Root Cause Analysis of Failed Cleaning Validation: A Practical Guide

One of the hardest experiences that any pharmaceutical company could encounter is the failure of the cleaning validation process. There are negative implications from such a failure relating to product launch, as the failure leads to considerable concerns about the reliability of the cleaning process in terms of the prevention of cross-contamination.

The answer to the question of whether the existing cleaning method is always capable of avoiding cross-contamination cannot be obtained by redoing the cleaning process or spending more time on the cleaning. The root cause of the failure must be identified.

The regulatory bodies expect that the manufacturers deal with cleaning validation failures just as they would deal with failures of any other significant quality event. Any case of Out-of-Specification (OOS) swab test result, visible residue left after cleaning or continued failure to limit the residue must be thoroughly investigated using scientific data. Simply stating that the problem occurred due to "operator error" will not be enough.

From what I've learned, cleaning validation does not generally fail because of just one issue. In most cases, it is a combination of multiple factors such as equipment design, limitations of the cleaning method, product considerations, operator issues, etc. Hence the objective of the investigation is to figure out the reason behind the failure of the cleaning process rather than finding out the location of the residue.

Identifying a Cleaning Validation Failure

A cleaning validation failure can happen in many different ways. For example, while the most obvious case of cleaning validation failure may be exceeding the acceptance limit for a cleaning agent, there are other examples indicating the lack of control over the cleaning processes.

Most common cleaning validation failure signs include:

• Swab sampling results that exceed acceptance criteria.
• Rinsing sampling results failing the tests.
• Residue visible after cleaning.
• Microbiological contamination levels above the limits established.
• Repeated deviations at the same sampling points.
• Discipline disruption in cleaning validation results obtained on different validation occasions.
• Failure of efficiency tests adversely affecting results of measurements.

All of the occurrences listed above must be investigated as each of the cases prompts suspicion of faults in cleaning processes or cleaning validation.

Initiate by Implementing Immediate Containment

Prior to starting a thorough assessment, the necessary containment procedures should be taken in order to minimize any further danger.

Actions typically taken in response to the situation include:

• Ceasing operation of any machines used in manufacturing.
• Quarantining affected batches where appropriate.
• Informing Quality Assurance and Validation departments.
• Keeping analytical data and original samples intact.
• Making sure that no changes are made to the equipment until the investigation has commenced.
• Examining latest cleaning records and equipment logs.

These steps ensure that the investigation will be successful and that contamination does not occur again.

Verify That Failure Is Real

It is important to remember that not every failure in cleaning validation is an actual failure in cleaning method. Thus, it is essential to first confirm the accuracy of the analytical results.

Questions that should be raised include:

• Was the analytical method executing correctly?
• Were calibration standards acceptable?
• Did the instrument function properly?
• Were the conditions for the system met?
• Was the sample preparation performed accurately?
• Were calculations assessed properly?

If the analytical errors are ruled out, then the next step in the investigation should be the cleaning process.

Review the Cleaning Procedure

Cleaning steps are usually the first that are analyzed by the investigators, but the evaluation needs to be deeper than just checking whether the SOP was adhered to in the process.

Analyze if the procedure itself has the technical capability to remove the contaminants. Consider questions such as:

• Is the cleaning agent used suitable for the product?
• Is the cleaning sequence appropriate?
• Are detergent concentration and contact time sufficient?
• Is the volume of rinse enough?
• Is the temperature of the water in the validated range?
• Are hard-to-clean areas included?

Thus, the procedure may be followed well but it may still be ineffective if at the design phase of manufacturing it has not been properly organized.

Evaluate Product Characteristics

The attributes of the product that is being cleaned plays an important role in cleaning effectiveness. Certain materials present more challenging cleaning issues than others.

Be especially careful while dealing with products with:

• Low solubility
• High concentration
• Viscous binders or polymers
• Fatty or waxy substances
• Intense dyes
• Excessive amounts of sugar
• Thermal degradation residue
• Hygroscopic material

For instance, a controlled-release tablet made of hydrophobic polymers may require a different cleaning method in comparison to an immediate-release product produced in the same equipment. Thorough knowledge of the composition of residue helps to explain why the cleaning is ineffective.

Examine the Machinery Design

Design of machinery is often a neglected factor in the failures of cleaning validation. Even though a cleaning procedure may work well, it may fail to remove residues inside badly designed machinery.

Carry out a detailed inspection of the machine for:

• Dead legs
• Cracks and gaps
• Faulty gaskets
• Bad welds
• Rough inside surface
• Old seals
• Product residue accumulation under the machines
• Unreachable areas in CIP systems

When necessary, use endoscopies or disassemble equipment to check hidden surfaces.

In multiple cases I was involved in during my work, residues were found under removable installations that were not listed in the cleaning protocol.

Evaluation of Cleaning Parameters

The effectiveness of cleaning is based on four elements, commonly known as Sinner's Circle:

• Time
• Temperature
• Chemical activity
• Mechanical activity

While one element is usually lowered, one of the others has to be raised in order to arrive at similar cleaning efficiency.

In the course of investigation, comparison of actual cleaning parameters with those determined during validation is required:

Parameter	Questions to Ask
Time	Was the validated cleaning duration maintained?
Temperature	Was the cleaning solution within the approved range?
Chemical concentration	Was detergent prepared correctly?
Mechanical action	Was spray pressure or manual scrubbing adequate?

Examine Human Factors

The term “operator error” must not be taken simply, nevertheless, personnel-wise assessment still needs to be performed with no bias.
Make sure you check if:

• The operators stuck to the approved SOP.
• Cleaning procedures checkpoints were filled out.
• Dismantling of the equipment was performed wherever necessary.
• Cleansing tools were suitable and fit for use.
• The staff has been trained regularly and on time.
• Check if the shifts had influence on cleaning interaction.

If different operators act in different ways under the same conditions, it exceeds operator error and means that either training was poor or cleaning procedure is too complicated.

Examining Sampling Procedures

There are instances when cleaning activities work smoothly but when sampling method introduces mistakes in the results.

The study should help in validating that:

• Swab points were located according to the approved document.
• Sampling in the most unfavorable locations was performed.
• The materials for swabbing were correct.
• Recovery factors were valid.
• Sampling method and pressure were the same for the entire study.
• Transport and storage of samples were performed according to the validated method.

Using inconsistent sampling procedure will result in incorrect data and will make it more difficult to find the cause of the problem.

Use Structured Root Cause Analysis Tools

The interviewer may take help of certain structured techniques to understand the problem or situation.

1. Fishbone Method

The Fishbone method is used to present all possible causes and problems in six different categories. These categories are:

• Equipment
• Materials
• Methods
• Man
• Environment
• Measurement

The method helps in identifying the actual cause instead of assuming one cause.

2. 5 Whys Technique

The technique of five whys focuses on asking “why?” more than once to arrive at the original cause of a problem.
For example, it can be asked:
Q1. Why did the swab fail?
A1. Residue exceeded the acceptance limit.
Q2. Why was there residue?
A2. Cleaning solution did not remove the product completely.
Q3. Why?
A3. Detergent concentration was lower than specified.
Q4. Why?
A4. The dosing pump delivered an incorrect volume
Q5. Why?
A5. Preventive maintenance for the pump was overdue.

Thus, the maintenance of the pump played the role of the actual cause while the cleaning solution was not effective.

Implementing efficient CAPA

Once a root cause has been confirmed, corrective actions and preventive actions will fix the actual problem at hand and will also deal with the underlying weakness of the system.
Examples are:

• Modifying cleaning process
• Changing the detergent
• Changing the design of equipment
• Updating preventive maintenance plans
• Improving training of operators
• Revising cleaning validation methods
• Add more in-process checks
• Update risk assessment

Effectiveness check is always necessary for CAPA to prove that the problem has been eliminated permanently.

Avoid These Common Investigation Mistakes

Cleaning validation investigations fail due to avoidable errors.
Some of the most common mistakes include:

• Repeating a cleaning procedure without investigation.
• Assuming the laboratory has made a mistake.
• No evidence to blame operators.
• Overlooking equipment design issues.
• Investigations are closed off before the root cause is verified.
• Non-valid implementations of CAPAs.

Failure to reconsider worst-case products assumptions after multiple failures.

Creating a More Efficient Cleaning Validation Process

The information obtained from failed validation studies should help to enhance the future cleaning validation program of a company.

Companies can minimize the chances of having a philosophy repeat itself by:

1. Conducting detailed worst-case product investigations
2. Evaluating cleanability of the equipment during qualification
3. Choosing the right detergent according to residue chemistry
4. Gathering and analyzing trends in data acquired due to cleaning validation
5. Reviewing cleaning protocols on a regular basis
6. Including engineering, production, analytical and quality personnel in the investigations

Cleaning validation should be treated as a procedure that develops over time as the products, equipment, and methods change.

The cleaning validation failure should not be interpreted as an isolated incident of laboratory testing. This is an opportunity to assess the efficiency of the whole cleaning process, from the moment of designing a piece of equipment to the moment of testing the cleaned equipment in the laboratory.

My experience shows that the root cause investigations that are effective challenge the specific assumptions, analyze all steps of cleaning and rely on objective evidence instead of convenient explanations.

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