Common Audit Findings in Analytical Method Validation

Analytical method validation establishes documentation for how an analytical test procedure is adequate for meeting its intended use. When the test will be performed for assays, impurities, dissolution, residual solvents, microbiology, or cleaning validation samples, the reliability of the method will directly impact the quality determination regarding the product. Once a method has been validated, it will provide the laboratory with data that is accurate, precise, reproducible and scientifically justified for the entire lifetime of the product.

A significant portion of the basis for an organization’s release of batches, stability studies, process validations and regulatory submissions will feature analytical data; therefore, most GMP audits will involve a consideration of analytical method validation by inspectors. During FDA and MHRA inspections, EU GMP audits and customer audits, shortcomings or deficiencies noted in the validation of analytical methods often signify that there are more substantial deviations from laboratory quality systems and data governance.

From my experience, most findings from audits occur because there was insufficient planning, poor documentation, weak scientific justification associated with the method being utilized and lack of ongoing maintenance of the validated state of the method after its use started, rather than a lack of appropriate technical knowledge. Organizations using a lifecycle approach for analytical methods will generally have fewer observations during audits and more confidence in data from the laboratory.

The Importance of Auditing Analytical Method Validation

Results from laboratory analyses are crucial in making quality decisions throughout the product life cycle of pharmaceutical manufacturing. If a method of analysis is identified as unreliable, then the decisions made on the result of that analysis can be called into question. An inadequate analytical method validation is likely to result in:

• Incorrect batch release
• Failure to detect impurities
• False out of specification OOS results
• Inaccurate stability data
• Regulatory observations
• Product recalls

Due to these issues, inspectors expect analytical methods to be compliant with scientifically accepted practices and regulatory guidance in current use.

Regulatory Expectations

Analytical method validation should demonstrate that a method can consistently perform as intended. When performing an audit, auditors typically review:

• Validation protocols
• Validation reports
• Raw data generated from the analytical method
• Statistical analysis of the analytical method
• Chromatograms
• Qualifications of the analytical instrument
• Training records for the analyst
• Documentation of any changes made to the analytical method
• Integrity of the data

Inspectors review and confirm that a lab continues to monitor performance after validation has been completed rather than considering validation to be a one-time event.

Common Audit Findings

1. Incomplete Validation Protocols

One of the most common findings in an audit is poorly defined validation protocols. Common areas of concern with validation protocols include:

• Unclear acceptance criteria
• Not identifying parameters for validation
• Uncertain roles and responsibilities
• Insufficient sampling plans
• No statistical methodology

A written validation protocol should include (1) clearly defined parameters for evaluation, (2) how the evaluation will be conducted and (3) the criteria for evaluation of acceptability.

2. Poor Scientific Justification

Validation studies must always be supported with sound scientific rationale. Auditors may question:

• Acceptance criteria that seem arbitrary
• System suitability criteria which have not been scientifically supported
• Inadequate sample size for testing
• Concentration ranges that haven't been justified
• Weak (or no) robustness test

In my professional opinion, one of the easiest ways to add strength to a validation dossier is documenting the rationale for every major validation decision.

3. Insufficient Specificity Studies

Specificity is used to show the ability of the analytical procedure to measure the analyte correctly without interference. Commonly found deficiencies within this aspect include:

• Placebo interference
• Degradation products
• Excipients
• Related impurities
• Cleaning agents

For stability-indicating methodologies, forced degradation studies must demonstrate that the analyte peak is unaffected by the presence of degradation products formed through potential decomposition of the analyte during storage or handling.

4. Inadequate Accuracy and Precision Studies

Accuracy and precision are two important parameters in validation. Common findings regarding audits include:

• Inadequate recovery levels
• Narrow concentration ranges
• Limited number of replicate analyses
• Insufficient statistical evaluation of data

Validation reports must document that analytical results are accurate and reproducible for the intended range of the analytical method.

5. Inadequate Robustness Evaluation

Robustness is the assessment of whether or not the method remains reliable when small intentional changes are made to it. Examples are:

• Flow rate
• Mobile phase composition
• Column temperature
• Detection wavelength
• pH
• Injection volume

One frequent finding in audits is that just a few variables were evaluated without being representative of what actually happens during the usage of the method(s).

6. Poor Statistical Evaluation

Inspectors are expecting statistical justification as part of all method validations more frequently. Examples of deficiencies are:

• Missing regression analysis
• No confidence intervals
• Insufficient calculations for the method
• Weak assessment of linearity
• Unsupported conclusions

Statistical evaluations give the objective evidence that a method consistently meets its performance requirements.

7. Insufficient Documentation

Poor documentation is still a leading area of nonconformance found in laboratories today. The following are all examples of insufficient documentation:

• Missing raw data
• Incomplete calculations
• Unsigned worksheets
• Missing chromatograms
• Unapproved reports
• Inconsistent data entries

As I've advised laboratory staff many times before, if a documentation record cannot be reconstructed, then no matter how scientifically valid it may have been, the laboratory will not receive credit for that validation.

8. Data Integrity Deficiencies

Data integrity remains a major regulatory concern. Auditors will normally review:

• Audit trails
• Electronic records
• User access controls
• Backup procedures
• Electronic signatures

Data modification without justification and/or without appropriate controls will generally be a major cause for regulatory concern.

9. Failure to Revalidate After Changes

Analytical methods constantly evolve over time. Changes can include:

• New HPLC Columns
• Replacing Instrument
• Software Upgrade
• Changes in Mobile Phase
• Change in Specifications

An audit exception that keeps appearing is that changes are made (significant) to a method without verifying how this might affect the validation of the method.

Have all significant changes reviewed under change control and have partial or full revalidation done where appropriate.

10. Inadequate Analyst Training

An analytical method which has a well-defined procedure can result in an “unreliable result”, therefore, the person conducting the analysis must be trained:

• No assessment of competency when they were trained
• No record of their being retrained
• Lack of instruction in the specifics of the method used
• Did not assess if they understood the method before being allowed to do independent testing

An analyst’s competency should be demonstrated by qualified documentation and not just by their attendance.

The majority of deficiencies in analytical method validation stem from long-standing systemic issues, as opposed to being the result of isolated laboratory errors.

Root Causes Behind Audit Findings

Some of the chief root causes of these types of validations are:

• Poor quality assurance
• Poor validation planning
• Poor documentation practices
• Poor science
• No lifecycle management
• No change control
• Resource limitations

By properly addressing these systemic weaknesses, you can often prevent many instances of observation in the future.

Preparing for Regulatory Audits

The best way to identify gaps prior to being inspected is by conducting an internal audit of your laboratory. An internal audit should include the following aspects:

• Compliance with ICH Q2 Guidance
• Validation report completeness
• Raw data traceability
• Statistical evaluation
• Instrument qualification status
• Data integrity controls
• Analyst training documentation
• Change control documentation

By regularly reviewing gaps, you will be able to improve your laboratory's overall compliance and efficiency.

The purpose of analytical method validation goes beyond fulfilling regulatory requirements. It is a common misunderstanding that there are many audit results due to the failure of an analytical method but most results that are found during an audit show that the problems come from the way the laboratories has planned, documented, provided scientific rationale and managed the analytical method during its lifecycle.

Through effective use of robust validation protocols, thorough documentation, appropriate application of statistical principles and the integration of the analytical method validation into the pharmaceutical quality system, laboratories can greatly reduce the number of audit observations.

My experience suggests that laboratories which view their analytical methods as living entities (i.e., requiring ongoing assessment) as opposed to being viewed as completed validation projects will have better compliance and will present greater confidence in the results of their analytical methods. Effective management of an analytical method validation program ultimately protects the quality of products, maintains regulatory compliance and safe care for patients.

Regulatory References

1. ICH Q2(R2): Validation of Analytical Procedures
https://database.ich.org/sites/default/files/ICH_Q2R2_Guideline_Step2_2022_0324.pdf
2. ICH Q14: Analytical Procedure Development
https://database.ich.org/sites/default/files/ICH_Q14.pdf
3. FDA Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics
https://www.fda.gov/media/87801/download

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