What is Purified Water?

Purified Water (PW) hasWaterrgone a treatment process to remove impurities, contaminants, and other unwanted substances. It meets stringent quality requirements and standards in various industries, especially in pharmaceutical and biologics manufacturing. The primary goal is to achieve high purity suitable for drug formulation, production, and equipment cleaning.

Why is Purified Water Required in the Pharma/Biologics Industry?

• Product Safety: Water is often used as an ingredient in pharmaceutical formulations. Impurities in water can contaminate products, affect their quality, or cause adverse health effects.
• Sterility: In biologics manufacturing, microorganisms or pyrogens can compromise the efficacy and safety of biopharmaceuticals, especially injectables.
• Cleaning & Sterilization: Purified water is essential for cleaning equipment and sterilizing manufacturing lines to ensure no contamination or residue is left behind.
• Regulatory Compliance: Pharmaceutical manufacturing requires strict adherence to regulatory standards for water quality to avoid contamination risks and ensure drug safety.

How is Purified Water Generated in the Pharma Setup?

The generation of Purified Water in pharmaceutical facilities involves several steps using various technologies, often in combination, to meet stringent quality specifications.

Common Water Purification Technologies:

• Pre-treatment: Raw water is first treated with pre-treatment, including filtration, to remove large particles, sediment, and organic matter.
• Reverse Osmosis (RO) removes dissolved salts, organic molecules, and most bacteria and pyrogens by passing water through a Wateri-permeable membrane.
• Deionization: Utilizes ion-exchange resins to remove ionized minerals and salts.
• Distillation involves boiling water and condensing the steam to separate contaminants and ensure high purity. It is used when high purity is required (e.g., for Water for Injection).
• Ultraviolet (UV) Sterilization: UV light can kill bacteria and other microorganisms.
• Filtration (Ultra-filtration and Nanofiltration): Further refines the water to remove water residual particles, pyrogens, and microorganisms.

Purified Water Specifications (General Guidelines)

According to various pharmacopeias (e.g., USP, Ph. Eur., JP), Purified Water must meet the following criteria:

• Conductivity: ≤1.3 μS/cm at 25°C (United States Pharmacopeia – USP)
• Total Organic Carbon (TOC): ≤500 ppb
• Microbial Limits: Typically <100 CFU/mL, depending on the intended use
• Endotoxin Levels: Must be controlled, especially for biopharmaceuticals, where low endotoxin content is crucial.

The limits between regulatory authorities and pharmacopeias may vary slightly, but the above represent typical industry standards.

Step-by-Step Qualification of Purified Water System

• Design Qualification (DQ): Ensure that the system is designed according to GMP guidelines and meets the water quality requirements based on the product and processes.
• Installation Qualification (IQ): Verify that the water system has been installed correctly, follows the design specifications, and that all components, equipment, and instruments are installed properly.
• Operational Qualification (OQ): Confirm that the water system operates within specified parameters and produces water of watered quality. This includes testing all system functions, such as pumps, filters, and control systems.
• Performance Qualification (PQ): Demonstrate that the system consistently produces purified water that meets Water’s required specifications under actual operational conditions over an extended period.
• Monitoring & Maintenance: Regular testing and monitoring for conductivity, TOC, microbial counts, and endotoxins to ensure ongoing compliance.

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Regulatory Requirements

Purified Water systems are subject to stringent regulatory oversight to ensure compliance with pharmaceutical and biologics standards. Key regulatory guidelines include:

• FDA (Food and Drug Administration): In the United States, PW must comply with Current Good Manufacturing Practices (cGMP) regulations under 21 CFR Part 211, which outline requirements for the production, testing, and maintenance of water systems. FDA Warning Letters often cite deficiencies in water system validation and maintenance.
• WHO (World Health Organization): WHO’s Good Manufacturing Practices for Pharmaceutical Products provide guidelines for water purification, storage, and distribution, emphasizing microbiological control and endotoxin levels.
• EU-GMP (European Union): The EU-GMP guidelines (Annex 1) specify requirements for water systems. They emphasize sterile product manufacturing, with a particular focus on microbiological purity and endotoxins.
• Health Canada: Health Canada’s GMP Guidelines (GUI-0001) outline similar requirements for water purity, including the validation, maintenance, and monitoring of water systems in the pharmaceutical industry.
• ICH (International Council for Harmonisation): The ICH Q7A Guideline for Good Manufacturing Practice for Active Pharmaceutical Ingredients also addresses water quality requirements, especially for non-sterile and sterile production.

Regulatory Citations and Warning Letters

Several regulatory agencies issue Warning Letters for non-compliance with water system validation, testing, and maintenance requirements. Common deficiencies include:

• Microbial Contamination: Failure to maintain water systems properly, leading to microbial growth.
• Poor System Validation: Inadequate validation and qualification of the water purification system.
• Endotoxin Levels: High levels of endotoxins detected in purified water.
• ImpropeWateritoring: Lack of continuous or periodic water quality monitoring, including microbial counts and TOC.
• Examples:
  FDA Warning Letter: In one case, a pharmaceutical company was cited for failing to validate their water purification system adequately. The system had a history of microbial contamination, yet corrective actions were insufficient.
• EU GMP Non-Compliance: A biologics facility in Europe was found non-compliant due to inadequate control of its purified water system, which led to endotoxin contamination in its final product.

Benefits of Purified Water in Pharma/Biologics Manufacturing

• Consistency in Quality: Ensures that products are made using water-free contaminants, leading to safe and effective pharmaceuticals.
• Regulatory Compliance: Avoids costly penalties, warning letters, and product recalls due to non-compliance.
• Operational Efficiency: Reduces the risk of equipment malfunction or contamination, leading to fewer production halts and reworks.
• Product Safety: Prevents adverse patient reactions by reducing impurities, endotoxins, and microbial contamination in drugs.

Conclusion

Purified Water is a more significant component in pharmaceutical and biologics manufacturing. Its generation requires carefully validated systems to meet regulatory requirements from agencies like the FDA, WHO, EU GMP, and Health Canada. Regular monitoring and proper water system qualification are essential to ensure product quality and safety.

Contact Us

GxP Cellators is a reputable contract services organization that provides comprehensive Good x Practices (GxP) services in Manufacturing, Laboratory, Distribution, Engineering, and Clinical practices to various industries, including Biopharmaceuticals (Biologics), Pharmaceuticals, and Medical Devicessadx. We closely collaborate with our esteemed life sciences clients to help them establish greenfield or brownfield projects, guiding them from the project stage to regulatory approval for their GxP sites.

Our team consists of highly qualified experts specializing in Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP), Good Clinical Practices (GCP), Good Distribution Practices (GDP), Cleanroom Operations, and Engineering Operations. Our Subject Matter Experts (SMEs) are extensively trained and possess the essential knowledge and skills to excel in their respective domains.

We also have a team of highly skilled validation specialists with expertise in equipment and utilities qualifications, computerized system validations (CSV), thermal validations, clean utilities validation, and cleanroom validations. Please get in touch with us at for assistance qualifying your facilities or site equipment.