Stability Study Failures and Investigations in Pharmaceuticals

Stability studies are extremely important scientific and regulatory functions in the pharmaceutical industry because they define your product's shelf life, recommend appropriate storage conditions, define packaging options and validate your product's quality from the initial stages of development through the final production of the product. When stability studies fail, the consequences can be quite large in terms of regulatory submissions, market availability/assured supply and patient safety, among other issues.

In my experience, stability failures often go far beyond what is initially thought out at the beginning of the investigation. Typically, companies will think of stability failures only as individual analytical issues; however, once you get through the initial investigation phase, they may identify multiple other issues, such as product formulation, packaging systems, manufacturing procedures, environmental controls and even data reliability.

Regulatory authorities have an expectation that pharmaceutical companies conduct solid scientific-based methodology-based investigations when unexpected stability trends or out-of-specification results are encountered. If you don't address stability failures properly, they can quickly escalate to major compliance observations subject to inspection under Good Manufacturing Practices (GMP).

The Serious Nature of Stability Failure in Pharmaceuticals

Stability failures, as opposed to normal in-process deviations, directly call into question the approved shelf life and long-term quality of products on the market. When a stability failure is confirmed, it may signal:

• Product degradation
• Packaging failure
• Manufacturing inconsistency
• Formulation instability
• Problems with storage conditions
• Problems with analytical methods

If not handled appropriately, stability failures can result in:

• Product recalls
• Regulatory action
• Complaints from consumers about their products
• Import alerts or issues with products coming into the US from overseas
• Product shortages

This is why stability-related deviations are very closely monitored by regulatory agencies and how companies investigate these types of deviations.

What’s a Stability Failure?

A stability failure is when the stability data does not comply with defined standards of stability or with expected stability trends collected from stability studies. The following could be some examples of stability deviations or stability failures:
- Out-of-Specification (OOS) results
- Unexpected degradation trends
- Dissolution Failures
- Reduction in Assay
- Increase in Impurities
- Change in Physical Appearance
- Microbiological Failures
- Increase in Moisture
Not every deviation will necessarily result in product failure, however, all unexpected results need to be evaluated scientifically.

Common Stability Failures in the Industry

Throughout my experience, most stability failures can be categorized into a few groups that appear repeatedly.

1. Assay Reduction

The loss of potency in the active pharmaceutical ingredient (API) is a frequent stability failure. The most common causes of this are as follows:

• Oxidation
• Hydrolysis
• Light exposure
• Thermal degradation
• API/excipient interactions

APIs sensitive to moisture, such as those with water as an excipient, are particularly susceptible to this.

2. Increase in Related Substances

Impurity growth during stability studies causes a lot of regulatory concern. Impurity growth can be attributed to:

• Degradation of the API
• Residual solvent
• Incompatible excipients
• Excessive heat exposure

Unexpected impurities usually lead to further investigations.

3. Dissolution Failures

Dissolution failures are frequently found in oral solid dosage forms. After reviewing the failure cases, I usually find that they relate back to the following conditions in each case:

• Granulation variation
• Variation in the compression force
• Coating defects
• Moisture uptake in storage

In many packaging integrity issues will be involved as well.

4. Changes in Physical Appearance

Visual changes include:

• Discoloration of tablets
• Brittleness of capsules
• Caking (aggregation) of powders
• Emerging of the container shape
• Separation of liquid

Visual changes are initially considered as cosmetic’s change in a product may give an indication that the formulation is not good.

5. Moisture Related Failures

Moisture is one of the major issues that affect pharmaceutical stability. Moisture related failures can occur due to:

• Poor barrier properties of the package
• Desiccant Failure
• Poorly sealed
• Exposure to high humidity levels during manufacturing

I personally have seen numerous examples of products with significant changes in the protective configurations that have affected their stability.

6. Microbiological Failure of Stability

Both non-sterile and sterile products may have a microbiological stability problem. Common reasons for microbiological failure include:

• Failure of preservatives
• Problems with closure integrity
• Change in water activity
• Poor sterilization processes

In sterile products the failure of microbiological stability usually generates high priority investigations due to patient safety.

The Most Common Mistake During Investigations

The first thing I frequently see in investigations is investigators reaching conclusions too soon. Too many organizations quickly reach conclusions about:

• Laboratory Errors
• Analyst Errors
• Instrument Issues

Without properly assessing the larger process or formulary risk.

Conclusions during an investigation should not be made based on assumption. To properly investigate a stability failure, the analyst needs to develop a systematic, risk-based plan and involve input from all parties.

Initial Response to a Stability Failure

The initial response is an extremely important phase due to the effect that the responses will have on the quality of the investigation and the regulatory credibility of the investigation. Typically, initial responses include:

• Quarantining of affected samples (if applicable)
• Analyzing analytical data
• Reviewing chromatography integration
• Verifying system suitability results
• Reviewing analyst activities
• Verifying possible data integrity concerns

At this stage of the investigation it is not the intent to identify blame instead the focus is on preserving evidence and gathering all facts.

Phase I Laboratory Investigation

First phase is frequently centered around the laboratory-related cause of the results in question. This phase may include a re-assessment of:

• Calibrations
• Calculation of the results (calculations & formulas)
• Sample preparation records
• Standard preparation
• Method verification/validation (matrix match, laboratory method validation)
• Integration parameters
• Suitability of an analytical method

If a cause can be determined and supported with scientific evidence, the investigation could stop at this point. However, in many investigations no laboratory errors can be found.

Evaluation of Manufacturing and Processes

Once all laboratory possibilities have been considered and found not to be involved, the investigation turns to the evaluation of manufacturing processes. Some of the key areas that are evaluated include:

• Records of batches
• Deviations from process
• Environmental monitoring records
• Performance of equipment
• Hold times during production
• Cleaning of equipment
• Performance of associated utility systems

I have seen situations where an unreported small deviation from a process subsequently became the cause of long-term stability failures.

Evaluation of Packaging System

Stability studies have typically not given due consideration to packaging. The container closure system is a major factor affecting the stability of the packaged product. The following considerations are very relevant to the evaluation:
- Integrity of the seal
- Blister leakage
- Moisture vapor transmission rate
- Compatibility of the container and closure materials
- Protection from light
Many studies have shown that the formulation was stable, but not adequately protected from accelerated degradation due to packaging.

Trend Analysis is Critical

A single isolated stability problem does not represent the total picture. Trend analysis can identify:

• Batch-specific
• Product-specific
• Site-wide
• Method-centric

Before examining any historical stability data, you should always pay close attention to it.

Gradual trends are of greater importance because they can give an early warning of a developing formulation or process deficiency prior to specification failure.

Role of Accelerated Stability Studies

Accelerated stability research often shows signs of weakness before they show up in longer-term studies. Accelerated failures do not, however, guarantee that the product will be unstable in real time. The interpretation of results must include scientific reasoning because:

• Some products are very temperature-sensitive
• Packaging is affected by stress testing conditions
• Some degradation paths are accelerated more quickly than others

Interpreting the results of accelerated stability studies requires a risk-based scientific approach.

Data Integrity Concerns During Stability Investigations

Regulators are increasingly focused on the data integrity of stability studies. Concerns include the following:

• Failure to report failed results
• Repeating testing without a valid reason
• Excluding data for particular reasons
• Manipulating integration data
• Failure to maintain audit trails

Based on my observations, poor documentation during stability studies generally are the most severe regulatory issue, even compared to the initial analytical failures.

Root Cause Analysis in Stability Failures

The process of identifying the root causes of stability failures needs a scientific understanding combined with an existing procedure to identify the root causes of stability failures. There are many tools which can be used for root cause analysis:

• Fishbone analysis (cause and effect diagrams)
• 5 why analysis
• Failure mode evaluation
• Trend studies

The root cause should always be established on the basis of evidence available. It is common to see unsupported root cause conclusions being challenged during inspections.

CAPA Following Stability Failures

The CAPA should take corrective and preventative actions (CAPA) to directly rectify the identified root cause(s). Examples could include the following:

• Optimization of formulation
• Modification of packaging
• Revision of process parameters
• Addition of work environmental controls
• Improvement of analytical methods
• Improvement of supplier qualifications

Repetition of stability failures can be caused by inadequate use of CAPA systems.

Regulatory Expectations During Stability Investigations

Investigation must meet these expectations by Health Authority:

• Scientifically Justified
• Timely
• Well Documented
• Risk Based
• Thoroughly Reviewed

Typical evaluation by Inspectors:

• Investigation Timeline
• Root Cause Rationale
• Impact Assessment / CAPA Effectiveness
• Trend Management

Laboratory errors with no justification or poor justification will create an issue for regulatory inspectors.

Product Recall Risk after Stability Failures

Product recall does not occur in every case of stability failure; nevertheless, the potential for product recall increases in situations where the following criteria exist:

• Marketed batch is impacted
• The safety of patients may be potentially compromised
• Degradation products exceed established limits
• Sterility assurance of product is compromised

During the decision-making process, it is important to assess health hazards associated with a product.

Managing Stability Programs Using Best Practices

Proactive quality systems as opposed to reactive investigation systems highlight strong organizational stability programs. Best Practice Recommendations:

• Use Formulations That Are Scientifically Validated
• Conduct Packaging Compatibility Testing
• Continuously Trend Stability Data
• Provide Analysts with Training on Data Integrity Principles
• Maintain Validated Analytical Methods
• Review Accelerated and Long-Term Data

By using proactive monitoring mechanisms, organizations can identify risks associated with product instability before a product is released to market.

Failures in stability studies are one of the most significant quality events in pharmaceutical production as they have a direct effect on product shelf life, regulatory compliance and patient safety. Investigations into these failures require more than just laboratory re-testing or reviews of existing procedures; they also entail a scientific determination of the behavior of the formulas, the performance of the packaging, the uniformity of manufacturing, how reliable the analytical methods are and what impact the environment has on each stability measurement.

In my experience, the best companies at responding to stability failures implement technical depth in their approach to completing stability investigations, engage in cross-functional teamwork and have a strong culture of quality instead of rushing to conclude the investigations. In today's highly regulated pharmaceutical industry, it is essential that stable investigations are scientifically sound and will ensure the quality of the product, the confidence of the regulatory agencies and the long-term viability of the product in the global marketplace.

Regulatory References

1. ICH Q1A(R2) Stability Testing of New Drug Substances and Products
2. FDA Guidance for Industry: Investigating Out-of-Specification Test Results
3. WHO Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products
4. EU GMP Guidelines Volume 4
5. FDA 21 CFR Part 211 Current Good Manufacturing Practice

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