Water System Validation After Major Maintenance in Pharmaceuticals

One of the most important utility systems at any manufacturing site is the pharmaceutical water system. Depending on whether purified water, water for injection (WFI) or Pure Steam is being produced, the pharmaceutical water system will have a significant degree of impact on product quality, cleaning operations, laboratory process and equipment operation. This is due to the fact that pharmaceutical water comes into direct/indirect contact with the product. Therefore, water quality deterioration can pose a significant risk to product and regulatory quality.

When performing major maintenance activities such as replacing storage tanks, pumps, heat exchangers, distribution loops, UV units, membranes, valves, piping sections, automated systems, etc., it will have an effect on the validated status of the water system. Although maintenance is an appropriate step in supporting long-term reliability, it also presents opportunities for contamination, biofilm formation, dead legs, construction debris and alteration of the system's operational integrity.

It has been my experience that one of the most common mistakes that pharmaceutical companies make is assuming that once maintenance has been properly completed, the water system can immediately return to a production state. Regulatory authorities have a much higher level of expectation than just having successful mechanical repairs performed. Regulatory authorities require documented evidence that all maintenance performed did not affect water quality and that the water system continues to operate within its validated status.

The Impact of Major Maintenance on Water System Validation

Pharmaceutical water systems require careful validation and operation under controlled conditions. Nevertheless, any major? This can affect hydraulic characteristics, flow patterns, sanitization or microbial. Major maintenance can affect:

• Water Flow Velocity
• System Temperature
• Distribution Pressure
• Turbulence in Piping System
• Sanitization Effectiveness
• Surface Integrity
• Microbial Control

For example, major repairs to any kind of pipe can introduce contaminants or create an area for microorganisms to proliferate; assuming proper commissioning and validation has not been completed.

Consequently, maintenance activities are subject to formal change controls prior to implementation as an additional measure.

What is Considered Major Maintenance?

Major maintenance does not always require revalidation. Certain maintenance activities can have a major impact on the operation of the system and often require additional qualification or revalidation. Examples of major maintenance activities include:

• Replacement of Reverse Osmosis (RO) membranes
• Replacement of Electro deionization (EDI) units
• Replacement of pumps
• Replacement of storage tanks
• Distribution loop modifications
• Replacement of Ultraviolet Sanitizing Units
• Major Modifications to Piping
• PLC Automation/Upgrade
• Replacement of Heat Exchangers
• Replacement of Ozone Generator Systems

The scope of validation is determined by the degree of risk to the operation of the system created by the maintenance activity.

Regulatory Expectations

The expectation of global regulatory agencies is that pharmaceutical manufacturers maintain water systems in validation for the entire life cycle. Examples of items commonly reviewed by inspectors are:

• Change control records
• Maintenance documentation
• Risk assessments
• Validation protocols
• Data sampling
• Trend reports
• Investigative records
• CAPA documentation

Simply returning equipment to operation does not demonstrate that the water system continues to be suitable quality for pharmaceutical use.

Perform a Risk Assessment Before Maintenance

Assessment of the potential danger to an area or object of maintenance before performing any major maintenance tasks with a documented Quality Risk Management (QRM) exercise. The assessment must consider the following:

• Impact on components
• Contamination risks
• Product risks
• Criticality of change
• Validation needed
• Additional monitoring requirements.

For example: The risk of replacing a sanitary diaphragm valve is significantly lower than replacing an entire storage tank or changing a distribution loop. The results of the risk assessment will determine the required validation strategy.

Change Control is Essential

Any substantial maintenance action must be managed via an approved change control system. Change control must include:

• Proposed maintenance description
• Technical justification for the proposed maintenance
• Risk assessment
• Validation impact assessment
• Approval workflow
• Implementation plan
• Post-maintenance verification

Organizing change control as part of a structured process allows for the planning of validation activities prior to the commencement of maintenance, rather than during the occurrence of any problems.

Engineering Verification After Maintenance

Prior to starting validation sampling, engineering must review that all maintenance is complete. Typical checks within engineering include:

• Visual inspection
• Weld Quality Verification
• Confirmation of slope
• Leak testing
• Pressure testing
• Instrument calibration
• Valve operation
• Pump rotation
• Control system operation

These are completed to verify that the system is mechanically appropriate for validation.

Cleaning and Sanitation

When performing maintenance on your internal water systems, you’ll be exposing the surfaces within those systems to the environment.

Prior to returning the system to service, you must perform a complete cleaning & sanitizing procedure. Depending upon the type of system you have, the methods of sanitization may include:

• Hot water sanitation
• Steam sanitation
• Ozone sanitation
• Chemical sanitation

Documentation of the sanitizing process must take place before any water sampling.

Requalification of Critical Components

Some components must be requalified after being replaced or changed in a significant way. A few examples are:

1. Reverse osmosis units
2. EDI modules
3. Ultra violet systems
4. Heat exchangers
5. Storage tanks
6. Distribution pumps
7. On-line conductivity meters
8. Total organic carbon (TOC) analyzers

The qualification process ensures that all replacement equipment operates within the designed specifications.

Water Sample Collection Strategy

Sampling post-maintenance validation is one of the most important aspects of the process. A scientifically sound sampling plan will consider the following locations for sampling:

• Generation Point
• Storage Tank
• Return Loop
• Use Points
• Worst Case Locations
• Newly Modified Areas

It is important to perform sampling over a sufficient period of time to substantiate a consistent level of system performance and not just rely on one positive result.

Tests Performed During Revalidation

Chemical and microbiological evaluations are both types of validation.

1. Chemical Testing

Examples of typical tests performed include:

• Conductivity
• TOC Analysis
• pH
• Nitrate Testing
• Heavy Metal Testing

2. Microbial Testing

Routine microbial tests may include:

• Microbial Count
• Endotoxin Tests (for WFI)
• Biofilm Assessments (if needed)

If the maintenance activity justifies additional testing, then that would be done.

Trend Analysis

When doing post-maintenance validation, trends have provided fundamental evidence. Firstly, comparisons need to be made between:

• Previous validation studies
• Routine monitoring data
• Seasonal variations
• Historical microbial counts
• Conductivity performance
• Trends of TOC concentrations

In my experience, the results of trend analysis frequently uncover gradual degradation of systems that single test methods might not discover.

Documentation Requirements

It is essential that detailed documentation be maintained to provide evidence of on-going compliance. The validation package shall include:

1. Change control
2. Risk assessment
3. Maintenance records
4. Calibration certificates
5. Sanitization records
6. Validation protocol
7. Sampling results
8. Investigation reports
9. Validation report
10. Quality assurance (QA) approval

Often, when regulators review a firm's records, they will review the above documents together and review to see if the validated state was restored.

Common Mistakes After Major Maintenance

The following types of regular errors are commonly associated with regulatory audits. Frequent errors include:

• Returning the system to use before the end of the validation process.
• Not enough sampling
• Insufficient cleaning and sanitizing
• Not reviewing the validation impact
• Inaccurate risk assessment
• Not monitoring historical trends
• Poor documentation
• Closing change orders without confirming that they were effective

These deficiencies highlight deficiencies in a company's entire quality system, rather than indicating problems with maintenance practices alone.

Best Practices for Water System Revalidation

Organizations with quality pharmaceutical water supply systems typically engage in proven methods.
Recommended Best Practices

1. Conduct risk assessment based on evidence prior to carrying out maintenance.
2. Use structured change control for any significant change in the system.
3. Requalify all components that are removed and replaced.
4. Conduct thorough sanitation of the water system prior to assigning a validation date.
5. A risk-based sampling program should be developed.
6. Review historical performance data to assist in determining the safety of a water supply.
7. If unexpected results are discovered, investigate the circumstances to identify what caused them.
8. Prior to re-releasing a water supply system, verify the effectiveness of CAPA.
9. Validate all documentation associated with the validation of the water supply.
10. Provide for ongoing monitoring (enhanced) of the water system after it has been returned to use.

By utilizing these practices, you will ensure that your maintenance of the water system does not interfere with product quality or regulatory compliance.

Pharmaceutical water systems need to undergo routine maintenance over their lifespan, but it is important that this does not alter or compromise the validated state of these systems. Each major alteration to a water system has the potential to impact microbial control and overall performance of the water system.

In order for a revalidated water system to return to routine use after major maintenance, it is critical that a structured approach is taken, such as risk assessment, engineering verification, sanitization, sampling and documented revalidation. I have seen many pharmaceutical manufacturing companies that have integrated their maintenance planning with their validation activities demonstrate fewer deviations, comply more readily with regulatory requirements and have greater confidence in the water systems they are using.

Water system validation should be considered a critical quality assurance function for products, patients and the integrity of the manufacturing process, in addition to meeting regulatory obligations after major maintenance.

Regulatory References

1. FDA Guide to Inspections of High Purity Water Systems
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/guide-inspections-high-purity-water-systems
2. USP General Chapter <1231> Water for Pharmaceutical Purposes
https://www.usp.org
3. EU GMP Guidelines Volume 4, Annex 1: Manufacture of Sterile Medicinal Products
https://health.ec.europa.eu/medicinal-products/eudralex/eudralex-volume-4_en
4. WHO Good Manufacturing Practices for Pharmaceutical Water Systems
https://www.who.int/teams/health-product-policy-and-standards/standards-and-specifications/gmp

Get ready to use editable Validation Protocols in MS-Word FormatView List

Share

Tweet

Share

Pin it

Share