under real-world conditions.

Track any visual or functional changes in the package alongside product degradation metrics to ensure system integrity.

Include comparative studies where needed:

If multiple packaging options exist (e.g., blister vs. bottle), conduct head-to-head studies. This helps justify packaging changes post-approval or respond to supply chain disruptions with data-backed flexibility.

Document observations like moisture uptake, visual changes, or assay drift to support packaging decisions with evidence.

Integrate packaging review into formulation lifecycle:

Don’t treat packaging as an afterthought—review and revalidate it at key stages such as formulation changes, line transfers, or regulatory submissions in new regions.

Update SOPs to include packaging verification checkpoints during each stability protocol approval cycle.

Why structured sampling intervals matter:

Stability testing isn’t just about storing products—it’s about analyzing them at critical intervals to track changes over time. Structured sampling intervals are essential to detect degradation trends and determine shelf life accurately.

Missing key time points can lead to incomplete datasets, failed regulatory audits, or inaccurate product expiration dates.

ICH minimum time points explained:

According to ICH Q1A(R2), the minimum sampling points for long-term and accelerated stability studies are 0, 3, 6, 9, and 12 months. Additional time points like 18 and 24 months may be required for shelf lives beyond one year.

These intervals offer a scientifically sound timeline for monitoring gradual degradation and ensuring trend consistency.

Reducing risk of non-compliance:

Failure to meet minimum sampling requirements can result in regulatory pushback or product approval delays. Including all expected intervals in your protocol—and executing them precisely—reduces the chance of repeat studies.

It also strengthens your position during regulatory inspections and improves the predictability of long-term performance.

Regulatory and Technical Context:

ICH Q1A(R2) guidance on time points:

The guideline stipulates that sampling should occur at defined intervals, based on the intended market and climatic zone. For long-term testing, the baseline requirement includes samples at 0, 3, 6, 9, and 12 months, and should continue annually thereafter if needed.

Accelerated studies typically require sampling at 0, 3, and 6 months to demonstrate short-term degradation trends.

Link to shelf life justification:

Regulators use data from these defined intervals to assess product stability and validate the proposed shelf life. Gaps in sampling create doubts about data continuity and trend accuracy.

Meeting these minimums ensures that your product’s expiration dating is well supported by scientific evidence.

Harmonization across regions:

Following ICH time point expectations ensures your data is acceptable across major regulatory territories such as the US, EU, Japan, and emerging markets. This avoids duplicative testing and streamlines global submissions.

It also facilitates centralized product development with fewer regional modifications.

Best Practices and Implementation:

Define all time points in your protocol:

Clearly list all required intervals—0, 3, 6, 9, 12, 18, 24 months—within your stability protocol. Include justification for each, especially if you’re targeting a shelf life longer than 12 months.

Ensure the protocol covers both long-term and accelerated arms with synchronized sampling schedules.

Coordinate lab readiness and inventory:

Maintain a calendar of planned pull dates and coordinate with the QC lab in advance. Ensure enough samples are retained for each time point, accounting for repeat or investigation testing if needed.

Track sample movement and documentation closely to ensure traceability and audit readiness.

Trend data across intervals for early insights:

Use stability software or spreadsheets to trend assay, dissolution, impurity, and appearance data over time. Early identification of degradation trends can prompt timely formulation or packaging adjustments.

Properly spaced data points support statistical analysis and confident shelf life modeling.

Why regional alignment matters:

Stability testing must reflect the environmental conditions of the markets where the product will be sold. Each region is assigned a specific climatic zone, and protocols must be tailored accordingly to meet local regulatory standards.

A universal protocol may not suffice when registering products globally, particularly in tropical or subtropical markets where stress conditions differ significantly.

Overview of climatic zones:

ICH and WHO have defined several climatic zones. Zone II represents temperate climates (e.g., Europe, Japan), while Zone IVb includes hot, humid regions such as Southeast Asia or parts of Latin America.

Failure to test under zone-appropriate conditions may lead to shelf life rejections, delayed registrations, or product recalls in those territories.

Link to labeling and marketing strategy:

Testing under applicable zone conditions ensures that labeled shelf life and storage instructions are scientifically justified. This avoids unnecessary overprotection or underperformance once the product enters distribution.

It also informs packaging and logistics decisions, especially when shipping to multiple regulatory zones with varying expectations.

Regulatory and Technical Context:

ICH guidance on zone-based stability:

ICH Q1A(R2) outlines core stability testing conditions and emphasizes that testing should match the climatic zone of intended use. For instance, Zone II uses 25°C/60% RH, while Zone IVb uses 30°C/75% RH for long-term testing.

This ensures real-world performance data and regulatory alignment with regional authorities like EMA, CDSCO, and ANVISA.

WHO and national agency expectations:

WHO guidelines reflect similar zone-based requirements and are often adopted by emerging markets. Countries in Zone IVb (e.g., India, Thailand, Brazil) generally require studies at higher temperature and humidity conditions for product approval.

Failure to meet zone-specific criteria can result in incomplete dossiers and extended review timelines.

Global registration complexities:

Pharmaceuticals intended for global markets must undergo stability testing across different zones or justify extrapolation from zone-compliant data. This requires careful planning of batch allocation and testing site qualifications.

Some companies opt for bracketing or matrixing designs to reduce testing burden while covering multiple regions efficiently.

Best Practices and Implementation:

Incorporate zone targets in protocol design:

During protocol creation, identify all target markets and corresponding zones. Include specific testing arms with relevant long-term and accelerated conditions for each zone.

Ensure storage chambers are validated and mapped for each required condition, and sample pulls are scheduled accordingly.

Use zone-specific labeling and packaging data:

Utilize zone-aligned stability data to justify storage statements such as “Store below 30°C” or “Protect from high humidity.” Align these outcomes with primary packaging selection to maintain efficacy in diverse climates.

Label language should be consistent with local regulatory phrasing to avoid marketing authorization queries.

Document clearly in submission dossiers:

Clearly reference zone-specific stability arms in your CTD submission. Provide environmental justification, batch distribution strategy, and how data supports market-specific shelf life.

This proactive clarity reduces regulatory questions and helps accelerate approvals in multi-zone product launches.

What stress testing reveals:

Stress testing, also known as forced degradation, involves exposing the drug substance or product to extreme conditions such as heat, light, oxidation, and acidic or basic environments. This approach intentionally accelerates degradation to uncover potential chemical instability.

Understanding how and when a compound breaks down helps formulation teams predict performance, identify potential degradation products, and implement controls early in the development cycle.

Importance in early development:

Conducting stress testing in the early phases allows for informed decision-making about formulation robustness, excipient compatibility, and packaging requirements. It enables preemptive mitigation strategies rather than reactive changes after stability failures.

This proactive approach also helps reduce regulatory delays and prevents the need for late-stage reformulations that can derail timelines.

Benefits for impurity profiling:

Stress testing supports the development of stability-indicating methods and impurity profiling. Identifying degradation products under different stress conditions helps ensure that analytical methods are sensitive, specific, and regulatory compliant.

Early knowledge of impurity formation also aids in setting appropriate specifications and ensuring toxicological safety of degradation products.

Regulatory and Technical Context:

ICH guidance on stress testing:

ICH Q1A(R2) and Q1B provide clear directives for conducting stress testing as part of stability assessment. These guidelines emphasize the importance of characterizing degradation pathways to support analytical method validation and shelf-life justification.

Stress testing is not just a scientific tool—it’s a regulatory expectation for product development and quality control.

Typical stress conditions and durations:

Common conditions include 60°C for thermal stress, exposure to 1N HCl or NaOH for hydrolysis, 3% hydrogen peroxide for oxidative stress, and 1.2 million lux hours for photostability. Duration varies depending on the sensitivity of the molecule, typically lasting from a few hours to several days.

The goal is not to mimic real-life conditions but to push the molecule to fail and understand its breaking points.

Documentation and regulatory submissions:

Data from stress testing should be thoroughly documented, including chromatograms, degradation pathways, and identified impurities. These findings are included in Module 3 of the Common Technical Document (CTD) for regulatory submissions.

Properly executed stress studies provide confidence to regulators that the applicant has a comprehensive understanding of the product’s stability profile.

Best Practices and Implementation:

Design a comprehensive stress testing protocol:

Include all relevant stress conditions, defined degradation targets (e.g., 5–20% loss), and replicate experiments. Document all observations including color changes, pH shifts, and unexpected peaks in chromatograms.

Align the protocol with ICH expectations and validate stability-indicating methods alongside the stress studies.

Leverage findings for smarter formulation:

If a product is prone to acid degradation, consider enteric coating or buffering agents. If light sensitivity is detected, choose opaque packaging. Each degradation pathway uncovered informs a critical design decision.

Stress testing not only predicts challenges but enables innovation in solving them early.

Integrate with your stability program:

Use stress test outcomes to refine your long-term and accelerated stability studies. Monitor specific degradation products over time and validate that your final formulation resists the pathways previously identified.

This integration improves data predictability, regulatory compliance, and product robustness throughout its lifecycle.

Why initiate both studies together:

Starting real-time and accelerated stability studies simultaneously ensures comprehensive data collection from day one. Real-time data builds the case for long-term shelf life, while accelerated data offers early insights into product behavior under stress.

This dual-track approach avoids delays in development and supports faster decision-making for regulatory submissions and product launch.

Complementary roles of both study types:

Real-time studies simulate actual storage conditions and are essential for determining the official expiration date. However, they take time—often 12 months or more.

Accelerated studies, on the other hand, expose the product to elevated conditions to predict potential degradation. Running both in parallel ensures a balanced strategy that is both timely and scientifically rigorous.

Improved planning and coordination:

Parallel execution allows better use of resources, from analytical labs to stability chambers. It also promotes clearer timelines and coordination among QA, QC, and regulatory teams.

Most importantly, it prepares the data package well in advance of key milestones like clinical trials or market approvals.

Regulatory and Technical Context:

ICH recommendations for stability testing:

ICH Q1A(R2) explicitly recommends conducting both real-time and accelerated studies to evaluate the stability of drug substances and products. Accelerated studies can indicate early signs of instability, triggering adjustments to formulation or packaging if needed.

Real-time studies, however, are non-negotiable when it comes to assigning a validated shelf life on the product label.

Storage conditions and timelines:

Real-time studies typically follow conditions like 25°C ± 2°C / 60% RH ± 5% RH for 12 to 24 months. Accelerated studies are conducted at 40°C ± 2°C / 75% RH ± 5% RH for 6 months.

Running both in parallel allows for direct comparison, enhances trend evaluation, and meets regulatory expectations in a structured, validated manner.

Global regulatory alignment:

Authorities such as the US FDA, EMA, and CDSCO often expect to see accelerated data upfront, followed by real-time data in final submissions. Running both studies concurrently ensures smoother interactions with regulators.

This strategy is particularly useful for global product registration, where timelines and documentation requirements vary significantly.

Best Practices and Implementation:

Design the protocol with parallel tracks:

During protocol development, include real-time and accelerated arms in a unified document. Define sample pull points, storage conditions, and acceptance criteria for each pathway based on ICH Q1A(R2).

This ensures that both study types are properly integrated and aligned from the start of the stability program.

Coordinate logistics and data flow:

Make sure stability chambers are validated for both real-time and accelerated conditions. Coordinate scheduling of testing intervals and ensure lab capacity matches the increased testing load.

Use a centralized system to document and trend results in real time. This supports quick decision-making and enables early identification of out-of-trend results.

Maximize regulatory value of parallel data:

Present parallel study data clearly in your regulatory submissions. Highlight correlations between accelerated and real-time outcomes, and show consistency in degradation patterns.

This strengthens your product’s stability justification and demonstrates proactive, scientifically grounded quality management to reviewers.

Why initiate both studies together:

Starting real-time and accelerated stability studies simultaneously ensures comprehensive data collection from day one. Real-time data builds the case for long-term shelf life, while accelerated data offers early insights into product behavior under stress.

This dual-track approach avoids delays in development and supports faster decision-making for regulatory submissions and product launch.

Complementary roles of both study types:

Real-time studies simulate actual storage conditions and are essential for determining the official expiration date. However, they take time—often 12 months or more.

Accelerated studies, on the other hand, expose the product to elevated conditions to predict potential degradation. Running both in parallel ensures a balanced strategy that is both timely and scientifically rigorous.

Improved planning and coordination:

Parallel execution allows better use of resources, from analytical labs to stability chambers. It also promotes clearer timelines and coordination among QA, QC, and regulatory teams.

Most importantly, it prepares the data package well in advance of key milestones like clinical trials or market approvals.

Regulatory and Technical Context:

ICH recommendations for stability testing:

ICH Q1A(R2) explicitly recommends conducting both real-time and accelerated studies to evaluate the stability of drug substances and products. Accelerated studies can indicate early signs of instability, triggering adjustments to formulation or packaging if needed.

Real-time studies, however, are non-negotiable when it comes to assigning a validated shelf life on the product label.

Storage conditions and timelines:

Real-time studies typically follow conditions like 25°C ± 2°C / 60% RH ± 5% RH for 12 to 24 months. Accelerated studies are conducted at 40°C ± 2°C / 75% RH ± 5% RH for 6 months.

Running both in parallel allows for direct comparison, enhances trend evaluation, and meets regulatory expectations in a structured, validated manner.

Global regulatory alignment:

Authorities such as the US FDA, EMA, and CDSCO often expect to see accelerated data upfront, followed by real-time data in final submissions. Running both studies concurrently ensures smoother interactions with regulators.

This strategy is particularly useful for global product registration, where timelines and documentation requirements vary significantly.

Best Practices and Implementation:

Design the protocol with parallel tracks:

During protocol development, include real-time and accelerated arms in a unified document. Define sample pull points, storage conditions, and acceptance criteria for each pathway based on ICH Q1A(R2).

This ensures that both study types are properly integrated and aligned from the start of the stability program.

Coordinate logistics and data flow:

Make sure stability chambers are validated for both real-time and accelerated conditions. Coordinate scheduling of testing intervals and ensure lab capacity matches the increased testing load.

Use a centralized system to document and trend results in real time. This supports quick decision-making and enables early identification of out-of-trend results.

Maximize regulatory value of parallel data:

Present parallel study data clearly in your regulatory submissions. Highlight correlations between accelerated and real-time outcomes, and show consistency in degradation patterns.

This strengthens your product’s stability justification and demonstrates proactive, scientifically grounded quality management to reviewers.

Why protocol design matters:

Stability protocols serve as the blueprint for determining a pharmaceutical product’s shelf life. They ensure that the product maintains its quality, safety, and efficacy under specific storage conditions over time.

Designing this protocol without foundational regulatory guidance often results in inconsistent data, regulatory delays, or failed submissions. Therefore, it is crucial to follow internationally accepted standards from the outset.

The role of ICH Q1A(R2) in stability testing:

ICH Q1A(R2) is the globally harmonized guideline that defines the expectations for conducting pharmaceutical stability studies. It sets the scientific and regulatory framework for long-term, intermediate, and accelerated testing.

By referring to this document at the protocol design stage, teams ensure alignment with regulatory authorities like the FDA, EMA, and PMDA, significantly improving the chances of global acceptance.

Ensuring consistency and reliability:

Protocols built on ICH Q1A(R2) offer greater reproducibility and defensibility. This standardization is not just about compliance—it’s about ensuring that the generated stability data is robust, predictive, and ready for inspection.

Moreover, a properly referenced guideline adds credibility to the pharmaceutical company’s quality assurance practices.

Regulatory and Technical Context:

Global recognition of ICH Q1A(R2):

The International Council for Harmonisation developed Q1A(R2) to unify regulatory expectations. It has been adopted by regulatory bodies across the U.S., Europe, Japan, and many other regions.

This universality allows companies to design a single protocol that is acceptable in multiple jurisdictions, reducing rework and streamlining approval timelines.

Prescribed storage conditions and timelines:

ICH Q1A(R2) recommends storage at 25°C ± 2°C / 60% RH ± 5% RH for long-term studies and 40°C ± 2°C / 75% RH ± 5% RH for accelerated conditions. For certain markets, intermediate conditions such as 30°C / 65% RH are also applicable.

These conditions are tailored to simulate environmental exposures and help predict a product’s real-world performance.

Guidance on technical parameters:

The guideline offers detailed instructions on sampling intervals, batch selection, packaging configuration, significant change criteria, and statistical evaluation. These parameters ensure that the protocol yields scientifically valid and regulatorily acceptable results.

It also promotes the use of validated analytical methods to ensure accuracy and reproducibility in test outcomes.

Best Practices and Implementation:

Build a protocol template around Q1A(R2):

Develop a master stability protocol template that follows Q1A(R2) structure. This should include predefined storage conditions, timelines, testing parameters, and justification references to the guideline itself.

Having a standardized template also helps maintain consistency across studies and products within the organization.

Cross-functional collaboration is key:

Bring together QA, QC, formulation scientists, and regulatory affairs early in the process. Each function contributes valuable insights, from study feasibility to submission strategy.

Aligning cross-functional teams around ICH Q1A(R2) prevents misinterpretation and ensures regulatory readiness from day one.

Train teams and audit for compliance:

Ensure your staff is trained on interpreting and applying Q1A(R2) in practice. Regular workshops and SOP updates help keep teams current with regulatory expectations.

Internal audits of stability protocols can help identify gaps and opportunities for alignment before external audits or submissions.

General Considerations:

For each dosage form:

• Evaluate appearance, assay, and degradation products.
• Limit degradation product testing for generic products to compendial requirements.

Note:

• The listed tests are not exhaustive.
• Not every test needs to be included in the stability protocol.
• Consider safety when performing tests, only conducting necessary assessments.
• Not every test needs to be performed at each time point.
• Consider storage orientation changes in the protocol.

Dosage Forms Specific Tests:

1. Tablets:

   Evaluate appearance, odour, colour, assay, degradation products, dissolution, moisture, and hardness/friability.

2. Capsules:

   For hard gelatin capsules, assess appearance (including brittleness), colour, odour of content, assay, degradation products, dissolution, moisture, and microbial content.

   For soft gelatin capsules, assess appearance, colour, odour of content, assay, degradation products, dissolution, microbial content, pH, leakage, pellicle formation, and fill medium examination.

3. Emulsions:

   An evaluation should include appearance (including phase separation), colour, odour, assay, degradation products, pH, viscosity, microbial limits, preservative content, and mean size and distribution of dispersed globules.

4. Oral Solutions and Suspensions:

   The evaluation should include appearance (including formation of precipitate, clarity for solutions), colour, odour, assay, degradation products, pH, viscosity, preservative content and microbial limits.

   Additionally for suspensions, redispersibility, rheological properties and mean size and distribution of particles should be considered. After storage, sample of suspensions should be prepared for assay according to the recommended labeling (e.g. shake well before using).

5. Oral Powders for Reconstitution:

   Oral powders should be evaluated for appearance, colour, odour, assay, degradation products, moisture and reconstitution time.

   Reconstituted products (solutions and suspensions) should be evaluated as described in Oral Solutions and Suspensions above, after preparation according to the recommended labeling, through the maximum intended use period.

6. Metered-dose Inhalations and Nasal Aerosols:

   Metered-dose inhalations and nasal aerosols should be evaluated for appearance (including content, container, valve, and its components), colour, taste, assay, degradation products, assay for co-solvent (if applicable), dose content uniformity, labeled number of medication actuations per container meeting dose content uniformity, aerodynamic particle size distribution, microscopic evaluation, water content, leak rate, microbial limits, valve delivery (shot weight) and extractables/leachables from plastic and elastomeric components. Samples should be stored in upright and inverted/on-the-side orientations.

   For suspension-type aerosols, the appearance of the valve components and container’s contents should be evaluated microscopically for large particles and changes in morphology of the drug surface particles, extent of agglomerates, crystal growth, as well as foreign particulate matter.

   These particles lead to clogged valves or non-reproducible delivery of a dose. Corrosion of the inside of the container or deterioration of the gaskets may adversely affect the performance of the drug product.

7. Nasal Sprays: Solutions and Suspensions:

   The stability evaluation of nasal solutions and suspensions equipped with a metering pump should include appearance, colour, clarity for solution, assay, degradation products, preservative and antioxidant content, microbial limits, pH, particulate matter, unit spray medication content uniformity, number of actuations meeting unit spray content uniformity per container, droplet and/or particle size distribution, weight loss, pump delivery, microscopic evaluation (for suspensions), foreign particulate matter and extractable/bleachable from plastic and elastomeric components of the container, closure and pump.

8. Topical, Ophthalmic and Otic Preparations:

   Included in this broad category are ointments, creams, lotions, paste, gel, solutions and non-metered aerosols for application to the skin. Topical preparations should be evaluated for appearance, clarity, colour, homogenity, odour, pH, resuspendability (for lotions), consistency, viscosity, particle size distribution (for suspensions, when feasible), assay, degradation products, preservative and antioxidant content (if present), microbial limits/sterility and weight loss (when appropriate).

   Evaluation of ophthalmic or otic products (e.g., creams, ointments, solutions, and suspensions) should include the following additional attributes: sterility, particulate matter, and extractable.

   Evaluation of non-metered topical aerosols should include: appearance, assay, degradation products, pressure, weight loss, net weight dispensed, delivery rate, microbial limits, spray pattern, water content, and particle size distribution (for suspensions).

9. Suppositories:

   Suppositories should be evaluated for appearance, colour, assay, degradation products, particle size, softening range, dissolution (at 37oC) and microbial limits.

10. Small Volume Parenterals (SVPs):

    SVPs include a wide range of injection products such as Drug Injection, Drug for Injection, Drug Injectable Suspension, Drug for Injectable Suspension, and Drug Injectable Emulsion. Evaluation of Drug Injection products should include appearance, clarity, colour, assay, preservative content (if present), degradation products, particulate matter, pH, sterility and pyrogen/endotoxin.

    The stability assessments for Drug Injectable Suspension and Drug for Injectable Suspension products should encompass particle size distribution, redispersibility, and rheological properties, along with the previously mentioned parameters for Drug Injection and Drug for Injection products.

    For Drug Injectable Emulsion products, in addition to the parameters outlined for Drug Injection, the stability studies should also cover phase separation, viscosity, and the mean size and distribution of dispersed phase globules.

11. Large Volume Parenterals (LVPs):

    Evaluation of LVPs should include appearance, colour, assay, preservative content (if present), degradation products, particulate matter, pH, sterility, pyrogen/endotoxin, clarity and volume.

12. Drug Admixture:

    For any drug product or diluents that is intended for use as an additive to another drug product, the potential for incompatibility exists. In such cases, the drug product labeled to be administered by addition to another drug product (e.g. parenterals, inhalation solutions), should be evaluated for stability and compatibility in admixture with the other drug products or with diluents both in upright and in inverted/on-the side orientations, if warranted.

    A stability protocol should provide for appropriate tests to be conducted at 0-,6- to 8- and 24-hour time points, or as appropriate over the intended use period at the recommended storage/use temperature(s). Tests should include appearance, colour, clarity, assay, degradation products, pH, particulate matter, interaction with the container/closure/device and sterility. Appropriate supporting data may be provided in lieu of an evaluation of photo degradation.

13.  Transdermal Patches:

    Stability studies for devices applied directly to the skin for the purpose of continuously infusing a drug substance into the dermis through the epidermis should be examined for appearance, assay, degradation products, in-vitro release rates, leakage, microbial limits/sterility, peel and adhesive forces, and the drug release rate.

14.  Freeze-dried Products:

    Appearance of both freeze-dried and its reconstituted product, assay, degradation products, pH, water content and rate of solution.