In pharmaceutical industry, water is the most critical utility used in manufacturing process and washing of equipment. It is used as the raw material, cleaning agent and a medium in formulation. Water should meet its quality standard because it comes in direct contact with the drug products.
Purified water grade water is used in non-parenteral pharmaceutical products. To ensure its quality, it must meet pharmacopeia specification and the entire water generation, storage and distribution system must be validated properly. This post will provide a detailed overview of purified water system validation including its procedure, stages, acceptance criteria and required documentation.
Purified water is generally used in preparation of nonsterile formulations, cleaning of equipment and containers, intermediate rinse in manufacturing and preparation of culture media used for microbiological analysis. Purification methods of purified water include reverse osmosis (RO) ,deionization (DI), distillation and ultrafiltration (UF).
1. Feed Water Treatment Unit: Feedwater is treated by filtration, softener and carbon filtration.
2. Purification Unit: Purification of water is done by reverse osmosis, ion exchange or distillation.
3. Storage Tank: Stored water is used for distribution to provide consistent supply. It maintains water quality and prevents contamination.
4. Distribution Loop: It circulates purified water to user points in manufacturing area through piping.
Each component of purified water system must be constructed from stainless steel (SS316L) or other non-reactive material with minimum dead legs and smooth internal surfaces to prevent microbial growth.
Conductivity: ≤ 1.3 µS/cm at 25°C
Total Organic Carbon (TOC): ≤ 500 ppb
Microbial count: ≤ 100 CFU/mL (as per USP)
Absence of pathogens such as E. coli, Salmonella, Pseudomonas and staphylococcus.
Additional analysis specification may be included such as pH, temperature and flow rate monitoring.
The demonstration should be done that the water system is producing the required quality and quantity of water while operated according to the relevant SOP.
Sampling is important in purified water system validation and routine monitoring. Sample must be collected from:
After validation of purified water system, routine monitoring frequency may be reduced to an established schedule defined by risk assessment.
Alert and action limits help detecting deviations before water quality fails.
Example for microbial control
Alert Limit: 50 CFU/mL
Action Limit: 100 CFU/mL
For conductivity and TOC, alert and action limits should be set on the basis of validating data and pharmacopeial criteria for these tests. If limit exceeds action limits, investigation should be conducted and take corrective action and possible revalidation.
B. Temperature Fluctuations: If water system runs at ambient temperature that supports microbial growth. Hot water circulation > 70° C minimizes the microbial growth in water system.
C. Sampling Errors: Simple from water system, storage tank and user points should be collected aseptically and in sterile containers. Improper sampling may increase microbial count during analysis.
D. Inadequate Design: Poor loop design with long pipelines and dead legs can cause stagnation of water. Proper design review at the time of design qualification (DQ) can prevent future issues.
From design and installation to performance qualification and continuous monitoring every step must be scientifically justified and well documented. A properly validated purified water system is the backbone of GMP compliance and it shows company’s commitment to product quality and patient safety.
Purified water grade water is used in non-parenteral pharmaceutical products. To ensure its quality, it must meet pharmacopeia specification and the entire water generation, storage and distribution system must be validated properly. This post will provide a detailed overview of purified water system validation including its procedure, stages, acceptance criteria and required documentation.
Understanding Purified Water
According to US Pharmacopeia, Purified Water is water that has been treated to remove chemical and microbial impurities. It must meet the standards for conductivity, TOC and microbial limits defined monograph Purified Water USP<1231>.Purified water is generally used in preparation of nonsterile formulations, cleaning of equipment and containers, intermediate rinse in manufacturing and preparation of culture media used for microbiological analysis. Purification methods of purified water include reverse osmosis (RO) ,deionization (DI), distillation and ultrafiltration (UF).
Purpose of Purified Water System Validation
Purified water system validation ensures that it consistently produces water that meets the specification under routine operating conditions. The objectives are to:- Verify design suitability of generation, storage and distribution systems.
- Confirm that microbial and chemical quality is controlled within specified limits.
- Demonstrates system reliability through consistent performance data.
- Establish operating, cleaning and sanitizing parameters.
Components of a Purified Water System
A pharmaceutical purified water system includes following components.1. Feed Water Treatment Unit: Feedwater is treated by filtration, softener and carbon filtration.
2. Purification Unit: Purification of water is done by reverse osmosis, ion exchange or distillation.
3. Storage Tank: Stored water is used for distribution to provide consistent supply. It maintains water quality and prevents contamination.
4. Distribution Loop: It circulates purified water to user points in manufacturing area through piping.
Each component of purified water system must be constructed from stainless steel (SS316L) or other non-reactive material with minimum dead legs and smooth internal surfaces to prevent microbial growth.
Key Parameters in Purified Water Quality
Purified water must meet pharmacopeia requirements in USP monograph <1231>. Key parameters are:Conductivity: ≤ 1.3 µS/cm at 25°C
Total Organic Carbon (TOC): ≤ 500 ppb
Microbial count: ≤ 100 CFU/mL (as per USP)
Absence of pathogens such as E. coli, Salmonella, Pseudomonas and staphylococcus.
Additional analysis specification may be included such as pH, temperature and flow rate monitoring.
Steps in Purified Water System Validation
Purified water system validation is performed in three major stages.A. Installation Qualification (IQ)
Installation qualification helps to verify that all components of the water system are installed according to design specification.Activities:
- Review design documents P&IDS and equipment drawings.
- Verify material certificates like SS316L for piping and gaskets etc.
- Check all welding records and surface finish for storage tank and distribution pipeline (Ra ≤ 0.6 µm).
- Verify all calibration of sensors, meters and conductivity probes for their proper working.
- Verify utilities and instruments used in the water system.
B. Operational Qualification (OQ)
Operational qualification helps to ensure that the water system operates according to the predefined standard parameters.Activities:
- Verify the alarm, interlocks and control sequences
- Test pumps, valves, sensors and sanitization cycles
- Check system for high and low flow conditions
- Check calibration and verify all online monitoring devices such as conductivity meter, TOC meter and temperature monitor.
- Establish operating ranges and alert/action limits for all testing parameters.
C. Performance Qualification (PQ)
Performance qualification is the main part purified water system validation. It helps to confirm that system is able to consistently produce purified water that meets established specification during extended operation. Performance qualification of purified water system is done in three phases.Phase I:
Water sampling and testing should be done for 2 to 4 weeks to monitor the water system. During this phase, water system should operate continuously without failure. Following things should be considered during this phase.- Sampling and testing of the raw water i.e. feed water should be done to monitor its quality.
- Sampling after each step should be done daily.
- Chemical and microbiological testing should be done as per the approved specification.
- Operating, cleaning, sanitizing and maintenance procedures should be finalized during this phase.
- Ensure the production of the required quantity of water.
- Alert and action limits should be verified after this phase.
Phase II:
A 2 to 4 week testing should be done again in phase II to monitor the water system intensively. Sampling frequency shall remain as per the previous phase. Water can be used for manufacturing during this phase of water validation.The demonstration should be done that the water system is producing the required quality and quantity of water while operated according to the relevant SOP.
Phase III:
After the successful completion of phase II, phase III runs for one year. We can use water for manufacturing during this phase.- The frequency of sampling and testing should be reduced in this phase after successful completion of phase I&II.
- Seasonal variations are observed in this phase of validation i.e. seasonal trending shall be done.
Sampling Plan
Sampling is important in purified water system validation and routine monitoring. Sample must be collected from: - Raw water inlet
- Post-treatment stages (softener, RO, UV, etc.)
- Purified water storage tank
- Return line and use points
| Parameter | Test Method | Frequency (During Validation) |
| Conductivity | Online/Offline | Daily |
| TOC | Online Analyzer or Offline | Daily |
| Microbial Count | Plate Count | Daily |
| Temperature | Continuous Monitoring | Continuous |
| pH | Offline | Daily |
After validation of purified water system, routine monitoring frequency may be reduced to an established schedule defined by risk assessment.
Sanitization and Maintenance
Microbial growth is a major concern in water systems. Sanitization of water tank and distribution system prevents microbial growth and formation of biofilm.Sanitization Methods
- Hot water sanitization at 80-85° C is most effective and widely used sanitization technique for water systems.
- Sanitization can be done by using chemicals like perchloric acid, hydrogen peroxide or ozone.
- UV sterilization is used for microbial control in storage tank and distribution loops.
Alert and Action Limits
Alert and action limits help detecting deviations before water quality fails. Example for microbial control
Alert Limit: 50 CFU/mL
Action Limit: 100 CFU/mL
For conductivity and TOC, alert and action limits should be set on the basis of validating data and pharmacopeial criteria for these tests. If limit exceeds action limits, investigation should be conducted and take corrective action and possible revalidation.
Documentation and Reports
Documentation of purified water system validation is important for regulatory compliance. Validation documentation includes following reports.- Design Qualification (DQ) Report
- IQ, OQ, PQ Protocols and Reports
- Calibration Certificates
- P&ID Diagrams and Flow Schematics
- Sampling and Test Records
- Deviation and CAPA Reports
- Final Validation Summary Report
Revalidation Requirements
Purified water system in pharmaceutical requires periodic revalidation to ensure consistent quality of water. Revalidation should be performed in following conditions.- Annually or biannual depending on the risk assessment.
- After major changes like equipment replacement, piping modification or software upgrade.
- After finding any microbial contamination in the system.
Common Challenges and Practical Tips
A. Biofilm Formation: Biofilm formation is the biggest problem of water systems in pharmaceuticals. Regular sanitization and maintaining turbulent flow having velocity > 1m/s help to prevent biofilm formation in water system and distribution line.B. Temperature Fluctuations: If water system runs at ambient temperature that supports microbial growth. Hot water circulation > 70° C minimizes the microbial growth in water system.
C. Sampling Errors: Simple from water system, storage tank and user points should be collected aseptically and in sterile containers. Improper sampling may increase microbial count during analysis.
D. Inadequate Design: Poor loop design with long pipelines and dead legs can cause stagnation of water. Proper design review at the time of design qualification (DQ) can prevent future issues.
Regulatory Expectations
Regulatory agencies require validation and control of water systems. Key guidance documents for validation and quality of water in pharmaceuticals include:- FDA Guide to Inspection of High Purity Water Systems
- WHO Technical Report Series No. 970, Annex 2 (2012)
- EU GMP Annex 1 and Annex 15
- USP <1231>: Water for Pharmaceutical Purposes
From design and installation to performance qualification and continuous monitoring every step must be scientifically justified and well documented. A properly validated purified water system is the backbone of GMP compliance and it shows company’s commitment to product quality and patient safety.
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Before starting phase-I, you should perform Challenging test for Auto dump valves and hold time study. During the phase-I validation drain time study also to be done.
ReplyDeleteWhat is the minimum velocity required in return loop of Purified water system as per USP?
ReplyDeleteActions to be taken after changing EDI of previously qualified water station?
ReplyDeletehii can anyone suggest how we can outsource purifies water and what document we have to prepare for it
ReplyDeletehii can anyone suggest how we can outsource purifies water and what document we have to prepare for it
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