Eliminating Dead Legs in Pharmaceutical Piping Systems

The piping systems and water systems are made to carry vital services like PW, WFI, pure steam, process gases and CIP solutions without compromising product quality or microbial safety. However, even the most efficient water systems can present a risk of contamination when stagnant regions inside the piping system appear. The presence of dead legs is one of the main culprits responsible for microbial contamination in pharmaceutical water systems.

During the inspections by health authorities, dead legs are frequently found because they create ideal conditions for the emergence of microbiological life, biofilm formation and other harmful pollutants. Once biofilm is formed in dead legs, it becomes practically impossible to eliminate it and sanitation measures may prove to be useless.

From my experience, the emergence of dead legs happens at the design stage rather than at the production facility. The occurrence of dead legs is often the product of poor design, unnecessary iterations and repositioning of piping systems as a result of plant modernization. Luckily, careful design and proper handling of any changes can help remove the opportunity for dead legs to appear in the first place, avoiding any issues with product quality.

Understanding Dead Legs

The term "dead leg" refers to a segment of pipe wherein there is practically no fluid flow in the normal operation of the system. These stagnant sections can result in microorganisms replicating and forming biofilms on the internal piping surfaces since they have enough time to thrive in stagnant water or process fluid remaining in these dead leg sections.

During the installation process, dead leg occurrence does not seem to be an important issue; still, this segment can cause microbiological issues in a pharmaceutical utility system at some point in time. 
Dead legs are often found in:

• Unused connections of branches
• Isolated sampling ports
• Spare connections of devices
• Rarely appliances
• Solution lines for future expansion
• Sections of sealing pipe
• Closed bypasses

Even though dead legs are mainly attributed to the pharmaceutical water systems, they can also happen in solutions for clean steam and the transfer of product.

Why Dead Legs are a Major GMP Concern

The goal of pharmaceutical water systems is to keep the water moving since motion helps inhibit bacteria. If water has stopped flowing in a portion of pipes certain unfavorable conditions appear.
They include:

• The water being stagnant
• A decrease in the efficiency of sanitization
• The formation of biofilms
• The appearance of bacteria
• The accumulation of particles
• The rise of endotoxins levels
• The difficulty in cleaning

When microorganisms create biofilms, they acquire much stronger resistance towards the chemical cleaning and heating processes involved in the daily upkeep of the system.

Regulatory Considerations

Regulatory authorities around the world require pharmaceutical companies to develop piping arrangements that will avoid areas where standing water might accumulate. During inspections, the regulatory authorities look at documents like:

• Piping and Instrumentation Diagram (P&ID)
• Isometric drawings
• Water system qualification documents
• Maintenance information
• Sanitization protocols
• Microbial trend reports
• Engineering modifications documentation

During inspections, specialists will go through the entire plant. They look for useless pipe branches, wrongly made valves, or dead-end sections.

Most of the time, regulations do not specify all the requirements related to engineering but they ask for the systems that should be designed to be cleaned, drained and meet microbiological requirements.

The 3D Rule

One of the most acknowledged principles of engineering to avoid the dead legs is the 3D Rule. It is about the length of the branch connection must not be more than three times the internal diameter of the main pipe.
Example:
Internal diameter of the main pipe: 25 mm
Maximum length of the branch: 75 mm

It is crucial to follow the ratio since any other length may not have sufficient flow of liquid during the normal circulation process. Though 3D Rule is regarded to be a good engineering principle, the use of engineering intuition is still requisite.

Common Causes of Dead Legs

Dead legs are often caused by slow changes in the design of a facility as it grows and changes. The most common causes include:

1. Poor Initial Design

The routing of pipes during construction of a facility can sometimes lead to unnecessary dead legs. Some examples of things that create dead legs include:

• Manifolds that are too large
• Pipes that are too long
• Pipes that do not lead anywhere
• Bad placement of valves

It is much more cost effective and easier to design a facility properly than to fix it after it has been installed.

2. Facility Expansion

Many pharmaceutical plants have unused pipe locations installed for growth. Unfortunately, these connections are not always used for years. Without flushing processes, they provide a perfect environment for bacteria.

3. Improper Valve Installation

Using a valve in the wrong position can create dead spots in the pipes. Even sanitary valves can cause dead legs if used improperly. Valves should be positioned in such a way that they aid in drainage and flow.

4. Rarely Used Sampling Locations

Sampling valves that are not utilized for long periods of time can often develop localized dead legs. Regular flushing as well as preventive maintenance should be included as part of standard practices.

Engineering Solutions to Avoid Dead Legs

A good dead leg management plan commences in the design phase and continues throughout the facility's lifecycle.

1. Design for Continuous Flow

Constant flow is key for avoiding biological contamination. Engineers should develop piping loops with the following characteristics:

• Even flow velocity
• Low-pressure drop
• Full circulation
• Good temperature control

All of the branches need to be supplied with sufficient flow during normal operation.

2. Minimize Unused Connections

Each additional branch raises the risk of contamination. As opposed to adding various spare connections, do that only when there are plans for expansion. Otherwise, empty connections should be removed whenever it is possible.

3. Install Hygienic Valves

The sanitary diaphragm valves are better compared to traditional valves and allow the limiting of the places in the valve where the fluid can dwell. It is important to pay attention to:

• Cleanability
• Draining
• Surface finish
• Maintenance requirements

4. Optimize Instrument Connections

Install pressure gauges, conductivity meters, temperature sensors, flow meters using hygienic connections. Avoid long instrument tees as much as possible.

Material Selection and Surface Finish

Even with optimal pipe design, the use of wrong materials may lead to contamination. Water systems in the pharmaceutical industry usually implement electropolished 316L stainless steel, which provides means:

• Good corrosion resistance
• Smooth surface inside the pipe
• Reduced ability of biofilms to develop on the surface of the pipes
• Better cleanability of the pipe system

Good quality welding of the pipes helps to decrease even more the presence of any imperfections in the liquid inside of the pipe to trap contaminants.

Validation Following Piping Modifications

Every time the changes are made in the pipe network, the manufacturers should find out if it is necessary to qualify again. The process of validation can include:

• Inspections conducted by engineers
• Boroscope inspection if necessary
• Review of the documentation regarding welding
• Verification of passivation
• Pressure test
• Verification of the flow
• Water treatment
• Control over the quality of water
• Microbiological testing

Validation makes sure that by making changes to the system, contamination is not increased.

Monitoring for Hidden Dead Legs

Systems that are designed properly still need to be reviewed regularly. There are signs of dead legs that can be identified:

• Repeated issues with microbes
• Local failures in endotoxin
• Delayed recovery of sanitization
• High total organic carbon (TOC)
• Continued contamination at certain sampling points
• Increases in microorganisms during certain times of the year

Trend analysis can often pick up potential problems before they become big quality issues.

Managing Dead Legs Through Change Control

It is important to follow the formal change control process for every piping alteration that takes place. The engineering assessment must consider:

• Possibility of formation of stagnation regions
• Impact on the movement of water
• Influence on the qualification status
• Necessary validation requirements
• Updated maintenance methodologies

In my opinion, involving Engineering, Validation, Production and Quality Assurance in the early stages of the design creates lower chances for dead legs to be generated during plant modifications.

Common Mistakes

Many engineering mistakes can lead to the presence of dead legs, including:

• Installation of extra pipes for future expansion with no clear purpose
• Disregard for the 3D rule when installing equipment
• Use of lengthy connecting branches for instruments
• Retention of unnecessary piping after removal of equipment
• Closing valves permanently without removing required pipes
• Lack of change control for pipes that are modified
• Failure to conduct necessary engineering evaluation of distribution pipes

Mistakes mentioned above could be avoided by better organization and management.

Engineering Recommendations for Implementation

The following engineering practices are recommended for organizations aiming to improve the design of pharmaceutical pipelines:

• Always review layout of pipes whenever there is a modification in the facility.
• Take out the unused pipes instead of leaving them behind.
• Keep the lengths of lateral connections used in sampling systems to a minimum.
• Ensure circulation is done continuously whenever possible.
• Use of hygienic fittings and valves.
• Conduct periodic engineering evaluation of the fluid distribution systems.
• Trend the results of microbiology to detect any local contamination.
• Make sure that piping evaluation forms a part of the yearly evaluation of pipe mapping.
• Re-qualify critical lines after modification.
• Educate engineering and maintenance personnel on hygienic design practices.

These practices will allow organizations to successfully address microbiological issues and ultimately streamline qualification and inspection.

When it comes to pharmaceutical pipe systems, dead legs continue to be among the sources of contamination that can be avoided. They may be viewed as insignificant engineering features, but in reality, dead legs can have a serious effect on microbial control, water quality and regulatory compliance. It is important to know that proper dead leg management starts at the design stage, continues with installation and validation and is an important part of long-term maintenance.

From my experience, the best pharmaceutical water systems are those systems designed with the principles of simplicity, continuous circulation and hygiene engineering modern concepts. By involving sound piping design, change control measures, regular inspections and etc., the manufacturers can significantly reduce microbiological risks, maintain their water systems in working order indefinitely, as well as ensure compliance with the requirements of GMP all over the world.

Regulatory References

1. FDA Guide to Inspections of High Purity Water Systems
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/high-purity-water-system-793

2. USP General Chapter <1231> Water for Pharmaceutical Purposes
https://www.usp.org

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