ISPE Baseline<sup>&#xae;</sup> Guide: Volume 4 &#x2013; Water and Steam Systems (Third Edition) cover image

ISPE Baseline® Guide: Volume 4 – Water and Steam Systems (Third Edition)

Published:September 2019

Pages:280

The ISPE Baseline Guide® Water and Steam Systems (Third Edition) aims to assist with the design, construction, operation, and lifecycle management of new and existing water and steam systems. It is intended to help meet Good Manufacturing Practices (GMPs) and comply with regulations and related guidance.



This latest version describes new variations in the European Pharmacopoeia for the manufacture of Water for Injection by methods other than distillation. Additional changes include discussions on the global harmonization of water quality attributes, comprehensive pretreatment design, rapid microbial monitoring, ozone for ambient sanitization, and membrane technologies. This version is aligned with the ISPE Baseline® Guide: Commissioning and Qualification (Second Edition).

The Guide was written by a global team of critical utilities experts with a combined experience of more than 500 years. Much of the team responsible for the earlier versions of the Water and Steam Systems Baseline Guide returned to contribute to the revised Guide, providing continuity and longevity of vision to the Guide’s contents.

  • 1 Introduction
  • 1.1 Background
  • 1.2 Scope of this Guide
  • 1.3 Key Topics included in this Guide
  • 1.3.1 Specifying Water Quality and System Planning
  • 1.3.2 Project Management
  • 1.3.3 Pretreatment, Purification, and Final Treatment
  • 1.3.4 Pharmaceutical Steam
  • 1.3.5 Storage and Distribution, and Sanitization
  • 1.3.6 Laboratory Water
  • 1.3.7 Rouge
  • 1.3.8 Instrumentation and Control
  • 1.3.9 Commissioning and Qualification
  • 1.3.10 Microbiological Considerations
  • 1.4 Guide Structure
  • 2 Key Design Philosophies
  • 2.1 Introduction
  • 2.2 Pharmacopeial Water and Steam
  • 2.2.1 Purified Water and Water for Injection
  • 2.2.2 Pure Steam
  • 2.2.3 Compendial Testing Requirements
  • 2.2.4 Validated (Verified) Backup Instrumentation
  • 2.3 Specification of Pharmaceutical Water Quality – Establishing Acceptance Criteri
  • 2.4 Critical Quality Attributes and Critical Process Parameters
  • 2.5 GMP Compliance Issues
  • 2.6 Design Range versus Operating Range
  • 2.7 Process Analytical Technology
  • 3 Water Options and System Planning
  • 3.1 Introduction
  • 3.2 Incoming or Source Water Characteristics
  • 3.3 Water Quality Options
  • 3.3.1 Determining Water Quality Requirements
  • 3.3.2 Total Cost of Ownership
  • 3.4 System Planning
  • 3.4.1 Establish Water Quality
  • 3.4.2 Characterize Use Points
  • 3.4.3 Establish System Criteria
  • 3.4.4 Revisit Water Quality
  • 3.5 System Design
  • 4 Pretreatment Options
  • 4.1 Introduction
  • 4.2 Process Design of Pretreatment
  • 4.3 Feed Water and Pretreatment Testing
  • 4.4 Pretreatment Unit Operations
  • 4.4.1 Unit Operation Descriptions
  • 4.4.2 Typical Pretreatment Unit Operation Selection
  • 4.4.3 Problems in Final Treatment Caused by Improper Performance of Pretreatment
  • 4.5 Control of Fouling: Removal of Turbidity and Particulates
  • 4.5.1 Clarification
  • 4.5.2 Media Filtration
  • 4.5.3 Barrier Filtration
  • 4.6 Control of Scaling: Removal of Hardness and Metals
  • 4.6.1 Water Softening by Ion Exchange
  • 4.6.2 Demineralization/Deionization for Specific Contaminant Removal
  • 4.6.3 Antiscalant
  • 4.6.4 Electric Scale Control
  • 4.7 Control of Dissolved Gases – Contact Membrane Degasification
  • 4.8 Organic Material and Removal
  • 4.8.1 Introduction
  • 4.8.2 Organic Contaminants
  • 4.8.3 Removal of Organics
  • 4.9 System Design for Control of Microbial Growth
  • 4.9.1 Continuous Chlorine Disinfection
  • 4.9.2 Periodic Sanitization
  • 4.9.3 Continuous UV Light Disinfection
  • 4.10 Removal of Microbial-Control Agents
  • 4.10.1 Chlorine Removal
  • 4.10.2 Chloramine(s) Removal
  • 4.11 Changes in Anion Composition/Concentration
  • 4.11.1 pH and Carbon Dioxide
  • 4.12 Materials of Construction and Construction Practices
  • 4.13 Water Conservation
  • 5 Final Treatment Options for Production of Compendial Purified Water, Compendial Water for Injection, and Non-Compendial Waters
  • 5.1 Introduction
  • 5.2 Ion Exchange
  • 5.2.1 Description
  • 5.2.2 Application
  • 5.2.3 Pretreatment Requirements
  • 5.2.4 Cost Savings Factors
  • 5.2.5 Microbiological Concerns, Cleaning, and Sanitization
  • 5.2.6 Advantages and Disadvantages
  • 5.3 Reverse Osmosis
  • 5.3.1 Description, Materials, and Configurations
  • 5.3.2 Applications
  • 5.3.3 Pretreatment Requirements
  • 5.3.4 Design and Performance Characteristics
  • 5.3.5 Controls, Instrumentation, and Automation
  • 5.3.6 Reverse Osmosis Concentrate Reuse
  • 5.3.7 Cleaning and Sanitization
  • 5.4 Distillation
  • 5.4.1 Heat Exchanger Design
  • 5.4.2 Distillation Technology Pretreatment Requirements
  • 5.4.3 Basis for Economic Comparison
  • 5.4.4 Construction Materials
  • 5.4.5 Surface Finish
  • 5.4.6 Process and Systems Description
  • 5.5 Polishing and Removal of Specific Contaminants
  • 5.5.1 Ultrafiltration
  • 5.5.2 Microfiltration
  • 5.5.3 Ultraviolet Light Treatment
  • 5.6 Continuous Electrodeionization
  • 5.6.1 Description
  • 5.6.2 Application
  • 5.6.3 Limitations
  • 5.6.4 Pretreatment Requirements
  • 5.6.5 Performance
  • 5.6.6 Cost Saving Factors
  • 5.6.7 Advantages and Disadvantages
  • 5.6.8 Sanitization
  • 6 Systems for Production of Compendial Purified Water, Water for Injection, and Non-Compendial Water
  • 6.1 Introduction
  • 6.2 Purified Water
  • 6.3 Water for Injection
  • 6.3.1 Water for Injection System Selection
  • 6.3.2 Pharmacopeial Requirements
  • 6.4 Non-Compendial Waters
  • 7 Pharmaceutical Steam
  • 7.1 Introduction
  • 7.2 Common Steam Terms and Definitions
  • 7.2.1 Plant Steam
  • 7.2.2 Chemical Free Steam
  • 7.2.3 Process Steam
  • 7.2.4 Pure Steam
  • 7.3 Types of Pharmaceutical Steam
  • 7.3.1 Plant Steam
  • 7.3.2 Pure Steam
  • 7.4 Regulatory and Industry Guidance
  • 7.4.1 USP Guidelines
  • 7.4.2 European Guidelines
  • 7.4.3 Industry Guidance
  • 7.5 Background and Industry Practices
  • 7.5.1 Purity of Sterilizing Steam
  • 7.5.2 Steam for Humidification
  • 7.5.3 Industry Best Practices for the Production of Steam
  • 7.6 System Planning
  • 7.6.1 Steam Requirements
  • 7.6.2 System Design
  • 7.6.3 Point of Use Criteria
  • 7.6.4 Distribution System
  • 7.6.5 System Planning Reevaluation
  • 7.7 Steam Generation
  • 7.7.1 Plant Steam (Utility Steam)
  • 7.7.2 Pure Steam
  • 7.7.3 Pure Steam from Multiple-Effect Stills
  • 7.7.4 Feed Water Pretreatment
  • 7.8 Steam Attributes and Condensate Sampling
  • 7.8.1 Treatment of Plant Steam
  • 7.8.2 Pure Steam Purity Sampling
  • 7.8.3 Pure Steam “Quality” Sampling
  • 7.9 Materials of Construction
  • 7.9.1 Materials of Construction for Plant Steam Conditioning and Distribution
  • 7.9.2 Materials of Construction for Pure Steam Generators
  • 7.10 Distribution
  • 7.10.1 Line Sizing
  • 7.10.2 Point of Use Design
  • 7.10.3 Instrumentation
  • 7.10.4 Moisture Removal
  • 7.10.5 Condensate Removal
  • 7.10.6 Non-Condensable Gas Removal
  • 8 Storage and Distribution Systems
  • 8.1 Introduction
  • 8.2 Purpose
  • 8.3 System Components
  • 8.3.1 Tanks
  • 8.3.2 Pumps
  • 8.3.3 Vent Filters
  • 8.3.4 Heat Exchangers
  • 8.3.5 Piping/Tubing/Fittings
  • 8.3.6 Valves and Other System Components
  • 8.3.7 Instruments
  • 8.3.8 System Components Comparison
  • 8.4 Materials of Construction/Finishes
  • 8.4.1 Hygienic Tubing and Piping
  • 8.4.2 Materials Comparison
  • 8.4.3 Process/Product-Contact Surface Finishes
  • 8.4.4 Fabrication/Installation
  • 8.5 Microbial-Control Considerations
  • 8.5.1 Hygienic Design and Operational Controls
  • 8.5.2 Sanitization Designs
  • 8.5.3 System Sanitization
  • 8.5.4 Monitoring for Sanitization Effectiveness and Ongoing Microbial Control
  • 8.6 System Designs
  • 8.6.1 General Considerations
  • 8.6.2 Distribution Loop Velocity
  • 8.6.3 Storage and Distribution Decision Flowcharts
  • 8.6.4 Storage and Distribution Design Concepts
  • 8.6.5 Design Concepts
  • 8.7 Sampling at Point of Use and Dedicated Sample Valves
  • 9 Laboratory Water
  • 9.1 Introduction
  • 9.2 System Design Considerations
  • 9.3 Determining User Needs
  • 9.3.1 Quality Needs
  • 9.3.2 Quantity Needs
  • 9.3.3 Data Collection
  • 9.3.4 Monitoring Needs
  • 9.3.5 Compliance
  • 9.3.6 Laboratory Environmental Needs
  • 9.3.7 Costs
  • 9.4 Water Purification Technologies
  • 9.5 Laboratory Water Supply Options
  • 9.5.1 Water Generation System and Distribution Options
  • 9.5.2 Packaged Water
  • 9.5.3 Related Considerations
  • 9.6 Maintenance
  • 9.7 Instruments and Calibration
  • 9.8 Commissioning and Qualification
  • 9.8.1 Importance of Internal Laboratory Water Specification Standards
  • 9.8.2 Tailoring Laboratory Water System Qualification to Intended System Capability
  • 9.8.3 Special Validation Considerations for Small Laboratory Systems
  • 10 Rouge and Stainless Steel
  • 10.1 Introduction
  • 10.2 Regulatory Stance
  • 10.2.1 Food and Drug Administration
  • 10.2.2 USP
  • 10.2.3 European Pharmacopoeia
  • 10.3 Surface Conditions and Treatments
  • 10.3.1 Oxidation
  • 10.3.2 Corrosion
  • 10.3.3 Corrosion and its Variables
  • 10.3.4 Passivation
  • 10.3.5 Electropolishing
  • 10.4 Rouge Formation
  • 10.4.1 Rouge Composition and Classification
  • 10.4.2 Rouge and its Potential Contributors
  • 10.4.3 Material Composition
  • 10.4.4 Fabrication and Installation Methods
  • 10.4.5 Process Environment
  • 10.4.6 Maintenance and Repairs – Basic Approaches
  • 10.5 Rouge Detection (Methodology)
  • 10.5.1 Process Fluid Analyses for the Identification of Mobile Constituents
  • 10.5.2 Solid Surface Analyses for the Identification of Surface Layer Composition
  • 10.6 Risk Analysis – Rouge and Its Remediation
  • 10.7 Rouge Remediation (Methodology)
  • 10.7.1 Rouge Observation
  • 10.7.2 De-Rouging
  • 10.7.3 Routine Cleaning of Equipment
  • 10.8 Conclusions
  • 11 Control and Instrumentation
  • 11.1 Introduction
  • 11.2 Principles and Purpose of Measurements and Instrumentation
  • 11.3 General Instrumentation Requirements
  • 11.3.1 Instrument Selection and Installation
  • 11.3.2 Types of Measurements/Instrumentation
  • 11.3.3 Instrument Calibration
  • 11.4 Design Conditions versus Operating Range
  • 11.5 Responses to Measurements
  • 11.5.1 Signal Filtering
  • 11.5.2 How to Handle Instrumentation Spikes
  • 11.5.3 Machine Learning and Artificial Intelligence
  • 11.6 Control Systems
  • 11.6.1 Level of Automation
  • 11.6.2 Control System Software
  • 11.6.3 Control Hardware and Operation Interface
  • 12 Commissioning and Qualification
  • 12.1 Introduction
  • 12.2 Sampling for Water and Steam Systems
  • 12.2.1 Sampling for Water Systems
  • 12.2.2 Sampling for Steam Systems
  • 12.3 Acceptance Criteria
  • 12.3.1 Chemical Attributes
  • 12.3.2 Microbial Attributes
  • 12.4 Change Control and Maintaining the Qualified State of the System
  • 13 Microbiological Considerations for Pharmaceutical Water Systems
  • 13.1 Introduction
  • 13.2 The Microbial Growth Process in High Purity Water Systems
  • 13.2.1 Low Level Nutrient Behavior
  • 13.2.2 Planktonic Cell Characteristics
  • 13.2.3 Biofilm Initiation and Growth
  • 13.2.4 Biofilm Regulation and Behavior
  • 13.2.5 Biofilm Microbial Selectivity
  • 13.2.6 Microbial Diversity as a Function of Seasons and Water System Ageing
  • 13.3 Detrimental Effects of Biofilm
  • 13.3.1 Potential Impact of Surface Alteration
  • 13.3.2 Potential Impact in Water Used
  • 13.4 Microbial and Biofilm Control Strategies
  • 13.4.1 Design and Operational Parameters
  • 13.4.2 Effective Sanitization Concepts
  • 13.5 Sanitizer Choices
  • 13.5.1 Physical Sanitizers
  • 13.5.2 Chemical Oxidizing Sanitizers
  • 13.5.3 Other Chemical Sanitizers
  • 13.6 Assessing Microbial-Control Success
  • 13.6.1 Microbial Enumeration Issues
  • 13.6.2 Rapid Microbial Methods
  • 13.6.3 Use of Microbial Enumeration Data for Quality Control versus Process Control
  • 13.7 Functional Microbiological Pharmacopeial Compliance
  • 13.7.1 Microbial Enumeration Test Method
  • 13.7.2 Establishing Appropriate Action Levels for Process Control
  • 13.7.3 Using Action Levels from Pharmacopeia
  • 13.8 Microbial and Endotoxin Control in Pure Steam Systems
  • 14 Appendix 1 – References
  • 15 Appendix 2 – Glossary
  • 15.1 Acronyms and Abbreviations
  • 15.2 Definitions
  • Robert M. Augustine, Eli Lilly and Company, USA
  • Andrew Baird, Jacobs Engineering, USA
  • Anthony Bevilacqua, PhD, Mettler-Toledo Thornton Inc., USA
  • Nissan Cohen (Co-Lead), Biopharmaceutical Water Doc, USA
  • Robert C. Coleman, IHL Consulting Group, Inc., USA
  • Martin Emery, AveXis, USA
  • Jamie Evans, GC Biotherapeutics, Canada
  • Diana Fischer, Bausch & Lomb, Inc., USA
  • W. Roderick Freeman, Kite Pharma, USA
  • Michelle Gonzalez, Amgen Inc. (retired), USA
  • Brian Hagopian, CPIP, Clear Water Consulting Inc., USA
  • Ariel Kehati, Omrix, Johnson & Johnson, Israel
  • Joseph Manfredi, GMP Systems, Inc., USA
  • Brian McClellan, Aqua-Chem Inc., USA
  • Chris Peterson, AbbVie, USA
  • Brian Pochini, CPIP (Co-Lead), Sanofi, USA
  • Shlomo Sackstein, Biopuremax Ltd., Israel
  • Ian Shanahan, MECO Ireland Ltd., Ireland
  • T.C. Soli, PhD, Soli Pharma Solutions Inc., USA
  • Philip E. Sumner, Pfizer Global Engineering, USA
  • Roland Thoendel, Takeda, Austria
  • John Walker, VWS/Elga, United Kingdom
  • Paul Whitehead, PhD, VWS/Elga (retired), United Kingdom
  • Anders Widov, Wiphe AB, Sweden
  • Steve Wisniewski, CAI, USA
  • Gary Zoccolante (Co-Lead), Plymouth Rock Water Consultants, USA

The global biopharmaceutical industry and regulators are responding to the challenge of significantly improving the way drug development, manufacturing, documentation, and compliance is managed. New concepts are being developed and applied including science-based risk management approaches, focus on product and process understanding, and quality management systems.

Uncertainty about the requirements for regulatory compliance may discourage innovation and encourage reticence in technological advancement, preventing the cost-effective implementation, adoption, and lifecycle management with new and innovative technologies. ISPE Guides aim to describe current good practices that can help a company develop an effective and cost-efficient approach in compliance with existing regulations and relevant guidances.

This third version of the Baseline® Guide: Pharmaceutical Water and Steam Systems describes new variations in the European Pharmacopoeia for the manufacture of Water for Injection by methods other than distillation. Additional changes include discussions on the global harmonization of water quality attributes, comprehensive pretreatment design, rapid microbial monitoring, ozone for ambient sanitization, and membrane technologies.