Cleaning Validation Failures and Their Root Causes in Pharmaceuticals

Validation of cleaning processes is an essential function in the pharmaceutical industry by providing documented proof that manufacturing equipment can be cleaned consistently to acceptable limits. Properly validating cleaning processes helps to avoid problems like contaminating one product with another product, carrying over active ingredients, having microbes on in-process materials, detergent residues, and having two products mixed.

Despite cleaning validation being a well-established regulatory requirement, finding deficiencies in cleaning validation during regulatory inspections remains one of the most consistent deficiencies identified in manufacturing facilities today. In my experience as a regulatory compliance consultant, typically there is no single cause of these cleaning validation deficiencies seen during regulatory inspections. Typically, cleaning validation deficiencies are indicative of a weakness in one or more of the following areas: equipment design, process understanding, cleaning procedures, cleaning validation strategy, or the overall pharmaceutical quality system.

Most companies will only focus on the failed analytical result itself. However, the most successful pharmaceutical compliance professionals realize that the failed analytical result is only the effect of a much more significant cause that must be identified and resolved.

A scientifically thorough investigation would not only identify and rectify an immediate validation failure, but would also strengthen the entire manufacturing process.

What is a Cleaning Validation Failure?

Cleaning validation fails when the process does not demonstrate compliance with predefined criteria. Cleaning validation failures can occur due to:

• The residues obtained after cleaning are above the thresholds established
• The presence of microbial contamination exceeding acceptable limits
• Product residues are seen on equipment after cleaning
• The amount of cleaning agent residue remaining on equipment is above defined limits
• Rinse/swab samples do not pass testing
• The cleaning effectiveness may vary between validation runs

One failed test should never be accepted without further investigation since it could indicate a major weakness in the process.

The Importance of Cleaning Validation Failure

Cleaning validation directly relates to patient safety. Residual active ingredient residues or contaminants could create:

• Cross-contamination
• Dose that is not delivered correctly
• Product wrongfully returned
• Batch rejected
• Regulatory fines
• Loss of customer confidence

FDA, EMA, WHO, MHRA and PIC Inspection Agencies routinely inspect cleaning validation programs as a concern. Ineffective cleaning is one of the leading causes for a GMP observation.

Regulatory Expectations

Globally, regulatory agencies expect manufacturers to set up cleaning validation programs with scientific basis. Review by inspectors covers:

• Cleaning verification protocols
• Selection of worst-case product
• Acceptance criteria
• Sample methods
• Analytical methods
• Investigation report
• CAPA Implementation
• Periodic review of cleaning programs

Additionally, regulators expect manufacturers to maintain the validated state for the duration of the equipment lifetime and not just as a one-time exercise.

Common Cleaning Validation Failures

Identifying common cleaning validation failure patterns allows companies to highlight potential issues prior to them turning into a regulatory issue.

1. Residue Levels above Acceptance Limits

This is the most frequently observed cleaning validation failure. The most frequent reasons for exceeding acceptable residue levels include:

• Insufficient cleaning duration
• Incorrect detergent concentration
• Ineffective cleaning process
• Difficult to clean surfaces
• Insufficient rinse cycles

The investigation must determine why cleaning residues were found on the surface after cleaning, despite cleaning per your approved cleaning procedure.

2. Microbial Limit Failures

Microbial contamination at validated microbial limits may be evidence of ineffective sanitization or inefficient drying of equipment after a sanitization process. Common causes of microbial validation failures include:

• Inadequate sanitization of equipment
• Standing water
• Dead legs in piping
• Poor environmental control
• Inadequate drying of equipment

Microbial cleaning validation failures typically require a broader investigative scope than does chemical residue, as there is potential for impact on many manufacturing processes.

3. Failed Swab Recovery Studies

Swab recovery studies are performed to verify that residues can be reasonably recovered from the surface of the equipment. Reasons for failed swab recovery studies include:

• Poor swabbing technique
• Inappropriate swabbed materials
• Improper extraction methods
• Incorrect analytical methods

Without a valid recovery study from swabbing, validation results become scientifically doubtful.

4. Visual Cleanliness Failure

Visible residue on an item represents inadequate cleaning, even if the analytical limits have been exceeded. Reasons for the inability to determine whether residue is present visually include:

• Improper equipment design
• Inaccessibility of certain portions of the equipment
• Inability to perform a thorough inspection of the equipment due to time constraints
• Inadequate lighting during visual inspection

Visual inspection is still an essential part of cleaning verification.

Causes of Cleaning Validation Failures

Investigations must look for root causes and not just symptoms of the problem.

1. Equipment Design Issues

Cleaning validation failures are very often due to the design of the equipment being cleaned. Examples of this type of failure include:

• Dead legs
• Crevices
• Rough welds
• Non-smooth surface finishes
• Difficult-to-reach product contact points
• Complex piping systems

Cleaning equipment should be designed for effective cleaning by following hygienic engineering principles.

2. Inadequate Cleaning Procedures

Cleaning validation failures are often the result of poorly developed cleaning procedures. Examples of poor cleaning procedures include the following:

• Improper cleaning sequence
• Insufficient contact time
• Incorrect detergent concentration
• Important cleaning steps missing
• No written instructions for all cleaning processes

Cleaning procedures should be developed according to process knowledge as opposed to trial and error.

3. Incorrect Cleaning Agent Selection

Not every cleaning agent can be used for cleaning every product. The wrong cleaning product may not effectively solubilize:

• Oily residues
• High potency compounds
• Water insoluble products
• Sticky excipients

When selecting cleaning agents, consideration must be given to:

• The chemistry of each product to be cleaned
• The compatibility of the cleaning agent with the material of construction of the equipment
• The environmental impact of the cleaning agent
• The ease of rinsing the cleaning agent

4. Inadequate Operator Training

Training deficiencies can lead to cleaning effectiveness being dependent on whether or not the operator was trained properly. The following are common examples of deficiencies seen in an operator’s cleaning system:

• Improperly dismantling the operational equipment
• Cleaning the operating equipment improperly
• Not inspecting the operational equipment
• Not preparing the cleaning solutions properly

Operator errors are indicative of weaknesses within the operator’s training system rather than the performance of the operator.

5. Poor Cleaning Validation Protocol Design

Weak validation protocols can produce results that are misleading and include the following:

• An insufficient number of samples collected
• A poor sampling location being selected for the collected samples
• Inadequate worst-case conditions selected for cleaning
• Missing acceptance criteria (or having acceptance limits that cannot be replicated)
• Lack of statistical justification for why a particular acceptance criterion was selected

Protocols should be able to test cleaning under the worst-case condition.

Analytical Method Problems

Cleaning validation relies on analytical method validation. In many instances, failures are caused by:

• Lack of method sensitivity
• Instrument Calibration Problems
• Sample Preparation Error
• Poor Recovery
• Method Interference

Analytical methods must be validated for the following criteria:

• Specificity
• Accuracy
• Precision
• Recovery
• Detection limit
• Quantitation Limit

Sampling Errors

One of the major overlooked areas of cleaning validation is sampling. Examples of common sampling problems are:

• Incorrect Swab Technique
• Improper Sampling Location
• Inadequate Volume of Rinse Solution
• Cross Contamination During Sampling
• Errors in Handling Samples

If sampling is conducted poorly, the results may be misleading in relation to the effectiveness of cleaning.

Investigation of Cleaning Validation Failures

A formal investigation should be initiated as soon as a cleaning validation (CV) failure is identified. The steps of an investigation should include:

1. Review of Cleaning Execution

Verify that:

• Standard operating procedures (SOPs) were followed
• Cleaning parameters were documented as required
• Cleaning agents were prepared correctly
• Contact times were sufficient
• Assessment of Equipment

2. Equipment Review

Assessment of:

• Maintenance history
• Surface condition
• Calibration history and documentation
• Equipment modifications
• Qualification status

3. Assessment of Historical Trends

Compare results with:

• Previous validation studies
• Routine cleaning verifications
• Environmental monitoring
• Maintenance trends

Historical data usually identifies patterns of gradual degradation of the overall cleaning process.

4. Risk Assessment

Risk assessments will evaluate:

• Impact to product
• Level of risk to a patient
• Risk of cross-contamination
• Required quarantine of product
• Requirement to do additional testing

Decisions made on the basis of risk will support a scientifically-based justification for taking the action required.

CAPA Following Cleaning Validation Failures

Corrective and Preventive Action should be focused on improvements both short term and long term.
Examples:

• Updating cleaning procedures
• Redesigning equipment
• Changing cleaning solutions
• Extending cleaning time
• Improving training of operators
• Improving visual inspections
• Updating validation protocols

It is critical that any Corrective or Preventive Actions are verified for effectiveness prior to closing the investigation.

Common Mistakes During Investigations

There are several repeating patterns of mistake that will undermine an investigation of cleaning validation.
The Most Common Errors:

• Investigating repeatedly without investigation
• Assigning cause of error to operator without evidence
• Failing to consider equipment design limitations
• Poor documentation
• Inadequate root cause investigation
• Inadequate CAPA
• Failure to evaluate impact of the product

Repeating the cleaning cycle until acceptable results are achieved is not considered good science, and would therefore most likely not satisfy a regulatory inspector.

Preventing Future Cleaning Validation Failures

In order to prevent future failures due to incorrect cleaning validation, organizations with established cleaning validation programs are on a preventative rather than corrective basis.
Recommended Best Practices

1. Design Equipment for Cleanability
2. Choose Scientifically Justified Worst-Case Products
3. Ensure Analytical Method Validation
4. Standardize Cleaning Processes
5. Regular Training of Operators
6. Monitor Cleaning Trends/Patterns
7. Conduct Periodic Review of Cleaning Validation
8. Ensure Cleaning Validation Integrated with Change Control
9. Conduct Regular Internal Auditing
10. Verify Effectiveness of corrective/preventive actions through continuous monitoring

These best practices have been shown to improve compliance and enhance overall effectiveness over the long term.

A singular cleaning validation failure should not portray the laboratory as displaying an isolated incident but rather highlighting broader improved aspects of design, operating procedures, training of operators, and overall quality systems of your entire organization. A proper, scientific investigative process utilizing proper evidence and complete root cause and corrective actions are all key elements to stay compliant and continue to uphold patient safety.

As a past pharmaceutical professional, I believe companies that implement and maintain cleaning validation programs on an on-going basis (lifecycle program) in lieu of being viewed solely as one single qualification activity, have far less regulatory observations or failures and can count on continued reliable performance of their entire manufacturing operations. Continuous monitoring, periodic review, and proactive process improvements are the necessary components to maintain an effective cleaning validation program.

Regulatory References

1. FDA Guidance for Industry: Process Validation – General Principles and Practices
https://www.fda.gov/media/71021/download
2. FDA Guide to Inspections of Validation of Cleaning Processes
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/guide-inspections-validation-cleaning-processes
3. EMA Guideline on Setting Health Based Exposure Limits (HBELs)
https://www.ema.europa.eu
4. PIC/S PI 006 Recommendations on Validation Master Plan, Installation and Cleaning Validation
https://picscheme.org
5. EU GMP Guidelines Volume 4, Annex 15: Qualification and Validation
https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en

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