One of the most commonly used utilities in the manufacturing of pharmaceuticals is water. Both Purified Water and Water for Injection are required to be high quality, which is necessary for both product safety and compliance with the relevant regulation (FDA). Thus, Purified Water and Water for Injection Systems are designed to continuously flow in a closed loop system to prevent microbial growth, and to ensure consistent quality.
One of the greatest concerns in the design of an energy-efficient potable water system is the establishment of dead legs. Even very small dead legs can be potentially contaminated if not properly managed. Therefore, the FDA is highly focused and aware of dead leg issues; in addition, GMP has established regulations for the management of dead legs. This creates a need for all pharmaceutical professionals to understand clearly the issue of dead leg, and manage them effectively.
What is a Dead Leg?
A dead leg refers to a part of the water supply line that has minimal or zero flow of water within the system. The stagnant water located at dead legs creates an environment conducive to the growth of microorganisms (or microbes), and the formation of biofilm.
Essentially, a dead leg is the “dead end” of a water system where there is insufficient circulation of water through it. Dead legs are often found at:
Having legs properly designed will assure that water can be delivered to all parts of the system effectively.
Some common methods are:
Pharmaceutical water systems contain dead legs, which can lead to microbially contaminated water being used and ultimately, compromising the quality of the product. In the design of a water system, dead legs appear to be minor design issues; however, if they are not adequately managed, they have the potential to cause significant issues with the production of a product.
The best way of managing dead legs is to design the system with no dead legs through monitoring and continuous validation; when dead legs cannot be eliminated from the system, then there are controls and monitoring mechanisms in place to manage the dead legs. A pharmaceutical manufacturing company must have a well-designed water system to ensure regulatory compliance, product quality, and patient safety.
What is a Dead Leg? 
A dead leg refers to a part of the water supply line that has minimal or zero flow of water within the system. The stagnant water located at dead legs creates an environment conducive to the growth of microorganisms (or microbes), and the formation of biofilm.Essentially, a dead leg is the “dead end” of a water system where there is insufficient circulation of water through it. Dead legs are often found at:
- Unused piping branches
- Poorly designed sample points
- Redundant connection points
- Valves or instruments that are poorly arranged
Why Dead Legs are a Serious Concern
Pharmaceutical water systems are designed to provide product with high levels of purity. A continuous flow of water within these systems helps to reduce the likelihood of microorganisms growing and multiply while stagnant will disrupt that balance. The risks associated with having dead legs include:- Microorganism contamination
- Biofilm formation
- Generation of endotoxins
- Challenges with cleaning and sanitizing
How Dead Legs are Formed
Dead legs develop frequently because of inadequacies in how a system has been designed or from changes made to that system over time. Some common causes include:- Branch lengths that are excessively long relative to the main loop
- Unused or seldom used pipe connections
- Valves or fittings that have been designed poorly
- Incorrectly sloped and/or oriented piping
- Changes to the system without conducting an adequate impact assessment
Regulatory Requirements
A number of regulatory agencies require that pharmaceutical water systems be free of dead legs or properly controlled. As outlined in Good Manufacturing Practices, all systems must be designed to:- Prevent stagnation
- Promote continual circulation
- Enable cleaning/sanitization
Design Criteria to Avoid Dead Legs
The most effective method of eliminating dead-legged installations is through proper design.1. The 3D Rule
According to WHO TRS 970 (page 83), dead-leg should not be more than 3 times (updated in) of internal diameter (ID) of the pipe. Nowadays no dead leg pipelines are installed to solve the water staging problems in water systems.Having legs properly designed will assure that water can be delivered to all parts of the system effectively.
2. Continuous Circulation
Water systems containing closed loop designs with continuous circulation will prevent stagnation and provide uniform quality of water throughout the system.3. Appropriate Drainage and Slope
Piping systems must have a slope that promotes total drainability to prevent water from remaining in low spots within the system.4. Hygienic Design
To minimize the potential for contaminating water or causing biofilm, only sanitary fittings, minimal joints, and smooth internal surfaces should be used.Identification of Dead Legs
Finding dead legs in a system that's being maintained and validated is essential. Ways to find a dead leg are by:- Using piping or instrumentation diagrams (P&ID)
- Physically inspecting
- Checking microbial trends or spikes
- Conducting risk assessments
Effect of Dead Legs on Water Quality
Dead legs can greatly impact the quality of water, especially high purity systems such as water for injection (WFI).- Increasing the number of microbes in water for injection (WFI)
- Hardening of biofilm (layer of living bacteria) will be difficult to remove
- Release of endotoxins into the system
- Fail routine water quality tests
Ways to Control Dead Legs
The ideal means to deal with dead legs is to eliminate them completely. However, there are some cases where controlling dead legs is required. Examples of common approaches to control dead legs:- Removal of piping that is no longer used.
- Redesigning branches to conform to the 3D rule.
- Encouraging increased flow through seldom used piping.
- Regular flushing of low used branches.
- Sanitization of low usage or seldom used branches through periodic application of heat or chemical.
The Importance of Sanitization
Sanitization is very important for reducing the potential for microbial growth in a water system.Some common methods are:
- Hot water sanitization
- Steam sterilization
- Chemical sanitization
Validation Considerations
At the time of validating a water system, the dead legs must be assessed as part of a design qualification. Some validation examples are:- Evaluating system design against the 3D rule
- Monitoring for microbial levels at various locations in the system
- Checking the effectiveness of the sanitization
- Making sure that the water quality is consistently met.
Common Mistakes in Managing Dead Legs
Often organizations will make errors that could otherwise have been avoided when it comes to dead legs. Some of the most typical behaviors to have occurred in managing dead legs are as follows:- Small dead legs or dead legs with low-risk potential are often ignored
- Failure to revise system after changes made to design
- Relying only on sanitizing rather than changing design to eliminate dead legs
- Not performing routine inspections and monitoring.
Best Practices for Managing Dead Legs
Utilizing a proactive strategy will enable you to reduce risk of dead legs. Key best practices include:- Designing systems with minimal dead legs
- Adhering to the 3D standard
- Conducting regular system review and trend analysis
- Monitoring and tracking microorganisms
- Implementing a systematic change management program
- Providing employee training on both system design and potential risk
Role of Quality Assurance
The role of QA in the management of dead legs is critical. Key QA responsibilities related to dead legs include:- Reviewing system design and/or modifications
- Approving validation/monitoring plans
- Ensuring compliance with GMPs (Good Manufacturing Practices)
- Monitoring and tracking deviations and corrective actions
Pharmaceutical water systems contain dead legs, which can lead to microbially contaminated water being used and ultimately, compromising the quality of the product. In the design of a water system, dead legs appear to be minor design issues; however, if they are not adequately managed, they have the potential to cause significant issues with the production of a product.
The best way of managing dead legs is to design the system with no dead legs through monitoring and continuous validation; when dead legs cannot be eliminated from the system, then there are controls and monitoring mechanisms in place to manage the dead legs. A pharmaceutical manufacturing company must have a well-designed water system to ensure regulatory compliance, product quality, and patient safety.
No comments:
Post a Comment
Please don't spam. Comments having links would not be published.