ISPE Good Practice Guide: Commissioning and Qualification of Pharmaceutical Water and Steam Systems

Executive Summary

The following Executive Summary represents the draft of the ISPE Good Practice Guide on Commissioning and Qualification of Pharmaceutical Water and Steam Systems. The document is undergoing final edit, and therefore it is possible that parts of this summary will change as part of the editing process. This summary should be considered as only a general indicator of the topics covered in this Guide.

PREFACE
The ISPE Good Practice Guide: Commissioning and Qualification of Direct Impact Pharmaceutical Water and Steam Systems focuses on the engineering approaches and practices involved in providing cost effective manufacturing systems in a timely manner that meet intended purposes. Specifically, this Guide addresses the process of designing, constructing, commissioning, and qualifying water and steam systems regulated by international healthcare authorities.

This Guide is intended as a supplement to the ISPE Baseline?µ Guide on Commissioning and Qualification, and aims to apply the principles discussed in that Guide to direct impact water and steam systems.

This Guide aims to describe how the capital project management process, commissioning and qualification activities and on-going monitoring work together in the Validation Life Cycle for direct impact water and steam systems.

The importance of the risk assessment process used during design is crucial to ensuring quality product. The risk assessment process allows system designers and operators to gain “process understanding” of those project attributes, which affect water or steam quality.

The Validation Life Cycle described in this Guide typifies the lifetime operation of many direct impact systems. The importance of this Guide is to show how impact assessment used to determine non-critical and critical components, definition of critical quality attributes/critical process operating parameters and identification/appropriate execution of quality preserving project activities can be used in the Validation Life Cycle. Those project aspects, which impact water or steam quality over the life of a system, are identified and documented. These items are subject to both commissioning and qualification processes. Other project items, which have no impact or only indirect impact on the preservation of water or steam quality, are commissioned only. Appropriate system life operating and maintenance programs may be identified.

The real benefit of this Guide is to identify and demonstrate a project execution, commissioning and qualification approach for direct impact water and steam systems, which is based on “process understanding”. Preservation of the Quality of water or steam is accomplished. But, it is achieved without unnecessary project expense due to duplication of effort and the inclusion of non-value adding activities.

TABLE OF CONTENTS

1 Introduction
1.1 Overview
1.2 Purpose
1.3 Scope
1.4 Benefits
1.5 Objectives for this Guidance
1.6 Structure of this Guidance
1.7 Key Concepts
2 The Validation Life Cycle
2.1 Project Controls Definition
2.2 Design Phase Items
2.3 Commissioning and Qualification Plan
2.4 Procurement and Construction
2.5 Commissioning
2.6 Qualification
2.7 Project Completion and Document Delivery
2.8 Qualification Final Reports
2.9 On-Going Quality Monitoring
2.10 Periodic Performance Evaluation
2.11 Re-Qualification

TABLE OF APPENDICES

Appendix 1 Typical WFI Generation and Distribution System
Component Classification Example

Appendix 2 Process Water, Pure Steam and Process Steam

4.1 Non-Monographed Process Water
4.2 Steam

Appendix 3 System Classifications at Points of Use/Sub-Loop

Appendix 4 Typical Specifications for Direct Impact Water and Steam Systems

6.1 Introduction
6.2 User Requirement Specification (URS)
6.3 Functional Design Specification (FDS)
6.4 Detailed Design Specification (DDS)

Appendix 5 Glossary

7.1 Definitions
7.2 Acronyms and Abbreviations

Appendix 6 References

1 INTRODUCTION

1.1 OVERVIEW

Pharmaceutical water and steam are used as utilities and ingredients for Good Manufacturing Practice (GMP) processes, which produce drug products and drug substances (Active Pharmaceutical Ingredients – (APIs), where the starting molecule is isolated). In addition, water may be used as a final product, such as USP packaged waters, including:

Sterile Water for Injection
Sterile Water for Irrigation
Sterile Water for Inhalation
Sterile Purified Water

Because of the importance of water and steam to the manufacturing of products, cleaning, and laboratory activities in pharmaceutical or biopharmaceutical environments, systems that generate and distribute water and steam, which come in contact with product, product contact surfaces, or are used in the testing of product, are subject to commissioning and qualification practices.

Commissioning brings the water or steam system into operation, following the design and construction project phases.
Qualification verifies that direct impact systems (components and equipment) create product (water and steam) with a consistent and repeatable quality. Qualification also verifies that the critical systems have been included in a Validation Life Cycle.

This Guide, the ISPE Good Practice Guide: Commissioning and Qualification of Pharmaceutical Water and Steam Systems, provides an approach on how commissioning and qualification correspond s to the Validation Life Cycle model. In addition, the Guide aims to provide alternative approaches for the validation life cycle of water and steam systems that undergo commissioning and qualification.

1.2 PURPOSE

The purpose of this Guide is to provide an expanded understanding by providing information and examples of how the principles discussed in the ISPE Baseline?µ Guide on Commissioning and Qualification can be applied to direct impact water and steam systems. Ultimately, the goal is to increase understanding of direct impact water and steam systems in the pharmaceutical and biotechnology industries.

This Guide provides an alternative approach on how commissioning and qualification corresponds and relates to the Validation Life Cycle model.

The main emphasis of this Guide is on high purity water. But, discussion and information on other pharmaceutical water and steam is also provided. The USP (US Pharmacopeia), EP (European Pharmacopeia), and JP (Japanese Pharmacopeia) define different types of compendial high purity water, including:

Water for injection
Purified water
Highly purified water

The type of water used for a specific process is dependent on a technical evaluation of which water is appropriate for that process.

It is important to note that the different compendial pharmaceutical waters have different specifications. The commissioning and qualification practices to create and preserve water quality, in both generation systems and distribution systems, may vary according to the type of compendial water.

This Guide is intended as a supplement to the ISPE Baseline?µ Guide on Commissioning and Qualification, and aims to apply the principles discussed in that Guide to direct impact water and steam systems. Although this GPG makes reference to design issues concerning direct impact water and steam systems, this GPG should not be considered as an update to ISPE Baseline Guide, on Water and Steam Systems.

The intended audience for this guidance is both central and local in an organization and in the following disciplines:

Project Management
Engineering
Business Process Owners
Validation Team
Quality Assurance

Experience in the understanding and knowledge of the ISPE Baseline® Guide on Commissioning and Qualification is considered a prerequisite to the use of this Guide.

1.3 SCOPE

The scope of this Guide is to cover practices and activities associated with the commissioning and qualification of pharmaceutical water and steam systems. Discussion is centered on those items which directly affect water or steam product quality production, storage, and distribution.

Historically, the qualification model has been based on a comprehensive verification of the entire system installation and operation. The ISPE Baseline® Guide on Commissioning and Qualification and this supplemental Guide changes this focus to an evaluation of individual system components or process steps (group of components). The component or process step is studied in order to understand how it can affect the final product quality. This shift, from qualifying an entire system to gathering process knowledge and understanding, results in robust commissioning, and a quality centric qualification.

Qualification now focuses on those aspects that can directly affect water or steam quality in a direct impact system, while commissioning ensures that the system is fully operational, robust, and challenged from an engineering perspective (paying close attention to quality, business, and safety aspects); important concepts include:

Significance of commissioning and qualification in the Validation Life Cycle
Boundary limits of the direct impact water or steam system
Typical indirect and no impact systems associated with direct impact water or steam systems
Impact assessment of process steps and/or components
Critical and non-critical components of a process step
Critical quality attributes and critical process operating parameters
Project scope activities associated with qualification of water and steam systems
User Requirement Specification (URS), Functional Design Specification (FDS), and Detailed Design Specification (DDS)

This Guide addresses compliance with national and international regulations and guidelines for water and steam systems, and considers:

New systems and extensions to existing ones
Existing validated systems to be maintained

A wide range of healthcare requirements related to water and steam system compliance have been taken into account, including:

GMP (Good Manufacturing Practice)
ICHQ7A

The following regulations and guidelines have been specifically considered in drawing up this document:

US Federal Food and Drug Administration (FDA) regulations and Compliance Policy Guides
Relevant sections of EU GMPs, e.g., Annexes.
USP
EP
JP

1.4 BENEFITS

This Guide provides an alternative approach to commissioning and qualification practices and activities associated with direct impact water and steam systems. Benefits and attributes of this approach include:

Water and steam Quality builders/preservation items are located and identified:

- Listing of URS, FDS, and DDS by way of the V-model. They are tested in PQ, OQ, and IQ, respectively.
- Component assessment will define non-critical and critical components. Focus efforts on “critical” items for product quality maintenance – save money and effort.
- Critical quality attributes measure and monitor quality, while critical process operating parameters are established to preserve quality.
- IQ and OQ items are executed to preserve quality, while PQ is first indicator of quality maintenance.

“risk-based” approach to the validation of direct impact systems is employed as compared to “qualify everything”.
project controls (e.g., change controls, scheduling, approvals, etc.) based on “risk assessment” are embedded into the project delivery process.
IQ/OQ/PQ builds on the results from commissioning.
Only “Quality Important/Influencing” aspects attributes of a project are identified and “qualified”. Other items are “commissioned only” or handled by GEP.
This Validation approach may be more logical and cost effective as compared with other system validation approaches

This Guide can be used by industry professionals involved in the design, construction, commissioning, and qualification of new or newly renovated water and steam systems, which are regulated by the international healthcare authorities.

Other benefits of a quality centric qualification approach to include:

Efficient and cost effective use of resource and minimum overlap in validation centrally and locally
Effective focus on objectives and deliverables through the entire life cycle
Minimal duplication and overlap in documentation
Efficient handling of audits, inspections and assessments

1.5 OBJECTIVES FOR THIS GUIDANCE

This Guide has eight principle objectives:

Provide understanding on the importance of C & Q and how it fits into the Validation Life Cycle
Explain and demonstrate the impact assessment process for water and steam systems and what are typical system boundaries and non-critical and critical components
Discuss critical parameters - critical quality attributes and critical process operating parameters
Discuss business essential parameters – key business considerations for design, construction, commissioning, and qualification. Some of these relate to non-product quality items like EHS considerations, IT, or other “commissioning only” project scope items.
Provide identification of and discussion on project scope activities included in the qualification of water and steam systems
Provide information on the User Requirement Specification (URS), Functional Design Specification (FDS) and Detailed Design Specification (DDS)
Ultimately, provide an alternative approach, based and “risk assessment” principles and “process understanding” for the commissioning and qualification of direct impact water and steam systems.
Demonstrate the theory by providing examples.

This Guide does not completely revisit subject matter covered by the ISPE Baseline® Guide on Commissioning and Qualification (or that of the ISPE Baseline® Guide on Water and Steam Systems). Some concepts are mentioned and discussed, based on providing clarification for the water and steam commissioning and qualification model. This Guide is not intended to provide complete guidance on the Validation Life Cycle of water and steam systems.

1.6 STRUCTURE OF THIS GUIDANCE

The ISPE Guide: Commissioning and Qualification of Pharmaceutical Water and Steam Systems is in three main sections:

1) Introduction
2) Validation Life Cycle
3) Appendices

The main section of the Guide, the validation life cycle is focused in on high purity water systems.

The appendices provide additional material and guidance in order to assist in the identification of regulations, issues and topics that should be considerd.

1.7 KEY CONCEPTS

The key concepts and principles of a global implementation are:

Validation Life Cycle
Critical Component
Non-Critical Component
Impact Assessment

2 THE VALIDATION LIFE CYCLE

Direct impact water and steam systems usually start off as capital construction projects. In order to understand the Validation Life Cycle concept, it is necessary to first understand the steps in the life cycle, along with the interdependencies and interrelationships between those life cycle components.

This Guide attempts to merge the capital project management process, the commissioning and qualification process, and the on-going operation into the Validation Life Cycle concept. The primary focus is on commissioning and qualification, with discussion of the major elements:

Project Initiation and Conceptual Engineering
Design – Preliminary and Detailed
Procurement and Construction
Commissioning and Qualification
On-Going Operations
Re-Qualification

Further details of these elements are addressed in this Chapter.

APPENDIX
The appendix sections are intended to provide examples of documents such as Component Classifications, Functional Design Specifications, and User Requirement Specifications, etc. The sample documents show the type of information typically included and tasks to be conducted. These examples are not intended to be absolute guidelines that must be explicitly followed. Equipment, processes, temperatures, flows, pressures, and other parameters are examples of current methods but several equally effective alternate methods and processes are also in current operation.

The thought process is the key objective. Consideration of sanitization temperature, minimum deadleg, minimum ozone level or other possible key operating parameters should be noted. The values that are shown are typically effective, but other values may also be effective.

APPENDIX 1: TYPICAL WFI GENERATION AND DISTRIBUTION SYSTEM COMPONENT CLASSIFICATION EXAMPLE

This chapter provides an example of the component impact assessment applied to a usual direct impact WFI generation and distribution system. In this system, typical public utility feed water, treated with chloramines as disinfectant, is fed to a WFI generation treatment train of equipment. The resultant WFI quality water is then fed to a WFI storage and distribution network.

Based on the results of the component impact assessment process applied to the entire direct impact system, it is logical to reason that the early potable water pre-treatment steps (which include the multi-media filter, initial duplex water softener, break tank, carbon filter and UV light) are made-up of process steps and components that are non-critical. However, the final two generation process steps (which include the trailing duplex softener for ammonium removal and WFI still) and distribution loop including many components within these sub-systems are critical to generation and distribution of WFI to points of use. However, as can be seen, even the final general steps and distribution loop contains non-critical components.

All components within the direct impact system (including pre-treatment and final treatment generation and distribution) are to be commissioned. But, only the critical components, which were deemed critical by the impact assessment, will go on to be qualified. These process steps include the trailing softener and WFI still and entire distribution loop.

APPENDIX 2: PROCESS WATER, PURE STEAM AND PROCESS STEAM

The main text of this Guide concentrates on high purity water. The purpose of this section is to give relevant information regarding qualification items to be included in the Validation Life Cycle for process water, pure steam and process steam direct impact systems. Specifically, this section is meant to provide guidance (via giving examples - not hard and fast generally applicable requirements) on those items, which may be included in these systems to establish or maintain quality of these products. A discussion on those items is provided.

APPENDIX 3: SYSTEM CLASSIFICATIONS AT POINTS OF USE/SUB-LOOP

Section 3 of this Guide provides examples of system classifications for a typical high purity water systems. The section provides examples of typical use point configurations used in high purity pharmaceutical water systems. These examples indicate system boundaries between various direct and indirect impact systems. This section is not meant to be a design guide on points of use or sub-loop design. But, the boundaries of systems are shown for classification information purposes.

APPENDIX 4: TYPICAL SPECIFICATIONS FOR DIRECT IMPACT WATER AND STEAM SYSTEMS

The qualification items listed for direct impact systems are described in the URS, FDS, and DDS. In this section, typical elements for inclusion in these specifications are given. These typical elements are given for demonstration purposes rather than as "absolutes" to include as-is. Also, brief descriptions of each specification are given.

Normally, these specifications are developed near the beginning of a project. As with other project documentation, it is important to achieve an adequate level of specification definition. Common pitfalls in the creation of these specifications include:

Not specifying
Over specifying
Under specifying
Specifying in multiple locations

One should be careful to avoid pitfalls or combinations of these pitfalls within these specifications. This section also provides some examples of the above pitfalls with application to pharmaceutical water and steam systems.

APPENDIX 5: GLOSSARY AND ACRONYMS

A glossary and list of acronyms relevant to this Guide.

APPENDIX 6: REFERENCES

A list of references relevant to this Guide.