Handling Unexpected Validation Results in Pharmaceutical Manufacturing

The purpose of validation activities is to provide evidence that pharmaceutical processes, equipment and utilities, computerized systems and cleaning procedures are consistently functioning as they were intended to consistently. In most cases, validation protocols have a clear definition of the acceptance criteria and expected outcome and provide details based on scientific principles and regulatory expectations. Nevertheless, there are occasions when unexpected results are produced, even with the best planning and execution.

I have found that the organization's response to unexpected validation results is indicative of their maturity in terms of the effectiveness of their quality system, rather than the validation activity. For example, most successful pharmaceutical companies do not view unexpected validation results as a failure to be hidden or explained but rather as an opportunity to learn more about process variation, identify process weaknesses and enhance the reliability of the process over the long term.

Regulatory agencies also require that companies have this approach to validation. Often, the inspector's review of the investigation and resolution will focus less on the unexpected result and more on how the organization determined the cause of the unexpected result in a scientific and objective manner.

What Are Unexpected Validation Results?

Unexpected validation results occur when validation (or qualifying) activities result in an outcome that is outside of both an organization’s predetermined expectations (or limits) and acceptance criteria. Examples of unexpected validation results include but are not limited to:

• Cleaning validation failures
• Temperature mapping excursions
• Unexpected variability within processes
• Sterility test failures during media fills
• Environmental monitoring excursions
• Equipment qualification failures
• Utility validation nonconformities
• Computerized system performance failures

Not all unexpected validation results are indications of process failure. Some unexpected results can occur due to sampling errors, analytical errors, or incorrect documentation. The purpose of investigating unexpected validation results is to identify the underlying causes through a systematic investigation.

Why Unexpected Validation Results Require Immediate Attention

If an organization does not investigate and resolve their unexpected results immediately, they are taking unnecessary regulatory and quality risks. Some of the consequences of not investigating unexpected results include:

• Invalidation of validation study results
• Quality of the product in question
• Final validation failures occur repeatedly
• Delays in product launches
• Regulatory observations and enforcement actions are taken
• Increased compliance risks and liabilities

My experience has been that organizations who conduct immediate investigations recover much quicker than organizations that attempt to justify their unexpected result without adequate supporting data.

First Response to an Unexpected Result

In response to a result that you did not expect, your first reaction should be one of control and methodical action rather than reactionary action. The steps taken immediately are to:

1. Stop any further validation activity where applicable
2. Notify all parties within the Quality Assurance and Validation area
3. Secure all raw data and record information
4. Review the protocol requirements to determine what is required or available to use
5. Preserve any samples and/or evidence that are involved
6. Start a Risk Assessment

Acting quickly can help to preserve information that may be vital to your investigation.

Verify the Result Before Drawing Conclusions

Before assuming that your result is damaging to your process, take the time to validate:

• The instrument was calibrated
• Your analytical methodology is working properly
• That your sample is correctly identified
• That correct calculations were made
• Data was properly recorded
• The correct environmental conditions occurred

Many times, simple procedural errors will create unexpected results that can be solved by verification in a timely manner, but it is imperative to document every verification that occurs between each step of the process.

Perform a Quality Risk Assessment

Risk assessment will help determine how serious the unexpected result is and help prioritize investigations. Typical evaluation questions may include:

• Does the result influence product quality?
• Will patients’ safety be impacted?
• Will this incident affect multiple batches of products?
• Is there still scientific justification for validation?
• Will there be a need to conduct additional testing?

A formal risk assessment will help to focus your resources on the highest risk issues.

Conduct a Comprehensive Root Cause Analysis

Root cause investigations need to determine not only the immediate causes of an event but also the systemic causes of that event. Common areas to investigate are:

1. Equipment Factors

Review:

• Calibration data
• Maintenance history
• Alarm logs
• Qualification status
• Settings for the equipment

Mechanical or computer-related issues could cause unexpected validation results.

2. Process Factors

Evaluate:

• Critical process parameters
• Operating range
• Process order
• Operator intervention
• Process variation

Even minor variations from the critical parameter values can have a major impact on validation performance.

3. Personnel Factors

Determine if:

• SOPs were followed correctly
• Operators had proper training
• Deviations occurred during execution
• There were communication failures

From my experience, training deficiencies are indicative of broader procedural deficiencies and not merely an isolated incident of human error.

4. Material Factors

Review:

• Quality of raw materials
• Supplier changes
• Batch-to-batch variation
• Storage conditions

Raw material variations can significantly influence validation results.

Evaluate Product and Process Impact

Surprising validation results may impact:

• Quality of the product
• Consistency in the process
• Performance of the equipment
• Effectiveness of the cleaning process
• Environmental controls

The investigations need to determine if:

• Prior products remain acceptable
• Further testing is necessary
• Product needs to be put on hold / quarantined
• Validation should continue

Each decision should have a scientific basis.

Trend Historical Data

Historical data offers valuable context. Review current results compared to:

• Previously completed qualifications
• Routine monitoring data
• Complete Process Capability reports
• Complete Maintenance records
• Complete Environmental System data

In a number of cases I’ve been involved with historically, the use of historical trend analysis has disclosed slow, but progressive decline. Many of the end-of-month data points had not identified that the process had declined, but rather showed an almost constant rate of success.

When Should Validation Be Repeated?

There are not always enough data to warrant a complete re-validation when an unanticipated finding has occurred. A re-validation may need to be conducted when:

• Acceptance criteria have not been met
• A root cause cannot be determined
• Critical process parameters have changed
• Equipment changes have been made
• The product quality is at risk

A re-validation decision should be science-based and should not be based merely on operational expediency.

CAPA Following Unexpected Validation Results

A corrective and preventive action plan must be established for every confirmed validation failure. Corrective and preventive actions may include but are not limited to:

• Revisions to standard operating procedures
• Revisions to equipment
• Revisions to operator training programs
• Preventive maintenance review process improvement
• Changes to sampling procedures
• Optimization of processes

The CAPA should address both the immediate correction and the preventive action to avoid a recurrence.

Documentation Expectations

Regulatory inspectors will scrutinize the documentation generated by a company during an inspection. The following should be included in an investigation record:

• Unexpected result's Description
• Timeline
• Risk Assessment
• Root Cause Analysis
• Supporting evidence
• Corrective and Preventive Action (CAPA) Plan
• Verifying the effectiveness of the CAPA
• Final Conclusion

Missing documentation can often be a larger regulatory concern than the original validation issue.

Data Integrity Considerations

Scientists should never delete, modify, or repeat any unexpected results without scientific justification. Organizations should also ensure that they will keep:
- Original Electronic Records
- Audit Trail
- Laboratory Worksheets
- Instrument Files
- Raw Data
Trying to invalidate legitimate results without evidence will create significant data integrity issues.

As I continue to remind my validation teams, unexpected results are acceptable when appropriately investigated. Unexpected results are not acceptable unless they are sufficiently documented and/or explained.

Cross-Functional Collaboration

Collaborating across multiple departments is important for successful investigations. Some commonly included members on the investigation team are:

• Quality Assurance
• Validation
• Production
• Engineering
• Quality Control
• Maintenance
• Regulatory Affairs

Collaboration across departments strengthens the identification of the root cause of problems found during validation and enhances the corrective and preventive action (CAPA) process.

Regulatory Expectations

The FDA, EMA, WHO and PIC/S authorities expect companies to investigate unexpected results scientifically. Commonly reviewed items when conducting an investigation include:

• Validation Protocols
• Investigation Reports
• Root Cause Analyses
• Risk Assessments
• Corrective and Preventive Action (CAPA) Plan Implementation
• Validation Reports
• Trend Analyses

If validation failures are recurring, with no or ineffective CAPAs, the pharmaceutical quality system may have organizational weaknesses.

Common Mistakes During Validation Investigations

Numerous common errors throughout the course of an investigation can diminish or degrade validation quality. Common errors include:

• Repeating tests without justification
• Prematurely closing investigations
• Only assigning "human error" as a root cause
• Disregarding historical trends
• Weak CAPA implementation
• Poor documentation
• Failure to evaluate product effect

Each of these issues frequently appears in observations made by regulators.

Building a Culture that Learns from Validation Results

Companies that operate with established validation programs value having open and honest communication and discussing science as a collective rather than pointing fingers at each other. Any deviations from the expected outcome should be seen as an opportunity to:

• Increase knowledge about the process
• Improve the overall quality systems
• Optimize the validation process
• Lower the number of future risks
• Achieve operational excellence

In my experience, the best validation teams are teams that may not always be successful but do thoroughly look into every unexpected outcome in a non-biased way with the goal of improving the company.

Best Practices for Managing Unexpected Validation Results

Pharmaceutical companies can better their validation programs with some key practices. Best practice recommendations:

1. All unexpected results should be investigated quickly.
2. All original documentation should be retained.
3. All risk assessments should be documented.
4. A root cause analysis should be completed systematically.
5. Use a cross-functional investigation team when performing an investigation.
6. All decisions will be based on validated scientific data when making decisions.
7. Measurable CAPA will be implemented.
8. CAPA will be verified for effectiveness prior to the closure of the validation.
9. Validation data will be trended on an ongoing basis.
10. Develop a culture of being transparent and continuously improving.

Unpredictable validation results are part of pharmaceutical production and will have to be handled by carrying out a system, science-based investigation. The aim of this investigation is not to cover up failure but to learn how process changes affect quality, to learn how to improve quality of product and to improve the overall quality system for all of the products produced.

In my opinion, companies that take unexpected validation results as an opportunity to learn will usually have much more solid processes, clearer validation programs and much better adherence to regulatory requirements. Being open and using a risk analysis process, objective data and effective corrective action/corrective action plans will meet all expectations by regulators and create confidence for a long time to come in your manufacturing operations.

Regulatory References

1. ICH Q9(R1) Quality Risk Management
https://database.ich.org/sites/default/files/Q9%28R1%29_Guideline.pdf
2. ICH Q10 Pharmaceutical Quality System
https://database.ich.org/sites/default/files/Q10_Guideline.pdf
3. FDA Process Validation: General Principles and Practices
https://www.fda.gov/media/71021/download
4. FDA Quality Systems Approach to Pharmaceutical cGMP Regulations
https://www.fda.gov/media/71023/download

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