WHO Good Manufacturing Practices: Water For Pharmaceutical Use
WHO Good Manufacturing Practices: Water For Pharmaceutical Use
This document provides guidance on the specifications, production, storage and distribution of water for pharmaceutical use. It covers different grades of water quality, water purification systems, storage and distribution, operational considerations, and inspection of water systems. The guidance is intended to be supplementary to general GMP guidelines for pharmaceutical products and applies to bulk water production in manufacturing facilities.
by GxP Cellators Consultants Ltd.
Introduction and Scope
This document provides guidance on water for pharmaceutical use (WPU), including:
Specifications for different grades of water
Guidance on which quality to use for specific applications
Good manufacturing practices for design, installation and operation of pharmaceutical water systems
The scope includes bulk water production but excludes water for administration to patients in formulated state or small quantities used in pharmacies. It is intended to supplement general GMP guidelines for pharmaceutical products.
Background on Water Requirements and Uses
Water is the most widely used substance in pharmaceutical production. Its unique properties allow it to dissolve, absorb, adsorb or suspend many compounds. This can introduce contaminants that may be hazardous or react with product substances. Therefore, control of water quality throughout production, storage and distribution is critical, especially for microbiological and chemical quality. Unlike other ingredients, water is usually drawn on demand and not batch released. Microbiological testing often lags behind use. Different grades of water are required depending on the product and route of administration.
General Principles for Pharmaceutical Water Systems
Design and Validation
Systems should be designed, installed, commissioned, qualified and maintained to ensure reliable production of appropriate quality water. The water production process must be validated.
Quality Assurance
Use of systems after validation or maintenance should be approved by QA using change control.
Capacity
System capacity should meet average and peak demand. Future demands should be considered in design.
Monitoring
Water sources and treated water should be monitored regularly. Performance of purification, storage and distribution systems should be monitored.
Water Quality Specifications
This section covers requirements for water processed, stored and distributed in bulk form. It does not cover specifications for water in dosage forms.
Drinking Water
Drinking water should be supplied under continuous positive pressure in a plumbing system free of defects that could lead to contamination. It may require limited treatment of water from natural sources. Quality should comply with relevant regulations.
Bulk Purified Water
Bulk purified water (BPW) should be prepared from drinking water as a minimum feed-water quality. It should meet relevant pharmacopoeial specifications for chemical and microbiological purity.
Bulk Highly Purified Water
Bulk highly purified water (BHPW) should be prepared from drinking water as a minimum feed-water quality. It must meet the same quality standard as water for injections (WFI), including endotoxin limits, but may use different production methods. Current methods include double-pass reverse osmosis coupled with other suitable techniques.
Bulk Water for Injections
Bulk water for injections (BWFI) should be prepared from drinking water or purified water as feed. It is the highest quality pharmacopoeial WPU. Some pharmacopoeias only allow distillation as the final purification step. BWFI should meet relevant chemical, microbiological and endotoxin specifications.
Application of Water Types to Processes and Dosage Forms
Product licensing authorities specify the minimum grade of WPU required for different dosage forms or manufacturing stages. The grade used should consider:
Nature and intended use of the product
Stage in the manufacturing process
Subsequent processing steps
BHPW can be used when high quality water is needed but without the production method constraints of BWFI. BWFI should be used for injectable products, final equipment rinses, and when no subsequent depyrogenization is applied.
Water Purification Systems: General Considerations
When selecting and designing a water purification system, the following should be considered:
Final water quality specification
Required quantity of water
Feed-water quality and variability
Pretreatment requirements
Purification steps needed
Sanitization strategy
Water treatment equipment reliability and robustness
System yield/efficiency
Ability to adequately maintain the system
Total lifecycle costs
Water Purification Systems: Equipment Specifications
Specifications for water purification equipment, storage and distribution systems should consider:
Design Factors
Plant room location
Temperature extremes
Risk of contamination from leachates
Adsorptive contact materials
Hygienic/sanitary design
Operational Factors
Corrosion resistance
Freedom from leakage
System capacity and output
Sanitization strategy
Instrumentation and sampling points
Production of Drinking Water
Drinking water is derived from a raw water source such as a well, river or reservoir. There are no prescribed methods for treatment, but typical processes may include:
Desalinization
Filtration
Softening
Disinfection or sanitization
Iron removal
Precipitation
Reduction of specific inorganic/organic materials
The quality should be monitored routinely to account for environmental, seasonal or supply changes. Additional testing should be done if there are significant changes to the source, treatment, or system configuration.
Production of Purified Water
Any appropriate qualified purification technique or sequence may be used to prepare purified water (PW). Common methods include:
Ion exchange
Reverse osmosis
Ultrafiltration
Electro-deionization
Distillation
Ambient-temperature systems are susceptible to microbiological contamination. Mechanisms for microbiological control and sanitization must be considered. The sanitization method for each purification stage should be defined and verified.
Production of Highly Purified Water
Highly purified water (HPW) can be produced by:
Double-pass reverse osmosis coupled with ultrafiltration
Other appropriate qualified purification techniques
The guidance provided for purified water production is equally applicable to HPW.
Production of Water for Injection
Some pharmacopoeias prescribe or limit the final purification stage for producing bulk water for injections (BWFI).
Distillation is the preferred technique, considered more robust based on phase change and high-temperature operation. The system configuration guidance for purified water also applies to water for injection.
Water Storage and Distribution Systems: General Principles
The storage and distribution system is a key part of the overall water system and should be fully integrated with the purification components. It should be designed to prevent microbial proliferation and recontamination of purified water. Key considerations include:
Materials that come into contact with water
Sanitization and bioburden control
Storage vessel requirements
Distribution pipework requirements
The system should be subject to a combination of online and offline monitoring to ensure the appropriate water specification is maintained.
Materials for Water Systems
Materials that come into contact with pharmaceutical water should be selected to satisfy the following objectives:
Compatibility
Materials should be compatible with the full range of operating temperatures and potential chemicals.
Prevention of leaching
Materials should be non-leaching at all working and sanitization temperatures.
Corrosion resistance
Materials must be appropriate to prevent system failure and water contamination. Stainless steel grade 316L or higher is commonly used.
Smooth internal finish
Surfaces should have an average roughness of not greater than 0.8 micrometers to avoid sites for contamination or corrosion.
System Sanitization and Bioburden Control
Water treatment equipment, storage and distribution systems should have features to control microbial proliferation during normal use, as well as sanitization techniques. Considerations include:
Operating at elevated temperatures (e.g. > 65°C) to inhibit microbial growth
Periodic hot water sanitization (> 70°C)
Use of ultraviolet radiation
Ozone or other chemical sanitization (with verification of removal)
Maintenance of turbulent flow in pipework
Minimization of dead legs in piping
Use of sanitary components like diaphragm valves
Storage Vessel Requirements
The water storage vessel serves important functions in the system. Key design considerations include:
Capacity
Buffer between generation rate and variable demand
Allow continuous operation of treatment equipment
Provide short-term reserve capacity
Contamination Control
Spray ball devices to wet surfaces
Nozzle configuration to avoid dead zones
Bacteria-retentive vent filters
Sanitary design of pressure relief valves
Water Distribution Pipework Requirements
Key requirements for water distribution pipework include:
Use of a continuously circulating pipework loop
Avoidance of dead legs
Sloped and fully drainable design for steam-sanitized systems
Use of sanitary tri-clamp fittings and diaphragm valves
Insulation from adjacent hot pipes for ambient systems
Provision for sampling at defined points
Filtration should not usually be used in distribution loops or at user points to control biocontamination, as filters can conceal system contamination.
Operational Considerations: Start-Up and Commissioning
Successful commissioning and qualification is essential before validation of water systems. The commissioning work should include:
Setting to work
System set-up
Controls and loop tuning
Recording of all system performance parameters
If commissioning data will be used within validation, the quality of work and documentation must meet validation plan requirements.
Qualification of Water Systems
Water purification, storage and distribution systems are considered direct impact, quality-critical systems that should be qualified. Qualification should follow the validation convention of:
Design qualification (DQ)
Installation qualification (IQ)
Operational qualification (OQ)
Performance qualification (PQ)
A three-phase PQ approach is recommended to demonstrate consistent and reliable performance over an extended period:
Two weeks of intensive monitoring1.
Two weeks of further monitoring with refined SOPs2.
One year of routine monitoring3.
Continuous System Monitoring
After completion of qualification, a routine monitoring plan should be established based on the results of Phase 3.
Monitoring should include: Online Monitoring
Flow
Pressure
Temperature
Conductivity
Total organic carbon
Sample Testing
Physical attributes
Chemical attributes
Microbiological attributes
Samples should be taken from points of use or dedicated sample points. Monitoring data should be subject to trend analysis with established alert and action levels.
Maintenance of Water Systems
Water purification systems should be maintained according to a controlled, documented programme that includes:
Defined frequency for system elements
Calibration programme
SOPs for specific tasks
Control of approved spare parts
Clear maintenance plan and instructions
Review and approval process for returning systems to use
Recording and review of problems and faults
System Reviews
Water purification systems should be reviewed at appropriate regular intervals by a team comprising representatives from:
Engineering
Quality Assurance
Microbiology
Operations
Maintenance
The review should consider changes, performance, reliability, quality trends, failures, investigations, out-ofspecification results, and the status of current SOPs and documentation.
Inspection of Water Systems
Water purification systems are likely to be subject to regulatory inspection. Users should consider conducting routine audits and self-inspections. Key aspects of inspection include:
Review of current system drawings and piping diagrams
Examination of sampling and monitoring plans
Review of training programmes for sampling and testing
Evaluation of monitoring results and trends
Inspection of maintenance, failure, and repair logs
Verification of instrument calibration
Physical inspection of system status and condition
Water Quality Specifications: Drinking Water
Drinking water used in pharmaceutical manufacturing should meet the following criteria:
Supplied under continuous positive pressure
Plumbing system free of defects that could lead to contamination
May require limited treatment of water from natural sources
Quality should comply with relevant regulations (e.g. WHO guidelines, national standards)
Pharmaceutical manufacturer is responsible for ensuring source water meets drinking water requirements
Periodic testing should be carried out by the water user to confirm quality
Water Quality Specifications: Bulk Purified Water
Bulk purified water (BPW) should meet the following specifications:
Prepared from drinking water as minimum feed-water quality
Meet relevant pharmacopoeial specifications for chemical and microbiological purity
Have appropriate action and alert limits established
Be protected from recontamination and microbial proliferation
BPW may be prepared by methods such as:
Reverse osmosis (RO)
RO/electro-deionization (EDI)
Vapor compression (VC)
Water Quality Specifications: Bulk Highly Purified
Water
Bulk highly purified water (BHPW) has the following characteristics:
Prepared from drinking water as minimum feed-water quality
Meets same quality standard as water for injections, including endotoxin limits
May use different production methods than water for injections
Typically produced by double-pass RO coupled with other techniques (e.g. ultrafiltration, deionization)
Should be protected from recontamination and microbial proliferation
Has identical microbiological requirements to water for injections
Water Quality Specifications: Bulk Water for Injections
Bulk water for injections (BWFI) is the highest quality of pharmacopoeial water for pharmaceutical use. Key specifications include:
Prepared from drinking water or purified water as minimum feed-water
Some pharmacopoeias only allow distillation as final purification step
Must meet relevant pharmacopoeial specifications for chemical and microbiological purity
Must meet endotoxin limits
Should be protected from recontamination and microbial proliferation
Application of Water Types to Manufacturing Processes
The choice of water quality for different manufacturing processes should consider:
Nature and intended use of the intermediate or finished product
Stage in the manufacturing process where water is used
BHPW: When high quality water is needed without WFI production constraints
BWFI: For injectable products, final equipment rinses, and when no subsequent depyrogenization is applied
WFI-quality steam: For direct contact with injectable products or preparation equipment
Continuous System Monitoring and Trend Analysis
Effective monitoring of water systems involves:
Online Monitoring
Conductivity
Total organic carbon (TOC)
Flow rates
Pressures
Temperatures
Offline Testing
Microbial counts
Endotoxin levels
Chemical analyses
Data should be subject to trend analysis, typically within 2 sigma control limits. Alert and action levels should be established based on historical data. Trends towards exceeding alert limits should trigger thorough investigation and corrective actions.
Conclusion and Key Takeaways
Proper design, operation, and monitoring of water systems is critical for pharmaceutical manufacturing. Key points include:
Different grades of water (PW, HPW, WFI) have specific quality requirements and applications
Water systems must be designed to prevent contamination and microbial growth
Qualification should follow a three-phase approach to demonstrate consistent performance
Continuous monitoring and trend analysis are essential for maintaining water quality
Regular system reviews and inspections help ensure ongoing compliance
By following these good manufacturing practices for water systems, pharmaceutical manufacturers can ensure the consistent production of safe, high-quality water for use in their products.
