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October 27, 2000
Dear Colleagues:
The Food and Drug Administration (FDA) has been pleased to cooperate with the
International Society for Pharmaceutical Engineering in the development of the Baseline®
Pharmaceutical Engineering Guide for Water and Steam Systems. We appreciate the
coopertive efforts and the dedicated intensive work of the engineers who voluntarily
initiated the development of this Guide. This is an excellent example of how through
public and private cooperative efforts, both industry and consumers can benefit.
This document covers engineering aspects of design, construction and operation of new
water and steam systems. It expands on existing FDA guidance on water systems.
This Guide is solely created and owned by ISPE. It is not an FDA regulation, standard or
guidance document and water and steam systems built in conformance with this Guide
may or may not meet FDA requirements. FDA has provided comments for ISPE's
consideration in preparing this Guide. It should be helpful to the engineering profession
and the industry for the design, construction and operation of new water and steam
systems
FDA is pleased with the development of this document and we look forward to a continued working relationship as future Baseline® Pharmaceutical Engineering Guides are
developed.
Sincerely,
This Document is licensed to
Janet Woodcock, M.D.
Director, Center for Drug Evaluation and Research
Mr. Shlomo Sackstein
Herzlia,
Dennis
Baker
Associate Commissioner for Regulatory Affairs
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WATER AND STEAM SYSTEMS
ISPE PHARMACEUTICAL ENGINEERING GUIDE
FOREWORD
For many years, the pharmaceutical industry has experienced increases in the cost of new facilities. These
increases in cost have been driven in part by uncertainty about the requirements for regulatory compliance.
Some significant areas of concern are validation, particularly related to automation systems, and the trend to
validate back to source utilities. The absence of a consistent and widely accepted interpretation of some
regulatory requirements has led to one-upmanship. This practice of building increasingly technically advanced facilities has led to increased cost, longer lead times and, in some cases, delays in bringing new
products to market.
In May 1994, engineering representatives from the pharmaceutical industry engaged in a discussion with the
International Society for Pharmaceutical Engineering (ISPE) and the Food and Drug Administration (FDA).
As a result of that discussion in November 1994, ISPE began work on nine facility engineering Guides, now
known as the Baseline® Pharmaceutical Engineering Guides. The first, “Bulk Pharmaceutical Chemicals,”
was published in June 1996. The second, “Oral Solid Dosage Forms,’” was published in February 1998. The
third, “Sterile Manufacturing Facilities,” was published in February 1999. This is the fourth such Guide, covering Pharmaceutical Water and Steam Systems. Each Engineering Guide was created by, and is owned solely
by ISPE. FDA provided comments on this and previous Guides, and many of their suggestions have been
incorporated.
As with the BPC Guide, OSD, and Sterile Guide, the Water and Steam Systems Guide has been sponsored
by ISPE’s Pharmaceutical Advisory Council, made up of senior pharmaceutical engineering executives from
owner companies, and ISPE senior management. Overall planning, direction, and technical guidance in the
preparation of the Water and Steam Systems Guide was provided by a Steering Committee most of whom
were involved in the BPC Guide. The Water and Steam Systems Guide itself was produced by a Task Team of
individuals who expended a great deal of their own time in its preparation and development.
The Water and Steam Systems Appendix contains material considered “informational” which, although necessary, would have been detrimental to the clarity of the dedicated chapter. The Appendix has not been
reviewed by and therefore is not endorsed by the FDA.
Editors’ Disclaimer:
This Guide is meant to assist pharmaceutical manufacturers in the design and construction of new
and renovated facilities that are required to comply with the requirements of the Food and Drug
Administration (FDA). The International Society for Pharmaceutical Engineering (ISPE) cannot ensure, and does not warrant, that a facility built in accordance with this Guide will be acceptable to
FDA.
This Document is licensed to
Limitation of Liability
In no event shall ISPE or any of its affiliates, or the officers, directors, employees, members, or agents of each
of them, be liable for any damages of any kind, including without limitation any special, incidental, indirect, or
consequential damages, whether or not advised of the possibility of such damages, and on any theory of liability
whatsoever, arising out of or in connection with the use of this information.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
© Copyright ISPE 2001. All rights reserved.
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All rights reserved. No part of this document may be reproduced or copied in any form or by any means – graphic,
electronic, or mechanical, including photocopying, taping, or information storage and retrieval systems – without
written permission of ISPE.
All trademarks used are acknowledged.
ISBN 1-931879-79-6
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3
WATER AND STEAM SYSTEMS
ACKNOWLEDGEMENTS
CHAPTER WRITERS AND REVIEWERS
The following individuals took lead roles in the preparation of this document:
Gerald L. Geisler, Bristol-Myers Squibb Co. was the Task Team Chairperson for the Water and Steam
Systems Guide. Moe Elmorsi, Boehringer Ingelheim, acted as the Guide mentor.
Technical Documents Steering Committee Chairperson
Paul Lorenzo, (Retired)/ Paul D’Eramo, Johnson & Johnson
The Core Team on the Water and Steam Systems Guide comprised:
Gerald L. Geisler, Bristol-Myers Squibb Co.
Jeff Biskup, Clark, Richardson & Biskup
Robert Myers, Kvaerner
Bob Bader, Kinetics
The Chapter Credits are as follows:
Gerald Geisler, Bristol-Myers Squibb Co.
Brian Owens, H2O Pure, Inc.
Chapter 1: Introduction
Gerald Geisler, Bristol-Myers Squibb Co.
Brian Owens, Water Pure, Inc.
Chapter 2: Key Design Philosophies
Jeffrey Biskup, Clark, Richardson & Biskup
Maria Capote, Source Tech
James C. Cox, Merck & Co.
Gerald L. Geisler, Bristol-Myers Squibb Co.
Ryan Schroeder, Clark, Richardson & Biskup
Chapter 3: Water Options and Programming
Sidney Brookes, DuPont Merck Pharmaceuticals
Chapter 4: Source Feed Water Quality and
Pretreatment
Michael Partow, Pfizer Inc.
Andrew Zaske, Osmonics
Gary Zoccolante, U.S. Filter
Chapter 5: Final Treatment Non-Compendial
and Compendial Purified Water
This Document is licensed to
Sharif Disi, Meco
Brian Owens, H2O Pure, Inc.
Brian Owens, H2O Pure, Inc.
Bob Bader, Kinetics
6: Final Treatment Compendial WFI
Mr. ShlomoChapter
Sackstein
Herzlia,
Chapter 7: Pharmaceutical Steam
ID number: 216389
Robert Myers, Kvaerner
Gary Gray, East Group
Bob Bader, Kinetics
Randolph Brozek, Pfizer, Inc.
James Cox, Merck & Co
Paul Skinner, Clark, Richardson & Biskup
Gerald Geisler, Bristol-Myers Squibb Co.
Chapter 8: Storage and Distribution Systems
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WATER AND STEAM SYSTEMS
John Linder, CE & IC
Debra Nahas, Eli Lilly & Co.
Chapter 9: Instrumentation and Control
John Fadool, Glaxo Wellcome
Robert Myers, Kvaerner
Manfred Septinus, Roche Carolina, Inc.
Phil DeSantis, Fluor Daniel
Chapter 10: Commissioning & Validation
Dominick Smith, Regeneron
Phil Desantis, Fluor Daniel
Sidney Brooks, DuPont Merk Pharmaceuticals
James C. Cox, Merck & Co.
Sharif Disi, Meco
Brian Owens, Water Pure, Inc.
Michael Partow, Pfizer
Paul Skinner, Clark, Richardson & Biskup
Gary P Zoccolante, U. S. Filter
Pat H. Banes, Oakley Services Co.
Chapters 11 and 12: Appendices
The above Guide Task Team worked on one or more chapters and volunteered countless hours to attend
meetings, and review the many drafts, which were prepared over an 18-month period.
The following members of the Water and Steam Systems Task Team also worked on one or more of the
chapters and reviewed drafts:
Georgia Keresty, Ph.D., Bristol-Myers Squibb
Paula Soteropoulis, Genzyme Corp.
Alex Konopka, Eli Lilly & Co.
John Trentacosti, Johnson & Johnson
Carl Roe, Abbott Labs
FDA Reviewers
We would like to thank the following FDA review team for their input to this Guide:
Sharon Smith Holston
(Deputy Commissioner for External Affairs)
Joseph Phillips
(Deputy Regional Food and Drug Director, Mid-Atlantic Region)
Tracy Roberts
(CDER, Office of Compliance)
This Document is licensed to
Robert Coleman
(Atlanta National Expert)
Richard Friedman
(CDER, Office of Compliance)
Mr.
Shlomo Sackstein
(Investigator,Herzlia,
Drug Specialist, New Brunswick, NJ Inspection Post)
ID number: 216389
Nancy Rolli
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WATER AND STEAM SYSTEMS
Also, ISPE acknowledges with gratitude the following companies who supplied the start-up funding
for this project:
Alcon Laboratories
Bayer Corp.
Boehringer Ingelheim
Bristol-Myers Squibb Co.
Eli Lilly & Co.
Glaxo Wellcome Inc.
Hoffmann-La Roche Inc.
Merck & Co., Inc.
Pfizer Inc.
Pharmacia & Upjohn Inc.
Wyeth-Ayerst Laboratories
Zeneca Pharmaceuticals
Zenith Goldline Pharmaceuticals
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TABLE OF CONTENTS
ACKNOWLEDGEMENTS ........................................................................................................................... 4
1. INTRODUCTION
1.1
1.2
1.3
1.4
1.5
BACKGROUND .....................................................................................................................
SCOPE OF THIS GUIDE ......................................................................................................
SOME APPLICABLE FDA CURRENT REGULATIONS AND GUIDES FOR
PHARMACEUTICAL WATER SYSTEMS ..............................................................................
KEY CONCEPTS ..................................................................................................................
GUIDE STRUCTURE ............................................................................................................
11
11
11
12
13
2. KEY DESIGN PHILOSOPHIES
2.1
2.2
2.3
2.4
2.5
2.6
INTRODUCTION ...................................................................................................................
UNITED STATES PHARMACOPOEIA (USP) ........................................................................
SPECIFICATION OF PHARMACEUTICAL WATER QUALITY ..............................................
CRITICAL PROCESS PARAMETERS ..................................................................................
CGMP COMPLIANCE ISSUES .............................................................................................
DESIGN RANGE VERSUS OPERATING RANGE ................................................................
15
15
20
21
21
22
3. WATER OPTIONS AND SYSTEM PLANNING
3.1
3.2
3.3
3.4
INTRODUCTION ...................................................................................................................
WATER QUALITY OPTIONS .................................................................................................
SYSTEM PLANNING ............................................................................................................
SYSTEM DESIGN .................................................................................................................
25
25
29
33
4. PRETREATMENT OPTIONS
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
4.10
4.11
4.12
4.13
INTRODUCTION ...................................................................................................................
PROCESS DESIGN OF PRETREATMENT ..........................................................................
FEEDWATER TO PRETREATMENT QUALITY: TESTING AND DOCUMENTATION ............
OUTPUT WATER FROM PRETREATMENT: QUALITY OF FEEDWATER TO
FINAL TREATMENT ..............................................................................................................
CONTROL OF FOULING: REMOVAL OF TURBIDITY AND PARTICULATES ......................
CONTROL OF SCALING: REMOVAL OF HARDNESS AND METALS .................................
REMOVAL OF ORGANICS ...................................................................................................
SYSTEM DESIGN FOR CONTROL OF MICROBIAL GROWTH ..........................................
REMOVAL OF MICROBIAL CONTROL AGENTS .................................................................
CHANGES IN ANION COMPOSITION / CONCENTRATION ................................................
THE IMPORTANCE OF PH IN PRETREATMENT .................................................................
MATERIALS OF CONSTRUCTION AND CONSTRUCTION PRACTICES ............................
PRETREATMENT SUMMARY ..............................................................................................
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35
35
37
38
39
39
40
41
42
42
43
43
44
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Herzlia,
INTRODUCTION ................................................................................................................... 47
ION EXCHANGE ...................................................................................................................
48
ID number: 216389
5. FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.1
5.2
5.3
5.4
5.5
CONTINUOUS ELECTRODEIONIZATION (CEDI) ............................................................... 51
REVERSE OSMOSIS ........................................................................................................... 53
POLISHING COMPONENTS - NON-IONIC CONTAMINANTS REDUCTION ....................... 56
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TABLE OF CONTENTS
6. FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.1
6.2
6.3
6.4
6.5
6.6
6.7
INTRODUCTION ...................................................................................................................
US PHARMACOPOEIA ISSUES ...........................................................................................
DISTILLATION ......................................................................................................................
DISTILLATION APPLICATIONS AND CAPACITIES ..............................................................
PROCESS AND SYSTEM DESCRIPTION ...........................................................................
REVERSE OSMOSIS (RO) ...................................................................................................
USP - WATER FOR INJECTION SYSTEMS COMPARISON ................................................
63
63
64
64
65
70
73
7. PHARMACEUTICAL STEAM
7.1
7.2
7.3
7.4
7.5
7.6
7.7
7.8
7.9
7.10
7.11
7.12
INTRODUCTION ...................................................................................................................
CGMP ISSUES .....................................................................................................................
TYPES OF STEAM ...............................................................................................................
BACKGROUND AND INDUSTRY PRACTICES ....................................................................
SYSTEM PLANNING ............................................................................................................
PHARMACEUTICAL STEAM PURITY DECISION TREE ......................................................
PROCESS AND SYSTEM DESCRIPTION ...........................................................................
SIZING THE CLEAN STEAM SYSTEM .................................................................................
COST IMPLICATIONS ..........................................................................................................
STEAM “QUALITY” ...............................................................................................................
DISTRIBUTION .....................................................................................................................
FOUR EXAMPLES OF CORRECT PIPING PRACTICE .......................................................
75
75
76
77
80
82
83
86
90
90
90
93
8. STORAGE AND DISTRIBUTION SYSTEMS
8.1
8.2
8.3
8.4
8.5
8.6
8.7
8.8
8.9
8.10
INTRODUCTION ................................................................................................................... 95
SYSTEM DESIGN ................................................................................................................. 95
SYSTEM DISTRIBUTION DESIGN ....................................................................................... 96
MATERIALS OF CONSTRUCTION ..................................................................................... 113
SYSTEM COMPONENTS ................................................................................................... 115
COMPARISON OF WFI SYSTEMS WITH STORAGE TANK AND WITHOUT
STORAGE TANK ................................................................................................................. 117
MICROBIAL CONTROL DESIGN CONSIDERATIONS ....................................................... 119
CONTINUOUS MICROBIAL CONTROL ............................................................................. 122
PERIODIC STERILIZATION/SANITIZATION ....................................................................... 124
SYSTEM DESIGN FOR STERILIZATION/SANITIZATION .................................................. 126
9. INSTRUMENTATION AND CONTROL
9.1
9.2
9.3
9.4
9.5
9.6
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INTRODUCTION .................................................................................................................
PRINCIPLES .......................................................................................................................
GENERAL INSTRUMENTATION REQUIREMENTS ...........................................................
DESIGN CONDITIONS VERSUS OPERATING RANGE ....................................................
INSTRUMENTATION SPIKES .............................................................................................
CONTROL SYSTEMS .........................................................................................................
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129
129
130
134
135
135
TABLE OF CONTENTS
10. COMMISSIONING AND QUALIFICATION
10.1
10.2
10.3
10.4
10.5
10.6
INTRODUCTION .................................................................................................................
SYSTEM QUALIFICATION DOCUMENTATION ..................................................................
SYSTEM QUALIFICATION SAMPLING PROGRAM ...........................................................
ACCEPTANCE CRITERIA ...................................................................................................
QUALIFICATION REPORTS ...............................................................................................
CHANGE CONTROL AND REQUALIFICATION .................................................................
137
137
138
140
141
141
11. APPENDIX
11.1
11.2
11.3
11.4
11.5
11.6
11.7
11.8
11.9
11.10
11.11
11.12
USP REGULATED WATER QUALITY .................................................................................
EUROPEAN PERSPECTIVE ..............................................................................................
PASSIVATION .....................................................................................................................
PRETREATMENT PROCESSES ........................................................................................
FINAL TREATMENT FOR NON-COMPENDIAL AND COMPENDIAL PURIFIED
WATER SYSTEMS ..............................................................................................................
DISTILLATION FOR HIGH PURITY WATER SYSTEMS .....................................................
CLEAN STEAM - CLEAN STEAM GENERATORS .............................................................
MICROBIAL CONTROL BASICS, TESTING, AND STERILIZATION/SANITIZATION
EQUIPMENT DESIGN AND INSTALLATION ISSUES ........................................................
FABRICATION/PROCEDURES FOR DISTRIBUTION SYSTEMS ......................................
DESIGN OF WFI/PURIFIED WATER DISTRIBUTION SYSTEM .........................................
FABRICATION OF A WFI/PURIFIED WATER DISTRIBUTION SYSTEM ............................
ABBREVIATIONS AND DEFINITIONS ................................................................................
143
151
153
162
175
182
187
190
198
205
206
213
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INTRODUCTION
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INTRODUCTION
1.
INTRODUCTION
1.1
BACKGROUND
The design, construction, and validation (commissioning and qualification) of water and steam systems for
the pharmaceutical industry represent key opportunities for manufacturers, engineering professionals, and
equipment suppliers. These systems are required to meet current Good Manufacturing Practice cGMP regulations while remaining in compliance with all other governing codes, laws, and regulations.
The cost of bringing these systems on line is highly variable, owing to interpretation of regulatory requirements and overly conservative design approaches. This Guide is intended to offer a practical, consistent
interpretation, while still allowing flexibility and innovation.
This Guide was prepared by ISPE, with feedback from industry representatives from all areas and disciplines, and comments provided by FDA. It reflects ISPE’s current thinking related to engineering of new water
and steam systems.
It is recognized that industry standards evolve, and this document reflects the understanding of them as of
the publication date.
1.2
SCOPE OF THIS GUIDE
This Guide is intended for the design, construction, and operation of new water and steam systems. It is
neither a standard nor a detailed design guide. The validation of water and steam systems, which comprises
commissioning and qualification activities, will not be discussed in-depth in this Guide, but is covered in the
Commissioning and Qualification Baseline® Guide.
The purpose of this Guide is to focus on engineering issues, and provide cost effective water and steam
systems. Where non-engineering issues (e.g., microbiological topics) are covered, the information is included
to stress the importance of such topics and the impact they have on water and steam system design. Such
non-engineering topics, therefore, are not covered comprehensively, and specific advice from QA departments and technical experts must be sought where technical input is required.
This Guide is intended primarily for regulatory compliance for the domestic United States (US) market, and
follows US standards and references. European and other non-US standards and references may be incorporated in future revisions.
1.3
•
This Document is licensed to
SOME APPLICABLE FDA CURRENT REGULATIONS AND GUIDES FOR PHARMACEUTICAL
WATER SYSTEMS
Food and Drug and Cosmetic Act
•
Mr. Shlomo Sackstein
The United States Pharmacopoeia XXIV Herzlia,
Title 21 CFR, Part 211
ID number: 216389
•
FDA Guide To Inspections of High Purity Water Systems
•
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INTRODUCTION
1.4
KEY CONCEPTS
The following key concepts covered in this Guide are:
a) Methodology for defining the required water quality and configuring a water delivery system.
b) Critical process parameters.
c) Good Engineering Practices.
d) Design Options
a) Methodology for defining the required quality and configuring a water delivery system:
Perhaps the most critical step in a new pharmaceutical water or steam system, from a regulatory as well
as technical and financial standpoint, is the specification of water or steam quality required. The specification established is likely to have a larger impact on lifecycle costs of the system than any of the subsequent design decisions. In addition, regulated industries must consider the costs of noncompliance and
water system failures. Therefore, it is essential for the designer to seek advice from the Quality unit and
technical experts early in the process.
Once process water and/or steam requirements are determined, system design options need to be
addressed. This Guide presents alternative baseline water and steam system building blocks and associated advantages and disadvantages of each. These baseline building blocks are qualified relative to
such things as capital costs; feed water chemistry; product water quality; chemical handling; water consumption; energy consumption; outside service costs maintenance requirements; and chemical/microbial/endotoxin removal performance.
Guide emphasis is on how the system design should be determined based on the quality of feed water;
the design of the pretreatment and final treatment system; the storage and distribution system design;
and operation/maintenance procedures.
The Guide aims to improve consistency of pharmaceutical water and steam quality throughout the industry, as a result of system performance and reliability improvements. It also provides the user with alternative basic system building blocks to permit reliable and consistent generation of the required water or
steam quality.
b) Critical process parameters
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Critical parameters are defined as those parameters that directly affect the product quality. For example,
since microbial quality cannot be directly monitored in real time, the parameters relied upon to control
microbial growth are normally considered critical. These may include temperature; UV intensity; ozone
concentration; circulating systems under positive pressure; etc. In regard to chemical purity, the quality
attributes themselves (properties of water produced), may be monitored at or after each process step,
and the proper performance of that operation confirmed directly. For a system producing compendial
water, properties mandated in the official monograph obviously constitute critical parameters.
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Critical instruments are those instruments that measure critical quality attributes. This concept is discussed in Chapter 2 and used as a basis for subsequent chapter discussions where appropriate.
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INTRODUCTION
c) Good Engineering Practice (GEP)
GEP recognizes that all systems in a facility, whether they are water systems, steam systems, elevators,
process reactors, safety valves, or rest rooms, require some form of commissioning and/or qualification.
Nearly all systems require documentation, inspection, and field testing. Good Engineering Practice capitalizes upon this practice suggesting that manufacturers engage all stakeholders (engineers, operators,
Quality Assurance, and others) very early in the planning, design, construction, commissioning/qualification phases to ensure that systems are documented only once.
d) Design Options
The Guide emphasizes that a water system can be designed in many different ways, yet meet the overall
requirements of the system. It encourages a well-thought-out, planned approach to the design with input
from many areas of the organization including Quality Assurance.
1.5
GUIDE STRUCTURE
The structure of the Guide is shown in Figure 1-1 below. The chapters have been organized to assist in a
logical decision process to determine the type of water required and the system design needed to provide it.
Figure 1-1 Pharmaceutical Water and Steam Baseline® Guide Structure
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KEY DESIGN PHILOSOPHIES
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KEY DESIGN PHILOSOPHIES
2.
KEY DESIGN PHILOSOPHIES
2.1
INTRODUCTION
Pharmaceutical water is the most widely used ingredient in drug manufacturing and the main component in
equipment/system cleaning. Therefore, systems for the production of pharmaceutical water constitute a key
component in every manufacturing facility. The nature of producing pharmaceutical waters is to minimize or
eliminate potential sources of contamination. This Guide considers this and the means by which engineers
can design out, or ensure control of the risk.
The quality of Pharmaceutical Water and Steam is not only critical from a regulatory point of view, but also
from a financial point of view. The Pharmaceutical Water and Steam specification has the largest impact on
lifecycle costs of the system.
It must be demonstrated that all pharmaceutical waters (non-compendial and United States Pharmacopoeia
(USP) monograph compendial waters) can be produced consistently to specification. Establishing the level of
microbial control needed in a pharmaceutical water and steam system used in the manufacture of a nonsterile product requires an understanding of both the use of the product and the manufacturing process.
Manufacturers need to define the appropriate water purity based upon sound process understanding and
system equipment capability. They must determine the specific purification capability for each processing
step, the limitations of the unit operation, and the critical parameters, which affect the specified water/steam
quality - chemically, physically, or biologically. Expert QA advice should be sought to provide further details
about this important area.
USP covers two compendial water qualities (USP Purified Water and USP Water for Injection). This Guide
supports both these water qualities plus additional non-compendial waters including “Drinking Water”. It is
common practice to name non-compendial waters (exclusive of “Drinking Water”) used in pharmaceutical
manufacturing by the final treatment step (i.e., Reverse Osmosis/RO water, deionized water/DI water, etc.).
Guidance on establishing specifications for monographed USP water is provided in the United States Pharmacopoeia (USP). Additionally, the FDA Guide to Inspections of High Purity Water Systems (which was
developed for FDA personnel) also provides useful information to the user.
2.2
UNITED STATES PHARMACOPOEIA (USP)
USP is a Guide to producing medicinal products for consumption within the US. USP specify standards of
quality, purity, packaging, and labeling for a number of waters including two bulk waters, “Water for Injection”
and “Purified Water” used in the preparation of compendial (USP) dosage forms. This Guide is concerned
with the production of these two compendial (USP) waters and does not address the other “packaged waters”
monographed by the USP. USP 24 (and supplements) is the current version, at the time this Guide was
prepared.
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2.2.1 USP Purified Water
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Official monograph requirements forID
“Purified
Water” require
that “Purified Water”:
number:
216389
•
Is obtained from water complying with the “U.S. Environmental Protection Agency National Primary Drinking
Water Regulations, or comparable regulations of the European Union or Japan, and will be referred to
subsequently as “Drinking Water”.
•
Contains no added substance
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KEY DESIGN PHILOSOPHIES
•
Is obtained by a suitable process
•
Meets the requirements for Water Conductivity
•
Meets the requirements for Total Organic Carbon (TOC)
2.2.2
USP Water for Injection (WFI)
Official monograph requirements for “Water for Injection” require that “Water for Injection”:
•
Meets all of the requirements for “Purified Water”
•
Is obtained by a suitable process and purified by distillation or Reverse Osmosis
•
Meets the requirements of the Bacterial Endotoxin test and contains not more than 0.25 USP Endotoxin
Unit per ml
•
Is prepared using suitable means to minimize microbial growth
2.2.3
Non-Monographed but accepted requirements
The USP “General Information” provides background information, which clarifies regulatory intent. The following information is included in Chapter 11:
•
Purified water systems require frequent sanitization and microbiological monitoring to ensure water of
appropriate microbiological quality at the points of use.
•
Water for Injection is “finally subjected to distillation or Reverse Osmosis”, implying that the Still or RO
unit is the last unit operation. “The system used to produce, store and distribute water for injection must
be designed to prevent microbial contamination and the formation of microbial endotoxins, and it must be
validated.”
•
An action limit of 100 colony forming units per ml (10,000 CFU/100 ml) for “Purified Water” is suggested.
•
An action limit of 10 colony forming units per 100 ml (10 CFU/100 ml) for “Water for Injection” is suggested.
•
Minimum sample sizes are 1 ml for USP Purified Water and 100 ml for WFI. (FDA recommends 100 ml for
Purified Water and 250 ml for WFI).
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Note: “It should be emphasized that the above action guidelines are not intended to be totally inclusive for
every situation where ingredient waters are to be employed. It is therefore, incumbent upon the manufacturer
to supplement the general action guidelines to fit each particular manufacturing situation” [USP24, page
2163]. When designing a pharmaceutical or medical device water system, it is critical for the designer to
consult with the manufacturers technical experts to ascertain what purity levels must be achieved.
Mr. Shlomo Sackstein
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ID number: 216389
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2.2.4
USP testing and instrument requirements
THREE STAGE CONDUCTIVITY TESTING
Method of Measurement
Acceptance Criteria
One
Use In-Line or grab sample and measure the
conductivity and operating water temperature
Use the stage 1 table from the latest revision
to USP to determine the conductivity limit.
Two
Retest at least 100 ml of the stage 1 grab
sample for conductivity after vigorous mixing
and temperature normalization to 25°C ±1°C
When change does not exceed a net of 0.1
µS/cm over 5 minutes, measure the conductivity. If less than 2.1 µS/cm the water meets
the requirements.
Three
If the stage 2 test does not meet the requirements, retest the sample within 5 minutes while
maintaining temperature. Add 0.3 ml per 100
ml of saturated potassium chloride solution and
determine the pH to the nearest 0.1 pH unit.
Use the stage 3 table from the latest revision
to USP to determine the conductivity limit. If
either the measured conductivity is greater than
the limit value or the pH value is outside the
range of 5 to 7, the water does not meet the
requirements.
Stage
CONDUCTIVITY INSTRUMENT REQUIREMENTS FOR ACCEPTABLE REGULATORY
MEASUREMENT
Temperature Measurement
± 0.25°C Accuracy
Resolution
< ± 0.1 µS/cm
Conductivity cell constant
± 2% Accurate
Reading accuracy
< ± 0.1 µS/cm
Location of In-Line meters
Must reflect the quality of the water used. Typically, the optimum location in a
distributed water loop is following the last “point of use” valve, and prior to the
storage tank return connection.
Instrument type
The above procedure is based on the use of a “dip” or “flow through” conductivity cell. Conductivity readings used to control USP compendial waters must
be non-temperature-compensated measurements.
2.2.5
Total Organic Carbon (TOC) and Requirements for TOC Control
TOC is an indirect measure, as carbon, of organic molecules present in high purity water. USP replaced the
USP 22 “Oxidizable Substance” wet chemistry test with an In-Line capable, TOC test. A limit was determined
by USP to be 0.5ppm or 500ppb, based on the results of studies and an industry wide survey of pharmaceutical water systems.
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Instruments are available for measuring TOC In-Line from slipstreams and from grab samples manually
removed from the water system. Automatic
Off-Line sample 216389
introduction systems are available for processing
ID number:
SYSTEMS AVAILABLE FOR MEASURING TOC
large numbers of grab samples. USP have not prevented acceptable technologies from being used, but limit
the methods to the following instruments that are capable of completely oxidizing the organic molecules to
Carbon dioxide (CO2), measuring the CO2 levels as carbon, discriminating between Inorganic carbon (IC)
and the CO2 levels generated from the oxidization of the organic molecules, maintaining an equipment limit of
detection of 0.05 mg per liter, or lower, and periodically demonstrating an equipment “suitability”.
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KEY DESIGN PHILOSOPHIES
A number of acceptable methods exist for measuring TOC in high purity water. All share the same basic
methodology, the complete oxidation of the organics to CO2 and the measurement of this CO2.
Three general approaches, based on the above concept are used in a variety of commercially available
instruments, which measure Organic Carbon in a water sample by completely oxidizing the organic molecules to Carbon dioxide (CO2) and measuring the CO2 levels as carbon. Four common oxidation methods
and four common CO2 measurement methods are used in different combinations in these TOC analyzers.
The total carbon (TC) result may be expected to include Inorganic carbon resulting from dissolved CO2 and
bicarbonate which must be subtracted from the TC to produce the Total Organic Carbon level in the sample.
Some TOC analyzers remove the Inorganic Carbon (IC) by acidifying the samples and either gas stripping or
vacuum degassing the CO2. In pharmaceutical waters the IC levels are generally very low and IC removal
processes are not usually required.
TYPES OF TOC ANALYZERS
•
Laboratory Instruments
•
In-Line Instruments
•
Laboratory Instruments capable of operating in-line
When USP accepted the well-proven technology for measuring TOC, they applied laboratory quality control
procedures to its application. While these techniques are common in a laboratory for setting a wide range
equipment for measurement over a specific range, they place unusual limitations on In-Line TOC applications. TOC instruments must be:
•
Maintained calibrated to ensure reliable and consistent readings
•
Periodically checked for “suitability”
•
Standardized
•
May be used In-Line or Off-Line
•
If installed In-Line, the instrument must reflect the quality of the water used
OUT OF RANGE EXCURSIONS
Out of range readings may be experienced as the direct result of the above types of organic contaminations.
Spikes may also occur as the result of extraneous electrical interference etc. All spikes must be identified and
formally explained.
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Procedures to handle out of range spikes should be available. These procedures should address short duration spikes, which occur following continuous acceptable readings and are followed by similar acceptable
readings, specifically in In-Line applications. Procedures should list the potential sources and allow the acceptance of such a spike without further investigation if the spike is preceded and succeeded by a number of
acceptable readings.
Mr. Shlomo Sackstein
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ID number: 216389
Unexplainable spikes may be minimized when using In-Line batch sampling systems by extending the sample
analysis period to 30 or 60 minutes rather than using shorter analysis periods. This technique measures
more sample in a longer time period, allowing the recorded result to be based on statistical analysis over the
extended time period.
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KEY DESIGN PHILOSOPHIES
Table 2-1
In-Line compared with Off-Line TOC Monitoring
In-Line
Off-Line
Features
Monitor should include built in alarms and
be programmable in respect to the “out
of spec.” excursions. Should have convenient method of conducting Limit Response and Suitability Tests.
Laboratory instrument should be capable
of achieving robust oxidation levels and
should include automatic Off-Line sample
introduction systems, for processing
large numbers of grab samples. A generous supply of scrupulously clean polymer based sample containers is required.
Laboratory instruments will require reagents and carrier gases.
Installed cost
Medium, based on above features and a
single installed unit. High, if multiple units
are installed.
High, based on above features
Operating cost
Low to high, depending on instrument
capability for suitability and limit response
testing and the number of instruments
installed.
High
Recommended
test frequency
4 to 48/day
1/shift
The recommended frequency is based
on the specific system requirement for
trending or concern for “out of spec.” excursions and their subsequent investigations. See paragraph on “Special Requirements”.
Frequency of
Suitability and
Limit Response
testing
2.2.6
Based on documented history
1/shift
USP 23 Microbial and Endotoxin Testing
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Microbial contaminants and Endotoxins are traditionally sampled at the points of use in a water system.
USP 24 has made no changes in this area.
Mr. Shlomo Sackstein
2.2.7 USP 23 pH testing
Herzlia,
Testing water for compliance with theID
USPnumber:
24 pH limits is required
as part of the stage 3 Off-Line conductivity
216389
testing. (pH must be confirmed as being in the range of 5 to 7.) Testing may use calibrated Off-Line meters.
Calibration should be performed using solutions of a known pH, covering the range of 5 to 7. The frequency
of calibration should ensure that the levels of accuracy are maintained. Refer to manufacturer for specific
recommendations on both method and frequency.
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KEY DESIGN PHILOSOPHIES
2.2.8
Validated Backup Instrumentation
Failure of a monitoring instrument should not be precluded when making decisions concerning type, location
and the extent of validation. Since each excursion from the acceptable limits must be investigated, In-Line
installations should be supplemented with a calibrated laboratory instrument as backup. Validation should
include the operation in Off-Line mode as a supplement or alternate to In-Line instrumentation. Off-Line
laboratory testing should also include a backup instrument to be maintained calibrated in case of failure of the
primary unit.
2.3
SPECIFICATION OF PHARMACEUTICAL WATER QUALITY
2.3.1
Specifying Water Quality
The quality of water supplied in any pharmaceutical process must be consistent with the quality required for
the final product. It may not be sufficient to specify a water quality that meets the specification of the two
compendial grades of water outlined in the USP. These grades, USP Purified water and WFI, are minimum
standards. A more stringent specification could be required depending on the intended use of the product
and on the process used to manufacture that product. It is the responsibility of each drug manufacturer to
establish the logic for their water quality specification based on the required quality of the end product.
Pharmaceutical water uses can be categorized as:
•
An ingredient in a dosage form manufacturing process
•
An ingredient in an Active Pharmaceutical Ingredient (API) process (the term API is used interchangeably with BPC, meaning Bulk Pharmaceutical Chemical)
•
Equipment cleaning or rinsing
Water intended for use as a dosage form ingredient must be USP monograph water and must be produced
consistently to specification. Evidence of control is required for all critical process parameters that may affect
the final drug characterization. USP WFI water would be expected to be used for parenteral manufacture,
some ophthalmic and some inhalation products.
The monographs for USP Purified and WFI compendial pharmaceutical waters stipulate the baseline requirements for water used in production, processing, or formulation of pharmaceutical activities.
For some applications where there are no requirements for compendial waters, the manufacturer may establish quality specifications equivalent to USP-WFI or Purified Waters, depending on the specific application.
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Specifications for water used as an ingredient (exclusive of sterile bulks) in the manufacture of API’s or as the
wash solvent in the wash or rinse cycles must be determined by the manufacturer. In some cases “Drinking
Water” may be acceptable, or certain chemical or microbial or endotoxin quality specifications may be established, or one of the compendial waters may be used. The specification should be based on the potential for
contamination of the final drug product. Any decision about water usage must be made with the approval of
Quality Assurance.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
With the appropriate justification, non-compendial pharmaceutical waters (including “drinking waters”) may
be utilized throughout pharmaceutical operations including production equipment washing / cleaning as well
as rinsing, laboratory usage and as an ingredient in the manufacture or formulation of bulk active pharmaceutical ingredients. Compendial water must, however, be used with preparation of (as an ingredient) compendial
dosage forms. In both compendial and non-compendial waters, the manufacturer must establish an appropriate microbial quality specification per the FDA “Guide To Inspections of High Purity Water Systems”. The
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KEY DESIGN PHILOSOPHIES
significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the
use of the product and the nature of the product and the potential harm to the user. Manufacturers are
expected to establish appropriate microbial alert and action levels for microbial counts associated with the
types of pharmaceutical waters utilized. These levels must be based on process requirements and the historical record of the system in question. The US Pharmacopoeia states action levels that are generally considered acceptable are 500 CFU/ml for drinking water, 100 CFU/ml for Purified Water, and 10 CFU/100 ml for
WFI, and may be more stringent depending on its use. Microbial system design considerations are discussed
later (see Chapter 8).
The user should consider whether microorganisms in pharmaceutical water could threaten product preservation or product stability, or whether water may contaminate product with pathogenic bacteria or endotoxins.
Specific microbiological objectives and standards suitable to the needs of the products manufactured must
be defined. A water system must meet these objectives and a monitoring program must be established /
implemented to document that the standards are consistently being met.
Engineers involved in water system design must understand the chemical and microbial quality attributes in
the water delivered to use points.
The final quality of pharmaceutical water and steam is determined by the manufacturing process and end
product, quality of feed water, pretreatment and final treatment sub-systems, storage and distribution system
design and operator/maintenance procedures. Expert QA advice should be sought out to give further details
about this important area.
2.4
CRITICAL PROCESS PARAMETERS
Critical parameters are defined as those parameters, which directly affect the water quality at, or after, a
treatment step. For example, water temperature during a heat sanitization cycle has a direct effect on water
quality.
Regarding chemical purity, the quality attributes may be monitored at or after each critical process step, and
the proper performance of that operation confirmed directly. Since microbial quality cannot be directly monitored in real time, the parameters relied upon to control microbial growth are usually (depending on the
system) considered critical, such as temperature, UV intensity, ozone concentration, circulation rate, sanitization procedures, positive pressure, etc.
For a system producing compendial water, properties mandated in the official monograph (including bioburden
and endotoxins) constitute critical attributes. Critical instruments are those instruments, which measure critical attributes or parameters.
2.5
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cGMP COMPLIANCE ISSUES
Satisfying regulatory concerns is primarily a matter of establishing proper specifications, and using effective
and appropriate methods to verify and record that those specifications are satisfied. Issues such as quality of
installation, sampling and testing procedures, operating and maintenance procedures, record keeping, etc.
often have greater significance than the particular technologies selected to purify and distribute the water.
Mr. Shlomo Sackstein
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ID number: 216389
Fundamental conditions expected to aggravate a microbial problem typically include system design conditions such as stagnant conditions, areas of low flow rate, poor quality feed water etc.
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KEY DESIGN PHILOSOPHIES
Measures to alleviate such problems include:
•
Continuous, turbulent flow
•
Elevated or reduced temperatures
•
Smooth, clean surfaces that minimize nutrient accumulation
•
Frequent draining, flushing or sanitizing
•
Flooded distribution loop (maintenance of positive distribution loop pressures)
•
Properly designed, installed and maintained system
While the control of chemical quality is important, the primary challenge in a pharmaceutical water system is
maintaining the microbial quality. The industry and the regulatory community have recognized the effectiveness of maintaining a continuously recirculated system at high temperatures (65°C-8O°C) in preventing
microbial growth. Distillation has a long and well-documented history of success, but need not be the only
technology considered for producing water with endotoxin limits. Reverse osmosis is the only other technology accepted by the USP for WFI. Ultrafiltration has been successfully used to produce waters with strict
endotoxin limits that meet WFI attributes, but it cannot, by regulation, be used to produce compendial grade
WFI.
Each pharmaceutical steam and water treatment system must be viewed in its entirety, as design and operational factors affecting any unit operation within the system can affect the whole system. It is useful to identify
both the quality parameters of water entering the system and the quality parameters of the water or steam to
be produced. Water quality should be enhanced with each successive step. It does not necessarily follow that
measures enhancing one quality attribute (such as conductivity, particulate level or color) will always enhance another (such as microbial population).
2.6
DESIGN RANGE VERSUS OPERATING RANGE
This Guide recognizes the distinction between “Design Range” and “Operating Range” and the impact this
distinction has upon validation and facility system operation. These criteria are defined as:
See Figure 2-1.
Design Range: the specified range or accuracy of a controlled variable used by the designer as a basis to
determine the performance requirements for an engineered water system.
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Allowable Operating Range: the range of validated critical parameters within which acceptable product
water can be manufactured.
Mr. Shlomo Sackstein
Normal Operating Range: a range which may
be selected by the manufacturer as the desired acceptable
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values for a parameter (i.e., conductivity) during normal operations. This range must be within the Allowable Operating Range.
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a) While a water or steam system should meet all stated Design Conditions, the acceptability of the system
for operation from a cGMP standpoint depends on operating within the Allowable Operating Range.
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KEY DESIGN PHILOSOPHIES
b) Performance criteria for a Pharmaceutical Water Generation System may require a final product water
quality conductivity of 0.5 µS/cm. (2 Mohm-cm) or better as a Design Condition. The Allowable Operating Range for this pharmaceutical water may, however, allow for generation of water quality with a
conductivity of 1.3 µS/cm. (0.77 Mohm-cm) or better. The Normal Operating Range for generating water
may, in the end, be set by the manufacturer at conductivity value approaching 1.0 µS/cm. (1.0 Mohm-cm)
or better to provide a comfortable environment for the operation.
c) Normal Operating Range cannot exceed the Allowable Operating Range for the product water. The
Design Condition selection should reflect Good Engineering Practice.
d) It is also good practice for manufacturers to apply the concept of Alert and Action limits along with
Normal Operating Range. Alert and Action limits should be based on the actual capability of the system.
Alert Limits are based on normal operating experience and are used to initiate corrective measures
before reaching an Action Limit, which is defined as the process condition established by product acceptance criteria. The Action Limit deviations must be kept as a part of the batch record as they represent
deviations from validated parameters.
Figure 2-1 Values of Critical Parameters for Product Water
Note: These are general guidelines.
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WATER OPTIONS
and
SYSTEM PLANNING
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WATER OPTIONS AND SYSTEM PLANNING
3.
WATER OPTIONS AND SYSTEM PLANNING
3.1
INTRODUCTION
This chapter outlines basic water system design criteria and, along with subsequent chapters, aims to provide a better understanding of pharmaceutical water, how it is used, and how it can be provided. The primary
goal of this chapter is to provide the user with a methodology for:
a) Evaluating water quality options for product manufacturing
b) Evaluating basic system configurations available to provide the water
Detailed information on unit operation design, maintenance and cost factors is addressed in later chapters.
The chapter also outlines the system planning effort for pharmaceutical water systems. This planning starts
with the selection of water quality based upon product requirements, processing operations, and end use. A
decision tree concept is included to assist in selection of compendial and non-compendial waters for production, cleaning, and support. The program then provides steps to guide the user through a use-point and
system analysis, to set-up the water system distribution strategy. Finally, evaluation points are provided for
the selection of the primary system configurations.
3.2
WATER QUALITY OPTIONS
Quality requirements for water used in pharmaceutical manufacturing and product development are driven by
the product characteristics, manufacturing processes, and the intended use of the product. To aid in the water
selection process, the USP Monographs define minimum requirements for general types of pharmaceutical
water used in almost every pharmaceutical application. However, there is also the opportunity for a manufacturer to determine water quality requirements, different from those in the USP, based on specific product
characteristics and processing operations. If this option is taken, the product manufacturer is responsible for
assuring that water used to manufacture the product is appropriate, to reliably produce safe product.
Though water quality requirements are product specific, it is impractical to reliably produce special water that
is specific to each situation. Manufacturing operations typically generate and distribute only a few, or perhaps
just one, quality of water. Therefore, products and operations requiring similar water qualities are commonly
grouped. The most common segmentation is that defined in the USP.
Manufacturers agree that in many if not most cases, the requirements defined in the USP are adequate for
production of safe product. More stringent water quality specifications may be appropriate for some products
and processes. Others may be appropriately less stringent. Typically, more stringent requirements may apply
to some processing operations involving significant concentration steps or products comprised of high water
content, which may be applied in large volume doses. Likewise, processes involving reliable sterilization and
purification steps which remove impurities may, in some cases, not require water qualities as strict as those
defined in the USP. Other process characteristics can affect water quality requirements as well.
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In manufacturing operations with only one quality of water, the water system must be designed to meet the
most stringent requirements of the most
product216389
or process. With more than one quality of water,
IDdemanding
number:
products and processes are often categorized and fed by the most appropriate system. The number of types
of water generated is most often a function of volume of water consumed and variation of quality. Large
consumers may find it economical to generate and distribute multiple grades of water, while small users often
will generate only one quality of water.
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WATER OPTIONS AND SYSTEM PLANNING
The three main categories of water used in pharmaceutical manufacturing are:
•
Drinking water: meeting EPA national primary drinking water regulations. In Figure 3-1 drinking water is
included in the category Suitable Non-Compendial.
•
Compendial water: meeting the compendial requirements for specific types of water in USP Monographs
(i.e., Purified Water USP, Water for Injection USP).
•
“Suitable” non-compendial process waters: meeting the requirements of drinking water, but with additional treatment to meet process requirements. It may, or may not, contain added substances for microbial control and does not have to meet full compendial requirements for USP Water. In this Guide, we
name the non-compendial process waters used in manufacturing by the final/major process step (i.e.,
Reverse Osmosis - RO water, Deionization - DI water, etc.).
Non-compendial water is not necessarily less critical, or less costly to produce or to qualify, than compendial
water. It can enable the manufacturer to set product specific quality and/or test criteria that are appropriate for
the specific product and processes.
Generally, more highly purified water is more expensive than less purified water. However, the specifics of
each operation are different. For example, a plant with existing excess capacity of WFI might elect to use WFI
over other grades even when unnecessary. In the example case, documentation defining water quality should
identify the quality required for the product and why the WFI was used instead.
Figure 3-1 provides the framework of a diagram that can be developed by a manufacturer to show the requirements for water used in the pharmaceutical manufacturing processes. This diagram should be accompanied by documentation supporting the options chosen, with review and approval of Quality Assurance. The
options chosen should be based on product and process specific requirements. Ultimately, water supplied to
any process must meet or exceed the requirements, as defined by the manufacturer, for the safe and reliable
manufacture of that product.
Figure 3-1 provides an overall summary of water requirements for a manufacturer supported by the necessary justification for specific products, processes, and areas. It is almost impossible to provide one generic
decision tree due to the diversity it would have to cover.
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WATER OPTIONS AND SYSTEM PLANNING
Figure 3-1 Pharmaceutical Water Quality Decision Tree
Note: Commitments made in drug applications override suggestions of this decision tree.
Notes:
1) By test procedure definition, some analytical methods require USP Compendial waters. Quality should
meet the needs of the analytical methods.
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2) Labs performing both cGMP and Non-cGMP operations should follow the cGMP path.
3) Non-compendial water may be more highly purified than compendial water. Endotoxin and microbial
quality is based on the process and quality standards of the product. Non-compendial water must at a
minimum meet EPA (or comparable EU or Japanese standard) drinking water requirements for microbiological quality.
4)
Mr. Shlomo Sackstein
Herzlia,
Quality of final rinse water is determined
by the type of product
and subsequent processing steps. Where
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product contact surface is subsequently sanitized, final rinse with Suitable Non-Compendial water may
be acceptable. Such practice may necessitate more stringent qualification criteria for the subsequent
sanitization steps.
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5) Where product is purified downstream
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WATER OPTIONS AND SYSTEM PLANNING
6) More stringent endotoxin requirements (e.g., WFI quality) should be employed for water used in the final
purification step for NON-Sterile parenteral grade APIs.
Figure 1-1 provides “Baseline” requirements for most product contact water applications. Water quality criteria for pharmaceutical manufacturing and product development are driven by the product characteristics, manufacturing process, and the intended use of the product. Specific product and process
characteristics may dictate that more or less stringent criteria than shown are appropriate. Figure above
gives engineers some general guidance on selection of pharmaceutical water quality. Expert QA advice
should be sought to give further advise on this critical of pharmaceutical water selection.
Once water needs are determined based on usage, Table identifies common design options for various types
of pharmaceutical water in the industry. The order of components and actual installed equipment varies
widely throughout the industry. Primary criteria in evaluating the options are:
•
To have suitable specification for water criteria (i.e., it must be adequate for the process and product)
•
To produce water consistent in composition and quality
•
To monitor key performance indicators for assurance that specifications are met.
Table 3-1
Typical Pharmaceutical Process Water Types
PHARMACEUTICAL WATER TYPE
TYPICAL
PROCESS
WATER
TYPES
DESCRIPTION
PROCESS UNIT OPERATION
Primary
Filtration
Softening
X
Activated
Ion
RO
RO Ion Exchange
Carbon Exchange (1st
(2nd (Mixed Bed Filtration
(Cation/ Pass) Pass) 2nd Stage)
Anion 1st Stage)
Double Pass
RO Water
Product Staged RO
System
X
DI Water
Either Conventional
Regenerable or Off
Site Regenerated Ion
Exchange/Mixed Bed
System
X
RO/DI Water
Variations of Single
and Double Pass RO
Followed by Mixed Bed
DI System
X
X
X
X
RO/EDI Water
Single Pass RO &
Electrodeionization
System
X
X
X
X
DI/UF Water
Regenerable Mixed
Bed/Ultrafiltration
System
X
RO/DI/UF
Water
Single Pass RO/
Non-Regenerable (or
off site regenerated)
Mixed Bed/
Ultrafiltration System
UF Water
Ultrafiltration often with
some pretreatment
Distilled Water
Various configurations
of stills often with some
pretreatment
X
X
X
Still
EDI
Ultra
filtration
X
X
X
X
X
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X
X
X
X
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X
X
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X
X
X
X
X
X
X
X
Various configurations of pretreatment,
primarily to prolong the still life.
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X
WATER OPTIONS AND SYSTEM PLANNING
3.2.1
Cost Implications
Determining the economics of pharmaceutical/medical device water production is complex. Costs are quite
predictable, but vary greatly depending on scale of operation, system design, actual usage, etc. The total
operating cost to produce pharmaceutical waters is obtained by adding the cost of feed water to the costs of
pretreatment (e.g., media filtration, carbon filtration, softening, and chemical addition) and final treatment
(e.g., primary ion removal and polishing).
Other significant costs should be anticipated for validation, ongoing QA/QC, as well as waste treatment and
sewerage. In addition, regulated industries must consider the risks (cost) of noncompliance and water system failures. Municipal feed water ranges from $1-3 per thousand gallons with even wider variations outside
of the U.S. Feed (surface or ground) water quality, generation technology and its associated capital cost, and
product water specifications are then utilized to determine the total pharmaceutical water system net present
value (NPV). The type of pharmaceutical water system design option selected is typically based on feed
water total dissolved solids and hardness levels, organic and colloidal content, as well as anticipated water
system utility costs (acid, caustic, salt, power, and source water). Consideration should also be given to
maintenance requirements and available resources.
Although water treatment systems for generating either compendial (USP purified) or non-compendial pharmaceutical process waters significantly vary in system operational costs, NPV for each of these various
types of process waters are quite similar. The only exception is DI process water generated through the use
of a non-regenerable mixed bed bottle system, typically regenerated off site. However, membrane based
systems do marginally produce the lowest net present values for pharmaceutical water generation. The NPV
analysis is usually based on the water system capital cost and a five-year system operating cost. The period
chosen has to be long enough to allow operating cost to be a significant factor, but short enough for reasonable analysis of operating cost returns versus increased capital expenditures.
Cost savings opportunities can be found in other places than just the quality of water and method of generation. Wastewater from the pretreatment or treatment systems can often be used for miscellaneous loads such
as lawn irrigation, humidification, boiler feed, etc. Each chapter of this Guide also addresses cost savings
issues based upon design criteria and approach for independent unit operations and systems.
3.3
SYSTEM PLANNING
High purity water and steam are the most widely used, and often the most expensive raw material or utility in
a pharmaceutical facility. Improper sizing or selection of a steam or water system could limit or even shut
down production if under sized; or compromise the reproducible quality and increase the capital cost if oversized. However, system sizing is not the starting point in design. Proper definition of water quality requirements and usage can save construction as well as operational costs.
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Figure 3-2 shows a graphic representation of the system boundaries, limitations, and restrictions the designer faces when planning a pharmaceutical water system. Initial system planning reveals primary boundaries that establish the cornerstone for design criteria. These primary system boundaries are Water Quality,
Use-Point Criteria, and System Criteria.
Mr. Shlomo Sackstein
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During initial planning, the limits of each boundary need to be established. The arrows encircling each boundary represent limitations that establish
specific operating
strategies and ranges. When documenting
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these limitations, the designer should always indicate ranges of acceptability, rather than a specific value or
position. This allows more flexibility in final planning and detailed design decisions.
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The reality of certain restrictions will sometimes force a specific strategy. As long as the decision leads to an
answer that is within the limits of the system boundaries, this is perfectly acceptable. An example is a facility
where the use-point criteria require non-compendial water with microbial control. However, there happens to
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29
WATER OPTIONS AND SYSTEM PLANNING
be an oversized WFI system in an adjacent area, so the designer decides to provide WFI to the use-point. In
the example case, documentation defining water quality should identify the quality required for the product
and why the WFI was used instead.
The primary emphasis of this section is to outline a systematic approach to planning a pharmaceutical water
system. Figure 3-2 outlines a planning methodology that begins with the selection of water quality, given its
own system constraints and limitations. Then the use point criteria are established, followed by an initial
system planning exercise. Often, these sequential steps are repeated as information in the design process
iterates, and further criteria about the overall system boundaries are identified.
Figure 3-2 Pharmaceutical Water System Planning
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WATER OPTIONS AND SYSTEM PLANNING
3.3.1
Establish Water Quality
The first step in the evaluation of water systems is the selection of water quality required for the specific
product and process operation. Selection is based primarily on the dosage and form, and the microbiological
and chemical purity criteria set for the product for which the water is used. The selection must consider
underlying factors that have impacts on quality control; installed and operating cost; maintenance and practicality.
See Section 3.2 in establishing possible water quality via development of the decision tree. Making notes as
the water quality is designated for each use-point, indicating the basis for each decision. Simple annotations
from the supporting documentation will be useful in later stages of the planning process. System design
constraints may provide the motivation to challenge water quality or other criteria, particularly when it can be
demonstrated that the change does not affect product quality or manufacturing controls.
3.3.2
Characterize Use Point
Once the initial selection of water quality has been established, the operational criteria should be characterized for each use point. A matrix should be developed to outline the primary criteria required for system
design.
Each use point should be annotated with the proper values for pressure, flow, and the temperature range of
water entering unit operation, or process point from the water supply system. Establishing a range, rather
than a fixed value, increases opportunities for system optimization by allowing a more flexible approach to
final design.
This data can be organized in many ways, but a well-planned spreadsheet can simplify the planning process
and provide clear decision pathways for future detailed design activities. Table 3-1 shows an example of a
spreadsheet used to characterize use-point flow and system demand. Flowrate is primarily used to size lines,
whereas Daily Use leads to storage and generation decisions. The Diversity Factor is one way to level-out
anticipated usage, assuming that not all loads happen every day or at the same time. This table indicates a
Clean in Place (CIP) system and stopper-washer that are both likely to be used on the same day, but never at
the same time. Therefore, only the higher flowrate is relevant to loop sizing as shown in the Design Flowrate
column. Demand flowrates are eventually used for branch line sizing.
Table 3-2
Use Point Criteria
FLOWRATE
DAILY USE
COMMENTS
EQUIPMENT
DEMAND
DIVERSITY
DESIGN
DEMAND
DIVERSITY
DESIGN
NAME
(LPM)
FACTOR
(LPM)
(LPD)
FACTOR
(LPD)
40.0
1
40.0
1200
1
1200
Assume a recirculating
cycle in 4 steps for a
total of 23 minutes.
20.0
0
460
Assume one cleaning
cycle per day, 100
liters/rinse, 3 rinse/
cycle, 1 overflow rinse/
cycle @ 2 LPM for 80
mins.
CIP Wash cycle
Stopper Washer
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0.0
460
1
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WATER OPTIONS AND SYSTEM PLANNING
Once the location and qualities are finalized, the various properties can be charted on a requirements analysis histogram. This can be done with the aid of a computer and either simulation or spreadsheet software for
larger systems, or done manually for small systems. At this point, basic Process Flow Diagrams also provide
a good pictorial view of the water qualities, locations and the point-of-use properties.
Figure 3-3 Water Usage Chart
3.3.3
Establish System Criteria
Histogram analysis is beneficial for determining overall system peak demand(s), average demand, and the
relationships between peak demand time periods and their flow rates. Figure 3-4 below shows a hypothetical
storage tank profile using the 24-hour demand profile from Figure 3-3.
There is no “Rule-of-Thumb” for minimum water level, or the optimum water level to turn on a still. However,
these charts provide the tools for creating various scenarios to simulate recovery times from a failure, future
expansion or reduction capabilities and analyze other factors that allow design of a properly sized water
generation, storage and distribution system.
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System planning and analysis also reveals other restrictions that influence design, and often lead the designer to re-evaluate the primary boundaries as discussed earlier. These restrictions might include items
such as:
•
32
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Must the system be available atID
all times?
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•
What are the constraints on a shutdown?
•
Is the plant/personnel able to handle chemicals properly? Are permits in place?
•
Is production batched or continuous?
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WATER OPTIONS AND SYSTEM PLANNING
•
Are the products dedicated or multiple product groups?
•
How is campaigning between products handled?
•
How much time is available for sanitization? Should redundancy be provided to allow adequate time for
sterilization?
Figure 3-4 Storage Tank Level Chart
3.3.4
Revisit Water Quality
With all use points characterized for temperature range, and demand, the quality of water is revisited. A
thorough review of use point criteria typically reveals a wide range of acceptable delivery conditions for the
water. Since it is typically not practical to operate multiple water systems to provide the exact water conditions
desired of the end product, compromises must be made. These compromises might include providing water
of a higher quality than required to simplify the water treatment or delivery systems, or provisions for controlling water consumption at a use point to limit peak demands. Whatever compromises are made, water must
be delivered at conditions within the boundary limits.
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3.4
SYSTEM DESIGN
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Once the support areas, back up requirements, future growth, or expansion capabilities are established,
detailed design of the system can begin. The process requirements determine all the points-of-use (POU) on
the distribution system. User locations determine how to distribute the system (e.g., central storage, multiple
loops/branches, etc.). One or several of the use points may need either different qualities or other properties
that single it out from the rest. In this case alternatives to the water system criteria are considered, such as
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WATER OPTIONS AND SYSTEM PLANNING
using an ambient or cold distribution versus a hot system. Plant shift operating hours must also be considered
since there may be an inability to perform regular heat sanitizations of cold systems, for example.
The boundaries, limitations, and restrictions that were identified in the initial planning stages should now be
integrated into the design approach. Further considerations might include the physical area a system needs
for support, one production area, one building, or multiple buildings on a site. This could determine the size of
the system and whether it is made up of multiple tanks, or multiple loop storage and distributed systems. For
example, central systems are higher in initial capital, but lower in operation and maintenance and possibly
lower overall cost on per unit basis. The capital is higher primarily due to the larger generation, storage, and
distribution equipment or system. Alternatively, multiple generation systems may require less initially for each
smaller system but more cost in terms of capital and operating and maintenance for the same total capacity.
All systems have a fixed capacity and will eventually have a failure. Therefore, if a piece of equipment fails a
plan should be in place to deal with the down time. Having backup generation equipment for the critical
components such as a still or deionization equipment, should be considered. The backup equipment can be
used in a lead-lag type operation and/or to meet a specific duration of a peak demand.
More detailed descriptions of the alternatives for the various unit operations required for production of pharmaceutical grade water are discussed in the following chapters. Rationale is provided for decisions that will
surface regarding quality, cost, performance, maintenance, and reliability as the system is developed in
detail.
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PRETREATMENT OPTIONS
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PRETREATMENT OPTIONS
4.
PRETREATMENT OPTIONS
4.1
INTRODUCTION
Pretreatment is all process steps or unit operations prior to the last (final) water treatment step. Pretreatment
is a series of unit operations to modify the feed water quality so that it will be of adequate quality to be fed to
a final treatment step. This final step may be Reverse Osmosis, Ultrafiltration, Multi or Mixed Bed Deionization
or Distillation. These final steps are discussed in Chapters 5 and 6.
Reverse Osmosis is unique since it can be a pretreatment step, in addition to being a final treatment step.
Reverse Osmosis applications in pretreatment are discussed in this chapter and Chapter 11, but Reverse
Osmosis as a technology is discussed in Chapters 5 and 6.
The initial sections of this chapter discuss the process design (programming issues) for pretreatment design
including feed water quality and output water quality from pretreatment. The chapter then discusses the
selection of treatment options (i.e. unit operations) for four groups of impurities:
•
Control of fouling--removal of turbidity and particulates
•
Control of scaling--removal of hardness and metals
•
Removal of organics and microbiological impurities
•
Removal of microbial control agents
Pre-treatment options are summarized in Figure 4-1 at the end of the chapter.
The final sections of the chapter discuss the importance of anion composition/concentration, pH, materials of
construction, and pretreatment system control.
This discussion is based on the description of these technologies presented in Chapter 11.
4.2
PROCESS DESIGN OF PRETREATMENT
Process design of the pretreatment system is the specification of the unit operations or process steps to treat
the feed water. Typical information includes flow rates, temperatures, pressure, and composition of all streams.
Detailed mechanical design of the equipment for a given unit operation or process step is beyond the scope
of this Guide.
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The process design (programming issues) for a pretreatment system may include:
a) Required quantity and quality of the water from the final treatment process.
b)
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Temperature constraints on the water used
in a pharmaceutical process and the approach to microbial
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control.
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c) The final treatment option that has been chosen, as this defines the required water quality leaving pretreatment.
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d) Quality of the feed water that is the input to the pretreatment system (water quality to be validated over a
one year period).
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PRETREATMENT OPTIONS
e) Difference between input water quality and desired output water quality. The difference determines impurities that must be removed by the pretreatment system. The difference is determined by performing a
material balance. Attention should be paid to impurities and minor components.
f)
Pretreatment options to provide the desired removal of impurities considering other factors such as
capabilities of the labor force, economics, waste disposal, environmental considerations, validation, and
the available space and utilities.
In addition to defining the options for removal of impurities, the approach taken to microbial control is an
integral part of the process design of the pretreatment system. Considerations include:
a) If the drinking quality water to the pretreatment system comes from a municipality in the United States, it
will typically contain chlorine, or chloramines, as a microbial control agent. In Europe, ozone is the more
common microbial control agent. The concentration of the agent should be sufficient to protect the initial
steps of the pretreatment.
b) If the quantity of microbial control agent is insufficient, additional microbial control agent may be added or
provision made to periodically sanitize the initial equipment in the pretreatment system. This is likely if
water comes from a source other than a municipality. Increased monitoring of feed water and the initial
steps may be warranted.
c) At some point in the pretreatment process, the microbial control agent must be removed before going to
the final treatment. At this point, a means of either continuous or periodic sanitization needs to be selected for the treatment steps following this removal.
The USP requirement that compendial waters should contain “no added substances” eliminates addition of
chemicals to “Purified Water” or Water For Injection. However, addition of chemical agents is not prohibited in
pretreatment. Substances are frequently added in pretreatment and subsequently removed in the pretreatment or final treatment. Some examples are:
•
Chlorine (to control microbial growth, removed in later stages of pretreatment)
•
Sodium ions (in softener with exchange for multivalent ions, removed in ion removal process)
•
Acid (for degasification to remove carbon dioxide, counter ions, removed in a subsequent ion removal
process)
•
Sulfite (to reduce chlorine to chloride, or chloramines, to ammonium and chloride while forming sulfate,
removal by softening or ion removal process)
•
Sequestrants (to prevent scaling in final treatment, removed by RO in final treatment)
•
pH control agents (removed in ion removal process)
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A final consideration is the relationship between investment and operating dollars in pretreatment, and the
performance and cost of the final treatment
process. The following
are generally true:
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Added substances are an issue if they result in an increase in microbial growth or endotoxins.
•
36
A final treatment system will not operate reliably over the long term, without reliable operation of the
pretreatment system.
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PRETREATMENT OPTIONS
•
Inadequate operation in pretreatment (breakthrough of particulates, hardness, or chlorine) may not immediately affect water quality from final treatment, but it will be reflected in long term maintenance and
operating reliability, and possibly in water quality.
•
Investment in pretreatment capability and reliability can return many times the investment in final treatment maintenance costs.
•
Pharmaceutical water systems are expected to generate water meeting final pharmaceutical product
water standards. The system should be designed to control impurity spikes in the incoming water quality,
or seasonal impurity profile changes. A robust pretreatment system design handles impurity spikes detrimental to final treatment.
There is no single “right” answer to the process design of the pretreatment system. Pretreatment system
process design is a series of choices and options, each with advantages and disadvantages.
4.3
FEEDWATER TO PRETREATMENT QUALITY: TESTING AND DOCUMENTATION
Compendial pharmaceutical water systems are required to use feed water complying with “Drinking Water”
standards.
Most pharmaceutical manufacturers utilize municipal water supplies. This water generally meets “Drinking
Water” quality standards and is treated with a microbial control agent. Historically in the US, the microbial
control agent is chlorine, but chloramine is now used with increasing frequency. Either feed water composition or microbial control agent concentration may be subject to occasional and seasonal variations. These
variations may negatively impact water quality, and can be detected only by extensive sampling. In addition,
water quality at the plant site may not be equivalent to that from a municipal treatment facility, due to potential
for contamination or loss of microbial control agent in the distribution system. Documentation of feed water
quality is recommended either by use of municipality testing (if applicable) supplemented by some testing at
the plant side or by extensive testing of feed water quality.
Typical contaminants in feed water include:
•
Particulates Silt, dust, pollen, pipe scale, iron and silica, undissolved minerals and organics
•
Inorganics
Calcium and magnesium salts, heavy metals (iron, aluminum, and silica) with their corresponding anions
•
Organics
NATURALLY OCCURRING BYPRODUCTS OF VEGETATIVE DECAY, I.E., HUMIC AND
FULVIC ACIDS AND “MAN-MADE ORGANICS” SUCH AS PESTICIDES AND AUTOMOTIVE POLLUTION (OILS)
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•
Bacteria
BACTERIAL CONTAMINATION AND ITS BYPRODUCTS, ENDOTOXINS, AND
PYROGENS
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Testing recommendations include:
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• Documentation that feed water
meets
drinking water
quality. This may be based on results of testing
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by the municipality, possibly supplemented by local or in-process testing. Frequency of in-process testing
will be affected by reliability of the municipality, importance of monitored variables, and company philosophy.
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PRETREATMENT OPTIONS
•
Monitoring for microbial control agent levels at the start of the pretreatment system. Chlorine level
is affected by pH. A chlorine level of 0.2 - 1.0 ppm is generally considered adequate to control microbial
growth and generally has negligible effects on pretreatment equipment or performance.
•
Specific testing for contaminants known or suspected of being present in the feed water. This is to
determine if data from the municipality is adequate; e.g., feed water from a surface source for pesticides
in an agricultural area where run off from farms may be seasonal.
4.4
OUTPUT WATER FROM PRETREATMENT: QUALITY OF FEEDWATER TO FINAL TREATMENT
The goals for pretreatment are to provide water quality that minimizes the operating and maintenance problems in the final treatment equipment and to permit the final treatment step to produce water meeting the
desired specifications for final treatment.
The impurities that must be removed in the pretreatment process to permit reliable operation of the final
treatment step depend on the final treatment step selected and the tolerance of a final treatment step for the
impurities. If pretreatment is inadequate, resulting problems can become very large in magnitude, as seen in
Table 4-1 below:
Table 4-1
IMPURITY
MAGNITUDE OF
PROBLEMS IN FINAL
TREATMENT CAUSED
BY TYPE OF IMPURITY
FOULING:
caused by
particulates
SCALING:
caused by
hardness and
minerals
CORROSION:
caused by
chlorides
DEGRADATION:
caused by
chlorine
Reverse Osmosis
Large
Large
None
Large*
Other Membrane Processes
Large-moderate
Large - moderate
None
Large*
Single Effect Distillation
Moderate
Moderate
Moderate - large
Large
Multi-effect Distillation
Large-moderate
Large - moderate
Moderate - large
Large
Vapor Compression
Distillation
Moderate
Moderate
Small
Large
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*Membrane dependent
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Pretreatment requirements for feed water to the final treatment process usually include:
FOR MEMBRANES
The concerns are fouling by suspended solids (particulates) and scaling (precipitating solids) as water is
removed. A typical goal for control in pretreatment might be a silt density index (SDI) of 3-5 and hardness of
<1 grain/gallon for on-site analysis. Membranes tolerate chlorides but only some membranes tolerate chlorine.
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PRETREATMENT OPTIONS
FOR DISTILLATION
The concerns are scale formation due to hardness and corrosion due to chlorides. Typical water quality might
be as high as 1.0 Mohm/cm, which often requires additional treatment beyond pretreatment, i.e. RO or ultrafiltration. Distillation has no tolerance for chlorine due to corrosion and carryover to the product. Distillation
has some tolerance for particulates.
Pretreatment generally has little effect on the other parameters indicative of water quality such as anions,
microbial levels, conductivity, total organic carbons (TOC), and volatiles.
Selecting pretreatment to reliably provide the required feed water quality to final treatment, in spite of spikes
in feed drinking water quality, will reduce operating and maintenance costs in final treatment.
4.5
CONTROL OF FOULING: REMOVAL OF TURBIDITY AND PARTICULATES
The principal methods for removing particulates and reducing turbidity are:
•
Clarification and the accompanying operations of flocculation, coagulation, and sedimentation
•
Depth or Media filtration including single and multimedia filtration (particles retained by the media)
The definitions, filtration mechanisms and typical removal processes for these are outlined in Chapter 11.
Clarification is not applicable, as feed water sources are potable quality or better.
Depth or media filtration is used in pharmaceutical water systems and is often the first step in a pretreatment system. Multi-sized sand is the most common media, but other media may provide better performance
with some feed waters. Removal of particulates down to 10 microns is possible and depends on selection of
media. Microbial growth is a key concern in a media filter, unless the feed water contains a microbial control
agent. Otherwise, microbial control in the depth filter is required (e.g., periodic sanitization using either heat
or a chemical sanitizing agent).
4.6
CONTROL OF SCALING: REMOVAL OF HARDNESS AND METALS
When water is separated from its impurities in the final treatment process, those compounds with low solubility are concentrated to the point where they precipitate. This precipitation, or scaling, is the result of exceeding the solubility of the divalent and trivalent cations, usually as a sparingly soluble salt such as carbonate or
sulfate. The methods of control are:
•
•
•
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Removal by ion exchange. These are principally calcium and magnesium and may include divalent and
trivalent ions such as iron, aluminum and silica. Pretreatment is usually water softening, (exchanging the
ions causing hardness and scaling for sodium ions).
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Removal of carbonate by acidification. Acidification
converts the carbonate to carbon dioxide, which is
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removed by subsequent degasification.
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Removal of the offending compound by a barrier filtration process such as nanofiltration. Water
passes through the membrane and compounds are retained by the membrane and removed as a purge
stream.
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These removal processes are detailed in Chapter 11.
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PRETREATMENT OPTIONS
Water softening ion exchange, which removes divalent and trivalent ions and replaces them with sodium, is
a very common process used in pretreatment of pharmaceutical water. It is applicable for all flow rates and all
hardness levels, and is well understood and easy to operate. It involves the handling of salt only, and produces a non-hazardous waste stream. However, the high total dissolved solids (TDS) in the waste stream
may limit disposal options. Water softening is also easily controlled manually or with a PLC.
For large flow rates (>50 gpm or 0.18 m3/min) and high hardness (>50 ppm) degasification (after acidification)
may be the process of choice. This degasification process is often employed between the two stages of an
RO and involves the handling of acid and base for two pH adjustments:
•
Lowering of pH before first stage of RO
•
Increasing of pH before second stage of RO
The principal advantage is that the carbon dioxide is released to the atmosphere rather than being a liquid
waste stream requiring disposal.
Nanofiltration is a membrane process that may be applicable with certain feed waters and specialized situations. The filtration is usually cross-flow and involves a significant purge stream. It is much like RO, the
differences being pore size in the membrane and the corresponding effect on ion removal. Removal of divalent ions can be greater than 98%.
Chemical injection is an alternate method to control the ions or compounds that contribute to scaling. This
process injects a compound (usually a proprietary organic compound) to the final treatment feed water.
These compounds are called sequestrants and act “to tie up and complex” the offending ions or compounds
to form a complex, or compound, that is more soluble and will not precipitate in the final treatment process.
The “complexed ion and sequestrant” have a large molecular weight and are removed as a purge stream in
the final treatment process. Sequestrants are almost always proprietary compounds, which require testing to
verify applicability and dosage level for the particular feed water, and analysis to verify removal in the final
treatment process.
A key choice in the process design of the pretreatment system is location of the softener. The two options are
either before or after removal of the microbial control agent (often chlorine) that is in the feed water, or which
may have been added for control of microbial growth.
Softener located prior to removal of microbial control agent: The principal advantage is protection of the
softener from microbial growth by the microbial control agent present in the feed water. If the microbial control
agent is chlorine, it will have only a minor effect on resin life and efficiency at the chlorine levels typically
encountered in chlorinated municipal feed waters (<1 ppm).
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Softener located after removal of microbial control agent: The advantage is better resin life and capacity
(due to absence of chlorine, if it is the microbial control agent). However, this must be balanced by the need
to protect the softener from microbial growth and endotoxin load (i.e., by periodic sanitization with the associated cost of heat or chemicals, labor, down time, and waste stream disposal).
4.7
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REMOVAL OF ORGANICS
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The types of organics and microbiological impurities typically present in water systems and the methods for
removal of them are discussed in Chapter 11. The methods for removal of organics are:
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•
40
Ozone
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PRETREATMENT OPTIONS
•
Strong Base Ion Exchange
•
Barrier filtration (microfiltration, ultrafiltration or Reverse Osmosis)
•
Polymer Flocculant
•
Carbon
Ozone is a powerful oxidant that controls microbial growth and reduces the concentration of organics due to
oxidation, but requires compatible materials of construction.
Strong base ion exchange removes organics but results in a purge stream containing high concentrations of
brine and organics, due to regeneration of the resin.
Barrier filtration, when appropriately sized, captures organics and microbial growth on the barrier and can be
aided by addition of a polymer flocculant. A potential problem with barrier filtration is microbial growth “growing through the barrier” which results in microbial contamination on the downstream side of the barrier.
Carbon is probably the most common method of reducing organics. It is used because it provides multiple
functions, including removal of organics as well as removal or reduction in the amount of chlorine and chloramines (if these are present and the carbon filter is appropriately designed). The advantages of using carbon are
that it is a frequently practiced technology, it performs multiple functions, and effectively “cleans up the feed
water”, and microbial growth can be controlled by periodic sanitization. The disadvantage is that it is a source
of microbial growth, as well as a source of nutrients.
4.8
SYSTEM DESIGN FOR CONTROL OF MICROBIAL GROWTH
The methods for control of microbial growth are summarized in Chapter 11. The methods used in pretreatment to control microbial growth are:
•
Microbial control agent such as chlorine or chloramine
•
Periodic sanitization (heat or chemical)
•
Ultraviolet light
•
Avoiding dead legs and avoiding water stagnation
A common strategy in the design of the pretreatment system is to leave the microbial control agent provided
by the municipality in the water through as many pretreatment steps as possible, in order to protect these
steps from microbial growth.
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However, at some point the microbial control agent (chlorine or chloramine) must be removed since it is not
compatible with the final treatment processes. At this point, the only option is periodic sanitization, either with
heat or a chemical disinfectant. This must be included in the design of the pretreatment system, along with
the provisions for validation and monitoring its effectiveness via sampling and testing. If a chemical disinfectant is used, provisions to remove it and monitor its removal are also required.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Ultraviolet light (UV) is effective in inhibiting microbial growth but is only effective when the light is present. UV
light is often used before a unit operation to minimize the microbial growth in the unit operation by controlling
the microbial counts in the feed water. The most common places for use of UV light are before Reverse
Osmosis units and some filters.
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PRETREATMENT OPTIONS
4.9
REMOVAL OF MICROBIAL CONTROL AGENTS
At some point in pretreatment, microbial control agents must be removed because of their detrimental effect
on final treatment equipment and performance. Chlorine causes deterioration of most Reverse Osmosis
membranes and is corrosive in distillation. Chloramines can pass through pretreatment and decompose in
the distillation process with an adverse effect on water quality.
The methods for removal of chlorine and chloramines are similar and are detailed in Chapter 11.
For chlorine removal, activated carbon is a straightforward process for the absorption of chlorine. The carbon
will reduce some of the chlorine to chloride ion, which is then removed in the final treatment ion removal
process. Sulfite reduction is also straightforward, with sulfite being oxidized to sulfate and chlorine being
reduced to chloride ion.
Chloramine removal is more complex. Chloramine adsorption on carbon occurs at a much slower rate than
chlorine, necessitating longer contact times and lower hydraulic flow rates. The potential for dissociation of
the absorbed chloramines into ammonium ion and ammonia is a problem. Ammonium is removed by Reverse
Osmosis but decomposes to ammonia in a distillation process. Ammonia passes through both Reverse
Osmosis and distillation processes in final treatment.
Sulfite reduction for chloramines results in ammonium and chloride ions. These can be removed by Reverse
Osmosis. The ammonium ion partially decomposes to ammonia in the higher temperature distillation process, resulting in carryover and affect on the water quality.
Removal of ammonia (from chloramine) and carbon dioxide requires proper pH control to maintain these
species as ions for removal in an RO. The equilibrium of carbonate, bicarbonate, and carbon dioxide is pH
dependent, with alkaline conditions required to maintain the ionic species. The equilibrium between ammonium and ammonia is pH and temperature dependent, with acidic conditions required to maintain the ionic
species. At no single pH point are these species all carbonate and ammonium ions. Thus two pH adjustment
steps followed by the appropriate removal technologies are required to remove both chloramines and carbon
dioxide.
4.10
CHANGES IN ANION COMPOSITION / CONCENTRATION
Pretreatment systems typically remove non-ionic impurities and cations. Thus, any change in anionic composition or concentration is usually secondary. However, some distillation processes in final treatment are affected by chlorides, which can be removed by an RO prior to the final treatment step.
The pretreatment processes that affect anionic composition are:
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•
Deionization
•
Degasification
•
Mr. Shlomo Sackstein
Carbon bed filtration for removal of chlorine
and chloramine
Herzlia,
Reduction to remove chlorine and
IDchloramine
number: 216389
•
Barrier filtration (nanofiltration, ultrafiltration and Reverse Osmosis)
•
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Ion exchange resins are designed to remove either cations or anions. An ion exchange resin that is designed
to remove anions (anionic resin) will typically exchange the anions (chloride, sulfate, nitrate, and carbonate;
42
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PRETREATMENT OPTIONS
and bicarbonate if the pH is appropriate) for the hydroxyl ion. The ion exchange may be in a single bed, mixed
beds, or twin beds and will affect anionic composition if an anionic resin is present. Ion exchange as a
deionization process to specifically remove anions is discussed in Chapter 5.
Degasification and the accompanying process of acidification, for removal of hardness, changes anionic
composition. The water is acidified with a non-volatile acid (usually sulfuric, based on cost and ease of
removal of the resulting anion i.e., sulfate) to convert carbonate and bicarbonate to dissolved CO2, which is
removed by degasification. The net effect is replacement of bicarbonate and carbonate with sulfate, (see
Chapter 11).
As discussed above, carbon bed filtration adsorbs chlorine and chloramines from feed water. However, some
of the chlorine is reduced to chloride and is removed in a subsequent ion removal process, usually in final
treatment.
The removal of chlorine and chloramines by reduction, often with bisulfite, changes ionic composition, and
concentration, as the bisulfite is oxidized to sulfate and the chlorine, or chloramines, are reduced to chloride
and ammonium.
Some barrier filtrations (particularly nanofiltration) remove some of the larger anions. Reverse Osmosis may
be used to remove chloride ion prior to some distillation processes.
4.11
THE IMPORTANCE OF PH IN PRETREATMENT
The effect of pH on the equilibrium between carbonate, bicarbonate, and carbon dioxide is discussed in
Chapter 11.
EPA drinking water standards require a pH range of 6.5-8.5. In reality, the pH range of most drinking feed
water is narrower, due to the corrosive nature of acidic water and the scaling potential of alkaline waters.
The pH of the feed water and its seasonal variations need to be known because of its impact on pretreatment
and final treatment process design. The pH determines the form of the carbon dioxide, its scaling potential
and where carbon dioxide (carbonate) is removed (see Chapter 11).
A complicating factor in pretreatment design is the potential presence of ammonia as a result of chloramine
presence in the feed water. Ammonia is a dissolved gas at the pH values where carbon dioxide is an ion
(carbonate), and exists an ion (ammonium) at pH values where carbon dioxide exists as a dissolved gas.
Thus it is not possible remove both carbon dioxide and ammonia at one pH. If both are present, two pH
adjustment steps are required:
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pH adjustment followed by removal of either carbon dioxide or ammonia
•
A change in pH to remove the other compound
Mr. Shlomo Sackstein
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MATERIALS OF CONSTRUCTION
AND CONSTRUCTION
PRACTICES
ID number:
216389
These operations may be part of pretreatment or final treatment.
4.12
Piping to the pretreatment system may be copper, galvanized steel, or a suitable thermoplastic. Piping in the
pretreatment system, where high temperatures are not encountered, is usually plastic (PVC, CPVC, polypropylene, or other material) based upon cost and corrosion resistance. Leaching from some plastics such as
PVC and CPVC may make these materials undesirable to the user. Vessels may be fiberglass, lined carbon
steel, or stainless steel.
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PRETREATMENT OPTIONS
The piping and equipment in a portion of the pretreatment system may encounter high temperature (periodic
heat sanitization) or high pressure (RO plus degasification). In these portions, piping is typically stainless
steel or a plastic that can be heat sanitized, such as PVDF. Equipment designed for high pressure may be
carbon steel, lined carbon steel, or stainless steel. Mill finish is satisfactory for these materials; electropolishing
is unnecessary.
The cost of sanitary construction practices such as orbital welding and sanitary fittings may not be warranted
in the pretreatment system. Use of plastic pipe that is solvent cemented or heat fused, stainless steel pipe
that is welded or flanged with mill finish, or tubing with compression fittings is common. Ball or diaphragm
valves predominate for flow diversion, with globe and needle valves for flow control. Selecting the minimum
cost piping components that will not degrade water quality is an area for major cost savings.
Sample points should be provided upstream and downstream of each piece of equipment for monitoring and
for troubleshooting. Points for field measurement of pressure and temperature are also useful for troubleshooting.
4.13
PRETREATMENT SUMMARY
The philosophy of control selected for pretreatment can have a major impact on both investment and continuing operating cost. Reliable operation and control of pretreatment can significantly reduce operating and
maintenance costs in final treatment. The important process steps in pretreatment are:
•
Removal of turbidity and particulates to minimize membrane and equipment fouling
•
Removal of hardness and metals to prevent scale formation in final treatment
•
Removal of organics and microbiological impurities
•
Control of microbial growth and removal of microbial control agents to prevent degradation of final treatment
These process steps are important because of their immediate effect on water quality from final treatment or
their long-term effect on final treatment equipment performance and hence, their indirect effect on water
quality from final treatment.
Pretreatment, like other parts of the water treatment system, should be subject to Good Engineering Practices. Validation of pretreatment, as a component of the water treatment system, is required as part of the
entire water treatment system validation and should include microbiological monitoring.
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PRETREATMENT OPTIONS
Figure 4-1
Note:
The order of unit operations may be different than shown.
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Herzlia,
ID number: 216389
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45
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Herzlia,
ID number: 216389
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FINAL TREATMENT OPTIONS:
NON-COMPENDIAL and COMPENDIAL
PURIFIED WATER
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Herzlia,
ID number: 216389
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Herzlia,
ID number: 216389
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.
FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.1
INTRODUCTION
This chapter discusses the final treatment technologies and basic system configurations related to the manufacturing process of USP Purified Water and non-compendial water.
Various system configurations are presented, and reflect a significant shift from ion exchange based systems
to membrane based systems. Equipment and system materials, surface finish and other design factors are
discussed to promote the use of Good Engineering Practice for proper selection of components, piping,
instrumentation, and controls.
USP Purified Water and non-compendial water can be produced by an almost unlimited combination of unit
processes in various configurations. The most common pretreatment and final treatment technologies used
in purified water production are shown in Figure 5-1, Figure 5-2, and Table 5-4 at the end of the chapter. This
chapter discusses the final treatment unit processes currently utilized, including ion exchange, reverse osmosis, electrodeionization, ultrafiltration, microfiltration, and ultraviolet light. These technologies as well as
distillation (see Chapter 6) are utilized in thousands of systems for the successful production of purified and
non-compendial water.
Ion exchange based systems were the dominant systems for decades in purified water production and are
still successfully utilized in facilities today. The last decade has seen the growth of reverse osmosis membrane based systems increase to the point where over 90% of new systems employ primary reverse osmosis, with final polishing by continuous electrodeionization, ion exchange, or a second reverse osmosis stage.
Membrane based systems usage has increased due to chemical consumption reduction, contaminant rejection (ionized solids, organics, colloids, microbes, endotoxins, and suspended solids), reduced maintenance,
consistent operation, and effective lifecycle cost.
The various membrane based system configurations are compared with ion exchange and distillation in Table
at the end of this chapter.
Equipment construction is discussed for each unit process section to promote proper selection of materials,
surface finishes, and other design factors. The total system capital cost is influenced more by equipment
design details than by process selection. Many aspects of equipment can be “overdesigned” and hence,
become unnecessarily costly. Proper thought must be given to the individual component’s function, location,
required microbial performance, sanitization, and other factors, to optimize design. It is not necessary to
construct every makeup system component with the same level of surface finish and detail as the distribution
system for successful operation in most cases.
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Many material selections are made erroneously to conform to cGMP requirements that do not actually dictate
the details of construction for most final treatment components. Good Engineering Practice should be employed to optimize the system for consistent operation to specifications and lifecycle cost optimization. Part of
the consideration is the need to replace system components (e.g., filters, RO membranes) at a frequency
that meets GMP.
Mr. Shlomo Sackstein
Herzlia,
This chapter does not differentiate between compendial and non-compendial water system equipment. Noncompendial water is often manufactured
validated in a 216389
manner consistent with compendial water.
ID and
number:
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.2
ION EXCHANGE
5.2.1
Description
Cation and anion exchange resins are regenerated with acid and caustic solutions, respectively. As water
passes through the ion exchange bed, the exchange of ions in the water stream for the hydrogen and hydroxide ions, held by the resin, occurs readily and is driven by concentration. Thus, the regeneration process is
driven by excess chemical concentrations. The important parameters of this system include resin quality,
regeneration systems, vessel linings, and waste neutralization systems. The operation of the system can be
monitored by conductivity (resistivity) of the product water.
A two-bed ion exchange system includes both cation and anion resin tanks. Two-bed ion exchange systems
often times function as the workhorse of a strictly deionization (DI) water system in terms of salt removal.
Mixed-bed ion exchange systems are typically used as a secondary or “polishing” system. Mixed-bed DI units
consist of a single tank with a mixture of anion and cation removal resin. A cation bed can also be used as a
“polishing” DI step, rather than a mixed-bed DI.
Ion exchange resins are available in on-site and off-site regenerable systems. On-site regeneration requires
chemical handling and disposal, but allows for internal process control and microbial control. Off-site regeneration can be accomplished through new resin to be used one time, or through repeated regeneration of the
existing resin. New resin provides greater capacity and some possible quality control advantages, but at a
higher cost. Regenerated resin produces a lower operating cost, but may raise quality control issues, such as
resin segregation, regeneration quality, and consistency.
Additional details on ion exchange can be found in Chapter 11.
5.2.2
Application
The major purpose of ion exchange equipment in USP purified water systems is to satisfy the conductivity
requirements of the USP. Deionization (DI) systems are often times used alone or in conjunction with reverse
osmosis to produce USP Purified Water. Typical ion exchange systems do not effectively remove other contaminants noted in the USP purified water specification. In the ion exchange process, salt ions, which are
common to potable water, are removed from the water stream and replaced with hydrogen and hydroxide
ions. Ion exchange systems are available in various configurations that include two-bed DI and mixed-bed DI.
Both configurations are available in on-site and off-site regeneration systems.
5.2.3
Pretreatment Requirements
Ion exchange systems require pretreatment to remove undissolved solids from the water stream and to avoid
resin fouling or degradation. Although dechlorination is also recommended to avoid resin degradation by
oxidation, the low levels of chlorine commonly found in most potable water supplies normally demonstrate
only long-term effects on most ion exchange resins.
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Herzlia,
Most of the cost savings opportunities for these systems revolve around the correct choices in materials of
construction, pretreatment options, instrumentation,
and sizing
of the DI system. Acceptable piping materials
ID number:
216389
5.2.4
Cost Savings Factors
of construction can vary from PVC to 316L SS. A correctly designed system will minimize the equipment size
and maximize the amount of time between regenerations, considering microbial control and maintenance.
Choosing to monitor only the critical parameters such as conductivity (resistivity), flow, pressure, etc., can
minimize instrumentation.
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
There are also cost savings choices that will need to be made with respect to capital purchase and on-going
operating costs. These choices will steer you towards DI off-site regenerable bottles, on-site regenerable DI
vessels (with automatic or manual controls) or another water treatment unit operation.
5.2.5
Advantages and Disadvantages
Advantages:
•
Simple design and maintenance
•
Flexible in water flow production
•
Good upset recovery
•
Low capital cost for single train DI systems
•
Removes ionizable substances (ammonia, carbon dioxide, and some organics)
Disadvantages:
•
High cost of operations on high total dissolved solids (TDS) in-feed-water
•
Requires chemical handling for on-site regenerable DI (safety and environmental issues)
•
Full on-site DI system can take significantly more floor space due to primary vessels, chemical storage,
and neutralization system
•
Off-site DI systems will require outside service and significant costs for regeneration services
•
Off-site regeneration involves consequent loss of control over the use, handling, and care of DI vessels
•
DI vessels are excellent places for microbial growth to occur between regenerations
5.2.6
Sanitization
All ion exchange resins can be sanitized chemically with various agents. The degree of resin attrition is a
function of resin type and the chemical agent. Chemical cleaners include peracetic acid, sodium hypochlorite,
and others. Some resins are capable of hot water sanitizations at temperatures between 65°C to 85°C. Ion
exchange resins suitable for limited thermal sanitizations include: strong acid cation resin, and standard
polystyrene cross-linked with divinylbenzene Type 1 strong base resin.
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
Table 5-1
Comparison for ion exchange unit operations
Off-Site Regenerated
On-Site Regenerated
Chemical Use:
N/A
Extensive
Sanitization Method:
Change Out or Hot Water
Regenerate
Capital Cost:
Minimal
Extensive
Water Consumption:
None
Medium
Energy Consumption:
Minimal
Minimal
Maintenance Requirements:
Minimal
Medium
Outside Service Used:
Extensive
Low
Reliability:
Good*
Good
Upset Recovery Operations:
Good, Replace
Good
*Note: Having the DI bottles regenerated by an outside service does not relieve the manufacturer of the
responsibility to have quality control of their ion exchange system.
Table 5-2
Limits of Operation and Expected Performance
Feed Quality:
• Total Suspended Solids (turbidity):
• Filtration of 10 micron is recommended
• Chlorine Tolerance:
• Varies with type of resin, generally at 0.5 ppm,
some resins are rated up to 1 ppm
• Total Dissolved Solids (TDS):
• < 200 ppm, operation at higher TDS levels is
possible but operating costs can be high
• Temperature:
• Most cation resin up to 121°C; most anion resin
40-70°C; some anion resin up to 100°C
• Conductivity:
• Can achieve conductivity below 1.0
microsiemen/cm depending on the system
pretreatment and regeneration schedule
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Regeneration and Chemical Efficiency:
• Linear variation is inverse to the feed water total
ID number:
216389
dissolved solids - best below 200 ppm
• Feed TOC:
• Product TOC:
50
• Ability to avoid
varies with type of resin
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• May increase or decrease incoming TOC levels
depending on resin type and feed water - difficult
to predict.
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5.3
CONTINUOUS ELECTRODEIONIZATION (CEDI)
5.3.1
Description
Electrodeionization removes ionized or ionizable species from water using electrically active media and an
electrical potential to effect ion transport. Electrodeionization is distinguished from electrodialysis or oxidation/reduction processes by the use of electrically active media, and is distinguished from other ion exchange
processes by the use of an electrical potential.
The electrically active media in electrodeionization devices functions to alternately collect and discharge
ionizable species and to facilitate the transport of ions continuously by ionic or electronic substitution mechanisms. Electrodeionization devices may comprise media of permanent or temporary charge and may be
operated batchwise, intermittently, or continuously. The devices can be operated so as to cause electrochemical reactions specifically designed to achieve or enhance performance and may comprise electrically
active membranes such as, semi-permeable ion exchange or bipolar membranes.
The continuous electrodeionization (CEDI) processes are distinguished from the collection/discharge processes (such as electrochemical ion exchange or capacitive deionization) in that the process is continuous
rather than batch or intermittent, and that the ionic transport properties of the active media are a primary
sizing parameter, as opposed to ionic capacity. Continuous electrodeionization devices typically comprise
semi-permeable ion exchange membranes, permanently charged media, and a power supply that can create
a DC electrical field.
A continuous electrodeionization cell is formed by two adjacent ion exchange membranes or by a membrane
and an adjacent electrode. CEDI units typically have alternating ion depleting (purifying) and ion concentrating cells that can be fed from the same water source, or different water sources. Water is purified in CEDI
devices through ion transfer. Ionized or ionizable species are drawn from the water passing through the ion
depleting (purifying) cells into the concentrate water stream passing through the ion concentration cells.
The water that is purified in CEDI units passes only through the electrically charged ion exchange media, and
not through the ion exchange membranes. The ion exchange membranes are permeable to ionized or ionizable species, but not permeable to water.
The purifying cells typically have permanently charged ion exchange media between a pair of ion exchange
membranes. Some units incorporate mixed (cationic and anionic) ion exchange media between a cationic
membrane and an anionic membrane to form the purifying cell. Some units incorporate layers of cation and
anion ion exchange media between ion exchange membranes to form the purifying cell. Other devices create
single purifying cells (cationic or anionic) by incorporating a single ion exchange medium between ion exchange membranes. CEDI units can be configured with the cells in a plate and frame, or spiral wound configuration.
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The power supply creates a DC electric field between the cathode and anode of the CEDI device. Cations in
the feed water stream passing through the purifying cell are drawn to the cathode. Cations are transported
through the cation exchange media and either pass through the cation permeable membrane or are rejected
by the anion permeable membrane. Anions are drawn to the anode and are transferred through anion exchange media and either pass through the anion permeable membrane or are rejected by the cation permeable membrane. The ion exchange membranes are oriented in a manner which contains the cations and
anions removed from the purifying cells in the concentrating cells so that the ionic contaminants are removed
from the CEDI unit. Some CEDI units utilize ion exchange media in the concentrating cells, while others do
not.
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As the ionic strength of the purified water stream decreases the high voltage gradient at the water-ion exchange media interfaces can cause water decomposition to its ionic constituents (H+ and OH-). The H+ and
OH- ions are created continuously and regenerate the cation and anion exchange media, respectively, at the
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
outlet end of the purifying cells. The constant high level of ion exchange media regeneration level allows the
production of high purity water (1 to 18 Mohm-cm) in the CEDI process.
5.3.2
Application
In some cases, where drug microbiological quality is of lesser concern, CEDI units may be utilized down
stream of reverse osmosis (RO) units in production of USP Purified Water or non-compendial water to increase the life of the CEDI units. For USP WFI water, the CEDI units are utilized up stream of reverse osmosis
(RO) units.
5.3.3
Limitations
CEDI units cannot remove all contaminants from water. The principal removal mechanism is for ionized or
ionizable species. CEDI units cannot purify 100% of the feed water stream, as a concentrate stream is always
required to remove the contaminants from the system. CEDI has temperature limitations for practical operation. Most CEDI units are operated between 10 - 40°C (50 - 104°F).
5.3.4
Pre-treatment Requirements
CEDI units must be protected from scale formation, fouling and thermal or oxidative degradation. The RO/
pretreatment equipment typically reduces hardness, organics, suspended solids, and oxidants to acceptable
levels.
5.3.5
Performance
CEDI unit performance is a function of feed water quality and unit design. Ionized solids reduction is generally
greater than 99% allowing production of 1 - 18 Mohm-cm quality water from reverse osmosis feed water.
Organic rejection typically varies from 50% to 95% depending upon the type of organic material present in
the feed stream. Ultraviolet light (185 nm) upstream of CEDI units can substantially increase organic rejection. Dissolved carbon dioxide is converted to bicarbonate ion and removed as dissolved ion. Dissolved silica
removal is in the range of 80 - 95%, dependent upon operating conditions.
5.3.6
Cost Savings Factors
Most of the cost savings opportunities revolve around the correct choices in materials of construction, instrumentation, and post-treatment equipment selection. Acceptable materials of construction for piping can vary
from PVC to 316L SS. Choosing to monitor only the critical parameters, such as resistivity, flow, and pressure
can minimize instrumentation. Many applications for Purified Water require no post-treatment after
electrodeionization. Some systems incorporate ultraviolet light and/or sub-micron filtration to either reduce
sanitization requirements or to provide microbial levels well below those allowed for Purified Water production
as outlined in the USP.
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5.3.7
Advantages and Disadvantages
Mr. Shlomo Sackstein
Herzlia,
Attainment of stage 1 conductivity
ID number: 216389
Advantages:
•
•
52
Elimination of chemical handling
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•
Elimination of outside service (off-site regenerated resin)
•
Electric field in membrane/resin module provides some bacterial control
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
•
Removal of ionizable substances (e.g., carbon dioxide, ammonia, and some organics)
Disadvantages:
•
Does not remove non-ionic contaminants
•
Unique designs for each manufacturer (modules are not interchangeable)
•
May require UV, sub-micron filtration, or reverse osmosis (RO) for further bacterial reduction
•
May require reverse osmosis pretreatment
•
Rinse up after chemical sanitization may take hours to reach peak resistivity and TOC
5.3.8
Sanitization
CEDI units are typically chemically sanitized with a number of agents including: peracetic acid, sodium
percarbonate, sodium hydroxide, hydrogen peroxide, and others.
5.4
REVERSE OSMOSIS
5.4.1
Description
Reverse osmosis (RO) is a pressure driven process utilizing a semi-permeable membrane capable of removing dissolved organic and inorganic contaminants from water. A semi-permeable membrane is permeable to
some substance such as water, while being impermeable to other substances such as many salts, acids,
bases, colloids, bacteria, and endotoxins.
RO membranes are produced commercially in a spiral wound configuration for pharmaceutical water production. Membranes are available in two basic materials; cellulose acetate and thin film composite (polyamide).
All of the membrane types have advantages and disadvantages. Membrane operating parameters are shown
in Table 5-3, below.
RO membranes without leading edge brine seals, allow controlled flow between the membranes and pressure vessels to minimize bacterial growth.
Table 5-3
RO Membrane Operating Parameters
Cellulose Acetate
4-7
1.0
Poor
15-28
90-98
30
30-1000
5
Polyamide/TFC
2-11
0.05*
Good
5-50
97-99
50-80
30-1000
5
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pH
Chlorine Limit, mg/l
Resistance to Bacteria
Operating Temperature Range °C
Rejection - %
Sanitization Temp. Limit, °C
Typical TDS Feed Range, mg/l
Silt Density Index, Max
*BEST OPERATION AT 0.0
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.4.2
Application
Reverse osmosis can be successfully implemented in pharmaceutical systems in several ways. RO units can
be utilized upstream of regenerable deionizers, or off-site regenerated deionizers, to reduce regenerant acid
and caustic consumption, or to minimize resin replacement costs. Two-pass RO units (product staged) with
proper pH control are generally capable of producing water that meets the requirements of the USP for TOC
and conductivity.
5.4.3
Limitations
Reverse osmosis cannot remove 100% of contaminants from water and has very low to no removal capacity
for some extremely low molecular weight dissolved organics. RO, however, quantitatively reduces bacteria,
endotoxins, colloids and high molecular weight organics from water.
RO cannot purify 100% of a feed water stream. A concentrate flow is always necessary to remove the
contaminants that are rejected by the membrane. Many users of RO utilize the waste stream from the RO unit
for cooling tower make-up water or compressor cooling water, etc.
Carbon dioxide passes directly through the RO membrane and CO2 will be in RO product stream at the same
level that present in the feed water stream. Excess carbon dioxide in the RO product stream may increase the
product conductivity beyond the USP Stage 1 limit. Carbon dioxide contributes to the loading of anion resin,
which may be downstream of the RO units.
Reverse osmosis has temperature limitations for practical operation. Most RO systems operate on feed water
between 5°C and 28°C.
5.4.4
Pretreatment Requirements
Reverse osmosis membranes must be protected from scale formation, membrane fouling, and membrane
degradation. Scaling is possible since the contaminants present in the feed water stream are being concentrated into the waste stream, which is an average of 25% of the feed stream. Scale control is normally
prevented by the use of water softening upstream of the membranes, the injection of acids to lower the pH of
the feed water stream, or an anti-scalant compound to prevent precipitation.
Reverse osmosis membrane fouling is reduced through the use of back-washable multi-media filters or cartridge filters for suspended solids, greens and filtration or softening for colloidal iron removal, and various
microbial control pretreatment methods to reduce biological fouling.
The principal causes of membrane degradation are oxidation of certain membrane materials and heat degradation. Membranes, which cannot tolerate chlorine normally, incorporate activated carbon or injection of
various sodium sulfite compounds for dechlorination. Protection against high temperature is normally incorporated where the feed water is preheated and the membrane material cannot tolerate high temperature.
This Document is licensed to
The reverse osmosis pretreatment unit operations are reviewed in Chapter 4.
Mr. Shlomo Sackstein
5.4.5 Performance
Herzlia,
A single stage of reverse osmosis elements
typically reduces
the level of raw water salts, colloids, organics,
ID number:
216389
bacteria, and endotoxin by 90 to 99%. Single stage reverse osmosis product water does not normally meet
the requirements of the USP without further purification steps. Some two-pass units (two sets of RO membranes in series) produce water that can pass the USP 24 Stage 1 conductivity requirements, allowing OnLine testing. Those units that do not meet the Stage 1 requirement normally meet Stage 2 or 3. Membrane
selection should be based upon pretreatment requirements, operating performance characteristics, sanitization options, warranties, capital and operating costs, and the feed water source.
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54
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5.4.6
Advantages and Disadvantages
Advantages:
•
Reverse osmosis units eliminate or significantly reduce chemical handling and disposal, relative to regenerable ion exchange systems
•
Generally, RO has more effective microbial control than ion exchange systems
•
Integrity testing can be accomplished by salt challenge and measurement of differential conductivity
•
RO removes a wide variety of contaminants including ionized solids and non-ionic materials (e.g., colloids, bacteria, endotoxin, and some dissolved organics)
Disadvantages:
•
Water consumption can be significantly higher than ion exchange systems unless the wastewater is
reused
•
Energy consumption is generally higher than ion exchange and less than distillation
•
No removal of dissolved gases (e.g., carbon dioxide and ammonia)
5.4.7
Cost Saving Factors
Capital costs can be minimized by reducing membrane area to the minimum suitable for the feed water
quality and membrane selected. Piping material and finish significantly impact capital cost. Some systems
incorporate PVC low-pressure piping and welded mill finish stainless steel high-pressure piping. Instrument
costs can be minimized by appropriate selection of critical and non-critical parameters of operation. These
parameters include:
•
Flow
•
Pressure
•
Temperature
•
Conductivity
5.4.8
Waste Water Reuse
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RO wastewater is frequently used as cooling tower make-up, or for non-contact cooling for compressors, or
other heat loads. Wastewater is sometimes re-purified in a wastewater reverse osmosis unit for reintroduction
as system feed water. RO wastewater is sometimes used for filter backwash. The wastewater from the second pass of a two pass RO is normally returned to the feed water stream of the first pass RO.
5.4.9
Sanitization
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
All RO membranes can be sanitized with some chemical agents that vary as a function of membrane selection. Specially constructed membranes are available for hot water sanitization at 60° to 80°C.
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55
FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.5
POLISHING COMPONENTS - NON-IONIC CONTAMINANTS REDUCTION
5.5.1
Ultrafiltration
5.5.1.1 Description
Ultrafiltration (UF) is a cross-flow process similar to reverse osmosis (RO). A pressurized feed stream flows
parallel to a porous membrane filtration surface. A pressure differential forces water through the membrane.
The membrane rejects particulates, organics, microbes, pyrogens, and other contaminants that are too large
to pass through the membrane. UF does not reject low molecular weight ionic contaminants, as does reverse
osmosis.
Membranes are available in both polymeric and ceramic materials. Polymeric membrane elements are available in spiral wound and hollow fiber configurations. Ceramic modules are available in single channel and
multiple channel configurations.
5.5.1.2 Application
Ultrafiltration is utilized in several ways in Purified Water systems. UF is frequently used down stream of ion
exchange processes for organic, colloidal, microbial, and endotoxin reduction. Purified Water with low endotoxin levels (<0.25 Eu/ml) is utilized by some manufacturers in ophthalmic solutions, topicals, and bulk pharmaceutical chemicals that will be utilized in parenteral manufacturing and other applications.
Ultrafiltration is frequently used in still feed water systems, in combination with ion exchange, to limit the
endotoxin and colloidal silica feed levels to the still.
5.5.1.3 Limitations
Ultrafiltration cannot remove 100% of contaminants from water. No ionic rejection occurs and organic rejection varies with the various membrane materials, configuration, and porosity. Many different nominal organic
molecular weight rejection ratings are available. Dissolved gasses are not rejected by UF.
Most ultrafilters require a waste stream to remove the contaminants on a continuous basis. The waste stream
varies, but is usually two to ten percent. Some UF systems run dead-ended.
5.5.1.4 Pretreatment Requirements
Pretreatment can include multimedia filters, activated carbon filters, ion exchange, membranes, or others.
The UF flux rate and cleaning frequency vary widely as a function of feed water and pretreatment. Most UF
membranes are chlorine tolerant and do not require dechlorination of the feed water.
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5.5.1.5 Performance
UF is utilized to remove a variety of contaminants. The proper UF membrane must be selected to meet the
performance requirements. Organic molecules can be rejected well, but the rating of UF membranes varies
in molecular weight cutoffs from 1,000 to 100,000. Reduction of typical raw water organics is not as effective
as reverse osmosis. Pressure drops vary with membrane selection and operating temperature. Some UF
membranes are capable of continuous operation at temperatures up to 90OC, to provide excellent microbial
control.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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UF reduction of endotoxin (pyrogens) varies from 2 log10 to 4 log10 as a function of membrane selection. UF
has been shown to be capable of consistent production of water meeting the USP WFI endotoxin limit of 0.25
Eu/ml in typical system applications. UF produces excellent microbial reduction with typical ratings of 3 log10
to 4 log10 reduction.
56
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
UF produces excellent particle reduction and is frequently used in other applications, such as semiconductor
production when particle control is far more critical than pharmaceutical water.
5.5.1.6 Advantages and Disadvantages
Advantages:
•
UF can remove some contaminants, such as endotoxin and organics, better than microfiltration
•
UF can have more effective operating costs than microfiltration, in high particle loading applications.
•
Some UF elements can tolerate more rigorous sanitization procedures using steam or ozone, than some
other membrane filters (MF or RO).
•
The waste stream is generally much less than waste from reverse osmosis units
•
Ultrafiltration is generally less energy intensive than reverse osmosis
Disadvantages:
•
UF cannot remove ionic contaminants, where reverse osmosis can
•
UF generally requires a waste stream, which can be a significant cost factor
•
UF membranes are sometimes more difficult to integrity test than microfiltration cartridges
5.5.1.7 Cost Savings Factors
Capital costs can be influenced by the optimum sizing of membrane area and membrane selection. Piping
material and finish significantly impact capital cost. Some systems incorporate various plastic piping materials while others utilize sanitary 316L SS. The sanitization method selected is a major factor in material selection. Instrument costs can be minimized by appropriate selection of critical and non-critical parameters of
operation.
5.5.1.8 Sanitization
UF membranes are sanitized in many different ways. Most polymeric membranes are tolerant of a wide
variety of chemical sanitizing agents such as sodium hypochlorite, hydrogen peroxide, peracetic acid, sodium hydroxide, and many others. Some polymeric membranes can be hot water sanitized and some can
even be steam sanitized.
This Document is licensed to
Ceramic UF elements can tolerate all common chemical sanitizing agents, hot water, steam, and ozone in
sanitization or sterilization procedures.
Mr. Shlomo Sackstein
Herzlia,
Most pharmaceutical UF units are fed deionized water for USP Purified Water production or special noncompendial water applications. TheID
wastewater
is therefore216389
still low conductivity water that can be recycled
number:
5.5.1.9 Waste Water Recovery
upstream to reverse osmosis units or fed directly to boilers, cooling towers, or other uses.
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.5.2
Microfiltration
5.5.2.1 Description
Microfiltration is a membrane process utilized for the removal of fine particles and microorganisms. No waste
stream is generally employed in microfiltration processes. Virtually all microfiltration cartridges are disposable and are available in a wide range of materials and pore sizes. In final filtration the filters general range
from 0.45 microns down to 0.04 microns. Microfilters are used in a wide range of applications, including
aseptic filling of pharmaceutical products, which are not tolerant of terminal sterilization.
Microfilters are generally employed in purified water systems for microbial retention downstream of components where some microbial growth may exist. Microfilters can be extremely effective in this area, but operating procedures must be in place to assure filter integrity during installation and membrane replacement to
insure proper performance. Microfilters are most appropriately employed in central purified water production
systems and their use is discouraged in distribution systems. The filters should not be the only microbial
control unit operation in the system. They need to be a part of a comprehensive microbial control plan.
Minimizing the number of locations of microfiltration makes proper maintenance easier. (See Chapter 8.)
5.5.2.2 Advantages and Disadvantages
Advantages:
•
Simple design and maintenance
•
Flexible in water flow production
•
No waste stream
•
Cartridges are integrity testable
•
Heat and chemical sanitization of microfilters
Disadvantages:
•
Can only be used as a safety net for microbial production
•
No ion or endotoxin removal
•
Shorter life due to dead head design, so replacement is required
•
Not recommended for use in distribution piping
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5.5.2.3 Performance
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Microfiltration can be as effective as ultrafiltration in microbial reduction and can minimize water consumption, as no waste stream is necessary. Microfiltration, however, cannot reduce dissolved organic levels as
ultrafiltration can, and microfiltration cannot remove particles as small as ultrafilters can, due to the difference
in pore size. Heat and chemical sanitization of microfilters is possible with the proper selection of material.
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
5.5.3
Ultraviolet Light Treatment
5.5.3.1 Description
Ultraviolet light rays strike microorganisms (bacteria, virus, yeast, mold, or algae) and break through their
outer membrane to modify the DNA. The modified DNA code brings about the destruction of the organism.
The ultraviolet radiation is a point of use application with no residual radiation characteristics. Proper prefiltration
should be implemented to keep particulate from shielding organisms from UV light. (See Chapter 8.)
5.5.3.2 Advantages and Disadvantages
Advantages:
•
Simple design and maintenance
•
254 nm design for microbial reduction
•
185 nm design for TOC reduction
•
No waste stream
•
Heat, ozone, and chemical sanitization are possible
Disadvantages:
•
Can be used only as a safety net for microbial production
•
No ion or endotoxin removal
•
No disinfection residual
•
Particulate can shield organisms from UV light
5.5.3.3 Performance
The UV light is used as a final treatment step to address microbial control and TOC reduction (where necessary), after deionization processes.
This Document is licensed to
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Herzlia,
ID number: 216389
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
Figure 5-1 Purified Water
Figure 5-2
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Herzlia,
ID number: 216389
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FINAL TREATMENT OPTIONS: NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
Table 5-4
Purified Water Systems Comparison Chart
Reverse Osmosis/ Reverse Osmosis/
On-Site
Reverse Osmosis/
Off-Site
Continuous
Regenerated Off-Site Regenerated Regenerated On-Site Regenerated
Electrodeionization
Ion Exchange
Ion Exchange
Ion Exchange
Ion Exchange
Two-Pass
Reverse
Osmosis
Distillation
CAPITAL COST
L
M
M
M
M
M
H
CHEMICAL
HANDLING
N
L
H
M
L
L
L (2)
ENERGY
CONSUMPTION
L
M
L
M
M
M
H
WATER
CONSUMPTION
L
H (1)
M
H (1)
H (1)
H (1)
M (3)
OUTSIDE
SERVICE COSTS
H
M
L
L
L
L
L
OPERATIONAL
MAINTENANCE
L
M
M
M
M
M
L
PRODUCT
CONDUCTIVITY
MICROSIEMEN /
CM @ 25°C
1.0 - 0.06
1.0 - 0.06
1.0 - 0.06
1.0 - 0.06
1.0 - 0.07
2.5 - 0.5
1.0 - 0.1
PRODUCT TOC.PPB
(4)
<500
(4)
<500
<500
<500
<500
MICROBIAL
PERFORMANCE
L
M
L
M
M
H
H
Ratings:
N = None
L = Low
M = Medium
H = High
Notes for Table 5-4:
1)
High-water consumption unless wastewater is reused - cooling tower makeup, etc.
2)
Total chemical requirement dependent upon pretreatment selection
3)
Total water consumption dependent upon pretreatment selection.
4)
USP TOC requirement is met in most cases but may not be if feed water is high TOC (>2 ppm)
5)
High microbial performance refers to low microbial count in relative terms
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Herzlia,
ID number: 216389
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Herzlia,
ID number: 216389
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FINAL TREATMENT OPTIONS:
WATER FOR INJECTION (WFI)
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Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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Herzlia,
ID number: 216389
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.
FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.1
INTRODUCTION
This chapter addresses the USP approved final treatment methods for the production of compendial WFI.
WFI is the purest grade of bulk water monographed by the USP and would be expected to be used for the
manufacture of parenteral, some ophthalmic and inhalation products, and for finishing steps of parenteral
grade active pharmaceutical ingredients (API’s).
Recommended systems include either distillation or RO as the final processing step, but may also include
ultrafiltration (UF), deionization (DI) and/or ion exchange (IX), to compliment the RO or distillation unit operation.
The technology, operation, maintenance, and relative cost issues for the approved process methods are
discussed. This chapter includes USP monograph information, regulatory issues, and subsections that cover
the unit operations:
•
Single effect (SE) distillation
•
Multi-effect (ME) distillation
•
Vapor compression (VC) distillation
•
Reverse osmosis (RO)
Feed water pretreatment is covered along with economic factors such as construction materials, surface
finishes, and instrumentation and controls. A comparison table on USP-WFI final treatment options and
relative attributes is provided.
6.2
US PHARMACOPOEIA ISSUES
The United States Pharmacopoeia (USP) allows WFI to be “purified by distillation or by RO”. This statement
does not imply that the regulated process step is the only process step, but the USP advisory section does
imply that it is the final step in the process.
•
Only distillation may be used to produce WFI under current European regulations
•
Distillation, RO and UF are allowable methods to produce WFI under the Japanese regulations
This Document is licensed to
There are few regulations, which govern the design and construction of pharmaceutical water purification
systems. There are no existing regulations governing materials of construction, type, or level of instrumentation, surface finish, or operating temperatures. Most practices commonly followed with respect to these and
other issues, have been adopted based on many factors.
Mr. Shlomo Sackstein
Herzlia,
Among U.S. government publications, including the Code of Federal Regulations (CFR) and the FDA Guide
to Inspection of High Purity Water Systems,
there are few stipulations
ID number:
216389related to design and construction of
WFI processing equipment. Two notable stipulations are:
•
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“Heat exchangers, other than the double concentric tube type or double tube sheet type, must employ a
pressure differential and a means for monitoring the differential.”
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63
FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
•
“All stills and tanks holding liquid requiring microbial control shall have air vents with non-fiber releasing
sterilizable filters capable of preventing microbial contamination of the contents.”
6.3
DISTILLATION
The pharmaceutical still chemically and microbiologically purifies water by phase changes and entrainment
separation. In this process water is evaporated, producing steam. The steam disengages from the water
leaving behind dissolved solids, non-volatiles, and high molecular weight impurities. However, low molecular
weight impurities are carried with the water mist/droplets, which are entrained in the steam. A separator
removes fine mist and entrained impurities, including endotoxins. The purified steam is condensed into WFI.
Distillation systems are available to provide a minimum of 3 log10 (99.99%) reduction in endotoxin concentration. Specific endotoxin loading limits should be reviewed with the manufacturer.
A variety of different designs are available including single effect (SE), multi-effect (ME), and vapor compression (VC). The distilled water quality expected from an SE still is equivalent to an ME design, by virtue of the
fact that water is distilled only once in both systems. The benefit to the user of ME versus SE distillation are
the significantly lower operating costs associated with utilities.
In an ME system, purified steam produced by each effect is utilized to heat water and generate more steam
in the subsequent effect. Due to this staged evaporation and condensation process, only the first effect
requires heat from an external source, and only the purified steam produced by the final effect is condensed,
using an external cooling medium.
VC stills can produce similar quality water using a different technique. Energy imparted to the generated
steam, by a mechanical compressor, results in compressed steam with increased pressure and temperature.
The higher energy steam is then discharged back into the evaporator/condenser vessel to generate more
steam in a continuous cycle.
Areas of concern are carry over of impurities, evaporator flooding, stagnant water, and pump and compressor seal design. These concerns may be addressed using mist eliminators, high water level indicators, use of
sanitary pumps and compressors, proper drainage, adequate blow down control, and conductivity sensing to
divert unacceptable water to drain.
6.4
DISTILLATION APPLICATIONS AND CAPACITIES
The majority of USP WFI currently produced in the United States is produced by distillation. WFI production
is shared by both ME and VC stills. SE stills are found in areas where only small quantities of WFI are
required. However, where large amounts of WFI are required, economics of operation dictate the use of either
ME or VC.
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Table 6-1 shows typical capacities and temperatures of WFI produced by each process.
Table 6-1
Mr. Shlomo Sackstein
Herzlia,
Single-Effect
Multi-Effect
ID number: 216389
Capacities and WFI Temperature Options
CAPACITY RANGE IN GPH
WFI Temperature
range/Options, °C
64
1 - 100
25 - 3,000
Vapor compression
100 - 6,000
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80 - 100
37 - 100
• Ambient
• 80 - 100
• Combination Ambient/Hot
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.5
PROCESS AND SYSTEM DESCRIPTION
6.5.1
Single Effect Distillation (SE)
SE systems incorporate a single evaporator heat exchanger, separator mechanism, and a condenser.
SE systems are available in electrically or steam powered versions, although electrical units are limited to
very small production rates (<30 gallons per hour).
Steam powered units typically require 30-60 psig plant steam. Cooling fluid is required for both steam and
electric powered versions. When water is the coolant, the rate is approximately 8-10 gallons per gallon of WFI
produced, based on a supply temperature of 4 - 16°C, and temperature rise of 67°C.
SE systems typically operate at atmospheric pressure and 100°C, and incorporate non-ASME code vessels.
WFI is delivered at atmospheric pressure and 80 - 100°C; thus a distillate transfer pump is required, unless
the WFI tank is at a lower elevation than the still.
6.5.2
Multi-Effect Distillation (ME)
ME systems incorporate two or more evaporator heat exchangers, separator mechanisms, and a condenser
into a staged evaporation and condensation process. Typical systems have 3-8 effects. Each effect includes
an evaporator and a separator (see Chapter 11).
ME systems typically require plant steam at 80 - 120 psig, and cooling fluid at a supply temperature of 4°C 16°C, based on a temperature rise of 65°C - 70°C. The quantity of steam and cooling fluid required varies
significantly based upon the WFI production rate and the number of effects. Capital costs increase while
steam and cooling fluid consumption decrease, as the number of effects to produce a given quantity of WFI
increases. ME systems operate under pressure, and typically deliver WFI at 80°C - 100°C.
Normally, water used for cooling is not the same as the feed water, and does not require special pretreatment
for the purpose of scale prevention. However, corrosion prevention measures, such as chlorine and chloramine removal, are necessary.
Some designs deliver the water at atmospheric pressure and require a transfer pump unless the WFI storage
tank is at lower elevation than the still. Other designs which may operate at 5-10 psig condenser pressure, do
feature a distillate transfer pump for higher pressure deliveries.
6.5.3
Vapor Compression Distillation (VC)
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VC is a distillation method where water is evaporated inside, or outside, a bank of tubes arranged in a
horizontal or vertical configuration. The horizontal design is normally of the forced circulation type with recirculation pump and spray nozzles, while the vertical design is of the natural circulation type.
Mr. Shlomo Sackstein
Herzlia,
The VC process operates on the same
as the mechanical
refrigeration cycle.
IDprinciple
number:
216389
Major system components are the evaporator, compressor, heat exchangers, deaerator, pumps, motors,
valves, instruments, and controls.
In a VC still, feed water is evaporated on one side of the tubes. The generated steam passes through the
disengagement space, through the separator, and into the compressor.
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
The energy imparted by the compressor results in compressed steam with increased pressure and temperature. The higher energy steam is then discharged back into the evaporator/condenser vessel. There, the
steam condenses and gives up its latent heat, which is transferred through the tube wall to the water. More
water is boiled off, generating more vapor, and the process is repeated. The outgoing distillate and blow down
streams preheat the incoming feed water, thus saving energy. Since the latent heat is recycled, there is no
need for a stand-alone condenser as in the SE or ME systems.
6.5.4
Distillation pretreatment requirements - General
All distillation units are susceptible to scaling and corrosion, if the appropriate feed water pretreatment is not
provided. VC and some SE stills operate slightly above atmospheric pressure, and the removal of calcium
and magnesium, by way of water softening, is normally required as a minimum. ME stills operate at a much
higher pressure and temperature, and require higher quality feed water in order to prevent scaling and corrosion. Normally, ion exchange beds are employed as feed water pretreatment to a multiple effect still. RO is
also used as feed water pretreatment for either the VC or multiple effect stills. All distillation units will invariably
experience some form of scale build-up and must therefore include routine visual inspections plus cleaning of
the still during shutdown periods when appropriate. Both types of stills are susceptible to attack by chlorine.
Chlorine removal is essential if damage is to be avoided. Activated carbon filters and sodium bisulfate injection are effective and common methods for chlorine removal.
From a microbiological perspective, the bacterial and endotoxin load should be consistently controlled to a
level that does not overload the still.
6.5.5
Pretreatment requirements – Specific
6.5.5.1 Pretreatment for Single Effect Still (SE)
See the “Pretreatment for ME still” paragraph and above for general information on distillation pretreatment.
6.5.5.2 Pretreatment for Multi-Effect Still (ME)
The baseline pretreatment for ME must provide very low TDS feed water, preferably less than 10 mg/l, and
less than 1 mg/l silica. Some manufacturers offer ME stills to operate on softened water. Others allow higher
levels of silica, up to 5 mg/l. The pretreatment must also remove chlorine and objectionable volatiles, such as
ammonia, if present.
Figure 6-1 A baseline system to achieve very low TDS may be DI or RO.
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
See Chapters 4 and 5 for more information on pretreatment.
6.5.5.3 Pretreatment for Vapor Compression Still (VC)
See Section 6.5.4 for general information on distillation pretreatment requirements. The baseline pretreatment for VC stills is softening, the removal of chlorine, and other objectionable volatiles such as ammonia, if
present.
Figure 6-2 Baseline Treatment for VC Stills
6.5.5.4 Economics
a) Economics of the Single Effect Still: Commercially available SE systems are inherently simple in
design, configured similarly, and offered with significantly fewer options, compared to ME and VC systems. As a result, fewer factors affecting costs are applicable by comparison. Operating costs of SE
systems are associated mainly with plant steam and cooling fluid. Utilities consumption rates are fairly
consistent among SE manufacturers.
b) Economics of the Multi-Effect Still: Although all commercially available ME systems are configured
similarly and supplied with the same basic components, opportunities for cost savings exist in the areas
of construction materials, surface finishes, and instrumentation. Operating costs of ME systems are
associated mainly with plant steam and cooling fluid. Utilities consumption rates vary among ME manufacturers.
c) Economics of the Vapor Compression Still: Significant opportunities exist to reduce capital cost associated with selection of construction materials, surface finishes, and instrumentation used in the construction of VC stills. Operating costs of VC systems are associated mainly with electrical power.
6.5.6
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Recommended Construction Materials
Materials shown Table 6-2 are based on available designs by leading manufacturers. However, other materials may be utilized based on the technical application.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
Table 6-2
Materials of Construction
Single-Effect
Multi-Effect
Vapor Compression
Evaporator
Shell
SS / Tin coated copper
316L SS
304/L SS
Tubesheets
SS / Tin coated copper
316L SS
304/L SS
SS
316/L SS; Titanium
304 SS
SS / Tin coated copper
316 SS
316 SS
SS or Tin coated copper
when used
316/L SS
316/L SS
Not used
Not Used
304L SS
Piping
SS / Tin coated copper
316/L SS, Sanitary
clamps*
316/L SS, Sanitary
clamps*
Pumps
SS when used
316 / 316L SS with
Sanitary clamps*
316 / 316L SS with
Sanitary clamps*
Not used
Not Used
316 SS / Inconel
SS
316 SS
316 SS
Carbon Steel
Carbon Steel
Carbon Steel
Other tube material
options are available
All 316 / 316L SS
Tubes
Separator
Heat
Exchangers
Deaerator
Compressor
Valves
Skid/Frame
Optional
*Some manufacturers may use sanitary clamps on distillate piping only.
6.5.6.1 Surface Finish
Mechanical polishing (MP), electropolishing (EP), and passivation processes are implemented in stainless
steel distillation systems in order to improve corrosion resistance. These processes are neither necessary,
nor applicable, to other alloys such as tin-coated copper, titanium, and Inconel, based on differences in metal
chemistry.
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MP and EP/passivation processes affect the microscopic amplitude and chemical composition, respectively,
of the stainless surface. These processes are not considered necessary to control microbial growth due to
the relatively high operating temperatures. MP is advocated for final finishing of mechanical welds and EP/
passivation for all stainless steel surfaces to optimize the formation of the corrosion resistant chromium oxide
barrier.
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The impact of progressive mechanical polishing on the capital cost of stills and other equipment is considerable, and often can account for 25% to 30% of a ME or VC still cost. MP processes, except when used to
smooth out a mechanical weld or misalignment etc., may be removed from the applicable specification without fear of compromising the water quality.
68
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.5.6.2 Instrumentation and Controls
For WFI applications, the level of instrumentation should be sufficient to monitor parameters considered
critical because they relate to ensuring proper hydraulic/thermodynamic functionality and the production of
the appropriate quality of WFI. Instrumentation for critical operating parameters should be calibratable using
National Institute of Standards and Technology (NIST) traceable equipment
6.5.6.3 Advantages and Disadvantages
Table 6-3
Process and Steam Comparison
Configuration
Single-Effect
Multi-Effect
Vapor Compression
• Evaporator
YES
YES
YES
• Condenser
YES
YES
NO
NO/optional
YES
YES
• Compressor
NO
NO
YES
• ASME Coded
Normally NO
YES
NO
• Distillate pump
Normally NO
Optional
YES
• Blowdown pump
NO
NO
YES
• Feed booster pump
NO
YES
NO
Steam or electric
Steam
Ambient WFI: -Steam
or electric
• Feed/Blowdown heat
exchangers
Makeup heat
HOT WFI: -Steam
LOW
HIGH
LOW
YES
YES
NO
Plant Steam Pressure, psig
30 - 60
100 - 120
30 - 40
Feed Water Pressure, psig
30 - 50
75 - 90
30 - 50
• Steam pressure
Cooling water
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Condensor Cooling Water
Pressure, psig
MAY BE USED TO
GENERATE CLEAN STEAM
30 - 50
30 - 50
Mr. Shlomo
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YES
YES (not common
ID practice)
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Not required
NO
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69
FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.6
REVERSE OSMOSIS (RO)
RO employs a semi-permeable membrane and a relatively high pressure differential to force water through
the membrane to achieve chemical, microbial, and endotoxin reduction, critical in USP WFI applications. The
feed water is converted into two streams, permeate and reject. The permeate water flows through the membrane and is produced cold and as such does not have the temperature protection for microbial growth
afforded by the alternate distillation processes. The reject stream discharges comparatively smaller volume
than the permeate, and contains virtually all of the feed water contaminants.
6.6.1
Application
RO systems are used as USP WFI pretreatment for distillation processes, or as final treatment for USP
Purified water systems. RO is also an accepted means of producing WFI, and may provide a low capital and
operational cost alternative to distillation.
Membranes that are hot water sanitizable at 80°C are now available for pretreatment and final treatment, thus
eliminating the need for chemical sanitization and simplifying the validation process. These membranes still
require periodic chemical cleaning.
Membranes, which may allow for continuous operation at 80°C, are under development. This may have a
significant impact on the use of RO as a means of producing USP WFI, since operation of the system at 80°C
may nearly eliminate biological concerns. Failure of a membrane or seal will result in permeate contamination. These problems may be controlled by:
•
Pretreatment of the feed water
•
Appropriate membrane material selection
•
Latest technology membrane design
•
Integrity challenges
•
Periodic sanitization
•
Monitoring of microbial levels, conductivity, total organic carbon and differential pressures
6.6.2
Description
Semi-permeable RO membranes are produced commercially for water purification in spiral wound and hollow fiber configurations. RO membranes are permeable to some substances such as water and dissolved
gases, while impermeable to other substances such as salts, high molecular weight organics, acids, bases,
colloids, bacteria, and endotoxins. Membranes are available in four basic materials; cellulose acetate, polyamide, thin film composite, and polysulfone. (Polyamide membranes are virtually identical in performance to
thin film composite membranes.) All three membrane types have advantages and disadvantages. (See Chapter
5 for more details.)
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Bacteria and endotoxin removal, required for WFI applications, can be performed at ambient temperatures.
This significantly reduces utility costs
compared
to alternative
elevated temperature processes (distillation).
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By operating at ambient temperatures, distribution piping may not require insulation and may not need to be
constructed of stainless steel.
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For WFI applications, opportunities exist for enhanced control of the single pass unit, by utilizing multi-passproduct-staged or other combination designs. These configurations improve reliability and efficiency, while
improving water quality and quality assurance over the single pass design.
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.6.3
Pretreatment Requirements
RO, as the final processing step, may require pretreatment using ion exchange, deionization, RO, and/or
ultrafiltration to improve operability and quality attributes.
Pretreatment requirements normally include gross particle filtration, scale prevention, and chlorine removal.
Carbon dioxide and ammonia gas, are not removed by the RO process, and may be removed by degasification,
caustic addition, ion exchange, or electrodeionization, prior to the final RO process step. (See Chapter 5 for
more details.)
Due to the stringent microbial and endotoxin control required for parenteral and other critical applications, the
pretreatment prior to the RO should incorporate additional provisions for control and monitoring of microorganisms.
Disinfectants, such as chlorine or chloramine, should be maintained, when tolerable, at appropriate levels
throughout the pretreatment chain. Stagnant water resulting from surge tanks or dead legs should be avoided
by design, or by the inclusion of recirculation systems, which should include In-Line microbial control devices,
such as UV sterilizers.
Regular and appropriate sanitization and cleaning of all unit operations subsequent to and associated with,
the disinfectant (chlorine or chloramine etc.) removal should be scheduled, to maintain and complete the
micro-organism control of the pretreatment system. (See Chapter 4 for further details.)
6.6.4
Economics
Opportunities are available to reduce capital costs associated with the selection of construction materials,
surface finishes, and instrumentation used in the construction of RO units without compromising the water
quality. Operating costs of RO systems are associated mainly with replacement membranes, water concentrate discharge, electrical power, cleaning and sanitizing chemicals, replacement filters, and pretreatment
cost.
6.6.5
Construction Materials
Construction material selection for RO systems are driven by:
•
Structural integrity, based on high operating pressure
•
Structural integrity, based on low pressure sections ahead and after the membranes
•
Chemical compatibility with the contact fluid and its constituents
•
Need to control micro-organism growth
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The low operating temperature of the RO system allows the use of non-metallic construction materials.
Sanitary piping and valves are generally optional features for RO systems, based on the specific manufacturer and location of the RO in the treatment chain.
Mr. Shlomo Sackstein
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For the final purification step, it mayID
be very
cost effective to216389
utilize mill finish 304 stainless steel for the feed
number:
and concentrate waste piping for the system, maintaining 316L stainless steel or PVDF and sanitary design
for the product piping only.
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6.6.6
Surface Finish
MP and EP processes are not applicable to non-metallic systems.
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
6.6.7
Instrumentation and Controls
RO control systems usually use local control and indication, and do not typically require programmable logic
controllers (PLC) as a standard feature. The type and level of instrumentation is similar among manufacturers. The level of instrumentation should be sufficient to monitor parameters considered critical because they
relate to ensuring proper hydraulic functionality and the consistent production of quality WFI. Instrumentation
for critical operating parameters should be calibratable using NIST traceable equipment. (See Chapter 9 for
more details.)
The typically monitored operating parameters for an RO system are feed pH, feed conductivity, and product
quality (TOC and conductivity). These three parameters should be measured using calibratable, NIST traceable instruments. Recording data may be accomplished manually or electronically using analog instruments
and paper/paperless recording systems.
6.6.8
Advantages and Disadvantages
Multi-pass can, in most cases, produce water quality consistent with the minimum requirements of USP WFI.
In cases where the feed water quality is such that this is not possible, the use of some type of deionization
(e.g., additional RO, UF, ion exchange, or electrodeionization) as a pretreatment may be required. This is to
allow the final point of purification to remain RO and the system to generate consistent and reliable water
within the USP WFI specifications.
Advantages associated with the design and operation of RO units used as the final treatment step for the
production of WFI are:
1) Depending on cost and complexity of pretreatment, RO systems designed for production of USP WFI
may provide for significantly reduced capital costs when compared with distillation processes, while
maintaining the appropriate USP WFI quality.
2) The utility requirements are significantly lower for RO systems (electricity for pump horsepower) than for
distillation, resulting in lower operating costs, which may be a very significant factor over the lifetime of
the system.
Disadvantages associated with the design and operation of RO units used as the final treatment step for the
production of WFI are:
1) Membrane fouling and integrity
•
Bacteria grow-through
•
Seal leakage or by-passing
•
Seal failure or damage caused by chemical attack etc.
•
Membrane damage during installation etc.
•
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2) Membrane material sensitivity to bacteria and sanitizing agents.
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FINAL TREATMENT OPTIONS: WATER FOR INJECTION (WFI)
3) Inherent sanitization limitations
•
Periodic chemical or hot water sanitization may be required
•
Periodic chemical cleaning may be required
4) Pretreatment cost may be high
RO systems provide a method for consistently producing ambient water in accordance with the USP WFI
requirements. This not only reduces utility requirements, but also may reduce installation costs, since thermal
insulation may not be required for storage and distribution.
6.7
USP - WATER FOR INJECTION SYSTEMS COMPARISON
Table 6-4
WFI Systems Comparison
RO
UNIT OPERATION (1,2)
DISTILLATION
2 pass RO
SE
ME
VC
Capital Cost
M
M
H
H
Chemical Consumption
L
N/A
N/A
N/A
Energy Consumption
M
H
H
H
M (3)
H
M
M
Outside Service Costs
L
L
L
L
Operational Maintenance
L
L
L
L
Water Consumption
Ratings:
L = Low
M = Medium
H = High
Notes:
1) All Indicators are relative to each other within the specific category
2) Optimum design and operating conditions are assumed
3) Total water consumption is dependent on pretreatment selected
4) RO may not meet USP TOC levels if feed water TOC is high (>3 ppm)
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PHARMACEUTICAL STEAM
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PHARMACEUTICAL STEAM
7.
PHARMACEUTICAL STEAM
7.1
INTRODUCTION
This chapter aims to simplify and standardize the process of selection, programming, and design of pharmaceutical steam systems. Guidelines, information, and options are provided, along with advantages and disadvantages, based on the best and most cost effective of current and proven practices and technologies.
The absence of regulations governing the use of steam in pharmaceutical processes has resulted in the
proliferation of differing practices and interpretations. Most interpretations are made on the side of conservatism. Unfortunately, in addition to increasing cost without an associated increase in benefits, excessive conservatism can result in system complexity, and possibly reduced reliability. One example is the use of clean
steam (non-utility boiler produced steam) where a form of utility steam (utility boiler produced steam) would
be adequate to maintain product quality. The installation of a clean steam generator when a simple steam
reducing station would suffice results in added equipment and the associated impact on cost, complexity, and
reliability.
In some instances, interpretations are based on inaccurate assumptions of what is important or critical. An
example is the over specifying of pretreatment or using WFI as feed to solve the perceived problem.
The chapter establishes standard definitions for terms commonly associated with pharmaceutical steam and
provides information that facilitates making correct and cost effective decisions.
7.2
cGMP ISSUES
The user has the ultimate responsibility for system design and performance, and for ensuring that the proper
type of steam is used for a given process.
There is no FDA or USP minimum standard for clean steam. However, cGMPs for large volume parenterals
(LVPs) issued in 1976 indicated that feed water for boilers supplying steam that contact components, drug
products, and drug product contact surfaces shall not contain volatile additives such as amines or hydrazines.
Few regulations govern the design and construction of clean steam generators. There are also no regulations
governing materials of construction, type or level of instrumentation, surface finishes, or operating temperatures.
Among US Government publications, the FDA’s Code of Federal Regulations (CFR) provides culinary steam
recommendations and stipulations related to heat exchanger and tank air vents design and construction. The
Culinary steam recommendations apply to food applications only.
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US Public Health Service/Dairy Industry Committee, 3A Sanitary Standards, Number 609-02, adds additional limitations to Culinary steam feed water additives for food applications. It should be noted that boiler
feed water additives permitted in food for human consumption may not be acceptable in drinking water or
orally ingested drug products.
7.2.1
Steam Attributes
7.2.1.1 Quality
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The term “Quality” when referring to steam indicates the level of steam saturation. There are no FDA or USP
regulations relating to minimum “steam quality” or the level of non-condensable gasses present in pharmaceutical steam. (See Section 7.4.)
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75
PHARMACEUTICAL STEAM
European regulators have defined specific criteria for pharmaceutical steam used for equipment sterilization.
(European Standard EN 285 - Steam Sterilizers - reference section 13.3) These cover acceptable levels of
saturation or dryness, the level of superheat, and the volume of non-condensable gases present.
7.2.1.2 Purity
Purity requirements for steam used in pharmaceutical manufacturing and product development are driven by
the product characteristics, manufacturing process, and the intended use of the product. The product manufacturer is responsible for ensuring that steam used to process the product is appropriate.
Though steam purity requirements are product specific, it may be impractical to reliably produce special
steam for each situation. Manufacturing operations typically generate and distribute only one or two steam
purity grades, commonly grouped.
7.3
TYPES OF STEAM
Pharmaceutical steam is classified into two (2) types based on their respective sources. These are:
1) Utility-Boiler produced steam, hereafter called Utility Steam.
2) Non-Utility Boiler produced steam, hereafter called Clean Steam.
7.3.1
Utility Steam
Utility steam is characterized with usually having:
•
Chemical additives to control scale and corrosion
•
Relatively high pressure with the potential of generating superheat during expansion
•
Relatively high pH
Chemical additives: Utility steam is produced, in most cases, using conventional fire-tube steam boilers,
normally of steel construction. Such boilers are almost always provided with systems that inject additives in
the feed water to protect the boiler and steam distribution piping from scale and corrosion. Some of these
scale and corrosion inhibitors may, and often do, include amines and other substances that may not be
acceptable in steam being used in pharmaceutical processes. The user must determine what additives are
used, and verify if they are acceptable in the particular application, i.e., do not add any impurities or create a
reaction in the drug product.
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Utility steam can be filtered to remove particulate matter, but filtration does not remove dissolved substances
and volatiles such as amines.
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Superheat: Superheated steam is produced in water tube boilers by reheating the steam or by generating
the steam at a higher pressure in a fire tube boiler and then reducing the pressure through a regulating valve.
When the pressure is reduced, the energy in the higher temperature steam is dissipated to generate steam at
the lower pressure and produce superheated steam above the corresponding saturation temperature. Superheat is dissipated downstream of the regulating valve due to heat loss in the line.
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pH control: In order to protect carbon steel from corrosion by the steam, it is necessary to use additives to
raise the pH to between 9.5 -10.5.
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PHARMACEUTICAL STEAM
7.3.2
Clean Steam (CS)
Pharmaceutical clean steam is generated from treated water free of volatile additives, such as amines or
hydrazines, and is used for thermal disinfection or sterilization processes. It is considered especially important to preclude such contamination from injectable drug products:
Clean steam is characterized as having:
•
No additives
•
No generated superheat except when the generated pressure is significantly higher than the use pressure of the steam. (See Section 7.3.1 - Superheat.)
•
Relatively low pH
There are many terms used in the pharmaceutical industry to describe Clean Steam. These include Clean
Steam, Pure Steam, Pyrogen Free Steam, WFI Steam, and USP Purified Water steam. There is no standard
or accepted definition for any of these terms. However, the most commonly used terms are “Pure Steam” and
“Clean Steam”. In this Guide, the term “Clean Steam” is used in lieu of all others.
The condensate of Clean Steam has no buffer, and may have a relatively low pH compared to that of utility
steam.
7.4
BACKGROUND AND INDUSTRY PRACTICES
7.4.1
Purity of sterilizing steam
When steam or the resulting condensed water comes in direct or indirect contact with the drug product, the
purity should be equivalent to the water purity acceptable for final rinsing of the drug contact surfaces.
Note: A continuous supply of Dry Saturated Steam at the point of use is considered necessary for efficient
steam sterilization. Water carried by the steam in suspension may cause damp loads and superheated steam
is considerably less effective than saturated steam when used for sterilization. Non-condensable gases if
contained in the steam may prevent the attainment of sterilization conditions in parts of the sterilizer load.
7.4.2
Steam used for humidification
When steam is used for indirect humidification, such as injection into HVAC air streams prior to final air
filtration, the steam does not need to be purer than the air that it is being mixed with. However, when humidifying process areas, the potential level of impurities, including amines and hydrazines should be evaluated in
order to ascertain the impact on the final drug product. This is particularly important in areas where open
processing takes place, such as aseptic filling suites and formulation areas. If the diluted water vapor is found
to contribute significantly to the contamination of the drug, a purer grade of steam should be selected.
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7.4.3 Common practices
Herzlia,
It is common practice to generate pharmaceutical
steam from
compendial waters and test the steam condenID number:
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sate for equivalency to the compendial standard. This practice ignores the ability of the pharmaceutical steam
generator to remove impurities. This overprocessing is wasteful and unnecessary. An exception is when the
steam quantity is small and the cost and maintenance of a dedicated feed water pretreatment system exceeds the cost of using compendial water. Pharmaceutical Clean Steam is commonly used in applications
were utility steam would suffice; such as non-critical room humidification and high purity water heat exchangers.
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PHARMACEUTICAL STEAM
Table lists the commonly accepted industry standards and highlights the trend in the pharmaceutical industry to provide “purer than necessary” steam and over-specified feed water.
7.4.4
Industry and Baseline Practices in the Production of Steam
Table 7-1
Practices in the Production of Steam
Intended Use of Steam
Method of generation of steam
Parenteral and Non-Parenteral Dosage form
applications where steam is in direct contact with
the drug.
The use of a sanitary clean steam generator with
entrainment for the control of endotoxins & liquid
carry-over (SCSG) is both baseline and common
industry practice.
Critical step in the manufacture of API where
steam is in direct contact with the Active Pharmaceutical Ingredient (API).
The use of an SCSG is both baseline and common industry practice.
Non-Critical step in the manufacture of an API
where added impurities may be removed in a
subsequent step.
SCSGs are commonly used; however, utility steam
is the acceptable baseline application.
Sterilization of USP water systems.
WHILE THE USE OF A SCSG IS COMMON
PRACTICE, AN ALTERNATIVE APPROACH IS
TO USE UTILITY STEAM PLUS HOT USP
WATER, FLUSHING & WASTE TESTING.
Process humidification for dosage form application
where steam is in direct contact with the drug,
where open processing takes place and where the
potential level of amines, hydrazine’s etc. in the
condensate has been determined to have a
detrimental effect on the drug product.
SCSGs are commonly used and are the Baseline
application.
Humidification of non-critical HVAC systems such
as rooms and areas where the drug is not directly
exposed to the room atmosphere.
SCSGs are commonly used but utility steam may
be totally acceptable.
HUMIDIFICATION OF PROCESS & CRITICAL
CLEANROOMS.
Where open processing takes place and where
the potential level of amines, hydrazine’s etc. in the
condensate has been determined to have a
detrimental effect on the drug product the baseline
and common practice is the use of a SCSG.
However, if it has been determined that the
impurities have an insignificant effect on the drug
product, a utility steam source would qualify as the
baseline approach.
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Energy source for non-critical & cGMP heat
exchangers.
It is common practice to use a SCSG as the
energy source. The baseline approach would be to
use a utility steam source coupled with a cGMP
heat exchanger design.
Sterilization of fermentation vessels.
It is common practice as well as the baseline
approach to use utility steam.
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Figure 7-1 Pharmaceutical Steam System Planning
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PHARMACEUTICAL STEAM
7.5
SYSTEM PLANNING
Pharmaceutical Steam System Planning, shown in the Figure 7-1 is a graphic representation of the system
boundaries, limitations, and restrictions. Initial system planning reveals primary boundaries that establish the
cornerstone for design criteria. These system boundaries are Steam Requirements, System Design, Use
Point Criteria, and Distribution System requirements.
The arrows encircling each boundary represent limitations that establish more specific operating strategies
and ranges. To allow more flexibility in final planning and detailed design the designer should always indicate
ranges of acceptability, rather than a specific value or position.
7.5.1
Steam Requirements
The planning process starts with the listing of all steam requirements and applications that include:
•
Company standards including QA/QC requirements and published Sop’s
•
The categorization of use-point by:
•
Type of application (Humidification, critical or non-critical, API, and Dosage for applications)
•
Purity selection (this is based primarily on the application and the endotoxin and chemical purity
criteria set for the product for which the steam, or its condensate, will be in contact with. The selection
must consider underlying factors which have impacts on purity control, installed and operating cost,
maintenance, and practicality)
•
Steam quality (dryness, non-condensable limits, and maximum superheat)
7.5.2
System Design
Pharmaceutical steam is generated using different methods. The most appropriate method for each application must be selected. (See the Pharmaceutical Steam Purity Decision Tree, Section 7.6.)
The process continues with an evaluation of the steam system requirements (generation) that includes: the
selection of the type of generation system that would satisfy each category, which would include:
•
The types of generation systems available. (If both pyrogen free clean steam and clean steam without
endotoxin limits is required, the practicality and economy of producing only the higher grade should be
raised.)
•
The source of utility steam or electrical power (The plant steam requirement for clean steam as well as
utility steam and the option of electric powered steam generators should be considered.)
•
The type and number of systems required based on feedback from the “Distribution System” evaluation
•
•
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The condensate sampling needs
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7.5.3
Use Point Criteria
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The third step defines the specific delivery requirement ranges for clean steam at the point of use including:
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PHARMACEUTICAL STEAM
•
Utilization, which is determined from each overall system peak demand(s), average demand, and the
relationships between peak demand time periods and their flow rates.
•
Pressures and flow levels
•
Use periods and histogram analysis, if available
•
Quality
•
Purity
7.5.4
Distribution System
The fourth step includes the distribution system evaluation, which includes:
•
Condensate, non-condensable and moisture removal
•
Pipe size and Insulation requirements including:
•
Materials of construction, sanitary design requirements and surface finish
•
Physical location of each use point
•
Heat and temperature losses
•
Natural drainage
Note: Since the steam quality will decline, due to heat losses, with time, the efficiency of the insulation and
the length of the distribution system, the quality at the use point will not be expected to reflect the generation
quality level.
7.5.5
Re-evaluation of system boundaries and constraints
These sequential steps are repeated and re-evaluated as information in the design process iterates, and
further criteria about the overall system boundaries are identified. (See Figure 7-3.)
In operations with a requirement for only one grade of steam, the steam system is designed to meet the most
stringent requirements of the most demanding product or process. With more than one purity grade of steam,
products and processes are often categorized and fed by the most appropriate system. The number of types
of steam generated is most often a function of the volume of steam consumed and variation of purity required.
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PHARMACEUTICAL STEAM
7.6
PHARMACEUTICAL STEAM PURITY DECISION TREE
Figure 7-2 Pharmaceutical Steam Purity Decision Tree
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7.7
PROCESS AND SYSTEM DESCRIPTION
7.7.1
Utility Steam
Utility Steam is produced in conventional plant utility boilers whose typical design and construction are well
known and will not be covered in this chapter.
7.7.2
Clean Steam (CS)
Clean Steam is produced in specially designed non-fired generators or from the first effect of multi-effect WFI
stills, which do not use scale or corrosion inhibitor additives. The generator is fed with water pretreated for the
purpose of removing elements that contribute to scaling or corrosion, and the materials of construction are
resistant to corrosion by steam that has no corrosion inhibitors.
The dedicated CS generator is very similar in design and construction to the first effect of a multi-effect still.
For information on multi-effect (ME) stills, see Chapter 6.
7.7.2.1 CS obtained from a ME still
When Clean Steam is obtained from the ME still, the first effect is usually fitted with two valves; one to isolate
the remaining effects and the other to isolate the Clean Steam use points. Depending on the manufacturer,
the still may or may not produce steam when the still is producing WFI.
Advantages:
•
Does not require a separate generator with the associated cost, space, installation, operation, and maintenance
Disadvantages:
•
Output is limited to the capability of the first effect of the ME still
•
May not produce steam when the still is producing WFI. In an ME, the steam generated in the first effect
becomes the motive (power) steam for the second effect, which in turn produces motive steam for the
third effect, etc. Therefore, the impact of the diverted steam is multiplied by the number of effects, and
WFI production is significantly reduced.
The still manufacturer should be consulted in advance, if simultaneous production of WFI and Clean Steam is
desired.
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7.7.2.2 CS Produced from a Sanitary Clean Steam Generator
CONFIGURATION OF A TYPICAL SANITARY CS GENERATOR
Mr. Shlomo Sackstein
Herzlia,
They can be of the vertical or the horizontal type, depending on the manufacturer and the overhead space
available.
ID number: 216389
There are various designs of CS generators. All are evaporators.
The disengagement space and the separator may be housed in the same vessel as the evaporator or in a
separate vessel.
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PHARMACEUTICAL STEAM
Sanitary construction includes orbital Tungsten Inert Gas (TIG) welding (see section on fabrication of distribution systems) wherever possible or mechanical welding with the inner surface ground smooth after welding. All removable connections use In-Line “sanitary” fittings. Flanges and threaded connections are not
considered “sanitary”.
Heat Exchangers, using Utility Steam as the heat source, including the evaporator should be of the doubletubesheet, tubular design to prevent the contamination of the Clean Steam by the heating medium.
Most CS generators, except those with very small output, are fitted with feed water heaters. In addition, a
blow down cooler is used to avoid discharge of very hot and flashing water.
A feed pump may be required if the feed water supply pressure is inadequate. Depending on system design
and the manufacturer, a feed pressure of approximately 8-10 psig above the maximum expected Clean
Steam pressure is required. This allows for pressure drop in piping and valves.
A sample cooler fitted with conductivity meter and alarms is often used to monitor Clean Steam condensate
purity. This is an optional feature whose use should be decided based on need. Conductivity of the condensate will provide information regarding the suitability and applicability of the distributed steam for its final use.
PROCESS AND OPERATING PRINCIPLE OF A TYPICAL SANITARY CS GENERATOR:
Clean Steam is normally generated in a shell-and-tube heat exchanger evaporator. Feed water is introduced
on one side of the tubes, while the heating medium is introduced on the other side. Heating of the feed water
to above the boiling temperature causes the water to evaporate, producing steam. The heating medium does
not come in direct contact with the feed water or with the clean steam, and is normally utility steam. However,
CS generators may be designed to utilize other heating mediums. The main differences in the designs are the
evaporator and separator.
a) Operation
Clean Steam pressure is maintained by a feedback control loop, which modulates the supply steam control
valve. The evaporator feed water is independently controlled using a level sensor and feed water pump.
b) Steam Supply
The utility steam supplied to the generator at typically 100 psig to 120 psig (7.0 to 8.5 Ks/cm2 gauge or 7.9 to
9.25 bars) must be at a higher pressure than the required clean steam pressure. In general, for a given size
generator, the greater the differential between the utility steam pressure and the clean steam pressure the
higher the clean steam production rate. Utility steam pressure should be at least 30-40 psig (2.25 Ks/cm2 or
2.0 bars) higher than the clean steam pressure, to optimize the production rate. Utility steam consumption will
be approximately 10% to 20% greater than the quantity of clean steam produced.
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c) Clean Steam Pressure
Mr. Shlomo Sackstein
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ID number: 216389
Clean Steam pressure is selected by the user. Typical units are designed for pharmaceutical applications at
40 - 60 psig (3.75 - 5.1 bars).
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d) Separator
Entrainment separators are normally designed to function over an optimum range of steam velocity. If the
volume of steam increases substantially, carryover of endotoxins can occur. This condition can exist if the
steam pressure differential significantly exceeds design conditions. Under these conditions, the velocity of
the steam through the separator may be excessive. The manufacturer should be consulted regarding the
output of the generator at the highest possible pressure difference. An alarm and equipment shutdown is
recommended and can be incorporated into the controls to protect against such conditions.
e) Feed Water Level
The Feed water level is controlled to protect against flooding of the evaporator and carryover of endotoxins by
a high level alarm and subsequent shutdown. Evaporator level condition does not affect clean steam purity,
but is an indication of insufficient feed water or excessive blow down.
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7.8
SIZING THE CLEAN STEAM SYSTEM
Figure 7-3 Sizing the Clean Steam System
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7.8.1.1 CS Produced from a Simple Clean Steam Generator
There are applications where pyrogen free steam and sanitary construction features are not required, and at
the same time, Utility Steam cannot be used. In such cases, it may be most economical to utilize a simple
Clean Steam generator of the most economical design. Savings may be worthwhile when the elimination of
the steam separator is combined with non-sanitary features such as:
•
Non-Sanitary pipe and fittings
•
Non-sanitary instruments and valves
•
No polishing
•
Minimum controls
The elimination of the separator alone does not provide significant cost savings. It is important to remember
that the separator’s function is more than removal of endotoxins. It removes entrainment, which includes all
types of contaminants present in the feed water, except volatiles. Without an entrainment separator, impurities from the feed water may well be entrained in the steam and the moisture content of the steam as it leaves
the generator, can be much higher than in the standard entrained generator. Thus the feed water purity
becomes a critical factor in controlling the steam purity if entrainment is not incorporated in the design.
Independent sanitary entrainment devices are available for installation at, or close to the point of use, and
may be used with typical “Simple CS generators” as well as to control additional moisture build up due to heat
losses in the distribution system of Sanitary CS Generators.
7.8.2
Steam Condensate Sampling
7.8.2.1 Purity Sampling
When required by the process, the steam purity shall be monitored through acceptable sampling techniques.
A slipstream of the steam may be passed through a sample condenser/cooler, fitted with a sampling valve.
(See Section 7.2.1 for information on Steam Attributes.)
To ensure that the steam does not contribute to drug product contamination, sampling should be included
during commissioning, as a good engineering practice, and/or prior to each time the steam is used.
If the sampling requirement is for endotoxin or pyrogen testing, the sample cooler, tubing and valve should be
of sanitary construction.
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Sample coolers can be fitted to the CS generator, or located in the distribution line, or at the use point
(recommended location), or a combination thereof. It is common practice to fit sample coolers with conductivity monitors and alarms.
Mr. Shlomo Sackstein
Herzlia,
Steam “Quality” SamplingID number: 216389
Endotoxin removal: The condensate sample from a Clean Steam generator with separator is expected to
show 3-4 log10 level reduction in pyrogens compared to the level in the feed water.
7.8.2.2
Steam “Quality” sampling may be employed to determine the level of saturation and non-condensable gasses. This can be determined by applying a steam calorimeter and measuring the dryness or saturation level.
A steam calorimeter measures the percentage by weight of steam in a mixture of steam and entrained water.
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7.8.3
Materials of Construction
7.8.3.1 Materials of Construction for Sanitary and Simple CS Generators
Structural integrity and chemical compatibility with the contact fluid and its constituents are two of the more
practical issues that drive construction material selection for CS systems.
The inherent corrosion potential forces CS manufacturers to consider relatively inert metal including stainless
steel or titanium etc. Sanitary piping and valves, considered unnecessary for utility and simple CS generators, are often standard features for CS systems based on the specific manufacturer and model. The materials chosen should not contribute to contamination of the drug product
Typical materials of construction for Sanitary and Simple CS Generators are:
Evaporator and separator:
Shell, tubesheets, and internals:
300 series S.S
Evaporator tubes:
300 series or titanium, or other suitable alloy
Heat exchangers
(FEED HEATER, BLOW DOWN &
SAMPLE COOLER):
300 SERIES
Piping:
300 series for water and Clean Steam, and carbon steel for utility
steam contact
Valves:
300 series and elastomers/diaphragms for water
Skid and structural:
Carbon steel
7.8.3.2 Materials of Construction for Utility Steam Generation
Chemical compatibility with the Utility boiler generated steam and the carried over feed water chemicals are
required for all materials used to condition the contaminated steam.
Based on the particulate levels in the steam and the required steam purity, more than one filtration stage may
be utilized.
Distribution of Utility Steam following filtration follows similar practices as CS to control condensate build up,
non-condensable gases and saturation levels as required for the application.
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Acceptable materials must be relatively inert and may include SS or tin-coated copper.
Mr. Shlomo Sackstein
Herzlia,
Mechanical polishing (MP), electropolishing (EP), and passivation processes are implemented in some stainless
CS systems. Chlorine and/or chlorides
damage the generator
regardless of the finish.
IDwillnumber:
216389
7.8.4
Surface Finish
The operating temperatures of these systems are more than sufficient for inhibiting microbiological growth.
Therefore, MP is advocated for final finishing of mechanical welds, with mill finishes and final passivation to
optimize the formation of the corrosion resistant chromium oxide barrier. Electropolishing will also optimize
the chromium oxide barrier, and should be considered if passivation is not an option.
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7.8.5
Pretreatment for CS (Sanitary and Simple) Generators
The feed water pretreatment for a CS generator is born from three separate and distinct considerations:
1) Scale formation.
2) Corrosion.
3) Volatiles which carryover with the steam and may affect steam purity.
7.8.5.1 Scale
Scale formation is a function of generator feed water chemistry, concentration (depends on blow down rate),
and temperature. It is independent of design and make, and is outside the control of the generator manufacturer or the operator.
Because scale inhibitors are not used, and because of the relatively high operating temperatures of the CS
generator, the total dissolved solids (TDS) of the feed water should be very low. Silica is of particular concern.
Most manufacturers stipulate a level of less than 1 ppm (parts per million); some go as high as 5 ppm. In
addition to having low TDS (Total Dissolved Solids), the feed water should have no measurable hardness. It
is therefore common to use DI or reverse osmosis as pretreatment to the CS generator. All CS generators will
invariably experience some form of scale build-up and therefore must include routine visual inspections, plus
cleaning of the generator during shutdown periods when appropriate.
Using compendial water as feed is wasteful, unless the steam quantity is small and the cost and maintenance
of a dedicated feed water pretreatment system exceeds the cost of using compendial water.
Some manufacturers offer generators to operate on softened water. Usually, the rate of blow down is increased in order to maintain low concentration.
Note: If the TDS of the soft water is relatively high, soft scale (such as sodium scale and sludge) can form.
7.8.5.2 Corrosion
The most common cause of corrosion is free chlorine, not chlorides.
Chlorine and chlorides, at any detectable level, are very detrimental to stainless steel. The higher the temperature and chlorine level, the more severe is the attack. Chlorine is known to migrate and concentrate in
localized cells where the level can reach tens, or hundreds of ppm, while the concentration in the main stream
is a fraction of a ppm.
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Chlorine can be removed from the feed water by chemical injection of a reducing agent such as sodium
bisulfate, or by passing the chlorinated water through carbon filters.
Mr. Shlomo Sackstein
Herzlia,
Dissolved gasses and substances that are volatile at the operating temperature of the CS generator will
carryover with the steam. If such substances
are objectionable
or may potentially compromise product qualID number:
216389
7.8.5.3 Volatiles
ity, they must be removed at the pretreatment stage. Ammonia and CO2 (carbon dioxide) are examples of
volatile gases that will have an effect on the conductivity, such that a condensate sample may not meet USP
requirements for Purified or WFI Water.
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For more details on pretreatment and the advantages and disadvantages of the different processes, refer to
Chapters 4 and 5 of this Guide.
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7.8.6
Treatment of Utility steam
When utility steam is considered, it may be necessary to filter/condition the steam. In certain applications, it
may also be necessary to change the steam boiler treatment and substitute additives that do not contain
amines or hydrazine.
Since the type and degree of conditioning are dependent on the application, as well as on the quality of the
utility steam and additives present, this Guide cannot address all possible scenarios.
Prior to the elimination of amines and hydrazines, by the substitution for standard boiler pretreatment additives, the Utility Steam boiler manufacturer should be consulted regarding the impact on equipment warranty,
performance and expected life. Some of the substitute additives are not as effective as the standard.
7.9
COST IMPLICATIONS
Determining the economics of pharmaceutical steam production is complex. Costs are quite predictable, but
vary greatly depending on scale of operation, system design, actual usage, etc. The total operating cost to
produce pharmaceutical steams is obtained by adding the cost of feed water to the costs of pretreatment and
final treatment (primary ion removal and polishing). The type of pharmaceutical steam system design option
selected is typically based on feed water TDS, silica and hardness levels, organic and colloidal content, as
well as anticipated steam system utility costs (acid, caustic, salt, power, and source water). Consideration
should also be given to maintenance requirements and available resources.
7.10
STEAM “QUALITY”
Steam quality is defined as the saturation percentage of steam to water or more explicitly, the ratio of the
vapor mass to the mass of the steam mixture.
Dry Saturated Steam with minimum superheat is necessary for efficient steam sterilization.
Water can be generated and carried by steam within distribution systems in two ways:
1) In suspension as moisture when the steam is not 100% saturated
2) As condensate separated from the steam
Water vapor carried in suspension may be reduced by: adding more heat or raising the temperature, reducing
the pressure, or adding a steam entrainment separator. Water moisture and condensate may be reduced by
steam traps.
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7.11
DISTRIBUTION
Mr. Shlomo Sackstein
Distribution systems for clean steam follow the
same good engineering practices commonly used for utility
Herzlia,
steam, with the exception that contact materials must be inert to the aggressive nature of clean steam.
Corrosion-resistant 304, 316, or 316L
grade
stainless steel “tubing”
or solid-drawn “pipe” are commonly used.
ID
number:
216389
Surface finish is not critical due to the self-sanitizing nature of the clean steam. Mill finish or 180-grit mechanically polished pipe or tubing is sufficient. TIG Orbital welding and post-installation passivation is considered
appropriate for this application. Piping must be designed to allow for thermal expansion and to drain condensate.
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Note: Drains should have air breaks.
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Sanitary clamps or pipe flanges are most commonly used where the piping must be broken, but welded
connections are used as much as possible to eliminate maintenance costs and potential for leaks. Threaded
connections may be suitable for instrumentation if positioned to drain condensate and remain hot. Ball valves
are commonly used for isolation because elastomeric diaphragms do not hold up well in this service. Where
diaphragm valves are used, Teflon-encapsulated EPDM diaphragms give the best long-term performance.
Steam quality sampling may be determined during “commissioning” and consistency ensured based on the
proper location and subsequent maintenance of traps, entrainment separators, and vents. (The subject of
maintenance cannot be over emphasized when these devises are involved due to the small orifices required
in the separation of gas and liquid.)
7.11.1 Line Sizing
The steam distribution header should be sized for a maximum velocity of 7,200 feet per minute (120 ft/sec or
37 m/sec) to limit erosion and extend the life expectancy of the piping. Condensate line sizing should follow
good engineering practices for utility condensate.
7.11.2 Water Moisture Removal
Water vapor forms in steam systems due to heat loss, causing a change in the liquid/vapor ratio or steam
“quality”.
Steam may be dried of moisture by reducing the generated pressure just prior to the point of use to coincide
with the steam temperature of saturation at the reduced pressure.
Moisture entrained in the steam can also be removed by installing an In-Line separator at the point of use, just
prior to, or just after, the regulator. If the separator is located upstream of the regulator, the regulator should
be protected from water damage (wire drawing) and impingement damage on the regulator diaphragms.
In-line separators are available in sizes from 1/2" to 6" (approx. 1 cm to 15 cm) and remove moisture with a
series of baffles on which the suspended water droplets impinge and fall out by gravity to the drain, which
must be piped to a trap. Separators have a separation efficiency of better than 99% in the removal of all liquid
and solid entrainment exceeding 10 microns.
7.11.3 Condensate Removal
Condensate is the water that has separated from the liquid vapor mixture and forms in steam systems due to
heat losses and natural separation effects. Lines should be designed to prevent the buildup of condensate to
avoid dangerous water hammer and to eliminate potential cold spots where bacteria can grow. Any untrapped
vertical length of pipe will quickly fill with condensate. If this condensate is allowed to stand for sufficient time,
it can cool and become a breeding ground for bacteria. This bacteria could possibly be entrained back into the
main distribution header and contaminate use points downstream. Worst case condensate removal locations
should be sampled monthly for presence of bacteria. The following practices are commonly employed to
minimize these concerns:
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•
•
Mr. Shlomo Sackstein
Each line is adequately supported to avoidHerzlia,
sagging and subsequent condensate accumulation.
Steam traps are installed at allID
pointsnumber:
where condensate
can collect (e.g., at least every 100 feet (30
216389
meters) of line, upstream of control valves, at the bottom of vertical risers, etc.). Steam traps used for
clean steam service should be sanitary design and self-draining.
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•
If the main distribution header is above the use points, the branches to the users should be routed from
the top of the header to avoid excessive condensate loads at the branch. Each branch should be trapped
to avoid condensate buildup.
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PHARMACEUTICAL STEAM
•
An alternative is to run the main distribution header below the use points. Then the branches can drain
back to the main distribution header, avoiding the need for additional traps.
•
The requirement to trap each branch can be waived for short drops from main headers to vessels or
other equipment that are in frequent use where the sterilization and water hammer is not impacted by the
collected condensate. An example is a drop from a main distribution header to a media storage tank,
which is sterilized daily. The condensate built up in the vertical drop line has only a limited time to cool and
is quickly eliminated by the trap at the bottom of the vessel when the block valve is opened. The vertical
drop is sterilized daily with the vessel, so there is little chance for bacteria to grow.
7.11.4 Non-Condensable Gas Removal
Air and other non-condensable gases should be minimized from pharmaceutical steam systems. Since air
acts as an insulator, incomplete sterilization can occur in the process. Air in a system offers a very effective
barrier to the heat transfer which will lead to a reduced temperature at the surface of a tube, system component or process equipment.
Air can be discharged using steam traps, however excessive levels may slow down the discharge of condensate. The subcooled condensate can then lead to insufficient sterilization temperatures due to the excess
water.
The removal of air can be achieved by placing thermostatic pharmaceutical steam traps with the inlet in the
upward position. These should be placed in positions where air is prone to collect such as the terminal points
of the main and large branches of the steam header, high points in the tanks, reactors and sterilizers, etc. In
the case of air and condensate discharge at the bottom of large vessels, the air and condensate should be
separated by correct piping practices.
7.11.5 Superheat
While higher-pressure steam can be used to compensate for superheat, the latent heat, or killing power of the
potentially superheated steam is reduced at higher pressures; leading to increased sterilization cycles.
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7.12
FOUR EXAMPLES OF CORRECT PIPING PRACTICE
Figure 7-4 Vessel Sterilization
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DISTRIBUTION SYSTEMS
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STORAGE AND DISTRIBUTION SYSTEMS
8.
STORAGE AND DISTRIBUTION SYSTEMS
8.1
INTRODUCTION
This chapter provides an overview of eight common distribution configurations and a decision tree to help
decide which system best suits the operating requirements. A comparison of tank versus tankless systems is
addressed, as well as alternative materials of construction available, and ancillary equipment related to
overall distribution systems. Common industry practices are listed as examples, to help clarify regulatory
requirements.
8.2
SYSTEM DESIGN
8.2.1
General Considerations
A storage system is used to accommodate peak flow requirements against usage rates. The storage system
must maintain the feed water quality to ensure the appropriate quality of the end use of product. Storage
allows a smaller, less costly pretreatment system to meet peak demand. A smaller treatment system operates closer to the ideal of continuous, dynamic flow. Large manufacturing sites, or systems serving different
buildings, may use storage tanks to separate one section of the loop, and others to minimize cross contamination.
The main disadvantage of a storage tank is its capital cost, and the cost of associated pumps, vent filters, and
instrumentation. However, this is usually less than the increased cost of pretreatment equipment sized to
handle the peak use rate in the facility.
Another disadvantage of storage is that it introduces a region of slow moving water, which can promote
bacterial growth.
8.2.2
Capacity
Criteria affecting storage capacity include the user’s demand profile or the amount of use, duration, timing,
and diversity, (in the case of more than one user), balance between the supply of pre- and final- treated
waters, and whether the system is recirculating or non-recirculating. Careful consideration of these criteria
will affect cost and water quality.
The storage tank must provide reserve to minimize cycling of the treatment equipment and to reduce pump
cavitation. It should provide sufficient reserve to enable routine maintenance and orderly system shutdown in
the event of an emergency, which can vary from few to many hours, depending on the size and configuration
of the system and maintenance procedures.
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8.2.3
Storage Tank Location
Mr. Shlomo Sackstein
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ID number: 216389
It may not be cost-effective to locate storage tanks as close as possible to the point of use, within high-cost,
GMP-finished areas. It may be more advantageous to locate them close to the generation equipment, for
ease of maintenance. Utility areas are acceptable for this purpose, if access is provided (and the area is kept
clean).
8.2.4
Types of Storage Tanks
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Vertical storage tanks are common but horizontal tanks may be necessary if overhead space is limited. For
recirculating systems, tank design should include an internal spray ball to ensure that all interior surfaces are
wetted for microbial control. Jacketing is usually provided in hot systems, to maintain water temperature over
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STORAGE AND DISTRIBUTION SYSTEMS
long periods without makeup, or to temper high influent temperatures, to preclude excessive rouging and
pump cavitation. To avoid the absorption of carbon dioxide and its effect on conductivity, inert blanketing of
the tank headspace should be considered. Storage tanks must be fitted with a sub-micron hydrophobic vent
filter to reduce bio-burden and particles.
The maximum size of a single storage vessel is often limited by the space available in the facility. It may be
necessary to resort to multiple tanks to obtain the desired capacity. In this case, interconnecting piping must
be carefully designed to assure adequate flow through all supply and return branches.
8.3
SYSTEM DISTRIBUTION DESIGN
8.3.1
General Considerations
Proper design of both the water storage and distribution systems is critical to the success of a pharmaceutical water system.
The optimal design of any water storage and distribution system must accomplish three things:
1. Maintain the quality of the water within acceptable limits.
2. Deliver the water to the use points at the required flow rate and temperature.
3. Minimize capital and operating expenses.
Although items 2 and 3 are well understood, item 1 is often misinterpreted. It is not necessary to protect the
water from every form of degradation, only to maintain the quality within acceptable limits. For instance, water
stored in the presence of air absorbs CO2, increasing the conductivity. This degradation can be avoided by
blanketing the storage vessel with nitrogen. However, for many systems this would be a wasteful expenditure
if the increased conductivity were still within the required specification.
As technology has improved over the years, many design features such as storage at elevated temperature,
constant circulation, use of sanitary connections, polished tubing, orbital welding, frequent sanitization, and
the use of diaphragm valves have become common place. To incorporate all of these features into each new
design typically leads to ever escalating costs with little if any reduction in risk of contamination. Although
each of these items provides a level of security, it is a mistake to assume that all of them need to be in every
system. Many systems operate successfully with one or more of these design features omitted. In such
cases, the cumulative effect of the other design features is adequate to prevent degradation of the water.
A more reasonable approach is to utilize design features that provide the greatest reduction in contamination
risk at the most reasonable cost, and add the more expensive features in the design phase, only if they are
required to maintain quality within acceptable limits. The systems should be designed to be robust, so features do not have to be added later, affecting cost and schedule. The idea of selecting design features based
on “return” on investment where “return” is defined as reduction in contamination risk, can be very helpful in
controlling system cost and in evaluating different alternatives. Ultimately, the effectiveness of each system
design is determined by the quality of the water delivered to the users. The challenge for the design engineer
is to know what features to include, to achieve the required degree of protection with the lowest lifecycle cost.
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EXAMPLE
Mr. Shlomo Sackstein
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ID number: 216389
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A USP compendial water system is designed with a 316L SS storage and distribution system and operates
normally at 80°C. The tubing is all sanitary, orbital welded, with minimal clamps and zero dead leg diaphragm
valves at the use points. Water is kept circulating through the tubing at a minimum return velocity of 3ft/sec. In
this case, use of high mechanical polish tubing (<20 Ra) with electropolishing may not be required. The risk
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STORAGE AND DISTRIBUTION SYSTEMS
of contamination for such a system is already low, and the impact of this upgraded surface finish is questionable. The benefits that will be achieved by further improving the quality of finish may not be justified.
However, if the same system were open to the atmosphere, consideration would be given to installing a
0.2micron vent filter on the storage vessel, as the reduction in contamination risk is quite large for a relatively
small investment. Similarly, if the zero dead leg valves were replaced with less expensive valves with larger
dead legs, you might consider increasing the minimal circulation velocity to help compensate.
The purpose of the following chapter sections is to provide information to help the user evaluate the advantages, disadvantages and cost effectiveness of many of the design features commonly used to protect water
from degradation. A method of selecting/optimizing system storage and distribution design is also presented.
As a general rule, a water system is optimized as a result of the following:
1) Minimizing the time the water is held at conditions which favor growth
2) Minimizing changes to water temperature
3) Contacting all areas during sanitization
One system design can be said to be better than another, if it accomplishes these goals to the same degree,
but at a reduced lifecycle cost. Examples of storage and distribution concepts commonly used today are
presented in subsequent sections of this Guide, to help demonstrate the idea of optimal system design.
8.3.2
Distribution Design Concepts
The two basic concepts developed for distribution of pharmaceutical waters are referred to as the “batch” and
“dynamic/continuous” distribution concepts.
The batch concept utilizes at least two storage tanks. While one is being filled, the other is in service providing
pharmaceutical waters to the various process users. After one tank has been filled from the water final
treatment system, it is isolated and the water inside is tested. Only after testing is that tank put into service.
The water is often drained after 24 hours, but can be validated for longer periods of time. At the completion of
the draining operation, the vessel and distribution system is usually sanitized before refilling.
The dynamic/continuous concept off-sets the peak instantaneous water demand, put on the overall water
system through utilization of a single water storage vessel which simultaneously receives final pretreatment
system make-up, stores the water in the vessel, and ultimately supplies it to the various process users while
maintaining water quality.
The advantage of the “batch” distribution concept, over the “dynamic/continuous” distribution concept, is that
the water is tested before use with tank QA/QC lot release (water used in each product batch lot is traced and
is identifiable). The advantages of the “dynamic/continuous” distribution concept include lower lifecycle costs,
as well as less complex piping around the storage vessel, and a much more efficient operation.
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Once a system distribution concept has been selected, the following additional storage and distribution design considerations should be carefully evaluated:
•
use, cooling requirements (steam-able, sub-loop or multiple branched heat exchanger assemblies), reheat requirements, if any, secondary loop tanks versus tankless system considerations, etc.
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•
Hot (65-80°C), cold (4-10°C), or ambient temperature process use point requirements
•
Sanitization method (steam, hot water, ozone, or chemical)
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STORAGE AND DISTRIBUTION SYSTEMS
8.3.3
Distribution Decision Tree
The decision tree in Figure 8-1 is presented to aid in the analysis of distribution design. Most of the systems
in use today are represented by one of these eight configurations, but other designs may also be acceptable.
In evaluating which configuration is optimal for a given situation, the designer needs to consider many factors,
including the requirements for Quality Assurance release, the desired specification of water (DI, USP WFI,
etc.), hydraulic limitations, the required temperature at each drop, the number of use points, and the cost of
energy.
Decision tree guide
1) Batched System
2) Branched/One Way
3) Parallel Loops, Single Tank
4) Hot Storage, Hot Distribution
5) Ambient Storage, Ambient Distribution
6) Hot Storage, Cool and Reheat
7) Hot Tank, Self-contained Distribution
8) Point of Use Heat Exchanger
Each configuration varies in the degree of microbial control provided and in the amount of energy required.
Better microbial control is usually achieved by minimizing the amount of time water is exposed to conditions
favoring microbial growth. Configurations that store water at sanitizing conditions such as hot, under ozone,
or circulation at turbulent velocities, are expected to provide better microbial control than those that do not.
Naturally, hot circulating systems are more forgiving than cold systems from a microbiological perspective.
However, adequate microbial control may be achieved in other configurations provided they are frequently
flushed or sanitized. In any case, system design should prevent stagnation, which promotes formation of
biofilm.
Energy usage is minimized by limiting the amount of water changing temperature. Configurations storing
water hot but supplying it to the use points at lower temperature must cool the water before use. Energy
requirements are minimized by cooling only that water drawn from the system. Configurations that constantly
cool and reheat water utilize more energy than systems that do not.
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The configurations delivering lower temperature water are shown with a single cooling exchanger for clarity.
Usually the cooling medium is tower water since this is the least expensive to generate. In most parts of the
world, tower water is not cold enough to allow use temperatures much below 25°C. A second cooling exchanger using chilled water or glycol must be added if the required use temperature is below 25°C. It is
usually cost prohibitive to cool water from 80°C to less than 25°C using chilled water or glycol alone as the
chiller size becomes quite large.
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Figure 8-1 Distribution Decision Tree
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8.3.4
Example System Descriptions
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The following describes the systems, contained in the accompanying decision tree, that can be used successfully to store and distribute high purity water. Figure 8-2 through Figure 8-12 present simplified schematic diagrams (not meant to be P&IDs) of each configuration.
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STORAGE AND DISTRIBUTION SYSTEMS
Figure 8-2 Batched Tank Recirculating System
This system is used where QA release is required on the water before it goes into the process. One batch
tank supplies water to the process, while the other is filled and tested for QA release (traditionally due to
unreliable means of water production). This is a cumbersome system to operate and is usually limited to
smaller systems. The disadvantages are the high capital and operating costs. In-line conductivity and TOC
measurements can provide nearly the same degree of assurance for less money.
Figure 8-2 Batched Tank Recirculating System
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Figure 8-3 Branched/One Way with Limited Points of Use
This configuration is sometimes used where capital is tight, the system is small, and microbiological quality is
of lesser concern. It is also useful where frequent flushing or sanitization of the piping is possible. It is a good
application where water use is continuous. It is less advantageous where water use is sporadic, as the line
stays stagnant when not in use. Microbial control is more difficult to maintain. A program must be set up to
flush (e.g., daily) and sanitize the loop to maintain microbial contamination within acceptable limits. More
frequent sanitization may be required, increasing operating costs. It is also more difficult to use On-Line
monitoring, as indicative of the quality of the water throughout the system, in a non-recirculating system.
Figure 8-3 Branched/One Way with Limited Points of Use
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Figure 8-4 Parallel Loops, Single Tank
This configuration is a combination of any of the loop distribution schemes off one storage tank. Figure 8-4
shows a hot storage tank with two separate loops; a hot distribution and a cool and reheat loop. Parallel loops
are very common and are most advantageous where multiple temperatures are required, or where the area
served is so large that a single loop becomes cost prohibitive or hydraulically impractical. The major concern
is to balance the various loops to maintain proper pressure and flow. This is accomplished either by using
pressure control valves, or by providing a separate pump for each loop. (Note: A different design is intentionally presented for each loop).
Figure 8-4 Parallel Loops, Single Tank
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Figure 8-5 Hot Storage, Hot Distribution
This is the configuration of choice when all use points require hot (greater than 65°C) water. Temperature is
maintained in the storage tank by steam supplied to the tank jacket or alternatively by a heat exchanger on
the circulating loop. Water is generally returned to the top of the tank through a spray ball to ensure that the
entire top surface is wetted. This system provides excellent microbial control and is simple to operate. In
addition, tank and loop sanitization is required less frequently, or not at all, if a temperature of 80°C is maintained. This type of system is universally accepted by regulatory agencies.
Areas of concern include protecting workers from scalding, cavitation in the circulation pump, moisture condensation on the vent filter, and the formation of rouge. Scalding is minimized by operating at lower temperature (65°C) or by proper training and personal protective gear. Cavitation is avoided by accounting for the high
vapor pressure of hot water in the net positive suction head (NPSH) calculations. Condensation is prevented
by positioning the hydrophobic vent filter for good drainage and by heating the filter with either a low pressure
steam jacket or electric tracing. Avoid overheating as this can melt the filter cartridge. Rouge formation is
controlled by passivation and by operating at a lower temperature. It can be eliminated by using non-metallic
or lined components.
Figure 8-5 Hot Storage, Hot Distribution
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Figure 8-6 and Figure 8-7 Ambient Storage, Ambient Distribution
This system is most advantageous when the water is generated at ambient temperature, will be used only at
ambient temperature, and there is adequate time for sanitization.
Since the water is stored at ambient temperature with no disinfectant, microbial control is not as good as in
hot storage system configurations. However, good microbial control is possible provided sanitization is conducted on a frequent basis. Frequent sanitization is usually accomplished by allowing the water level in the
storage tank to drop through use, then heating the remaining contents, and circulating through the loop for a
set amount of time. Reducing the water level limits the energy and time required to sanitize. Heat is provided
by steam supplied to the tank jacket, or alternatively, by a heat exchanger on the circulating loop. Cooling may
be required to prevent temperature increases due to heat buildup from the pump, and for cool down after
sanitization. Water consumption is low if the level in the storage tank is allowed to drop through use prior to
sanitization and moderate if it is drained.
The capital and operating costs of this system are minimal. Another advantage is that it can provide high flow
rates of ambient pharmaceutical water, without need for complex points of use heat exchangers. Its major
disadvantage is the time required to sanitize, which is longer than the previously described systems, due to
the need to heat and cool the contents of the storage tank.
Figure 8-6 Ambient Storage and Ambient Distribution
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Many pharmaceutical water users have found that storing and distributing water at ambient temperatures
with periodic sanitization, (utilizing either clean steam or heating to 80°C for microbial control) to be safe and
cost effective. The ambient system can also be effectively operated with an ozonated storage and a periodically ozonated loop, in lieu of hot water sanitization (see Figure 8-7). Levels of 0.02ppm to 0.2ppm of ozone
protect the water from microbial recontamination. Ozone needs to be completely removed from process
water prior to usage, using UV radiation. Consideration therefore must be given to verifying/assuring that
ozone has been eliminated, such as the use of In-Line monitors.
One advantage of ozonation or chemical sanitization, is that these methods allow the use of plastics as a
material of construction (popular in Europe for purified water systems).
Figure 8-7 Ozonated Storage and Distribution
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Figure 8-8 Hot Storage, Cool and Reheat
This system is most advantageous when the water is generated hot, tight microbial control is required, and
there is little time for sanitization. It provides excellent microbial control and is easily sanitized. It requires less
capital than point of use exchangers, if there are multiple low temperature use points. Hot water from the
storage tank is cooled through the first heat exchanger, circulated to the use points, and then reheated in a
second exchanger before returning to the storage tank. Sanitation of the loop is accomplished by turning off
the cooling medium on a periodic basis. Water consumption is minimized since no flushing is required. The
major disadvantage of this configuration is it’s high energy consumption, since it cools and reheats the circulating water regardless of whether it is drawn out of the loop.
Figure 8-8 Hot Storage, Cool and Reheat
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Figure 8-9 Hot Storage, Self-Contained Distribution
This configuration is most advantageous when water is generated hot, there are many low temperature water
users, and energy consumption is critical. It provides the benefits of the cool and reheat loop without the large
energy requirement. Hot water from the storage tank is cooled through the heat exchanger, circulated to the
use points, and then returned to the pump suction bypassing the storage tank. The loop is sanitized on a
periodic basis by turning off the cooling medium and opening up the return to the storage tank, allowing hot
water to flow through the loop. An alternative is to flush the lower temperature water to drain until the loop
becomes hot and then return the flow to the storage tank. The water in the storage tank is kept hot through a
steam jacket or heat exchanger on an external pump around loop.
When water is drawn out of a point of use valve, hot water from the storage tank flows into the loop and is
cooled by the heat exchanger. The hot water flushes the short section of line between the storage tank and
the circulation pump preventing a deadleg. In most pharmaceutical installations, this happens many times per
day so the line stays relatively hot. If the usage rate is low, a small amount of water can be returned to the
storage tank on a continuous or timed basis, keeping this line flushed. A third alternative is to return the
circulating water to just downstream of the storage tank outlet valve, so the deadleg is negligible.
Figure 8-9 Hot Storage, Self-Contained Distribution
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Figure 8-10, Figure 8-11, and Figure 8-12 Hot Storage, Hot Distribution, Point of Use Heat Exchanger
This configuration is identical to Figure 8-5 except that use points requiring water at lower temperature are
equipped with point of use heat exchangers. Figure 8-10, Figure 8-11, and Figure 8-12 show three different
designs for these exchangers. All three allow flushing water to drain to lower microbial counts and adjusting
temperature before opening up the point of use valve. All three also allow for sanitizing the exchanger and
downstream piping when water is not called for at the drop. The schemes differ in capital cost, sanitation
method, and in the amount of water used for flushing. Sanitization is accomplished using low pyrogen steam
in Figure 8-10. In Figure 8-11 sanitization is accomplished by circulating hot water from the loop, through the
point of use exchanger, back to the main loop. The operation in Figure 8-11 can be facilitated by installing a
block valve at the return of the main loop. The valve would be closed immediately prior to starting the sub
loop, to prevent back flow from the main loop. The initial draw of point of use water would be diverted to drain.
Figure 8-12 is sanitized by flushing hot water from the main loop once through to drain. Tube-in-tube or
serpentine type coolers could be used, as well as double tube sheet exchangers, which are depicted.
Point of use exchangers are most advantageous when there are both hot and lower temperature water use
points off the same loop, and the number of low temperature users is small. Since they maintain the water hot
until it is drawn from the loop, they provide excellent microbial control, provided they are frequently flushed or
sanitized when not in use. As the number of low temperature users increases, the capital costs and space
requirements become prohibitive, and one of the other configurations should be considered. Water consumption is high due to flushing, although this is minimized by the scheme shown in Figure 8-11. Energy consumption is moderate because only water drawn out of the loop is cooled but additional energy must be spent to
make up water flushed to drain. Maintenance requirements are high due to the added exchangers and valves.
Complexity is high as each exchanger must be properly flushed and sanitized. Each drop is limited in capacity by the sizing of the exchanger. The scheme shown in Figure 8-11 results in added pressure drop in the
main loop, which leads to a larger circulation pump.
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Figure 8-10
Single Point of Use, Steamed
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STORAGE AND DISTRIBUTION SYSTEMS
Figure 8-11
Point of Use Installed in Sub-loop
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Figure 8-12
8.3.5
Point of Use Heat Exchanger with Multiple Branch Users
Storage and Distribution Comparison Table
Table 8-1 compares several storage and distribution options currently used in the pharmaceutical industry.
Comparisons are made based upon capital, energy, operating costs, maintenance, validatability, and other
factors. Each category is rated low (L), medium (M), or high (H) for each system relative to the other systems
presented. The particular storage and distribution choice for a given scenario will depend upon the specific
situation being addressed, and the priority the end user gives to each of the categories, with quality being the
foremost priority.
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STORAGE AND DISTRIBUTION SYSTEMS
Table 8-1
Comparison of Storage and Distribution Options
Category
1. Batched 2. Branched /
System
One Way
4. Hot
5. Ambient
3. Parallel
Storage, Hot
Storage,
Loops,
Ambient
Single Tank Distribution
Distribution
6. Hot
Storage,
Cool and
Reheat
7. Hot Tank,
Selfcontained
Distribution
8. Point of
Use Heat
Exchanger
9. Tankless,
Ambient
Loop
Capital Cost
H
L
M
L
L-M
M
M
H
L
Water
Consumption
H
H
M
L
L-M
L
M
H
M
Energy
Consumption
L
L
Depends on
loops
L
L
H
M
M
L
Validatability
Simple
Complex
Complex
Simple
Average
Simple
Average
Average
Average
Complex
Complex
Depends on
loops
Simple
Average
Average
Average
AverageComplex
Average
Maintenance
Requirements
M
L
Depends on
loops
M
L
M
M
H
M
Tank Turnover
Non-Critical
Limited
Average for Non-Critical
ambient tank,
non-critical
for hot tank
Average
Average
Limited
Non-Critical
Not
Applicable
Line Flushing
Requirements
Critical
Critical
Depends on
loops
Non-Critical
Average
Non-Critical
Average
Critical
Average
Limited by
QA hold
Excellent
Average to
Excellent
Excellent
Excellent
(Cold Surge
Volume)
Average
AverageExcellent
Limited by
exchanger
sizing
Average
Loop Balancing
and Control
Requirements
Average
Simple
Critical
Simple
Average
Average
Average
Critical
Average
Microbial/
Endotoxin
Growth Potential
L-M
H (3)
Hot = L
Amb = M
L
M (1)
L - M (2)
L - M (2)
M
Hot = L
Amb = M
Operability
Ability to
Respond to
Large Peak
Demands
Most
Advantageous
When:
High Peak
Multiple
Hot Water is High Peak
Method of
Both hot
Tight
Tight
Demands for and warm
Temperatures Required, Demands for
Generation is
Capital,
Microbial
Ambient to temperature
Water is
Not Reliable, Continuous Required or
Ambient or
Control,
Hydraulic
Generated
QA release
water
Cold Water, Limited Time Cold Water
Use,
and Unit
Limitation
Hot, or
required
required and
Water is
Frequent
for
Energy
Microbial
before water Flushing or
number
Generated at Sanitization,
Costs a
Control is
use. Small Sanitization.
of low
Ambient
Energy cost
concern,
Critical
system is
temperature
Temp
not a
many low
required.
users is low
concern,
temperature
many low
users
temperature
users
Space
Constraints
or Tank
Turnover a
concern,
Limited
Capital
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Least
Advantageous
When:
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Hydraulic
Per Unit
Initial Capital Sanitization
Capital and
Space, Initial
Sporadic
High
Per Unit
or Energy will not fit into Energy Cost Energy Cost
operating Demand Use balancing is
Capital or
demands for
difficult
is High, or
Availability is
cost is a
operating
Energy
Profile, or
Ambient or
is High
tank turnover Availability is Cold Water
Tight
concern
schedule
operating cost
is a concern
Tight
a concern
L = Low
M = Medium
H = High
Amb = Cold or Ambient Conditions
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Notes:
1)
Lower with hot water sanitization once every 24 hours.
2)
Storage tank is always hot, loop is cold or ambient, and hot water sanitized once every 24 hours. Loop return is heated prior to reentering storage
tank.
3)
Frequent hot water flushing or steaming can effectively control bioburden. High turnover of the water in each branch due to use (at least once daily)
can significantly reduce bioburden.
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8.4
MATERIALS OF CONSTRUCTION
Pharmaceutical equipment and piping systems rely extensively on stainless steels to provide the non-reactive, corrosion-resistant construction needed in manufacturing and heat sterilization. However, thermoplastics are available that may offer improved qualities, or lower cost. Less expensive plastics such as polypropylene (PP) and polyvinyl chloride (PVC) may be acceptable for non-compendial systems. Others, such as
polyvinylidene fluoride (PVDF) offering greater heat resistance, may be suitable for compendial waters, although they require continuous support in hot applications. The cost of a PVDF system may be approximately
10-15 percent lower than the cost of a stainless steel system once factors such as passivation, boroscope,
radiographic inspection, etc., are included. New methods of joining PVDF tubing leave a weld much smoother
than possible with stainless steel. At higher temperatures, however, thermal expansion of the plastic becomes a major concern.
While certain changes to higher grade materials (higher alloys such as AL6N and Hastelloy) and methods of
fabrication to assure compliance can yield minor improvements, others may only provide minor gain despite
considerable additional expense.
Material selection should be consistent (all 316L or all 304L etc.) throughout the distribution, storage, and
processing systems, if regular passivation is planned.
For compendial water, the use of 316L stainless steel is preferred.
Insulation for stainless piping should be free of chlorides, and hangers provided with isolators to preclude
galvanic corrosion.
304L and 316L stainless steel has been the industry preference in tanks for the storage of compendial
waters. Jacket material in contact with the shell should be compatible, to avoid chromium depletion in the
weld-affected zones. Non-compendial water storage may not require the same level of corrosion resistance
or the use of low carbon nickel chromium alloys and special finishes, depending on the owner’s water specifications.
High purity water distribution systems, using the material and finishes specified by the design, should be
joined using acceptable welding or other sanitary techniques. The distribution and storage systems should be
installed in accordance with cGMPs and fabricated, manufactured, procured, and installed in strict accordance with explicit operating procedures.
Orbital welding has become the preferred method for joining high purity metallic water piping systems, due to
the greater control over critical weld parameters and the smooth weld bead characteristics of the process.
However, hand welding is still employed and may be required in certain situations.
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304 and 316 stainless steel have been preferred grades for use in metallic piping systems due to their high
chromium and nickel content and ease of automatic welding. Low carbon and low sulfur grades of stainless
steel are preferred for compendial systems, and control and inspection of the welding process is necessary
to limit corrosion and crevices in the system. A maximum sulfur content of 0.04% would be ideal for welding
but any mismatch in the sulfur content of the mating parts will easily cause the weld to weaken, outweighing
the advantages lower sulfur levels.
Mr. Shlomo Sackstein
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Where possible, all fittings, valves, tubing,
and weldable pieces
of the same nominal size (diameter) should
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8.4.1
Comparison of Materials of Construction for Tanks and Distribution Systems
Table 8-2
Comparison of the relative values of key factors in the design and installation
of water systems
PVDF
ABS
POLYPRO
PVC
316LSS
TUBING
304LSS
TUBING
316LSS
PIPING
304LSS
PIPING
Installed Cost
M
M
L
L
M
M
M
M
Ease of Installation (1)
H
M
M
H
M
M
H
H
Steam Sanitizable
Y
N
N
N
Y
Y
Y
Y
Hot Water Sanitizable
Y
N
N
N
Y
Y
Y
Y
Ozone Sanitizable
Y
N
N
N
Y
Y
Y
Y
Chemical Sanitizable
Y
Y
Y
Y
Y
Y
Y
Y
Rouging Susceptibility
N
N
N
N
Y
Y
Y
Y
Corrosion Resistance
H
H
H
H
H
M
H
M
Availability
M
L
M
H
H
M
H
H
Extractables
L
M
L
H
L
L
L
L
Degree of Thermal
EXPANSION
H
H
H
N/A
L
L
L
L
Joining Method
-TRICLAMP
-Solvent
-THERMAL FUSION
-WELD
Y
N
Y
N
N
Y
N
N
Y
N
Y
N
N
Y
N
N
Y
N
N
Y
Y
N
N
Y
Y
N
N
Y
Y
N
N
Y
External Support
H
H
H
M
L
L
L
L
Legend:
Y = Yes
N = No
H = High
M = Medium
L = Low
Notes:
1)
Based on skilled labor requirements, ease of welding, ease of visual inspection, shop fabrication requirements, etc.
2)
The steam pressure and steam temperature control is critical to keep both below the manufacturer’s ratings.
8.4.2
Workmanship
Fabrication should be performed by certified welders in a controlled environment to preclude contamination
of equipment and material surfaces. Facilities dedicated to the fabrication of stainless steel (or higher grade
alloys) are preferred, to avoid contamination by carbon steel. Fabrication must follow an approved quality
assurance plan. There needs to be adequate documentation in the design and construction of the system,
including up to date P&IDs, system isometrics, weld test reports, etc.
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Tubing and piping welds, whether orbital or manual,
must have a smooth internal diameter contour without
Herzlia,
excessive concavity or convexity, bead wandering, misalignment, porosity, or discoloration. One hundred
percent photographic or radiographic
analysis,
while utilized
to an increasing extent, is neither cost effective
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8.5
SYSTEM COMPONENTS
8.5.1
Heat Exchangers
Shell and tube, tube-in-tube, and plate and frame heat exchangers are employed. Although plate and frame
units may offer a cost advantage, they are used less often in the distribution portion of the system in compendial
service because of the perceived greater risk of contamination. However, they are common in the pretreatment side prior to final purification. In a shell and tube exchanger treated water flows through the tube bundle;
the risk of contamination from cooling or heating media can be significantly reduced by means of a double
tube sheet. Complete drainability of the u-tube bundle is achieved by weep holes located at the low point of
each chamber in the exchanger channel. Ensuring a positive pressure differential on the “clean” side can
further reduce contamination risk. Similarly, a plate and frame unit should be operated with the cleaner water
side at higher pressure than the heating or cooling medium. Conductivity meters may be used for monitoring
leakage. Unit design should permit full drainage and ready access for inspection and cleaning.
8.5.2
Vent Filters
Used on storage tanks in compendial water service to reduce contamination during drawdown. Units are
constructed of hydrophobic PTFE or PVDF to prevent wetting and generally rated at 0.1 to 0.2 microns.
Filters should be capable of withstanding sterilization temperatures and sized for maximum fill or drawdown
rates to effectively relieve the negative pressure created by high temperature sanitization cycles. Filters in hot
systems are usually jacketed to minimize condensate formation that could result in blinding vessel exhaust
hydrophobic filters. Storage tanks should be rated for full vacuum, (or have vacuum protection), if steam is
used for sterilization. Installation should also allow for drainage of condensate caused by high operating or
sanitizing temperatures, and ease of replacement. The filter cartridges need to be appropriate for the filter
housing. Vent filters should be integrity tested for compendial water storage tanks, but may not need to be
validated as sterile filters.
8.5.3
Pumps and Mechanical Seals
Centrifugal pumps are commonly employed in distribution systems. Performance curves and suction head
requirements should be reviewed to preclude cavitation, which might lead to particulate contamination. The
generation of pump heat over extended periods of low or no draw off should also be considered, since
significant temperature rise in cold systems, or cavitation due to vapor pressure in hot systems could occur.
Casing drains allow for full system drainage, where the pumps are at the low point of the distribution. Although
with double mechanical seals, with WFI or other compatible seal, water flushing may minimize the possibility
of contamination; single mechanical seals flushed to the outside have also been used. In extremely critical
applications, polished rotating elements may be warranted. The installation of dual pumps, for standby purposes, should ensure flow throughout the system.
8.5.4
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Piping System Components
a) Piping and Tubing: Extruded seamless and/or longitudinally welded tubing is commonly used in systems two inches in diameter and smaller. Recently, welded steel tubing (ASTM A-270), similar to seamless in appearance, has become available at significantly lower cost. PVDF has also been shown to be a
viable alternative.
b)
Mr. Shlomo Sackstein
Herzlia,
Fittings: Single fittings may beID
manufactured
from as 216389
few as one, to as many as five pieces. This can
number:
materially affect the suitability of the end product, in terms of weld content, documentation, and cost.
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c) Valves: The trend in the industry has been to use diaphragm valves in high purity systems, particularly in
isolation applications. For steam service, sanitary ball valves may be acceptable and require less maintenance.
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The following is a summary of water system components, listing the common industry practice, and listing
advantages and disadvantages:
8.5.5
System Components Comparison Table
Table 8-3
System Components Comparison
Item
Industry Practice
Advantages
Disadvantages
Valves
Diaphragm
Drainable*
Sanitizable
Cleanable
No steam seal
No body pockets
Higher initial cost and
maintenance
Wears out quicker
Not absolute shutoff for high
pressure systems
Plug/Ball
Low cost
Tight shutoff
Low maintenance
Need stem seal
Have body pockets where
bacteria may linger, making
sanitization difficult
Butterfly
Low cost
Tight shutoff
Low maintenance
Need stem seal
Have body pockets
Elastomers, including Viton
Temperature resistant
Less expensive
Chemical resistant
Silicone
Temperature resistant
Less expensive
Chemical resistant
EPDM
Temperature resistant
Less expensive
Steaming not
recommend
Teflon
Best temperature resistance
Inert
Cold flow in service
More expensive
Teflon encapsulated
Good temperature resistance
Good chemical resistance
Expensive
Sensitive to pinching
Vent Filters
0.2 Micron Hydrophobic
Membrane
Steam jacketed or electric traced
housing
Bioburden and
particulate reduction
Possible plugging due to wetting
Cost
Heat Exchangers
Double tube sheet
(Shell and tube)
Sanitary design
Protection against plant to clean
side leaks
More expensive
Single tube sheet
(Shell and tube)
Less expensive than double tube
sheet
Need to maintain a higher Delta P
on clean side is operationally
difficult
Gaskets
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Concentric pipe
Pumps
Low leak potential
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Low heat transfer coefficient,
requiring a large surface area
Plate and Frame
Least Expensive
Greatest leak potential
Needs double gasketing
Centrifugal
Commonly available
Less expensive
Lower maintenance
Positive Displacement
Commonly available
More efficient when higher
discharge pressure is required
More expensive
Higher Maintenance
Double
Constantly being flushed
Higher on-stream reliability
More expensive, both installation
and operation
Single
Less expensive
For non-shrouded impeller type,
cleanability an issue
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Mechanical Seals
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Table 8-3
System Components Comparison
Item
Industry Practice
Advantages
Disadvantages
Connection Types
Sanitary clamped
Minimal crevicing
Ease of inspection
Ease of Disassembly
Pressure limitations
Size limitations
Flanged
Easier in piped systems
Good in high pressure
applications
Recommended for >4” OD
High cost
Gasket protrusion
Greater chance for crevicing
Jacketed (1/2 pipe)
Good thermal efficiency
Significant welding required
Jacketed (full jacket)
Less welding leading to lower
probability of weld failure
Less thermal efficient
Non-Jacketed
Allows for complete external
inspection of the tank
Requires an external heat
exchanger
Tanks
Safety relief device prevents tank
rupture should vent filter become
blocked
Tank to be designed as an
atmospheric tank rather than a
pressure vessel
Rupture Discs
*If canted at the correct angle, and installed in pitched lines
8.6
COMPARISON OF WFI SYSTEMS WITH STORAGE TANK AND WITHOUT STORAGE TANK
Figure 8-13
Tankless Ambient Distribution
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ID number: 216389
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It is possible to feed sub-loops off a single main loop without the use of an intermediate storage tank (Figure
8-13). This configuration is most advantageous when space or capital constraints are tight. The sub-loop is
generally a circulating loop. Water drawn out of the main loop when a point of use valve is opened cannot
return to the main since the sub-loop is at a lower pressure. This provides a degree of isolation between the
sub-loop and the main, or other, sub-loops. The major disadvantage is that there is no storage capacity.
Usually this capacity is provided by a storage tank on the main loop.
Table 8-4
Comparison of WFI Systems: with Storage Tank and without Storage Tank
STORAGE TANK SYSTEM
Advantages
Disadvantages
Provides air break to minimize back contamination
of hot WFI supply.
Added capital expense of tank, filter, etc.
Minimize WFI cooler capacity by averaging hot
WFI feed flow into tank.
Sanitization/steamout may be more involved than
for a tankless system.
Provide cooled WFI “surge” volume ready on
demand to facilitate production schedules.
If the system is drained daily, potential loss of WFI
may be greater than tankless loop.
Positive point to relieve system pressure due to
normal venting or hot water sanitization.
Once operational, conditions easier to maintain
than tankless system. Potential problems easier to
isolate.
Eliminate back pressure control valve cavitation by
dividing pressure drop between valve and spray
balls.
TANKLESS SYSTEM
Advantages
Disadvantages
Decreased capital expense (no tank, filter, etc.)
WFI tank may be required to satisfy peak
demands of ambient system.
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Increased perception of improved system sterility
due to “totally welded tubing”
Thermal expansion of WFI during hot water
sanitization has nowhere to relieve, except flush to
drain.
Mr. Shlomo Sackstein
More difficult to isolate than storage tank system.
Herzlia,
ID number:
216389
System hydraulics more difficult to manage/control
If system is drained daily, potential WFI lost may
be less than storage tank system.
than storage tank system.
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8.7
MICROBIAL CONTROL DESIGN CONSIDERATIONS
In any given water storage and distribution system, there are certain fundamental conditions that can always
be expected to aggravate a microbial problem. Likewise, several basic measures will always tend to counteract such problems. Fundamental conditions that typically could aggravate the problem include:
•
Stagnant conditions and areas of low flow rates
•
Temperatures that promote microbial growth (15-55°C)
•
Poor quality supply water
Some basic measures that have been shown to alleviate such problems are:
•
Maintaining ozone levels of 0.02ppm to 0.2ppm
•
Continuous, turbulent flow
•
Elevated temperatures
•
Proper slope
•
Smooth, clean surfaces that minimize nutrient accumulation
•
Frequent draining, flushing, or sanitizing
•
Air breaks in drain piping
•
Ensuring no leaks in the system
•
Maintaining positive system pressure
All pharmaceutical water must meet the EPA standard for microbiological quality of potable water; which
means it must basically be free of specific indicator organisms. Beyond that, microbiological quality for noncompendial water should be based upon its intended use and the types of products that will be formulated
with it.
It is important to note though that although the required microbial population acceptance level for USP
compendial purified water is 100 CFU/ml, reliance on such a single parameter can be misleading. The 100
CFU/ml limit may generally be applied to the manufacture of solid oral dosage forms. Many times, however,
aqueous or topical formulations require tighter controls to maintain product quality. The USP points out that
these types of products have been the subject of recalls when found to be contaminated with gram negative
organisms, and the typical microbiological flora of water are gram negative organisms.
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Herzlia,
ID number: 216389
A common appropriate approach to dealing with this key issue involves the use of trend analysis. Using such
an approach, alert and action levels are related to the system norm. In this context, strategies for responding
to the alert and action levels can, and should, be developed. Even with the most conscientious design, there
may be places in which biofilm can form. Good Engineering Practices, such as eliminating deadlegs, ensuring adequate flow velocities through out the system, and periodic sanitization help control microbial activity.
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It is common practice, therefore, to store and distribute water in a circulating system under any of the following scenarios:
•
At conditions which are self-sanitizing such as above 65°C or under ozone.
•
At conditions that limit microbial growth such as below 10°C with periodic sanitization.
•
At ambient temperatures where sanitization is determined by the validated methods that control microbial growth
8.7.1
Regulatory Clarification to Common Industry Practices
The following are industry practices that are all Good Engineering Practices (GEPs), and have been perceived in the past to reduce the chance of microbial growth.
If you collectively ignore all of these items, you increase the likelihood of having a bioburden problem. These
items include finishes, storage tank orientation, storage tank isolation, storage tank turnover, piping slope
and drainability, deadlegs and velocity.
8.7.1.1 Finishes
Common industry practices typically range from milled pipe to 320 grit (0.38 microns Ra) mechanical polish
with electropolish. Electropolishing is a reverse plating process, which improves the surface finish of mechanically polished stainless steel piping and equipment. It reduces surface area and removes surface intrusions caused by mechanical polishing, which may cause subsequent rouging, and/or discoloration. After
mechanically polishing or electropolishing the system, the polishing compounds should be confirmed to have
been completely removed from the pipe, so as not to accelerate corrosion.
The benefits for electropolish or finishes smoother than 0.76 microns Ra (approx. 180 grit or 30 micro inch)
are questionable.
Systems operating at ambient temperature or with infrequent sanitization may require a smoother surface
finish. The interior surfaces of stainless piping systems, in compendial water service, are typically ground
and/or electropolished, at considerable cost, to achieve a smooth surface of minimal porosity (0.4 to 1.0
microns Ra), in order to reduce bacterial adhesion and enhance cleanability. A viable alternative is extruded
PVDF piping, which can produce a smoother surface than most metallic systems, without recourse to polishing, although PVDF has other disadvantages. (See Section 8.4.)
8.7.1.2 Storage Tank Orientation
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Vertical orientation is the most common because of the following advantages:
120
•
Lower fabrication cost
•
Less dead volume
•
Simpler spray ball design
•
Less floor space required
•
Horizontal vessels are used where height is a constraint
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Herzlia,
ID number: 216389
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8.7.1.3 Storage Tank Isolation
Common practice for compendial and non-compendial waters where microbial contamination is a concern is
to use a 0.2 micron hydrophobic vent filter.
For hot storage vessels, the vent filter must be heated to minimize moisture condensation. An alternate
practice is to blanket the tank with 0.2 micron filtered air or nitrogen. Nitrogen blanketing can be used if CO2
absorption is a concern, or if final product oxidation is a problem.
8.7.1.4 Storage Tank Turnover
Common practice is 1-5 tank turnovers per hour.
The turnover rate may be important for systems using external sanitization or polishing equipment.
The turnover rate is less important when storage is under sanitizing conditions, including hot storage or
ozone. It may be less important under conditions that limit microbial growth, such as cold storage (4-10°C),
but this must be demonstrated by documentation.
Some storage tank turnover is required to avoid dead areas.
8.7.1.5 System Drainability
Systems that will be steam sterilized must be fully drainable to assure complete condensate removal.
Systems that will never be steam sterilized do not need to be fully drainable, as long as water is not allowed
to stagnate in the system.
It is good engineering practice to allow for the draining of equipment and associated piping.
8.7.1.6 Deadlegs
Good engineering practice is to minimize or eliminate deadlegs where possible. Common practice is to limit
deadlegs to less than 6 branch pipe diameters or less. This stems from the “6D” rule contained in the proposed CFR 212 regulations of 1976. Recently, industry experts have suggested using a guideline of 3D or
less. However, this new guideline causes confusion since the proponents of this standard generally are
discussing the length of dead leg from the outer wall of the pipe, while the original 6D rule describes the
distance from the center line of the pipe to the end of the deadleg. Obviously, if a 1/2” branch is placed on a
3” main, the distance from the center line of the pipe to the outer wall of the pipe is already 3D. Thus, even a
zero deadleg valve might not meet the 3D requirement.
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To avoid confusion in the future this Guide suggests that the length of the deadleg be considered from the
outer wall of the pipe. We propose avoiding a hard rule of thumb for maximum allowable deadlegs.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Ultimately, the water must meet the required quality regardless of the length of the deadleg. Good Engineering Practice requires minimizing the length of deadlegs and there are many good instrument and valve
designs available to do so.
It should be recognize that any one-way system can constitute a deadleg if it is not frequently flushed or
sanitized.
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8.7.1.7 Positive Pressure
It is important to maintain the system under positive pressure at all times. One common concern is systems
designed with insufficient return flow, which could draw a vacuum at points of use under periods of high water
usage. This causes an unexpected microbial challenge to the system.
8.7.1.8 Loop Velocity
Common practice is to design circulating loops for a minimum return velocity of 3 feet/second or higher, and
for Reynolds numbers in the turbulent region of greater than 2,100.
Return velocities less than 3 feet/second are acceptable for short periods of time, or in systems that do not
favor microbial growth, such as hot, chilled, or ozonated loops.
A minimum return flow is required to maintain the loop in a flooded condition under positive pressure.
8.8
CONTINUOUS MICROBIAL CONTROL
Process water systems generally employ both continuous methods of microbial control, and periodic sanitizations. This section discusses continuous methods for controlling microbial growth.
8.8.1
“Hot” Systems
The most effective and reliable means of preventing the growth of bacteria is to operate the system at temperatures above which bacteria can survive. If the distribution system is maintained in hot conditions, sanitization on a routine basis can be eliminated.
Systems operating at 80°C have a long history of data showing the prevention of microbial growth. More
recently, companies have been validating water systems at 65°C. The advantages of operating at lower
temperature include energy savings, lower risk of injury, and reducing the amount of rouging. Systems operating at the higher end of this range have a greater safety margin with regard to microbial contamination. The
effectiveness of temperatures below 80°C must be verified with test data, on a case by case basis.
Note that these temperature ranges will not destroy endotoxin. As noted in Chapter 6, where endotoxin is a
concern, the treatment system must be designed to remove it.
8.8.2
“Cold” Systems
The use of the term “cold” in this case implies that a system is maintained at a low enough temperature to
inhibit microbial growth. While this has been shown to be effective, the energy costs associated with it generally make this type system costly to operation. Generally, “Cold” systems are operated from 4°C to 10°C.
Microbial growth rates drop off significantly below 15°C, so the sanitization frequency of cold systems may be
reduced compared to ambient systems. The effectiveness of a specific temperature, and the associated
sanitization frequency in any particular system, must be determined by statistical analysis, on a case by case
basis.
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8.8.3
“Ambient” Systems
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Circulation temperatures of any pharmaceutical water system are dictated by either the required microbial
specification or the required temperature for usage. “Ambient” temperature purified water systems using
either ozone and/or hot water sanitizations are common throughout the industry, and normally result in lower
lifecycle costs, as well as reduced energy consumption compared with either the “hot” or “cold” systems.
However, without increased levels of system sanitizations, the lack of temperature control at the water stor-
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age vessel and distribution loop could result in the formation of a biofilm within the system, which could
sporadically and unpredictably produce water failing microbiological specifications and necessitate non scheduled water system shutdowns.
8.8.4
Ozone
Ozone has been shown effective for microbial control. It is a strong oxidant, which chemically reacts with
organisms and destroys them. The destruction of these organisms results in organic compounds, which may
be further degraded by ozone, ultimately to carbon dioxide. Ozone is twice as powerful an oxidant as chlorine
and needs to be dosed continually to maintain concentration.
In any compendial water system and most other applications, water at the use points is expected to be totally
free of ozone. Ozone removal is commonly effected through ultra violet radiation. 254 nanometer UV light
converts ozone to oxygen. A common design is to maintain an ozone concentration between .02 ppm and
0.1ppm in the storage tank, and use a UV light at the beginning of the distribution loop for removal. To sanitize
the loop itself, the UV light can be turned off during periods of no use, and the ozone will circulate through the
loop. The UV dosage required for ozone destruction is generally 2 to 3 times that required for microbial
control. Testing should be done to verify absence of ozone at the use points.
8.8.5
UV Light
Ultraviolet lights have been shown to reduce microbial populations in storage and distribution systems. UV
energy is germicidal in the wavelengths of 200 to 300 nanometers, which falls below the visible spectrum. UV
light de-activates DNA leading to bacteria reduction. A UV light is not a sterilization device, as it is often
referred to. The effectiveness of the light will depend on the quality of the water in which it is acting, the
intensity of the light, flow rate of water, contact time, and the type of bacteria present.
8.8.6
Filtration
Along with other particulate matter, bacteria and endotoxins may be removed via filtration. This filtration
media can be either of the microfiltration (2-0.07 microns) or ultrafiltration (0.1-0.005 micron) scale. The
integrity of these filters must be maintained.
8.8.6.1 Microfiltration
Microfiltration includes the use of depth cartridge filters, pleated filters, and cross flow filtration membrane
elements. These filters can remove particles ranging in size from 100 microns down to 0.1 micron. Depth and
pleated filters allow water to flow through a wall of fibers perpendicular to the water direction (dead ended
filters). The particles are then trapped on the outside wall of these filters, or within the filter walls (for depth
filters), due to the pore size of the filter. The filter will fill up with these particles and then needs to be replaced
with a new filter.
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8.8.6.2 Ultrafiltration
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Ultrafiltration can be used to remove organics and bacteria, as well as most viruses and pyrogens from a
water source. Filtration is typically from 0.1 micron down to 0.01 micron. Cross flow ultrafiltration forces the
water to flow parallel to the filter media, and the particles which are too large to pass through the membrane
elements are then expelled from the system in a concentrate stream to drain (typically 5-10% of the feed
flow). This allows the filters to be self-cleaning and eliminates the need to replace these membrane elements
frequently. This type of filtration can be used as a “maintenance “ step downstream of the storage tank in
certain situations.
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In general, for any purified water system, filtration downstream of the storage tank is not recommended. This
comes from concerns of “grow through” where bacteria will colonize on the upstream side of the filter, and
ultimately be found on the downstream side even though the pore size of the media may theoretically be
smaller than the size of the bacteria. An additional concern is the potential for accumulation of nutrients on
the filter media, which may in fact increase the opportunity for microbial growth. However, filters downstream
of a circulation pump are sometimes used in water systems. System designs should be predicated on obtaining the desired water quality upstream of the storage tank, using the treatment train. Filters downstream of
the storage tank should not be relied on to purify the water.
8.8.7
Circulation
Most new water systems use a circulating loop for distribution. The primary purpose of circulation is to reduce
the chance of microbial growth, or microbial attachment to the surfaces of the system. Although the mechanisms are not universally agreed upon, it is thought that the shear forces associated with turbulent water flow
inhibit nutrient concentration and attachment of bacteria to surfaces. The velocity required to obtain these
benefits is generally agreed to be greater than 3 feet per second, or Reynolds numbers greater than 2,100.
Velocity may drop off for short periods of time during high use times without adversely affecting the system,
so long as positive pressure is maintained in the system. Circulation also serves to maintain proper temperature throughout the system in hot and cold systems.
Studies have shown that the velocities required to remove biofilm are higher than practical for a water system
(above 15 ft/sec). However, a combination of high velocity (5 ft/sec or greater) with an antimicrobial agent,
such as ozone or chlorine, may, over a long enough period of time, effectively remove biofilm.
A turbulent condition may be maintained in short dead ended pipe stubs if the length of the stubs is limited.
This limiting length varies with the pipe stub diameter and to a lesser degree with the main pipe diameter. A
rule of thumb for the maximum dead leg is 6 branch pipe diameters. This “rule of thumb” may be difficult to
achieve in large mains with small branches, and may result in unacceptably long dead legs in large branches.
Rather than universally applying “rules of thumb”, it is important to recognize dead legs as an area of concern
and take appropriate steps to prevent them in the original design or implement special provisions to address
them if unavoidable. Some of the factors to consider include operating temperature, velocity in the main, and
frequency of use (if the dead leg is a use point).
8.9
PERIODIC STERILIZATION/SANITIZATION
Periodic sanitization of storage and distribution systems is generally required. Based on monitoring the microbial quality of the system, a required frequency of sanitization should be formally established. Sanitization
may also be done in response to reaching an “action limit” during routine testing. Various methods of periodic
sanitization are discussed below.
8.9.1
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Chemical
Various chemicals or combinations of chemicals can be used to periodically sanitize storage and distribution
systems. Chlorine solutions on the order of magnitude of 100 ppm are very effective at killing organisms, but
are not generally used in distribution systems because of corrosion problems associated with stainless steels.
Hydrogen peroxide in concentrations on the order of 5% is a more practical alternative. Peracetic acid can
also be used, generally in concentrations of 1% or less. Many different mixtures of these and other chemicals
are commercially available for the purpose of sanitization.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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Verification of the removal of the sanitizing agent is critical. Commercially available indicators (test strips or
sticks) are commonly used to indicate when the amount of rinse water is sufficient. A rinse water analysis is
then required to verify the absence of objectionable chemicals before the system is placed into service.
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8.9.2
Ozone
Sanitation can be done either periodically or continuously with ozone. Storage tanks are typically continuously ozonated, and then the ozone is removed prior to the distribution loop or individual use points through
the use of ultraviolet radiation. The distribution system can be periodically sanitized by turning off the UV light
and, if necessary, increasing the ozone concentration while allowing it to circulate through the distribution
loop. Concentrations as high as 1 ppm may be needed for periodic sanitization, particularly if biofilms must be
removed.
8.9.3
Heat
It has been found that periodic sanitization by heating of the process water system is highly reliable and
effective. The frequency at which sanitization must occur will vary depending on many factors.
•
System design
•
Size of distribution system
•
Components of system
•
Volume of process water in the system
•
Frequency of use of the process water (turnover volume)
•
Temperature of the circulating process water
Each distribution system must develop its own microbial profile, and the sanitization cycle and frequency will
have to be developed to fit that system.
The most straightforward method of sanitization is to heat the circulating process water in the distribution
system to 80°C ± 3°C and hold it at that temperature for a validated period of time. The use of this heat
sanitization has been proven to be very effective and if designed properly can also be economical. Controls
needed to perform this cycle of sanitization can be either manual or automatic.
Because of the types of bacteria found in purified water systems, the use of steam is not required for effective
microbial kill. Steam sterilization of distribution piping may require additional valving for vents and drains, and
may require a higher pressure rating than otherwise needed. Storage tanks are by their nature more easily
steam sterilized and this practice is common, although not required.
Hot systems inherently are continuously sanitized. Thus, the need for sanitization should be based on microbial testing results, or when the system is off line for an extended period of time and the temperature of the
loop drops to below the validated temperature range.
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Depending on the process water specification, a conservative initial sanitization frequency should be assigned for “cold” systems. After the operating characteristics of the system are determined through microbial
testing, the routine sanitization frequency can be determined.
8.9.4
Mr. Shlomo Sackstein
Herzlia,
Initial Sanitization (Ambient
IDSystem)
number: 216389
Steam sanitization has a successful history, and is probably the most reliable method for sanitization. However, there is no requirement for steam sanitization in Purified Water or WFI systems. The following procedure
is suggested as one option for hot water sanitization of an ambient system.
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Immediately after passivation (for a SS system), the system should be flushed with process water at a high
temperature (80°C ± 5°C) and all valves opened and points of use flushed. Normally two (2) times the volume
of the system (after conductivity readings), or rinse water tests indicate that no passivation chemicals are
detected, is required. This is the initial sanitization of the system.
Once it has been determined that the chemical characteristics for the quality of the process water have been
achieved by USP chemical testing, then microbial samples should be taken after each component, the points
of use, and the storage tank. This initial sampling should show that the distribution system at any sampling
point has no viable bacterial contamination. Once this is achieved, the system should be brought down to its
operating temperature and allowed to stabilize.
8.10
SYSTEM DESIGN FOR STERILIZATION/SANITIZATION
The following sections highlight particular aspects of storage and distribution system design, which are relevant to sanitization.
8.10.1 Materials of Construction
The sanitization methods used must be compatible with the materials in the system. By far the most widely
used material for storage tanks and piping is 300 series stainless steel (generally 316L). This choice provides
the most flexibility with regard to sanitization options. Sanitization with heat, UV, or ozone can be used in
stainless systems practically without restriction. Chemical sanitization must be carefully managed with regard to concentration, pH, and temperature to avoid corrosive effects on stainless distribution systems.
Other material used for distribution piping is PVDF. PVDF is susceptible to degradation by UV light. It is
common to use stainless piping immediately adjacent to the UV light in a PVDF system to compensate for
this problem. The temperature limitation of PVDF is approximately 140°C, which is high enough to allow heat
sanitization or sterilization.
In stainless systems, the gaskets used must be reviewed for compatibility with the sanitization method. A
widely used gasket material is PTFE or EPDM, both of which have good thermal memory and excellent
resistance to temperature, ozone, and chemical sanitizers. Other gasket materials must be carefully reviewed for compatibility with the sanitization methods, and to ensure that they will not leach substances into
the water.
The key is to recognize that the materials of construction “shall not be reactive, additive or absorptive so as to
alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established
requirements” (21 CFR 211.65). The sanitization procedures must be considered when selecting materials to
comply with this requirement.
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8.10.2 Storage Tank Design
Storage tanks are an area in the system that could be considered at high risk for microbial contamination
because of the large surface area, low velocities, the need for venting, and potential for “cold spots” in the
head space.
Mr. Shlomo Sackstein
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Tank size is generally based on economic
considerations in
combination with the pretreatment train sizing.
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216389
From a bacterial standpoint, smaller tanks are preferred because they have higher turnover rates, which
reduce the likelihood of bacterial growth. They also reduce surface areas and make it easier for ozone to
permeate the water, if the tank is ozonated.
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STORAGE AND DISTRIBUTION SYSTEMS
Spray balls may be used on the return loop to wet the head space of storage tanks. The use of a spray ball
serves to keep the top of the tank at the same temperature as the water, in heated systems, and avoids
alternately wet and dry surfaces, which could promote corrosive action with stainless steel and allow microbial growth. Connections on the top head (relief devices, instrument connections, etc.) should be kept as
close to the head as possible to simplify the spray ball design and get the benefit of the spray action. An
exception is the vent filter, which should be removed far enough from the storage tank to avoid direct contact
from the water spray, which could blind the filter. If dip tubes or instruments project down from the head,
multiple spray balls may be needed to avoid a “shadow” being created in the spray pattern.
The tanks must be vented to allow filling, and a filter should be used at the vent to avoid airborne particulate
and microbial contamination. To avoid the problem of condensation in the filter and the resultant potential for
colonization and grow through, hydrophobic vent filters are used and/or the filters are maintained at a temperature above the tank temperature with steam jacketing or electric tracing.
To help avoid microbial growth, and avoid the change in conductivity resulting from absorption of atmospheric
gasses into the water, nitrogen blanketing on the head space may be used. This eliminates outside air passing into the tank through the vent filter. Note that gasses added to storage tanks should be appropriately
filtered to avoid objectionable contamination.
Table 8-5
Comparison of Alternate System Designs for Microbial Control in Storage
and Distribution
Installed Cost
Operating Cost
Relative
Effectiveness/Reliability
Ambient system, with ozonated
tank, periodic ozone in
distribution piping
Low
Low
Good
Ambient system with periodic
hot water sanitization (note 2)
Low
Low
Good
Continuous “Cold” system
(4-10°C) with periodic hot water
sanitization
Medium
High, unless
cold water is
required for
process
Better
Continuous “Hot” system
(65-80°C) with multiple Point of
Use Coolers
High
Medium
Best
Microbial Control
Methodology
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Note 1: All systems are circulating
Note 2: Operating costs and effectiveness will increase with frequency of sanitization
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INSTRUMENTATION and
CONTROL
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INSTRUMENTATION AND CONTROL
9.
INSTRUMENTATION AND CONTROL
9.1
INTRODUCTION
Instrumentation and controls are often used within pharmaceutical water systems to:
•
control the operation of equipment and components
•
monitor and document the performance of critical equipment
•
monitor and document pharmaceutical water quality
The concepts and regulatory philosophy of defining critical versus non-critical parameters is discussed as it
relates to instrumentation and controls. This definition could be summarized as:
“All instruments and control systems should be commissioned following Good Engineering Practices. Critical
instruments and control systems should be commissioned and qualified.”
There is no regulatory requirement that requires the use of On-Line instrumentation. A monitoring program
may include a combination of On-Line instrumentation, manual documentation, and laboratory analysis.
If On-Line instrumentation is used to measure or record a critical parameter, action and alert limits may be
established. The methods of addressing “spikes” are also discussed.
Automation can have a significant impact on the cost and performance of a pharmaceutical water system.
There is no single optimum level of instrumentation and control for all systems. The optimum level for a given
system balances the benefits of improved process control, improved documentation, and lower labor costs
against the cost of procuring, installing, validating, and maintaining the instruments and control systems. In
many cases, the level of automation for a pharmaceutical water system should be consistent with that utilized
for the manufacturing process it supports.
9.2
PRINCIPLES
a) To achieve GMP compliance, the manufacturer must demonstrate, through documented evidence, that
the pharmaceutical water system is in control and consistently produces and delivers water of acceptable quality.
b) Although many quality attributes can be continuously monitored using On-Line instrumentation, there is
no compendial or regulatory requirement for On-Line monitoring of pharmaceutical water quality. A monitoring program typically includes a combination of On-Line instrumentation, manual documentation of
operational parameters, and laboratory analysis of water samples.
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c) Instruments and control systems are critical and must be qualified when they are used to measure,
monitor, control, or record a critical process parameter. A critical parameter is a processing parameter
that affects the final water quality.
For example, the temperature of the final water product may be considered critical for microbial control. In
this case, the temperature controls (e.g., sensors and alarms) would be considered critical. However, it is
not necessary to consider the temperature of the heating media (e.g., steam) as a critical parameter.
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Documentation should clearly indicate which instruments are critical and which are not. It is also advisable to identify non-critical instruments as such on the field device.
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INSTRUMENTATION AND CONTROL
d) All instruments and control systems should be designed, installed, calibrated, and maintained appropriately, according to Good Engineering Practice. All critical instruments and controls require qualification.
e) Items that should be recorded in the system documentation include maintenance procedures and maintenance work performed, procedures for sampling and analysis, reporting the results, and trend analysis
of the laboratory data. The monitoring program during start-up typically defines maintenance frequency
and alert and action levels for the process variables.
9.3
GENERAL INSTRUMENTATION REQUIREMENTS
9.3.1
Instrument Selection and Installation
a) Instruments should be selected for accuracy and reliability over the entire process range.
b) Instruments should be selected and installed in a way that reduces the potential for contamination.
•
Water contact surfaces should be constructed of materials that are compatible with the water they
contact. Materials of construction and surface finishes (see Chapter 8) are commonly specified for
instruments installed in distribution systems.
•
Sensors in direct contact with waters with strict microbial limits should be of sanitary design. Nonsanitary instrumentation is commonly used in feed water and pretreatment systems.
•
Instruments may be installed directly in the water system or in a side stream that may, or may not, be
returned to the main system.
•
Deadlegs should be avoided.
c) When possible, instruments should be installed such that exposure to harsh process conditions, such as
pH and temperature extremes, is avoided. For example, In-Line sensors used to monitor effluent from a
deionizer should be positioned such that exposure to regeneration chemicals is avoided.
Instruments that are not compatible with passivation agents, sanitization agents, or sanitization temperatures should be installed so that they may be easily removed or bypassed. Such devices may need to be
sanitized off line.
d) Instruments should be installed in accordance with manufacturers’ requirements to ensure proper operation. For example, flow meters should be installed in the proper orientation and with the correct upstream
and downstream straight run of pipe. The impact of process and ambient conditions on an instrument’s
accuracy and reliability should be addressed.
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e) Conductivity cells are especially sensitive to the presence of air or steam bubbles, which can be present
where there is turbulence, cavitation, or flashing. Such locations should be avoided.
f)
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Accessibility for maintenance should be Herzlia,
considered, but improving control response is usually more
critical. Poor response time may be a consequence of the poor placement of a device and, in most cases,
can be improved by installing the
device
closer to the point
of measurement.
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number:
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9.3.2
Instrument Calibration
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a) The calibration of critical instruments should follow a regular program, which provides evidence of consistently acceptable performance. Non-critical instruments may be calibrated on a frequency deemed
appropriate for the service.
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INSTRUMENTATION AND CONTROL
b) Calibration should follow approved procedures and the results should be documented. Each component
in a control loop should be calibrated individually or the loop may be calibrated in its entirety. All calibrations should be traceable to certified standards (e.g., NIST).
c) Vendor-supplied calibration certificates should reference the applicable instrument serial numbers. The
impact of shipment and installation on the vendor’s calibration should be addressed.
9.3.3
Types of Instrumentation
9.3.3.1 Conductivity
a) Although non-ion specific, conductivity is a valuable tool for measuring the total ionic quality of water and
is a critical parameter for many high purity water systems. Conductivity limits for Purified Water and WFI
are specified in the USP.
b) On-Line conductivity instrumentation is frequently used to monitor and control the performance of many
types of purification equipment and to continuously monitor the quality of pharmaceutical waters. On-line
conductivity instrumentation may also be used for final quality assurance testing, thus eliminating the
need for periodic laboratory analysis of water samples.
c) Temperature has a profound impact upon conductivity measurement. To eliminate this temperature dependence, most instruments include a temperature sensor in the conductivity probe and one or more
algorithms to correct the actual measurement to a standard temperature. However, due to he inaccuracy
inherent in temperature compensation algorithms, compensated conductivity measurements are not
suitable for critical quality assurance testing of USP purified water and WFI. When In-Line conductivity
measurements are used for final quality assurance testing of USP purified water and WFI, a non-compensated conductivity value and the water temperature must be measured as required by the USP.
Compensated conductivity values used strictly for process control and monitoring are not subject to USP
requirements.
d) To operate properly, conductivity sensors must be installed such that there is continuous water flow
through the sensor and air bubbles or solids cannot become trapped inside the electrodes. Air bubbles
will result in lower-than-expected conductivity readings while solids can impact the conductivity in either
direction. Clean steam must be condensed prior to conductivity measurement.
e) Conductivity meters may be used throughout a pharmaceutical water system to monitor and control
purification processes or to monitor pharmaceutical water quality. Some examples are:
•
Feed water monitoring can detect seasonal or unanticipated quality changes that could impact pretreatment equipment operation.
•
RO influent and effluent monitoring allows calculation and trending of percentage rejection. Changes
in percentage rejection may be a sign of membrane failure, scaling or fouling, seal failure, improper
pH, inadequate feed pressure, or too high a recovery rate.
•
•
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Deionizer effluent or in-bed monitoring
detects, or predicts, resin exhaustion and allows automatic
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initiation of regeneration cycles.
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The conductivity of pharmaceutical water may be monitored after the final treatment step to verify
acceptable quality prior to delivery to a storage tank. In addition, conductivity meters are often installed in the return piping of distribution loops downstream of the final point of use. Many systems
include provisions for automatic diversion to drain or recirculation back through purification equipment when water quality entering the tank is outside the acceptable range.
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9.3.3.2 Total Organic Carbon (TOC)
a) Total Organic Carbon (TOC) is a measure of the carbon dissolved in water in the form of organic compounds. It is a valuable tool for measuring the aggregate level of organic impurities in pharmaceutical
water systems. A TOC test with a nominal limit of 500 ppb for USP Purified Water and WFI is a required
test in the USP.
b) TOC meters are relatively sophisticated analytical instruments. The USP provides guidance on how to
qualify an instrument and how to interpret the instrument results.
c) In addition to “continuous” monitoring of equipment performance and pharmaceutical water quality, OnLine TOC meters may be used for final quality assurance testing, thus eliminating the need for periodic
laboratory analysis. When used for critical assurance testing of USP purified water and WFI, instrument
precision, system suitability, test methodology and calibration procedures must meet USP requirements.
Instruments used strictly for process control and monitoring are not subject to USP requirements.
d) TOC is often monitored at several locations in a pharmaceutical water system. Some examples are:
•
Feed water monitoring can detect seasonal or unanticipated quality changes that could impact pretreatment equipment operation or the potential for resin or membrane fouling.
•
Monitoring TOC downstream of carbon filters, organic scavengers, RO units, and UV lights can verify
proper equipment operation and provide advance warning of bed exhaustion, compromised membranes, or the need for lamp replacement.
•
TOC levels of pharmaceutical water may be monitored after the final treatment step to verify acceptable quality prior to delivery to a storage tank. In addition, TOC meters are often installed in the return
piping of distribution loops downstream of the final point of use. Many systems include provisions for
automatic diversion to drain or recirculation back through purification equipment when water quality
is outside the acceptable range.
e) There has been much interest in the possible use of TOC analyzers to indicate endotoxin contamination.
While this type of contamination will lead to higher TOC levels, there is no quantitative correlation to TOC
levels. TOC results cannot substitute for microbial or endotoxin testing.
9.3.3.3 PH
a) pH measurement is relatively straightforward for high conductivity water. Reliable results can generally
be obtained using pH indicators or laboratory, field, or On-Line pH meters.
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b) Accurate pH measurement is difficult in many pharmaceutical waters due to the low conductivity. Low
conductivity water is susceptible to pH swings due to contaminants introduced from the air, sample
containers, and test equipment, as well as instrument difficulties associated with measuring low ionic
strength solutions.
c)
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Common locations for On-Line pH measurement
and control include:
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• Upstream of cellulose acetate
membranes, where
acid is injected to minimize membrane hyIDROnumber:
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drolysis
•
132
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Upstream of a degasifier, where acid is injected to increase C02 removal
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d) While pH limits for purified water and WFI are no longer specified in the USP, On-Line pH meters are
rarely used for process control or for final quality assurance testing of pharmaceutical waters for several
reasons:
•
Conductivity is a more sensitive measurement of overall ionic quality since changes in pH reflect
logarithmic changes in water quality
•
A pH sensor’s reference electrode contains a buffer solution that may leak through the reference
electrode into the water being measured. To prevent contamination of the pharmaceutical water
system, a pH sensor is installed in a side stream that flows to drain. The water flow rate through the
meter must be controlled and held constant to achieve repeatable results.
•
pH meters require frequent (daily in some cases) calibration with standard buffer solutions
9.3.3.4 Ozone
a) Dissolved ozone levels should be monitored in storage and distribution systems that utilize ozone for
microbial control. Ozone levels can be determined periodically in the laboratory using several wet chemistry methods, or continuously using an On-Line analyzer. On-line analyzers are relatively inexpensive
and easy to maintain, but they should periodically be calibrated against laboratory methods.
b) For effective and safe system operation, ozone levels should be monitored at the following locations:
•
At the storage tank discharge to control operation of the ozone generator
•
Downstream of the UV light to ensure ozone destruction prior to water use
•
In loop return piping to ensure proper ozone levels are maintained during sanitization
c) Since Oxidation Reduction Potential (ORP) analyzers are nonspecific and unable to differentiate ozone
from other oxidants, ORP analyzers should not be used for controlling ozone levels in pharmaceutical
water systems.
9.3.3.5 Flow
A wide variety of flow meters may be used in the feed water and pretreatment portion of a pharmaceutical
water system including magnetic flow meters, mass flow meters, vortex shedding meters, and ultrasonic
meters. All meters should be installed according to the manufacturer’s instructions, to ensure proper operation.
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Water flow rate (or velocity) may help to reduce microbial growth and maintain temperature within hot or cold
systems. It is commonly verified upon startup, but not continuously monitored. Flow rate may vary. It may be
monitored for information only.
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Temperature is often monitored and/or controlled at various locations to ensure optimum equipment operation and/or for microbial control. Temperature
interlocks may
be used to prevent damage to membranes,
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9.3.3.6 Temperature
resins, or equipment if water temperatures drift outside allowable ranges.
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In distribution systems where temperature is controlled or where heat sanitization is used, temperature is
considered critical to ensure proper system operation or effective sanitization.
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9.3.3.7 Pressure
Pressure may be monitored and controlled throughout the purification process to ensure optimum equipment
operation. Monitoring differential pressure across filters indicates when backwashing or element replacement is needed. Differential pressure measurement across resin beds is useful in detecting resin fouling and
poor flow distribution. Monitoring RO feed, interstage, permeate, and concentrate pressures provides early
warning of membrane fouling and scaling. Back pressure control in distribution systems may be critical, if
minimum pressures are required at points of use.
Pressure is not normally considered a critical parameter, however, the system should maintain positive pressure at all times. It may typically be monitored for information only.
9.3.3.8 Level
Various types of level measurement are used in the feed water and pretreatment portion of a pharmaceutical
water system, including simple float switches, ultrasonic sensors, capacitance sensors, and differential pressure transmitters. The stub from the tank must be kept as short as possible to minimize deadlegs. Calibration
of this type of transmitter is time consuming, since it requires filling the tank to verify proper operation. Tank
nozzles with integral valves minimize deadlegs and allow calibration while the tank is in service.
Tank level may be monitored to control the supply of water into a tank and for control and protection of
downstream pumps.
In some instances, level may not normally be considered a critical parameter and may be monitored for
information only. In these cases, it is usually not validated.
9.4
DESIGN CONDITIONS VERSUS OPERATING RANGE
The control system may recognize the distinction between design conditions and operating ranges, and the
impact this distinction has upon validation and facility operation. These criteria are defined as:
•
Design Condition: the specified range, or accuracy, of a controlled variable used by the designer as a
basis to determine the performance requirements for an engineered system.
•
Allowable Operating Range: the range of validated critical parameters within which acceptable water
product can be produced.
•
Normal Operating Range: a range that may be selected as the desired acceptable values for a parameter during normal operations. This range must be within the Allowable Operating Range.
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a) While it is desirable that a facility should meet all stated design conditions, the acceptability of the water
system for operation from a cGMP standpoint depends on operating within the Allowable Operating
Ranges.
b)
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Normal Operating Ranges cannot exceedHerzlia,
the Allowable Operating Range for the product water. Design
condition selection should reflect Good Engineering Practice.
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c) It may be desirable to apply the concept of Alert and Action points along with Normal Operating Range.
Alert levels are based on normal operating experience and are used to initiate investigations or corrective
measures, before reaching an Action level. Action levels are defined as the level at which some corrective
action must be taken to avoid jeopardizing water quality.
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9.5
INSTRUMENTATION SPIKES
“Spikes” may be experienced in the measurement of some parameters. These excursions may be the result
of the measurement technique or sensor and may not be representative of the actual parameter value. If a
spike occurs in a system with a significant physical lag or mass, the rapid changes in a parameter as evidenced by spikes may be physically impossible and consequently can be treated as instrumentation spikes.
In other cases, it may be decided to treat these spikes as Alert Level deviations based upon their frequency
and duration even though their magnitude may exceed the Action level.
A procedure for defining and handling spikes should be developed in conjunction with Quality Assurance
based on the specific water system.
9.6
CONTROL SYSTEMS
9.6.1
Level of Automation
Selection of a control strategy for a pharmaceutical water system should consider feed water quality and
reliability, the complexity of the purification and/or distribution system, labor costs, personnel skill levels and
capabilities, and documentation and reporting requirements. Options for control include:
a) Local instrumentation with manual control: In this option, a combination of instrumentation, periodic
samples, and visual examination is used to monitor critical process parameters. Data is collected and
recorded manually, and analysis and trending capabilities are limited. Excursions of critical parameters
outside acceptable ranges typically trigger local alarms to reduce the risk of unacceptable water quality.
Satisfactory manual operation requires significant human intervention. This requires detailed operating
procedures and conscientious documentation of critical quality parameters. This option has the lowest
installed cost, but is very labor intensive and may be subject to human error.
b) Semi-automatic control: These systems use local operator control panels, relay logic control, local
chart recorders and printers, and some manual data collection to monitor and control the water system.
These systems are less labor intensive over the manual systems, but are still labor intensive due to the
manual data collection and monitoring required to control the process.
c) Automatic control: Automated systems use a computer (PLC or DCS), or computers, to control the
pharmaceutical water system. The computer system utilizes appropriate process monitoring instrumentation (conductivity probes, flow meters, etc.) to gather data and make appropriate adjustments to the
system automatically. As water generation systems become more sophisticated, relying on human intervention to control and monitor the water system becomes more difficult and labor intensive. An automated system requires less operator involvement, but requires a more highly trained maintenance and
engineering support staff.
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d) Fully integrated systems: These systems include a fully automated system and a wide area network
connected to other computer systems in the building or site. These systems allow for central site monitoring, automatic electronic data collection, centralized alarm monitoring with automatic recording, response,
and report generation.
Mr. Shlomo Sackstein
Herzlia,
Additional information on control system
is available216389
in the Good Automated Manufacturing Practice
ID design
number:
(GAMP) Guide and in various guidelines by the Instrument Society of America (ISA).
Whichever level of automation is selected, the validation effort should verify operation of the complete system, including vendor-supplied sub-systems.
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9.6.2
Control System Software
The software/control system may be used to measure, monitor, control, or record critical process parameters. Programming and design standards, especially concerning operator interface, control techniques, alarm
handling, and interlock processing should be applied during the development, validation and maintenance
phases of the project. The control system software consists of:
a) Firmware, Operating System and Application Software: This is software permanently loaded into
memory that may or may not be accessible to the user. While the functions performed by the control
system may be divided between critical and non-critical functions, it is impossible to divide or isolate the
firmware, operating system, application software, and associated hardware functions. Therefore, if some
of the functions of a control system are considered critical, all of the above software is considered critical,
and should be validated.
b) User Configurable Software: The functions of the user configurable software may be defined as critical
or non-critical. The critical functions or modules require enhanced documentation, including validation. In
some cases, it may be impossible to divide or isolate software adequately. In such cases, if some of the
functions are critical, it may be necessary to validate all the software.
The type of process control required is often the determining factor in the type of software needed, and
software requirements often define the type of system selected. Major considerations are:
•
Number of I/0 points
•
Mathematical or statistical functions required
•
Reporting features required (particularly if the control system is to be further integrated into higher systems)
•
Whether or not advanced control techniques are required (e.g., neural nets; fuzzy logic controllers; adaptive gain; dead-time compensation)
9.6.3
Control Hardware and Operation Interface
a) Critical software requires enhanced documentation and should be designed and tested in accordance
with the Lifecycle Methodology.
b) The water system, field instruments and control requirements all affect control hardware selection. Plant
standards, or a large installed base of a particular system may drive the selection.
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COMMISSIONING and
QUALIFICATION
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COMMISSIONING AND QUALIFICATION
10.
COMMISSIONING AND QUALIFICATION
10.1
INTRODUCTION
Commissioning and qualification comprise the validation process by which a system is put into service and
demonstrated to consistently produce water of a specified quality, under various conditions, while operated
under set procedures. Although commissioning and qualification are typically separated within a project schedule, they are in essence, one continuous process.
The specific activities and processes during commissioning and qualification will not be discussed in this
Guide. These are considered by a separate ISPE Baseline® Guide on Commissioning and Qualification, and
pharmaceutical water systems are used as examples throughout. A summary of key concepts are listed
below:
a) Due to the interdependence between activities and those involved, excellent communication, planning
and coordination between operations, engineering, commissioning, and validation personnel will enable
timely and cost-effective project completion.
b) Each component of the system should be built in accordance with plans and specifications and should be
inspected, tested, and documented by qualified individuals. These activities, and the production of supporting documentation, are defined as Good Engineering Practice (GEP).
c) GEP recommends a minimum level of documentation for all systems and equipment. This encompasses
design, fabrication, vendor testing, construction, field inspection, and commissioning. If these documents
are appropriately planned, organized, and authorized, they may become an integral part of qualification
support documentation, thus avoiding redundancy and saving time and money.
d) Design criteria and documentation requirements should be clearly defined early in the design phase, to
ensure clear expectations and appropriate planning, and facilitate timely commissioning and validation.
Engineering firms, vendors, and contractors should be required, per the system specifications, to provide
the necessary documentation, to avoid unnecessary costs and delays associated with obtaining or creating these documents.
e) During construction, timely review of documentation and periodic “walk-throughs” can ensure that Installation Qualification requirements are met.
f)
Commissioning takes the system from a state of substantial completion to a state of operation. It is the
phase of a project that includes mechanical completion, start-up, and turnover. Commissioning incorporates a systematic method of testing and documenting the system at the conclusion of construction, and
prior to the completion of validation activities.
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g) Commissioning documents should not be created and executed for the purpose of regulatory compliance. However, commissioning tests and documentation will typically satisfy many installation and operational qualification requirements.
10.2
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SYSTEM QUALIFICATIONID
DOCUMENTATION
number: 216389
Good Engineering Practice dictates that documentation be developed to provide evidence of the design, and
that the water system operates in accordance with the design. This documentation encompasses engineering, installation, inspection, and testing. Such documentation is common to all system commissioning activities and is partially summarized below:
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COMMISSIONING AND QUALIFICATION
•
A system description stating design intent
•
A schematic drawing of the system (P&ID)
•
Written system specifications
•
Detailed design drawings
•
Vendor manuals and drawings
•
Field inspection and test reports
•
System qualification test results
Because of their critical impact on pharmaceutical production, water systems require additional emphasis on
certain sections of this documentation. Specific design requirements for water and steam systems are contained within the body of this Guide. When compiling documentation related to water systems, particular
attention should be paid to the following:
a) Schematic documentation may be enhanced by the inclusion of a system isometric diagram (or diagrams) indicating location and numbering of welds, relative elevations, slope of lines, and points of drainage.
b) The system specification should indicate performance criteria, as well as design parameters.
c) Field inspection and test reports should include cleaning and passivation procedure and record, weld
parameter documentation and inspection reports, slope verification, and verification of the absence of
“dead-legs”.
d) System qualification tests may or may not be subject to a pre-approved protocol addressing qualification
test requirements. In either case, test results should be reported in direct comparison to acceptance
criteria derived from system design and operating specifications.
e) System qualification tests should include verification of all automated functions, specified temperature
control, distribution system velocity, and initial water quality determination.
Additional details regarding water system qualification may be found in the associated “ISPE Baseline® Guide
on Commissioning and Qualification”.
10.3
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SYSTEM QUALIFICATION SAMPLING PROGRAM
The qualification of water systems is unique in that performance must be proven over an extended period of
time, and is subject to variations in use rate and initial feed water quality. Therefore, the sampling program
associated with pharmaceutical water systems validation is unique and specialized.
Mr. Shlomo Sackstein
Herzlia,
Extensive sampling is required to establish and confirm that the entire system will operate within specified
operating ranges, to develop and evaluate
the system operation
and maintenance procedures, and to verify
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that the water produced and delivered to the points of use consistently meets the required quality specifications and acceptance criteria. This portion of the program is sometimes termed performance qualification.
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Because of the critical impact that water has upon pharmaceutical quality, the sampling program and evaluation of results is usually subject to a pre-approved plan or protocol, with clearly defined acceptance criteria.
Also included should be procedures to deal with deviations from specified parameters and analytical results.
138
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COMMISSIONING AND QUALIFICATION
The sampling program consists of three successive phases, each with a specific purpose and sampling
scheme, as outlined below. The initial phase of the sampling program typically begins after the water system
is shown to be fully operational, as demonstrated through integrated system testing in Operational Qualification.
The water generated during the various phases may be used for manufacturing as long as analytical results
are acceptable. The intended applications and impact of water quality should be considered in determining
how much data is required before use.
Table 10-1 Sampling Program
Phase
Primary Objectives
1
• Develop appropriate operating ranges.
Typical
Duration
2-4 weeks
• Develop and finalize operating, cleaning, and maintenance procedures.
• Demonstrate production and delivery of water of the required
quality.
2
• Demonstrate consistent operation within established ranges.
2-4 weeks
• Demonstrate consistent production and delivery of water of the
required quality.
3
• Demonstrate extended performance.
One year
• Ensure that potential seasonal variations are evaluated and
treated.
10.3.1 Phase 1
The purpose of this phase is to establish appropriate operating ranges and provide data for the development
of cleaning and sanitization procedures and frequencies. Sampling should be performed after each step in
the treatment process and from each point of use. In addition, the incoming feed water to the water system
should be tested and verified to comply with the relevant “Drinking Water” regulations. The FDA Guide to
Inspections of High Purity Water Systems suggests daily sampling for two to four weeks, but recognizes that
other sampling programs may be acceptable.
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In devising the sampling scheme, consideration should be given to the system configuration, maintenance
cycles, how the water is drawn for use, and the expected or potential variation in chemistry and microbiological attributes, at each potential sample point. In treatment, chemistry testing is specific for each processing
step and microbiological testing between each component is important to determine the microbial load and
the component’s ability to manage the load.
Mr. Shlomo Sackstein
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ID number: 216389
At the end of this phase, the SOPs for system operation and maintenance should be developed and approved
for continued interim use during the next phase. System logs, documentation for critical parameters (e.g.,
conductivity and TOC data, sanitization data, etc.), and responses to critical alarms or action levels should be
reviewed, to verify the appropriate procedures are in place. In addition, the process that will be followed to
investigate a confirmed test failure should be developed at this time. The intent of this process is to assess
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139
COMMISSIONING AND QUALIFICATION
whether a failure is localized (i.e., isolated to a specific port) or systematic, and to define how different types
of failures will be handled.
10.3.2 Phase 2
The second phase is intended to demonstrate that the system consistently operates within pre-determined
operating ranges and delivers water of the required quality when operated in accordance with the SOPs. The
FDA Guide suggests that the sampling scheme and duration should be the same as for phase one. During
phases 1 and 2, multiple samples should be taken from each point of use. Sampling methodology should be
representative of the way water will be used. For example, sampling should not involve a lengthy preliminary
purge if water usage will be direct and immediate. If water is used through an attached hose, then the sample
should be taken from the hose.
It is recommended that each point be sampled at least once per week as a minimum. In this manner, localized
contamination may be discovered. (Note that too frequent sampling of little used points may mask incipient
localized microbial growth by artificial purging.) Phase 2 allows the gathering of sufficient data to establish
microbial alert and action limits (see Section 10.4).
10.3.3 Phase 3
The third phase is intended to demonstrate that, when operated for an extended time period (typically one
year), the system produces and delivers water of the required quality, despite possible seasonal variations of
the feed water. Sample locations, frequencies, and test requirements are based on the established procedures. For WFI systems, the FDA Guide recommends sampling daily from a minimum of one point of use,
with all points of use tested weekly. At the end of this phase (i.e., after a full year of testing), the validation is
considered completed. In most cases, ongoing monitoring will establish a continuing record of water quality.
10.4
ACCEPTANCE CRITERIA
Acceptance criteria for water are dependent upon its use. For both Purified Water and WFI, the chemical
acceptance criteria are clearly described in the US Pharmacopoeia (USP). It is expected that a well designed
water system, operating within specified design parameters will consistently be able to meet these criteria.
Therefore, failures in chemical analysis during phases 1 and 2 must be investigated, the reason for failure
corrected, and (except where errors in sampling or laboratory error are clearly indicated) the sampling phase
extended to re-establish consistency of performance.
Microbial quality is not specified by the USP, but is established by the user based upon water use. The USP
does recommend action limits for the different waters in its General Information chapter. These are 10 CFU/
100ml for WFI and 100 CFU/ml for Purified Water. These may be employed as initial acceptance criteria for
system qualification, although some flexibility is allowable, depending upon system design and use. It is
permissible that a single excursion, followed by acceptable re-sampling would not constitute a failure. In
addition, because of the inherently bacteriostatic nature of WFI production and distribution systems, it should
be expected that the large majority of samples should be well below the initial acceptance criterion. Therefore, for WFI it is prudent to establish a sample average acceptance criterion, which will be below the limit for
a single sample. Failure investigation would be handled similarly to chemical analysis failure.
This Document is licensed to
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Herzlia,
During phases 1 and 2, normal system
limits may216389
be established. Acceptance criteria may then be
IDmicrobial
number:
converted to alert and action limits for use during phase 3 and beyond. These would take into account
repeated excursions from the norm as well as step increases in micro count.
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COMMISSIONING AND QUALIFICATION
10.5
QUALIFICATION REPORTS
Qualification data should be compiled and conclusions written into a summary report. This is to be reviewed
and approved by those responsible for operation and quality assurance of the water system. An interim report
should be written and approved at such time during the qualification sampling program, as it is desired to use
water in production activities. A summary report should be prepared at the conclusion of phase 2, periodic
updates provided throughout phase 3 and a major update issued at the conclusion of phase 3.
10.6
CHANGE CONTROL AND REQUALIFICATION
Changes to the system must be assessed with regard to potential impact of the change on the entire system.
Required action would be determined based on that assessment. It may involve extensive re-qualification,
localized increase in sampling frequency, or inclusion in the routine monitoring program.
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ID number: 216389
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ID number: 216389
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APPENDIX
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Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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APPENDIX
DISCLAIMER:
The Water and Steam Systems Appendix contains material considered “informational” which, although necessary, would have been detrimental to the clarity of the dedicated chapter. The Appendix
has not been reviewed by and therefore is not endorsed by the FDA.
11.
APPENDIX
11.1
USP REGULATED WATER QUALITY
See Chapter 2, Section 2.3 on USP Regulated Water Quality for more details.
In order to set the maximum allowable conductivity, USP determined the limit concentration of the least
conductive water attribute species used in USP 22 to be chloride at 0.47 ppm and 1.01 µS/cm at the standard
temperature. When actual measurements of conductivity are evaluated at temperatures above the standard
25°C, the least conductive water attributes between pH 5 and 7, changes to favor ammonia at the maximum
acceptable concentration of 0.3 ppm, using chloride as the electro-neutrality-balancing counter ion. Thus by
maintaining a water conductivity less than the value corresponding to the least conductive water attributes
between pH 5 and 7 at the specific water temperature, failure of any single Ionic chemical test in USP 22 is
precluded.
11.1.1
USP Three Stage Conductivity Levels
Stage 1
Primarily intended as an in-line test
Measure water conductivity and temperature using a non-compensated conductivity sensor using a suitable
container or an in-line measurement. See USP Stage 1 table.
Stage 2
An off-line test using a “grab” sample
If the sample fails the Stage 1 test, adjust the temperature to 25°C and stir. If the sample stabilizes to the
minimum conductivity value listed in the Stage 3 table, the water meets the requirements.
Stage 3
Additional test to account for the variation in conductivity with respect to alkalinity
Measure pH within 5 minutes of the Stage 2 conductivity reading after increasing its ionic strength to allow a
pH reading, using saturated potassium chloride solution at 3%. See “Stage 3 Conductivity Levels at 25°C”
chart.
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11.1.2
Derivation of USP Stage 1 Conductivity Levels
Mr. Shlomo Sackstein
Herzlia,
Due to the difficulty experienced inID
accurately
measuring 216389
pH of high purity water, USP have selected the
number:
The following chart shows conductivity levels for temperatures between 0°C and 100°C for the chlorideammonia model at the least conductive water attributes between pH 5 and 7.
minimum conductivity levels, occurring at pH 5 and 7, to limit the water quality at each temperature increment.
These levels are listed in the table following the chart.
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143
APPENDIX
Figure 11-1
11.1.3
Conductivity Levels for Chloride-Ammonia Model
In-Line (Stage 1) Conductivity Limits for Temperatures 0° to 100°C
Temperature Range
Maximum In-Line (Stage 1)
Conductivity (µS/cm)
Temperature Range
Maximum In-Line (Stage 1)
Conductivity (µS/cm)
Temperature Range
Maximum In-Line (Stage 1)
Conductivity (µS/cm)
0 TO 4.9°C
5 to 9.9°C
10 to 14.9°C
15 to 19.9°C
20 to 24.9°C
25 to 29.9°C
0.6
0.8
0.9
1.0
1.1
1.3
30 to 34.9°C
35 to 39.9°C
40 to 44.9°C
45 to 49.9°C
50 to 54.9°C
55 to 59.9°C
1.4
1.5
1.7
1.8
1.9
2.1
60 to 64.9°C
65 to 69.9°C
70 to 74.9°C
75 to 94.9°C
95 to 99.9°C
100°C
2.2
2.4
2.5
2.7
2.9
3.1
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APPENDIX
11.1.4
Derivation of Stage 2 and 3 Conductivity Levels
When the least conductive water attributes are plotted for water exposed to atmospheric CO2 at 25°C, the
following chart is produced:
Figure 11-2
11.1.5
Derivation of Stage 2 and 3
Total Organic Carbon (TOC) and Requirements for TOC Control
TOC is an indirect measure, as carbon, of organic molecules present in high purity water. A TOC limit was
determined by USP to be 0.5 ppm or 500 ppb, based on the results of studies and an industry wide survey of
pharmaceutical water systems.
Special Requirements
Organic contamination may be detected from different sources, and once a commitment is made to monitor
using a sensitive TOC meter, care must be exercised in controlling TOC in numerous materials used to
support and maintain the water purification systems. These materials may include:
•
Replaced Filter Cartridges
•
Particles from Valves, Seats, Gaskets, etc.
•
Soap and Detergent
This Document is licensed to
•
Mr. Shlomo Sackstein
Chemicals used for General Cleaning, etc.Herzlia,
Regeneration and Sanitization Materials
ID number: 216389
•
Alcohol and other solvents used to clean and sanitize seals and gaskets
•
Plastics used for sampling apparatus (beakers, bottles etc.) or other applications that may leach out
organic chemicals into the water samples to be tested.
•
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145
APPENDIX
•
DI resin, detected after regeneration or when beds are switched. Sources of TOC from ion exchange
resin beds include: unconverted monomers or low molecular weight polymers; decomposition products
and compounds resulting from oxidation or hydrolysis of the organic resins; organics in water used to
regenerate and rinse ion exchange beds.
New or replaced DI resin may be recycled five or six times to remove leachables, or resin may be specified as
preconditioned. A TOC rinse down certification curve is available from most resin suppliers.
Sample containers for off-line sampling must be scrupulously cleaned of organic residues and care must be
exercised in handling the containers to avoid transferring natural skin oils onto the container surfaces.
11.1.5.1
Systems Available for Measuring TOC
Instruments are available for measuring TOC in-line from slip streams and from grab samples manually
removed from the water system. Automatic off-line sample introduction systems are available for processing
large numbers of grab samples. USP have not prevented acceptable technologies from being used, but limit
the methods to the following instruments that are capable of completely oxidizing the organic molecules to
carbon dioxide (CO2), measuring the CO2 levels as carbon, discriminating between Inorganic Carbon (IC)
and the CO2 levels generated from the oxidization of the organic molecules, maintaining an equipment limit of
detection of 0.05 mg/l or lower, and periodically demonstrating an equipment “suitability.”
A number of acceptable methods exist for measuring TOC in high purity water and all share the same basic
methodology, the complete oxidation of the organics to CO2 and the measurement of this CO2
Three general approaches, based on the above concept, are used in a variety of commercially available
instruments which measure Organic Carbon in a water sample by completely oxidizing the organic molecules to carbon dioxide (CO2) and measuring the CO2 levels as carbon. Four common oxidation methods
and four common CO2 measurement methods are used in different combinations in these TOC analyzers.
The Total Carbon (TC) result may be expected to include Inorganic carbon resulting from dissolved CO2 and
bicarbonate which must be subtracted from the TC to produce the TOC level in the sample. Some TOC
analyzers remove the IC by acidifying the samples and either gas stripping or vacuum degassing the CO2. In
pharmaceutical waters, the IC levels are generally very low and IC removal processes are not usually required.
11.1.6
TOC Measurements
USP have applied laboratory quality control procedures, common in a laboratory for setting wide range
equipment for measurement over a specific range. These include: Standardization (Limit Response Test) and
Suitability (USP Suitability Test).
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These tests are in addition to calibration requirements and in no way replace or compensate for an acceptable calibration program.
Types of TOC Analyzers
Method of Oxidation
Mr. Laboratory
ShlomoInstruments
Sackstein
Herzlia,
Method of CO Detection
ID number: 216389
2
High temperature combustion
Require the Addition of
Chemicals or Gases
NDIR
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146
Yes
Heat activated persulfate
NDIR
Yes
UV activated persulfate
NDIR or CO2 selective conductivity
Yes
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APPENDIX
These instruments require the injection of pure carrier gasses and/or persulfate to achieve more robust
oxidation levels allowing the successful analysis of high levels of TOC in unknown water samples.
In-Line Instruments (Simplified TOC Analyzers)
Method of Oxidation
UV light
Method of CO2 Detection
Require the Addition of
Chemicals or Gases
Direct conductivity or CO2
selective conductivity
No
These instruments are designed for TOC measurement of deionized water, with or without CO2. These conditions allow the accurate measurement of the IC in the sample. If they are used in water that has significant
levels of other ions, the IC results and therefore the TOC results will be in error. Waters that do not meet these
requirements should use the laboratory type TOCs (in-line or off-line).
Laboratory Instruments Capable of Operating In-Line and Unattended
Method of Oxidation
Method of CO2 Detection
Require the Addition of
Chemicals or Gases
Heat activated persulfate
NDIR
Yes
UV activated persulfate
NDIR or CO2 selective conductivity
Yes
These instruments require the injection of pure carrier gasses and/or persulfate to achieve more robust
oxidation levels allowing the successful analysis of high levels of TOC in unknown water samples.
11.1.6.1
Typical Organic Oxidation Methods used in Commercial TOC Analyzers
The four most common oxidation methods for TOC are: high temperature combustion, thermally activated
persulfate, UV activated persulfate, and UV light only.
The “high temperature combustion” (>500°C) oxidation method is rapid and can easily oxidize large particles, but requires a source of compressed oxygen or air as a carrier gas for the sample.
This Document is licensed to
The “thermally activated persulfate” method uses heat to activate the persulfate to form highly oxidative
sulfate and hydroxide radicals which then react with the carbon in the organics to produce CO2.
The “UV activated persulfate” method uses ultraviolet light (<280 nm) to activate the persulfate to form the
highly reactive sulfate and hydroxide chemical oxidizing radicals. In both of these persulfate methods, the
persulfate is a source of oxygen and can be added at higher levels to allow the complete oxidation of higher
concentrations of organics. TOC levels (without sample dilution) of 50 to 100 ppm can be measured. Each
persulfate method can easily oxidize macromolecules and biomolecules to CO2, but can have difficulty oxidizing large particles (>30 µm) in reasonable periods of time.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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The “UV light only” method uses short wave ultraviolet light (<195 nm) to activate dissolved oxygen or water
to produce powerful oxidizing agents such as the hydroxide chemical radical which react with the carbon in
the organic molecules to form CO2. The “UV light only” method does not require the addition of a chemical
reagent, but the upper levels of TOC are limited. With this method, the short wave UV light will activate
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147
APPENDIX
dissolved oxygen free water molecules to completely oxidize organics at TOC levels of up to 250 ppb, and in
the presence of oxygen, saturated water (at 25°C) will completely oxidize organics at TOC levels of up to
1500 to 2000 ppb (1.5 to 2.0 ppm).
11.1.6.2
Typical CO2 Detection Methods used in Commercial TOC Analyzers
There are four CO2 detection methods currently used in commercial TOC analyzers: Non-Dispersive Infrared
(NDIR), CO2 selective conductivity, direct conductivity, and differential conductivity.
The “NDIR” method measures the infrared absorption of CO2 in the gas phase. This method requires the
CO2 in the water sample to be removed and transferred to the IR absorption cell by a carrier gas stream. The
“NDIR” absorption detectors also measure water vapor; therefore, it must be removed from the CO2 gas prior
to measurement. This detector responds quickly, must be calibrated regularly, has a dynamic linear range of
about 1.5 to 2 orders of magnitude, and a limit of detection of 2 to 10 ppb. It is the most common TOC detector
used in laboratory type analyzers.
The “CO2 Selective Conductivity” method uses a special membrane to selectively diffuse CO2 from the
water sample into a deionized water collector. The CO2 ionizes in the collector water, the temperature and
conductivity are measured and the concentration of CO2 calculated. This detector is slower responding than
an NDIR, but has excellent long term calibration stability (typically six to 12 months), a linear dynamic range
of five to six orders of magnitude and a limit of detection of 0.05 ppb.
The “Direct Conductivity” CO2 detection method measures the conductivity of the sample water directly. To
accurately measure CO2 with this method, the water sample must be composed of only CO2, deionized
water, OH-, HCO3- and H+(deionized water in equilibrium with CO2). When this is true, the CO2 concentration
can be calculated from the conductivity and the temperature measurements of the sample water. If other ions
are present, the accuracy decreases with increasing concentration of these other ions. This method can be
applied to the sample water before oxidation to measure the level of IC. The same method can be applied
after the oxidation of the sample to measure TC. Although not as specific or selective to CO2 measurements
as the prior detectors, it is fast, has excellent calibration stability (typically six to twelve months), and has a
low limit of detection (about 0.05 ppb).
The “Differential Conductivity” CO2 detection method produces a differential conductivity signal (pre and
post oxidation). The analyzers using this method are designed to only partially oxidize the organics to the
very conductive organic acids stage (not completely to CO2) and measure organic acids not CO2. The analyzer measures the difference between the initial sample water conductivity and the post oxidation sample
conductivity, and relates this to specific organic compound calibration tables.
11.1.7
Limit Response and System Suitability Testing
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Apparatus Requirements for Limit Response and System Suitability Tests
a) Reagent Water (r W) complying with the USP definition in section 661 of USP 23, having a TOC level of not
more than 0.25 mg/l.
b) Standard Solution (r S
105° C for 4 hours)
Mr. Shlomo Sackstein
) containing 1.19 mgHerzlia,
of sucrose (produced from r
ID number: 216389
W
and USP Sucrose RS dried at
c) System Suitability Solution (r SS) produced from r W and USP 1,4-Benzoquinone RS (containing 0. 5 mg/l of
carbon)
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Instrument Standardization (Limit Response Test)
USP require that TOC instrument must be standardized by performing a test on each water sample or “test
solution.”
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APPENDIX
The test solution meets the requirement if the response for the standard solution less the response for the
reagent water used to produce the standard solution is greater than the test solution response, or:
r t < ( r S - r W ).
For in-line testing, standardization (determination of the limit response) may not be practically performed with
each TOC reading; therefore, standardization (determination of the limit response) once per operating day (or
less frequent) may be appropriate. Support data generated from standardizations performed over a suitable
period could be used to justify modifications to the testing frequency, based on system reliability, repeatability
and stability, i.e., TOC levels may be maintained, nominally, far below the limit response over a suitable
period, thus decreasing the risk in supporting less frequent standardization testing.
Standardization (Limit Response) Testing for In-Line Instruments
In-line instruments must be disconnected from the water system to conduct Standardization (Limit Response)
tests. At once per day, these tests represent a considerable investment.
TOC meters with built in provisions for automating these tests and minimizing materials have the potential for
considerable savings in both time and expense.
Instrument Suitability or Response Efficiency
An instrument is “suitable” if its response efficiency is within ±15% of the theoretical response.
Suitability tests may only be performed off-line, or with the in-line instrument disconnected.
TOC measuring equipment must be tested for suitability “periodically” which may range from, each water
sample test for off-line lab testing, to once per month for in-line testing, depending upon the experience with
the system and the data produced from suitability tests.
The Instrument Suitability Response Efficiency is equal to 100 times the ratio of the Suitability solution response and the Standard solution response, or:
100[(r SS - r W)/(r S - r W)] = 100% ± 15%.
Suitability Testing for In-Line Instruments
In-Line instruments also must be disconnected from the water system to conduct Suitability tests. Suitability
tests may be conducted together with the standardization tests.
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TOC meters with built in provisions for automating both the standardization and suitability tests have the
potential for further savings.
Prepackaged traceable and certified standards are available from some manufacturers for both standardization and suitability testing.
Special Requirements
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Organic contamination may be detected from different sources. Once a commitment is made to monitor using
a sensitive TOC meter, care must be exercised in controlling TOC in numerous materials used to support and
maintain the water purification systems. These materials may include:
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•
Replaced Filter Cartridges
For individual use only. © Copyright ISPE 2001. All rights reserved.
149
APPENDIX
•
Particles from Valves, Seats, Gaskets, etc.
•
Soap and Detergent
•
Chemicals used for General Cleaning, etc.
•
Regeneration and Sanitization Materials
•
Alcohol and other solvents used to clean and sanitize seals and gaskets
•
Plastics used for sampling apparatus (beakers, bottles, etc.) or other applications that may leach out
organic chemicals into the water samples to be tested
•
DI resin detected after regeneration or when beds are switched. Sources of TOC from ion exchange resin
beds include: unconverted monomers or low molecular weight polymers; decomposition products and
compounds resulting from oxidation or hydrolysis of the organic resins; organics in water used to regenerate and rinse ion exchange beds.
New or replaced DI resin may be recycled five or six times to remove leachables, or resin may be specified as
preconditioned. A TOC rinse down certification curve is available from most resin suppliers.
Sample containers for off-line sampling must be scrupulously cleaned of organic residues and care must be
exercised in handling the containers to avoid transferring natural skin oils onto the container surfaces.
Calibration of TOC Meters
Calibration should be performed using solutions of a known carbon content, covering the normal range of the
instrument. The frequency of calibration should ensure that the levels of accuracy are maintained. Refer to
manufacturer for specific recommendations on both method and frequency.
Calibration should be performed independent, and in addition to, Standardization and Suitability testing.
Dual Purpose TOC/Conductivity Meters
A number of TOC meters designed for in-line applications include conductivity measurements that are claimed
to be in accordance with USP. These instruments use the conductivity method of CO2 detection and utilize the
conductivity reading taken prior to water processing. To use this dual purpose instrument to measure compendial
water conductivity, it is important to be able to calibrate the conductivity cell separately and ensure that it
contains a cell constant adjustable and maintainable to the limits defined; an accurate temperature measurement being included since most modern conductivity instruments monitor temperature; a conductivity and
resolution accuracy as defined and a conductivity calibration which must be accomplished by replacing the
conductivity cell with a NIST-traceable precision resistor, accurate to ±0.1% or by an equivalently accurate
adjustable resistance device.
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Microbial and Endotoxins are traditionally sampled at the points of use in a water system. See Chapter 2,
Section 2.3 USP Regulated Water Quality.
ID number: 216389
11.1.8
USP Microbial and Endotoxin Testing
11.1.9
USP pH Testing
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See Chapter 2, Section 2.3 USP Regulated Water Quality (pH testing to support in-line conductivity testing
was eliminated in May 1998.)
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APPENDIX
11.1.9.1
Calibration of pH Instruments
See Chapter 2, Section 2.3 USP Regulated Water Quality.
11.2
EUROPEAN PERSPECTIVE
11.2.1
Regulatory Structure
The pharmaceutical industry within the nations that make up the European Union (EU) is regulated by the
European Agency for the Evaluation of Medicinal Products (EMEA), based in London. This Agency is funded
by the EU under the authority of the European Commission (EC), the EU’s policy making body. EMEA is
established as an autonomous body to promote public health and free circulation of pharmaceuticals. It is
charged with coordinating the resources of the national drug regulatory authorities and has three major
functions:
•
Centralized drug approval, granting marketing authorization across Europe. This procedure is mandatory
for biotech products and optional for other drugs. The EMEA also coordinates the mutual recognition of
marketing authorization among the Member States when a decentralized method (application to one or
more selected Member States) is used.
•
Supervision of continued use of medicinal products, using the resources of the national agencies, including site inspections and monitoring of adverse effects (“pharmacovigilance”).
•
Coordination of European and internal harmonization of guidance and regulations, particularly within the
framework of the International Conference of Harmonization.
Within the Member States, each national has established a national agency. Examples are the Medicines
Control Agency (MCA) in the United Kingdom and the Bundeinstitut fur Arzneimittel and Medizinprodukte
(BfArM) in Germany. These are responsible for national registrations, inspections, and enforcement of regulations within their national boundaries.
Another important body with membership from several nations both within and without the EU, is the Pharmaceutical Inspection Convention (PIC), which has been superseded by the Pharmaceutical Inspection Cooperation Scheme (PICS). These bodies provide entirely non-binding guidance to member nations, most of
which are harmonized with the EU.
11.2.2
Regulations Governing Water and Steam
The EC recognizes the European Pharmacopoeia (EP) as the source of compendial water standards for
Purified Water and Water for Injection. The use of these waters parallels that in the United States. Nations
outside the EU may maintain national compendia, which differ in some parts from the EP.
This Document is licensed to
The EP does not regulate Clean Steam. In Europe, the requirements for the chemical quality of steam to be
used in the sterilization of medicinal products in autoclaves are governed by European Standard EN 285. The
EU cGMP Annex for Sterile Products requires that steam be “of suitable quality and does not contain additives which could cause contamination of product or equipment.” Although similar in concept to US requirements, interpretation of this standard by European investigators may be quite different. Insight into interpretation by inspectors may be found in important guidance on the quality of steam found in Health Technical
Memorandum HTM-2010, published by the United Kingdom National Health Service (NHS Estates). [Editor’s
Note: criteria described in HTM-2010 are of major concern in the sterilization of porous autoclave loads and
present less of an issue in the sterilization of product in vials, hard goods, or equipment.] In addition, UK
HTM-2031 deals directly with the quality of steam to be used in sterilizers.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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APPENDIX
11.2.3
Water Issues
•
While USP requires that the starting point for compendial waters must meet the national drinking water
standard, the EP requires only that the history of the starting water be documented.
•
The EP does allow the production of Water for Injection by distillation only. There are some pharmacopoeias,
notably among the former Soviet bloc, which allow WFI produced by reverse osmosis.
•
The EP requires sample sizes of 100 ml for purified water and 500 ml for WFI. The USP is not definitive
on these sample sizes.
•
EP has not accepted the substitution of conductivity/resistivity for the traditional wet chemistry analyses
of ionic contaminants. There is some early discussion about adopting a conductivity test, but it is likely
that this may be quite different from the USP test.
•
The EP has not added the test for TOC.
•
EP continues to require the test for pH as an independent test. This is likely to remain, even in light of
potential changes.
•
European inspectors seem to be sensitive to the drainability of systems through points of use. Additional
low point drains are acceptable only if necessary. Guidance in this area remains unclear.
11.2.4
•
Steam Issues
HTM-2010 emphasizes the dryness requirements for steam. If steam is too wet, it may cause dampness
in porous loads (e.g., hospital gowns). If it is “too dry,” it may become superheated upon expansion into
the chamber, reducing the sterilizing effectiveness. [Editor’s Note: considering the use of modern, wellcontrolled steam generators which produce saturated steam, and the large mass made up by the sterilizer and the load, excess dryness is seldom a problem. Excess wetness is controlled by proper insulation
of steam lines and judicious use of steam traps to remove condensate.]
Standard EN-285 requires steam for use in sterilizers to have a dryness value of not less than 0.9 (0.95
for metal loads). In practice, dryness between 0.9 and 1.0 will not present a problem if the final pressure
reduction into the chamber is around 2:1. A method of testing dryness may be found in HTM-2010, part
3.
•
Superheat is also an issue of concern. Superheated steam is not as effective a sterilizing medium as is
saturated steam. It may result from adiabatic expansion (as across a control valve) an exothermic reaction resultant from the re-hydration of a hygroscopic load, or the application of jacket heat above the
saturation temperature of the internal steam. A specification and test method for superheat may be found
in HTM-2010. [Editor’s Note: again, considering the production of saturated steam by modern generators, the control of jacket heat, and the condensate resulting from loss of heat to the sterilizer and load,
superheat is an uncommon problem.]
This Document is licensed to
•
Mr. Shlomo Sackstein
The third area of concern which European Herzlia,
inspectors have focused on is Non-Condensable Gas (NCGs).
Major NCGs in steam are air and carbon dioxide. These may result from the failure to degas boiler/
generator feed water. They present
in those areas
where localized “pockets” of gas are allowed
IDa problem
number:
216389
to accumulate, preventing the penetration of steam. This may be effected by preheating the feed water in
a vented tank at above 80°C. A test of method may be found in HTM-2010. [Editor’s Note: the presence
of air in a well-mixed sterilizer is common practice and does not reduce the effectiveness of sterilizing
steam.]
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APPENDIX
11.3
PASSIVATION
11.3.1
Introduction
Pharmaceutical equipment and high purity water systems are designed so that product contact surfaces are
not reactive, additive, or absorptive so the drug product is not adversely altered. High purity water systems
are primarily composed of austenitic stainless steel (SS) materials due to their corrosion resistant and contaminant free properties. Passivation is performed to maximize the metal’s corrosion resistance. The stainless steel is sulfuric/nitric/hydroflouric acid pickled at the mill to remove manganese sulfide inclusions, scale,
and other impurities or imperfections from the surface of the steel. As the steel is removed from the pickling
bath, a thin oxide layer forms immediately over the surface. This oxide layer is what renders the stainless steel
passive and non-reactive to corrosion. Any 300 series chromium steels containing 17% or more chromium
that has been handled, welded, or worked should be passivated prior to service and suitably cleaned prior to
passivation.
Passivation is the method used to fortify the steel surface by strong oxidizing chemicals such as nitric acid.
The acid depletes the steel surface of acid soluble species, leaving the highly reactive chromium on the
surface in a compounded oxide form.
11.3.2
Advantages of Passivation
When SS systems are fabricated, the welding process destroys the existing passive film and compromises
the metal’s ability to ward off the corrosive process. This is particularly applicable in those zones that are
either heat affected or have had residues remain in contact with the metal surface for prolonged periods.
Passivating then provides a method to restore the integrity of the metals corrosion resistant surfaces that
were disturbed. Passivation must be proceeded by a cleaning process.
11.3.3
The Chemical Process
Excessive electron depletion of the upper film and an inadequate supply of oxygen (molecular O2) will ensure
the formation of surface corrosion products. When this occurs, the chromium (Crn+) separates from the surface and opens the way for oxidation of the iron (Fe) and nickel (Ni), lower in the metal lattice.
Establishing a passive surface or film on austenitic SS is essential to maximize the corrosion resistance that
the metals offer. Passive surfaces on these metals occur naturally when exposed to an oxidizing environment. Sources of oxygen include air, aerated water, and other oxidizing atmospheres. Formation of a substantial uniform oxidized corrosion resistant surface or film is the result of passivation.
Besides natural occurring passivation, chemical and electro-chemical processes can be used to obtain an
anodic oxide film. Nitric acid solution (HNO3), is an oxidizing acid (depletes electron from the metal surface)
which erodes the metal. This initial reaction or oxidation resists further chemical reaction on the metal surface. Metals that have such a state are called “passive” and the phenomenon itself is called “passivity.”
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The chromium oxide film thickness typically ranges from 0.5-5.0 nm, averaging 2.0-3.0 nm. The chrome to
iron ratio measured in atomic percent within the chromium oxide should be at least one with ratios of two or
more being optimal.
11.3.4
Mr. Shlomo Sackstein
Herzlia,
Passivation Procedures
ID number: 216389
Numerous procedures are available for passivating; they share the commonality of consisting of four main
steps which are:
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1) Wash (Solvent Degreasing)
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153
APPENDIX
2) Water Rinse
3) Acid Wash (Passivation Step)
4) Final Water Rinse
Proper preparation of the metal surface to obtain a uniform non-defective passive film mandates the metal
surface be completely clean and void of any organic or inorganic soils, free iron, metallic contaminants, or
corrosive products.
The First Step (Degreasing) of the procedure is designed to remove dirt, dust, oil, and grease. A watersoluble detergent is used to accomplish this, or a solvent.
The Second Step (Water Rinse) is required to remove dissolved and freed soils and the detergent itself from
the metal being cleaned.
The Third Step (Acid Wash) is to remove free iron, metallic residues, oxides, and other corrosion products
from the surface of the metal. By removing these soils from the metal surface and providing an oxidizing
atmosphere, the passive film is allowed to form and the passivation is accomplished. Inorganic acids are
typically used in this step of the procedure.
The Fourth Step (Final Water Rinse) - The acidic solution is flushed and the system is rinsed until the quality
of the effluent is equal to that of the influent.
The American Society for Testing and Materials, ASTM A 380-96, “Standard Recommended Practice for
Cleaning and Descaling Stainless Steel Parts, Equipment and Systems,” is an excellent source of information
about passivation. It includes cleaning and passivation procedures, chemical applications, methodology, and
testing procedures. The standard is valuable in establishing specific passivation and other specialized cleaning procedures.
Establishing an effective passivation procedure can be obtained by using the following guidelines:
•
Start with an accepted or specified procedure. (See the chart on the next page.)
•
Obtain weld coupons from the system or have weld coupons made for testing purposes.
•
Perform specified procedure along with alternate procedures to offer a choice, meeting specific situations, or requests.
•
Confirm the effectiveness of the procedures tested with specified field and/or laboratory testing.
•
This process for confirming the effectiveness of a specified procedure or qualifying alternative procedures should be included in the passivation documentation being submitted as part of the final validation
package.
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Mr. Shlomo Sackstein
11.3.5
Passivation Chemical Alternatives
Herzlia,
Nitric acid, a strong oxidizing acid, is
the number:
most common acid
specified for passivation. Besides its ability to
ID
216389
produce a free iron surface, the acid supplies the oxidizing atmosphere needed for passivation to occur.
Because nitric acid is a corrosive chemical, extreme care must be used with handling, storage, and use.
Federal Specification QQ-P-35C (1988) is an excellent reference for obtaining guidelines when using nitric
acid on a variety of stainless steel alloys.
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APPENDIX
Although nitric acid has traditionally been the preferred passivating acid, the trend in use of passivating
solutions is to reduce chemical aggressiveness and to make safety, cost, and the environmental impact of the
waste solution effluents a consideration.
Citric acid and ammonium citrate (ammoniated citric acid) are gaining popularity as alternatives to using nitric
acid. The safety these chemicals offer the personnel and the work environment are desirable qualities. The
ASTM Standard A 380 (1996) refers to these acids as cleaning acids, not passivating acids. This distinction
has probably been made because the acids are not oxidizers as is nitric acid. The standard states that the
citric acid-sodium nitrate treatment is the least hazardous for removal of free iron and other metallic contamination and light surface contamination. To achieve a true oxidation chelating agents in conjunction with citric
acid and ammonium citrate has recently been introduced to the pharmaceutical/biotech industry.
Phosphoric acid is a weak oxidizing acid sometimes specified in passivation procedures; however, there is no
formal documentation referencing the use of phosphoric acid as a passivating acid.
Chelants, otherwise known as sequestering agents or co-ordination compounds, which include all the standard water softening compounds such as Sodium tri-polyphosphate (STPP), Nitrilotriacetic acid (NTA), and
Ethylene Diamine Tetra Acetic acid (EDTA) may be compounded into acid passivation solutions to enhance
metal ion extraction.
Orbital welding in conjunction with the increased use of electropolished tubing decreases the aggressiveness
required of the passivating acids during the initial passivation. Decreasing acid contact time, temperature,
and/or concentration accommodates the quality of the welds and already passive surface of the electropolished
stainless steel.
11.3.6
Chemical Application Methods
Passivation can be accomplished using a variety of applications. Among these are:
Circulation
Recirculating through distribution
systems
One Way Intermittent Flow
Large non-recirculating
distribution
Spraying
Tank interiors
Tank Immersion
Numerous small parts
Prefabricated tubing
Swabbing/Wiping
Isolated Areas/Tank/Equipment
Exteriors
Equipment that does not allow
spraying or other applications
Long one way pipe runs systems
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
When detergent washing, agitation or impingement provides the best results. During the acid wash step,
chemical contact is usually sufficient. Recirculation is the preferred application method for performing passivation procedures. Recirculating allows flow rate criteria, usually specified at 5 feet per second (1.5 m/sec), to
be achieved. Meeting flow rate requirements of a procedure should not be confused with particle removal.
Many people assume when high flow rates are used that particle removal will be achieved. This is not true.
Particle removal is achieved by including the total linear feet of the system into the appropriate mathematical
equation. A recirculating water system of 1000 feet (300 meters) with a consistent tube diameter would
require as much as 25 hours of filtered recirculation time for total particle removal.
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155
APPENDIX
11.3.7
Tests for Cleanliness and Passivity
There are several tests available to determine an acceptable level of cleanliness. Should confirmation of
cleanliness be required prior to continuing with the passivation procedure, the water break free surface test,
wipe test, or ultraviolet light testing are just a few of the tests that could be performed. These tests are for
gross cleanliness inspections as stated in the ASTM Standard A 380 (1996).
Once the passivation procedure is completed, a test method should be used to confirm or establish confidence that the passivation procedure has been successful. One inexpensive method is the Ferroxyl Test for
free iron as set forth in the A380 (1996). The test is used to detect surface iron contamination, i.e., iron salt
residue from pickling, iron tool scratches on the stainless steel surface, iron deposits at weld areas, and iron
oxides. The testing solution is applied to the surface being tested. A blue stain appearing within 15 seconds of
application indicates presence of free iron.
Testing for a passive surface is usually accomplished by looking for traces of free iron on the metal surface.
The assumption is made that if there is no detectable free iron, the metal surface is clean enough for a
uniform oxide film to develop. Another excellent source for specific testing methods is the Military Standard
753B (1985). Both Standards discuss specific tests for detecting free iron. They include Water Immersion/
Water Wetting and Drying Test, High Humidity Test, Copper Sulfate Test, and Ferroxyl/Potassium Ferricyanide-Nitric Acid Test.
Direct testing for a passive surface can be accomplished by X-ray Photoelectron Spectroscopy (XPS) testing
which is used to measure the oxidation states of elements found on the metal surface. Another direct, destructive testing method is Auger Electron Spectroscopy (AES) which measures the elemental chrome/iron
ratio on the metal surface and sub-surface with depth profiling. The direct testing methods for passivity supply
detailed information about the oxide film itself rather than indirect observations. XPS or AES testing offers
direct evidence as to whether the passivation procedure being used is effective or not. These methods of
testing are more costly than the other above mentioned tests and are ideal for use with weld coupons to
determine the effectiveness of the passivation procedure for the system.
11.3.8
Modified Passivation Procedures
A passivation procedure can be modified to deal with a variety of soils, surface finishes and weld area
conditions. Adjusting contact times and solution’s temperature and concentration would be the simplest way
to modify a specific procedure. Sometimes detergent wash or acid wash chemicals are changed or modified
with additives to remove certain soils. For example, when removing rouge, solutions containing sodium hydrosulfite can be substituted for the detergent wash step of the procedure. Citric and Phosphoric Acid also
could be used as they do have some ability to remove light rouging. Another example would be the use of
Hydrofluoric Acid, or more specifically, Ammonium Bifluoride to remove silica scale. The descaling step and
associated rinse would necessitate additional steps being added to the standard procedure.
This Document is licensed to
It is important when developing a passivation procedure, that laboratory testing is performed to determine the
effectiveness of your procedure. Without preliminary laboratory testing, an educated guess would have to be
made and the results may not prove satisfactory.
Mr. Shlomo Sackstein
Below is a guide that can be used for passivating
and de-rouging stainless steel components, piping, and
Herzlia,
equipment. The chart has some possible options for determination of the contamination and a course of
action.
ID number: 216389
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APPENDIX
Cleaning and Passivation
Condition/Status
Contamination
Analytical Method
Cleaning &
Passivation
Method
System
Chemistry
Procedure
New Component
Electropolished
N/A
2,4
3
2
Component Newly Welded
N/A
1,3,4
1,2,3
1,2
New System - Tubing
N/A
2
2,3,4
2
Component/System Discolored
(Gold Color)
1
1,2,3,4
1,2,3,4,6
2
Component/System Discolored
(Brown, Red/Brown Color)
1,2
2,3
4,5,6
3
Component/System Discolored
(Black, Blue/Black Color)
2,3
2,3
4,5,6
3
11.3.9
Contamination Analysis
Method 1
Filtration of 1 liter sample through a 0.2-0.5 µm filter and inspect.
Method 2
Quantitative analysis of the specified metals and organic compounds with wet chemistry techniques or as available.
Method 3
SEM or Auger Electron microprobe/spectroscopy for analysis of surface chemistry and contamination.
11.3.10
Cleaning and Passivation Method
Method 1
Clean surface with aqueous cleaning solution, apply passivation paste to surface, rinse surface
with DI water until traces of chemicals are removed.
Method 2
Circulate cleaning solutions through piping or vessels by circulation method. Circulate cleaning
solutions as required by procedure. Circulate passivation solution as per recommended conditions. Rinse surfaces once through with DI water until conductivity of inlet and outlet fluids are
within tolerances.
Method 3
Spray cleaning and passivation solutions onto surfaces of vessels, containers, and equipment
as per recommended conditions. Rinse surfaces for minimum of 30 minutes per each rinse
stage, and perform triple rinse.
Method 4
Soak components or equipment items in treating solutions or tanks as per recommended conditions. The minimum soak time per each solution is two hours. Process requires cleaning, passivation, and rinsing as a minimum. The cleaning system should include circulation, filtration, and
heating.
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Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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APPENDIX
11.3.11
System Chemistry
Chemistry 1
Nitric acid passivation is performed at Ambient Temperature for 30 to 60 minutes and at 5060°C for 20 to 40 minutes.
Chemistry 2
Alkaline degreasing is performed with detergents (phosphates, sodium hydroxide, and potassium hydroxide), pH buffers, and surfactant. The process will remove organic films and
particulate debris from the surface of the stainless steel. Utilize approximately 1.0-2.0%
detergent, 0.2-0.5% buffer and 0.01-0.2% surfactant.
Chemistry 3
Citric acid/chelant passivation is performed with chelants, reducing agents, surfactants, and
pH buffers. These systems are proprietary processes and the exact chemistry and percentages are not available. The chelant systems are able to remove most metal contamination
from the surface including iron, manganese, aluminum, and copper. The systems include
3.0-5.0% Citric acid and a variety of chelants, reducing agents, pH buffers, and surfactants.
Chemistry 4
Mineral acid cleaning and passivation can be performed for iron oxide removal or passivation. Typical mineral acids include phosphoric, sulfuric or sulfamic acid. These acids can be
utilized at 3.0-10.0% concentrations and at a variety of temperatures. Sulfuric acid is not
typically used due to its highly hazardous nature.
Chemistry 5
Intensified acid/chelant systems are utilized for removal of high temperature iron oxide films,
silica scales, and organic/carbon films. These systems are a citric based solution with additional organic acids, strong reducing agents, and acid chelants. These systems can use
fluorides for silica removal. After strong acid cleaning in a reducing environment, it is recommended that an oxidizing flush be used to ensure oxidation at the surface, removal of organic films, and sanitization of the system.
Chemistry 6
Sodium Hydrosulfite, a strong reducing agent, typically used at 5% by weight at 120 to 160°F
for two to four hours.
11.3.12
Procedures
11.3.12.1
Procedure 1
Clean surface of organic film and other debris.
a) Rinse surface with DI water.
b) Apply gelled acid onto surface at ambient temperature.
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c) Brush passivating agent on surface very 15 minutes, maintain a wet surface.
d) After one hour minimum, brush surface with sodium bicarbonate solution until all reaction ceases.
Mr. Shlomo Sackstein
e) Rinse surface with DI water until all tracesHerzlia,
of chemicals are removed.
11.3.12.2 Procedure 2
ID number: 216389
a) Fill system with DI water and perform leak test with circulation pump.
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b) Circulate for a minimum of one to two hours with alkaline degrease stages and heat to 60-80°C with
filtration.
c) Drain and rinse with DI water.
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APPENDIX
d) Circulate for a minimum of one to two hours with passivating acid solution and heat to 60 - 80°C.
e) Drain and rinse with DI water.
11.3.12.3
Procedure 3
a) Fill system with DI water and perform leak test with circulation pump.
b) Circulate for a minimum of two hours with alkaline degrease stages and heat to 60 - 80°C with filtration.
c) Drain and rinse with DI water.
d) Circulate for a minimum of eight hours with intensified passivating acid solution and heat to 60 - 80°C.
e) Drain and rinse with DI water.
f)
Flush with oxidizing/sanitization solution.
g) Drain and rinse with DI water.
11.3.13
Rouging
Rouging is seen in many water systems, usually high temperature (80°C) distilled water and clean steam
systems. Rouge is not limited to storage and distribution systems; it also can be found in distillation and clean
steam generating equipment. The main constituent of the rouge film is ferric oxide, but it can contain iron,
chromium, and nickel of different forms. From Auger Electron Spectroscopy, it has been found that the outer
layer of a rouge film is carbon rich, and the underlying region is iron and oxygen rich, probably iron oxide.
Over time, the film uniformly distributes itself throughout the system. The exact mechanism of the rouge
formation and proliferation is unknown. Because the phenomenon occurs in systems that offer the most
corrosive environment, it is thought that low molecular weight ions of the stainless steel, such as iron, are
drawn to the metal surface or are dissolved and uniformly re-deposited throughout the system. Others feel
the rouge is an external contaminant probably colloidal in nature that once in the system, uniformly deposits
itself.
Rouging would seem to be very site (facility) specific because of the variety in appearance and texture.
Rouge can be observed in a variety of colors including; orange, light-red, red, reddish-brown, purple, blue,
gray, and black. It can be a very loose film, dust like in appearance and texture that can be readily wiped off
to a tight pertinacious film that requires scraping with a sharp instrument to be removed. In addition to the
diversification already discussed, rouge can be multi-layered exhibiting different colors and textures. Traditionally the red rouges are most common in high purity high temperature water systems, while the blue/black
rouges are typically found in clean steam systems.
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Evidence of the migration of rouging in distribution systems can be demonstrated by monitoring a system
over a period of time. Key places to look for rouging are still and clean steam generator discharge lines, tank
water/vapor interface, pump heads, Teflon® diaphragms on diaphragm valves, interior surface of tank spray
ball, and heat effected area of welds. Rouge deposition seems to have an affinity for Teflon® and would be one
of the first places to look for signs of system rouging.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
In some cases, the rouging appears as quickly as a month or two after system start up. In other cases, it is
several years before rouging is observed. In either case rouging is an industry wide phenomena. In a specific
case, a facility cold WFI system would re-rouge within a week of being derouged and passivated. The system
was derouged and passivated a total of three times. Each time, within a week, the system was totally rouged
again. The specific cause was never determined.
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159
APPENDIX
The presence of rouge in high purity water systems has not been proven to effect water quality. The FDA has
no written position addressing rouging, its existence, or presence in high temperature high purity water and
clean steam systems. Their criterion has and remains to be in meeting established USP standards for water
quality. There is some fear that as the unwanted film develops, it might eventually slough off and be dispersed
throughout the system. This, in fact, does occur and is manifested in systems with filtered use points. Filters
become discolored with the typical reddish-brown rouge color.
Phosphoric, citric, oxalic acids, and ammonium citrates are used depending on the severity of the problem.
Oxalic acid solutions are used for the worst cases of rouge. Passivation with nitric acid is required after an
oxalic acid rinse.
11.3.14
Preparing Systems for Passivation
Hydrostatic pressure testing is the first test in preparing a system for passivation. All newly constructed or
modified systems require pressure testing prior to implementing any chemical procedure. The second check
prior to passivation is to confirm the compatibility of the system, its components, and the passivating solutions. This would include in-line instrumentation, flow meters, regulating valves ultraviolet lights, pumps, pump
seals, filter membranes, gasket and seal materials, and other specialized in-line devices. The manufacturer
or supplier should be consulted to determine whether their equipment is compatible with passivating solutions. Items that are not compatible should be removed from the system and replaced with a blank, valve,
spool piece, or temporary jumper hose. In some cases with in-line instrumentation, chemical incompatibility
may lie in the effect it has on instrument calibration. Incompatible components should be processed independent of the main system.
Once the system/chemical compatibility has been established, the system to be passivated should be isolated from existing systems, process equipment, utility tie-ins, etc. In most cases, in-line heat exchangers
(excluding plate and frame design) and small filter housings (filter elements removed) are left in place and
flowed through. This is acceptable as long as the ability to vent and drain is available.
Isolated equipment that requires passivation should be handled independently from the main system unless,
by agreement, it is left in-line and flowed through. All isolation points must be valved to avoid forming dead
legs in the system being passivated.
Elimination of all dead legs is critical to ensure chemical contact and complete rinsing.
High point vents and low point drains are desirable for complete filling and draining of systems. In distribution
systems where high point vents are not installed, high velocity flow and flow restriction techniques can be
used to ensure complete filling of the system.
After the system has been pressure tested, compatibility has been confirmed, the system isolated and dead
legs valved, consideration must be given to automated controls that govern the system.
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Are all the automatic valves operational?
Mr. Shlomo Sackstein
Herzlia,
Will in-line temperature sensors open diverter valves if unusual temperatures are detected?
ID number: 216389
Will valve alignments atypical of normal system operation be permitted?
Can the desired flow path safely and effectively be achieved.
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Passivation contractors generally supply temporary equipment such as circulating vessels, pumps, heat
exchangers, flow meters, filters, hoses, spray heads, fittings, specialized adapters or transition fittings, and
neutralization vessels. All this equipment should be inspected to assure it meets the requirements for its
intended use.
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APPENDIX
11.3.15
Disposal of Passivation Chemicals
Disposal of waste solutions is an important issue. The chemicals discussed for cleaning and passivating are
all water-soluble and can easily be neutralized. Except for heavy metals dissolved in the acid wash solution,
the only criterion that makes the waste solutions hazardous is having the pH outside the range of 2 to 12.5. It
is the heavy metals contained in the waste effluent that can cause an environmental or disposal problem. Of
the 13 priority pollutant metals tested for, two are found in elevated levels in passivation waste effluent waters.
The two heavy metals are chromium and nickel.
Fluids discharged must meet the site’s discharge temperature requirements.
There are three options for dealing with waste solutions generated when passivating:
•
They can be put into chemical drains. This can only be done where compatible drain and treatment
systems are available.
•
Neutralize waste solutions in contractor-supplied equipment and discharge through chemical drain to
site treatment system.
•
Off-site disposal is the final option. It is the most costly form of disposal.
Should a site waste treatment system not be available, permission could be obtained from the municipal or
private sewer authority to put neutralized waste solutions to sanitary drains. Under no conditions should any
waste solutions in any form be permitted to enter storm sewer systems
You will, however, receive documentation confirming proper disposal of waste solutions. Documentation would
include a bill of lading or hazardous waste manifest and receipts from the state certified treatment facility
where the waste solutions are being transported and treated. When off-site disposal is being used, it is
important to verify the credentials of the hauler and final destination site before utilizing their services.
Ultimately, disposing of waste solutions in a proper and legal manner is the responsibility of all involved
parties. The owner of the property where the waste solutions are generated, contractors, subcontractors
involved with the use of the chemicals, haulers, and the final waste treatment facility would all have some
liability for proper disposal of waste solutions.
11.3.16
Documentation
Complete and detailed documentation should be kept as the procedure is being performed. Specifics on
chemical concentrations, temperatures, contact time, quality of rinse water supply, and effluent sample readings should all be recorded.
This Document is licensed to
Some contractors use job log sheets to record chronological job data including specifics from the time the
contractor arrives on-site until the time he leaves. In addition to job log sheets, passivation log sheets should
be completed. Detailed information, as discussed above, can be plugged into a “fill in the blank” form supplied
by passivation contractor, validation firm, or owner. No matter how the information is recorded, the important
thing is that detailed and accurate documentation is kept. The following information can be submitted to the
owner and become incorporated into the final validation documentation:
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
•
Passivation Procedure
•
Miscellaneous Pertinent Information
•
Procedure Development Data
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161
APPENDIX
•
Testing Procedure and Equipment
•
Calibration Documentation
•
Passivation Log Sheets
•
Chemical Batch Record Information
•
Marked up system drawings, completed using point check list or line identification list.
11.4
PRETREATMENT PROCESSES
11.4.1
Turbidity and Particulates
11.4.1.1
Definitions
Particulates are insoluble suspended materials present in the water. Concentrations are measured in mg/l.
Sources of particulates are dust, pollen, silica, insoluble minerals, and corrosion products.
Turbidity is a cloudy appearance in water caused by the presence of suspended and colloidal materials.
Rather than a physical property, it is an optical property based on the amount of light reflected by the suspended particles and is measured in Nephelometric Turbidity Unit (NTU). The EPA limit for turbidity in drinking
water is 1 NTU. Turbidity cannot be related to particulates since it is affected more by particle size, shape, and
color rather than concentration. Light colored particles reflect more light than dark colored particles and many
small particles reflect more light than a few larger particles of equivalent concentration. Removal of particulates and turbidity is required to prevent fouling/plugging of final treatment processes using a membrane
(RO).
11.4.1.2
Filtration Mechanisms
The principal methods for removal of turbidity and particulates are:
•
clarification and the accompanying operations of flocculation, coagulation, and sedimentation
•
media filtration including single and multimedia filtration
•
barrier filtration included pre-coat filter, surface, and depth media such as cartridges and finer barriers
such as nanofiltration or ultrafiltration
This Document is licensed to
Factors affecting the removal of turbidity and particulates are:
•
•
•
particle size and shape relative to the filtration media
Mr. Shlomo Sackstein
Herzlia,
surface effects including surfaceID
tension,
hydrogen bonding,
and electrostatics
number:
216389
tendency of the particles to adhere to each other or the media which may be enhanced by addition of a
flocculating agent or alum (agglomeration)
11.4.1.3
Clarification
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Clarification is one method used by municipalities and large water treatment suppliers for removal of particulates and turbidity. Addition of alum, lime/FeCl3, or other flocculating agents, and pH adjustment aids the
sedimentation and clarification to remove particles larger than 25µm. Flow rates are generally large and cost/
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APPENDIX
gallon is low. This process is typically not found in the production of purified water because it would be
redundant to the treatment typically done by a municipality. The scale of these systems is much larger than
most purified water systems and clarification is not 100% efficient so that some additional filtration method
would be required to prevent particulates from being retained by filtration and cause blockage in subsequent
pretreatment operations such as ion exchange, carbon beds, and fine barrier filtration.
11.4.1.4
Media Filtration
Media filtration using a depth filter is the most common method of removing particulates from the water in
pharmaceutical water systems. It also may have some minor effect on turbidity. Design can be with either a
single size media or multi-sized media in a tank that has the means to support the media. With multi-sized
media, the larger media is typically at the top with the main flow direction downward through progressively
finer layers of media. The porosity of the media bed selected permits removal of particles down to a size of
10-40 µm. Accumulated particulates are removed by a back flush operation based on increase in pressure
drop or time. This back flush in the upward direction also decompresses the filter bed and is followed by a
rinse to resettle the media and remove fines. This back flush is generally considered a sanitary rather than
chemical waste and is typically 3-10x the design flow rate for a period of about 30 minutes. Following the back
flush, a short flush to drain in the direction of the process flow is required to resettle the bed and remove fines.
The filtration media in a depth filter may be sand, anthracite, carbon, or manganese. Sand is the most common because of cost and availability in a wide range of sizes and purities. Anthracite might be used where
leaching of the silica from a sand filter is a problem due to high temperatures or alkalinity. Depth filters using
anthracite often have higher filtration rates over extended runs and require less back washing (and regeneration) because of the sharply angular particles rather than the rounded silica particles. A depth filter using
carbon might be selected if the water has a high loading of organics, or if there is a particular reason to
combine removal or particulates, organics, and chlorine. The carbon is usually a course retention layer under
an extended layer of an activated granular carbon such as coconut, lignite, or anthracite. A depth filter using
particles coated with potassium permanganate or manganese zeolite as the depth media might be selected
for water having high concentrations of iron or manganese. It also may oxidize sulfur or hydrogen sulfide.
Generally, an oxidant, potassium permanganate or chlorine and permanganate is added prior to this filter to
convert the metals to the higher oxidation states that are insoluble. Removal down to levels of 0.03 mg/l of
iron and 0.05 mg/l of manganese are possible.
Microbial growth is a key consideration in any filter, but particularly a depth filter. This occurs because of the
large surface areas and relatively low velocities. In the case of a carbon filter, the media also is a source of
nutrient. Design of the system should include the presence of a disinfectant such as chlorine or chloramine in
the feed water, an added disinfectant, or the ability to periodically sanitize with a disinfectant or heat. The filter
bed also may be designed with constant recycle to ensure continuous flow through the bed to minimize
stagnation and growth.
This Document is licensed to
Advantages: filtering material; works well in a chlorinated environment; large capacity at low cost
Disadvantages: filter out only large particles; can be a source of microbiological growth
Mr. Shlomo Sackstein
Herzlia,
Barrier filtration includes cartridge filtration, pre-coat filtration, ultrafiltration, and nanofiltration. This type of
filtration has a “barrier” through which
the number:
water must flow. The
barrier retains particulates that are removed
ID
216389
11.4.1.5
Barrier Filtration
by changing the barrier (cartridge and pre-coat) or by a purge stream (ultra and nanofiltration).
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Barrier filtration is typically not used as the primary method for removal of particulates because of cost of the
barrier, labor, and the frequent need for replacement of the barrier due to the relatively high particulate
loading in the water entering pretreatment. It is frequently used as a “final clean-up” after the other pretreatment process such as ion exchange or carbon bed filtration, and before going to a final treatment step such
as reverse osmosis.
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163
APPENDIX
As a “final clean-up,” the barrier is often cartridges that might typically have a nominal particle size retention
of 1-10 µm for just the removal of particulate carry-over from the previous operations. If, however, the objective is to remove insoluble forms of silica and iron and achieve a SDI (silt density index) of less than 5 for feed
to an RO system, the absolute particle size retention might be <1 µm and as such are at the lower end of
microfiltration or the upper end of ultrafiltration. An absolute rated cartridge filter or a pre-coat filter can
achieve this. The later is usually not used unless the high particulate loading offsets the associated labor
cost.
Ultrafiltration (0.1-0.001 µm) and nanofiltration (0.005-0.0005 µm) are methods of barrier filtration. They are
not used as for primary removal of particulates for the reasons noted above, particularly cost and rapid
blinding of the membrane. Ultrafiltration is discussed in Section 11.4.4.3E.
Advantages:
low initial cost; can vary particle size retention by cartridge selection
Disadvantages: Cartridge filtration is an expensive way to remove solids due to the cost of cartridges and
labor if solids concentration is high; potential for microbial growth in a non-chlorinated environment.
11.4.2
Hardness and Metals-Ion Exchange
An ion exchange system consists of a tank containing small beads of synthetic resin. The beads are treated
to selectively absorb either cations or anions and exchange these ions based upon their relative activity
compared to the resin. This process of ion exchange will continue until all of the available exchange sites are
filled, at which point the resin is exhausted and must be regenerated by the appropriate chemicals. For
removal of hardness and metals, a cation exchange system will remove positively charged ions (metals) and
exchange them for sodium ions. Ion exchange resins that remove cations or anions and replace them with
hydrogen and hydroxyl ions are discussed in Chapters 5 and 6.
The presence of calcium (Ca) and magnesium (Mg) in a water supply is commonly known as “hardness.” It is
usually expressed in grains per gallon (gpg). Ion exchange is the principal method of removing hardness from
water in a pretreatment system. The process of removing hardness is often called “softening.” This is required
to prevent scale formation in final treatment operations such as RO and distillation.
11.4.2.1
Water Softening
Hardness in a water supply can result in “scale formation,” which is a deposit of minerals left over after the
water has been removed or evaporated. This can be found in boilers, cooling towers, reverse osmosis machines, clean steam generators, and distillation systems.
The function of an ion exchange water softener is removal of scale forming calcium and magnesium ions
from hard water. In many cases, other multivalent ions such as soluble iron (ferrous) and ionized silica also
are removed with softeners.
This Document is licensed to
A standard water softener has four major components: a resin tank, resin, a brine tank, and a valve or
controller. The softener resin tank contains the treated ion exchange resin - small beads of polystyrene.
Capacity depends on volume of the resin bed. The resin beads initially absorb sodium ions during brine
regeneration. The resin has a greater affinity for the multi-valence ions such as calcium and magnesium than
it does for sodium. As a result, when hard water is passed through the resin, calcium, magnesium, and other
multivalent ions such as iron and silica adhere to the resin, releasing the sodium ions until equilibrium is
reached. The water softener has exchanged its sodium ions for the calcium, magnesium, and iron ions in the
water.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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Regeneration is achieved by passing a sodium chloride (NaCl) solution through the resin, exchanging the
hardness ions for sodium ions. The resin’s affinity for the hardness ions is overcome by using a highly concentrated solution of NaCl (brine). The spent brine solution plus the associated water back-flushes and rinses
164
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APPENDIX
are waste streams and might typically approximate the nominal throughput for one hour for each regeneration cycle.
Water softening is a simple, well-documented ion exchange process. It solves a very common form of water
contamination: hardness. Regeneration with brine is simple and inexpensive and can be automatic with no
strong chemicals required.
Advantages:
Industry standard, low cost and effective. Works well in a chlorinated environment for microbial control with chlorine having only minor effect on resin life and efficiency. Inherent in the
regeneration is flushing of some microbial growth, but this should not be relied on as the sole
means of microbial control.
Disadvantages: salt handling for brine regeneration and disposal of spent brine solution
11.4.2.2
Demineralization/De-ionization
Three multivalent ions (iron, silica, and aluminum) present unusual removal problems.
a) Iron
Iron is a common water contaminant. It is one of the more difficult contaminants to remove because it
may change valence states--that is, change from the water-soluble ferrous state to the insoluble ferric
state.
In solution, ferrous iron behaves like calcium and magnesium; however, when oxygen or an oxidizing
agent is introduced, ferrous iron becomes ferric and precipitates, leading to a rusty (red brown) appearance in water.
Certain bacteria can further complicate iron problems. Organisms such as Crenothrix, Sphaerotilus, and
Gallionella use iron as an energy source, eventually forming a rusty, gelatinous sludge that can plug up
piping and equipment, particularly barrier processes such as nanofiltration and reverse osmosis. One
removal method for iron in the oxidized state is a replaceable barrier filtration such as a cartridge filter
with an absolute rating of <1 µm. It also can be removed by nanofiltration or reverse osmosis with some
membrane fouling, or with sequestering agent dosing that is removed further downstream in RO.
b) Silica
Like iron, silica may be present in more than one form and is a major problem in some parts of the
western United States. It may be a soluble ionized species or an insoluble material, sometimes as a
colloidal mixture with organics and other metals. The concentration of ionized silica will be reduced by a
water softener and insoluble silica forms can be removed by a replaceable barrier filtration with an absolute rating of <0.5 µm (ultrafilter). The insoluble silica also can be removed by nanofiltration or reverse
osmosis with some membrane fouling or by strong base ion exchange.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
Like iron and silica, aluminum can exist in multiple valences and its chemistry is complex. It also can be
a component of colloid complexes.
solubility, particularly
as hydrated oxide compounds, is a function
IDItsnumber:
216389
c) Aluminum
of pH. Aluminum may be present in the water either naturally or as a result of the alum treatment used by
a municipality as part of coagulation. Aluminum that is present as a colloidal component can be removed
by fine barrier filtration. Softening or de-ionization removes aluminum in an ionized form. Aluminum also
can be removed by reverse osmosis if the pH is <6 or >8. However, between these pH values that are
often common in an RO unit, the hydrated aluminum oxides are only partially (about 80%) rejected by RO
and often lead to fouling in an RO. If aluminum is a major problem, softening or de-ionization followed by
pH adjustment and then RO may be required for removal.
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165
APPENDIX
11.4.2.3
Ion Removal
Ion exchange (softening) is often part of the pretreatment process where it is used for removal of hardness.
Ion exchange as a total ion removal process (cations are exchanged for hydrogen ions and anions are
exchanged for hydroxyl ions) is discussed in Chapters 5 and 6.
11.4.3
Hardness and Metals-Other Processes
This section covers two alternate means (acidification/degasification and nanofiltration) for removing scale
forming components in water destined to be further purified in RO systems.
11.4.3.1
Acidification and Degasification
a) Carbon Dioxide
Use of a pH adjustment step is common in the process design to favor or inhibit the formation of CO2. As
discussed in the section on pH (Section 4.11), injecting acid to a pH of approximately 5.5, will maximize
the concentration of CO2 whereas, the addition of a base to a pH of 8.3 will minimize the formation of CO2,
converting it to carbonate ion. See Sections 4.6 and 4.11.
If high levels of CO2 are present in the water, it can be removed down to a concentration of about 5-10 ppm
with an atmospheric degasifier. An atmospheric degasifier has the potential of increasing bacterial burden
and should be located where bacterial control measures are available. One example is to locate the degasifier
between the stages of a two pass RO system.
b) The Acidification/Degasification Process
The process is well known and accepted in water purification systems. It is usually used where there is a
high flow rate (>50 gpm or 0.18 m3/min) or high hardness (>50 ppm). The incoming water is acidified
before the RO unit and a degasifier is used to remove residual CO2 prior to moving on to a second pass
RO or a mixed bed de-ionization (DI) unit.
In this pretreatment process, the incoming water is adjusted to a pH in the range of 3.8-4.2 with sulfuric acid.
The acidified water is sent to a packed column degasifier for removal of free CO2 by air. Removal efficiency of
CO2 is better than 98% (typical commercial degasifiers are designed to reduce outlet CO2 to less than 5
ppm). This residual CO2 should not pose a problem for downstream single and mixed bed de-ionization units
or electro-deionization. The residual CO2 also can be removed by addition of a base to increase the pH to ³
8.5 that converts it to CO3= which is removed in the second stage of the RO.
Commercial degasifiers are typically from 18 in. in diameter for 50 gpm to 72 in. diameter for 680 gpm (0.46
m for 0.18 m3/min to 1.83 m for 2.57 m3/min). Fan power requirements will range from 1/2 HP to 10 HP for the
preceding sizes. Smaller and larger units are possible to meet exact needs. Standard packed tower design
methods are used.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
The pH after removal of CO2 will be in the range of 6.5-7.0. Just prior to feeding the RO unit, the pH should be
adjusted to approximately 8.0-8.5 in order to minimize the amount of free CO2 still remaining in the water and
enhance removal of remaining carbonate in the second pass of the RO.
The acidification/degasification process has some associated problems. Air borne bacteria, if a problem or
concern, can be removed by a HEPA filter in the inlet-air line. The air also may oxidize any iron present to form
solids.
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Water from the degasification column is usually collected in a holding tank. Further treatment in this tank is
possible for TOC removal and microbial control. A multimedia filter usually follows the degasifier for removal
166
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APPENDIX
of initial incoming solids and any solids generated in the degasification step. When using gasification as a
“softening” process, addition of an anti-scaling agent is recommended just before the RO (if used as the first
stage in the final treatment step). The anti-scaling agent will be removed along with minerals, high molecular
weight organics, and endotoxins in the RO. Monitoring for removal of the anti-scaling agent by the RO is
required.
Advantages:
Replaces softener and the handling of large amounts of salt for softener regeneration; the
CO2 is released to the atmosphere rather than being purged as an ion in a waste steam; the
added sulfate ion from acidification is easier to remove in RO than added sodium ion from
softening.
Disadvantages: Handling acid for acidification; instrumentation and chemical handling for two pH adjustments.
11.4.3.2
Nanofiltration
Nanofiltration is a pressure driven membrane process with performance characteristics between RO and
ultrafiltration. The theoretical pore size of the membrane is one nanometer (10-9 meter). These membranes
are sometimes referred to as “softening membranes” and will remove anions and cations. The removal of the
larger anions (sulfate for example) is easier than the removal of a smaller anion (chloride) as discussed
earlier.
The nanofiltration membrane offers high rejection of salts of divalent anions as well as organics with molecular weights above 200. This includes color bodies, trihalomethane precursors, and sulfates. The rejection is
lower, but effective for salts with monovalent anions or non-ionized organics with a molecular weight above
150. Typical rejections (based on pure salt solution--mixtures may differ) are shown in the following table:
Solute Descriptive
Solute formula
MW
Rejection-%
Sodium chloride
NaCl
58
60
Calcium bicarbonate
Ca(HCO3)2
162
80
Magnesium Sulfate
MgSO4
120
98
Glucose
C6H12O6
180
98
Sucrose
C12H22O11
342
99
This Document is licensed to
Final product conductivity will range from 40-200 µS/cm depending on the inlet water total solids and mineral
species make-up. A single pass RO unit will produce conductivity of 5-20 µS/cm.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
The investment cost and size of a nanofiltration system is about the same as for a RO system. Energy use is
lower because they operate at 70-150 psig (4.76-10.2 bar) as opposed to 200-350 psig (13.6-23.8 bar) for
reverse osmosis membranes. Operating pressures are always a function of temperature, feed water salinity,
and recovery.
Nanofiltration membranes, like other membranes, are to a large extent application dependent. Key factors are
the quality of the feed water and the quality of the product water required. The feed water should be processed through a multi-media filtration system prior to going to the membranes. Potential applications are:
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•
Removal of color
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167
APPENDIX
•
Removal of trihalomethane precursors and organic carbon compounds from surface waters
•
Removal of hardness, radium, and TDS from well water
•
Feed waters with high silica
Industrial uses are where moderate water quality is required.
11.4.4
Organics and Microbiological Impurities
11.4.4.1
Introduction
Organic and microbiological contaminants need to be addressed in water treatment systems. The concerns
are twofold: contaminants entering the system and contaminants created/growing in the system. Organics
usually enter with the feed water, but also may leach from some non-metallic materials of construction.
Microbiological contaminants may enter with the feed water or grow in the system and are classified as viable
and non-viable. Viables are those organisms that can proliferate, given specific conditions. Non-viables are
derived from a breakdown of or a product of a viable organism.
The first issue to consider is water source since it affects organic loading. If the water is drawn from a well,
organic loading is usually not very great. Surface water (lake, river, or reservoir) will probably contain relatively high levels of organics and the composition and quantity may show seasonal variation.
Water from a municipal system is usually chlorinated, sometimes with ammonia added to form chloramines.
Microbiological content of the feed water will be low and will generally be inhibited until the chlorine/chloramine is removed.
The second issue to address is biological growth occurring within the water pretreatment system. Most
pretreatment systems are designed to keep an oxidant in the water for as long as possible to minimize the
potential for growth. Special design and maintenance requirements need to be addressed in all equipment
that operates without a microbial control agent, chlorine, or chloramine present. These include materials of
construction and piping layout (set up and fittings for sampling and periodic sanitization and instrumentation
for monitoring) compatible with the sanitization method selected.
11.4.4.2
Organic Contaminants
The organic contaminants found in many water sources are:
a) Bacterial Contamination
This Document is licensed to
Bacterial contamination is usually expressed as “total viable microbial counts per ml” or as “Colony
Forming Units (CFU) per unit volume.” CFUs are determined by counting the growth resulting from incubating samples. Each colony is assumed to form from one bacterium.
Mr. Shlomo Sackstein
Herzlia,
Pyrogens are substances that can produce a fever in mammals. The pyrogens are often endotoxins,
organic compounds (lipopolysaccharides)
that are shed216389
by bacterial cells during growth, or are the resiID number:
b) Pyrogenic Contamination
due of dead cells. They are chemically and physically stable and are not necessarily destroyed by conditions that kill bacteria. Their molecular weight may vary, generally 12,000 to 320,000. Pyrogen levels are
quantified in Endotoxin Units (EU) per milliliter. Pyrogens are of great concern to the pharmaceutical
industry, since high concentrations may cause responses in humans ranging from fever to shock or
death.
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APPENDIX
c) Total Organic Carbon (TOC)
TOC is a measure of organic materials contaminating the water and is specified in mg/l or µg/l. TOC is a
direct measure of the organic material that is oxidizable. TOC is a very fine measurement used in sophisticated water treatment systems where any organic contamination can adversely affect product quality.
TOC is not a good measure of microbial contamination.
d) Dissolved Organic Compounds
Organics occur both as the product of the decomposition of natural materials and as synthetic compounds such as oils or pesticides. Naturally occurring organics include Tannin, Humic acid, and Fulvic
acids. They detract from the aesthetics of water (i.e. color), but unless they come in contact with certain
halogens, they have no known health consequences in normal concentrations. Under conditions of free
halogen compounds (principally chlorine and bromine), they form chlorinated hydrocarbons and
trihalomethanes (THMs), which are suspected carcinogens.
11.4.4.3
Removal of Organics
A number of technologies are available to remove organic materials, and these have differing benefits and
drawbacks. The use of chlorine and chloramines to remove bacterial contamination are the most common
and are discussed in the next section. Treatment devices used to remove one or more of the other types of
organic material are:
a) Ozone
Ozone is twice as powerful an oxidant as chlorine. It will prevent microbial growth as well as reduce the
concentration of organics. Ozone is not used frequently in pretreatment systems due to the preference
for chlorine and materials of construction that are readily degraded by ozone. Ozone is discussed more
fully in Chapter 8, Storage and Distribution Systems.
b) Strong Base Ion Exchange
Organic scavengers or traps are ion exchange resins that contain strong-base anion resins and are
regenerated with sodium chloride brine. Most naturally occurring organics have a slightly negative charge
and are absorbed by the anion resin. After the resin is loaded, the organics can be displaced by high
concentrations of chlorides during regeneration.
Advantages:
removes most natural organics; can be regenerated
Disadvantages: disposal of brine and organic solution; requires chemicals for regeneration; brine carryover
may result after regeneration
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c) Carbon
Mr. Shlomo Sackstein
Herzlia,
Carbon is also one of the methods
to remove chlorine.
Use of carbon for this and its advantages
IDused
number:
216389
A carbon bed containing activated carbon will remove organics by adsorption of the organics on the
carbon. Periodically the carbon must be replaced when its capacity to adsorb diminishes.
and disadvantages are discussed in Sections 4.7 and 11.4.4.4.
d) Microfiltration
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Microfiltration includes the use of depth cartridge filters, pleated filters, and cross-flow filtration membrane elements. These filters can remove particles ranging in size from 100 µm down to 0.1 µm, thus
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169
APPENDIX
capturing bacteria, giardia cyst, and large molecular weight organics. Depth and pleated filters allow
water to flow through a wall of fibers perpendicular to the water direction. The particles are trapped on the
outside wall of these filters, or within the filter walls (for depth filters), due to the pore size of the filter. The
filter will fill up with these particles and then needs to be replaced with a new filter. Cross flow microfiltration
forces the water to flow parallel to the filtering media, and the particles which are too large to pass
through the filter are then expelled from the system in a concentrate stream to drain (typically 5-10% of
the feed flow). This allows the filters to be self-cleaning and eliminates the need to replace these filters
frequently.
See Section 5.5 for additional discussion.
e) Ultrafiltration
Ultrafiltration can be used to remove organics and bacteria, as well as viruses and pyrogens from a water
source. Filtration is typically from 0.1 down to 0.001 µm. Cross flow ultrafiltration forces the water to flow
parallel to the filter media, and the particles which are too large to pass through the membrane elements
are then expelled from the system in a concentrate stream to drain (typically 5-10% of the feed flow). This
allows the filters to be self-cleaning and eliminates the need to replace these membrane elements frequently. The UF membrane elements will need to have any suspended solids removed from the feed
stream prior to the UF system.
Advantages:
effective filtering barrier; no by-products; works with chlorine
Disadvantages: medium to high capital cost; 10% constant concentrate stream; can be source of microbial growth
f)
Reverse Osmosis (RO)
RO, if included in a pretreatment system to remove anions and/or cations, also will remove organics and
microbiological impurities. Like ultrafiltration, a purge stream removes impurities that are too large to
pass through the RO membrane. Advantages and disadvantages are similar to ultrafiltration but tolerance to chlorine depends on membrane selection. RO as a unit operation is discussed in Chapter 5.
11.4.4.4
Control of Microbiological Growth
The methods of controlling microbiological growth in pretreatment systems are periodic sanitization, ultraviolet (UV) light and chlorine/chloramine.
a) Periodic Sanitization
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Periodic sanitization methods, employed on a scheduled or as needed basis, include heat, chemical
sanitization, regeneration or replacement of media, flushing, or drainage. With heat, USP indicator organisms are killed above 60°C and the majority of pathogenic organisms will not proliferate. Temperatures
above 80°C result in complete kill. Sanitization times might be one to two hours at temperature. Total
cycle time including heat-up and cool down might be four to eight hours. Heat is commonly used in
carbon beds, filters, and distribution systems.
Mr. Shlomo Sackstein
Herzlia,
Chemical sanitization agents (when
cannot be216389
used) include hydrogen peroxide, iodine, ammoIDchlorine
number:
nium compounds, and organic or inorganic per-oxygen compounds. Sanitization times might be 0.5-4
hours with additional time for set up to feed the sanitization agent and to flush it from the system. Total
cycle time might be eight hours.
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170
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APPENDIX
Controlling temperature to minimize microbial growth permits increasing the period between sanitizations. Temperatures below 15°C slow microbial growth. Avoiding stagnation and dead legs also minimizes microbial growth. Recycle loops around various unit operations can be utilized during shutdown
periods, i.e. recycle around depth filter and softener while sanitizing carbon bed or while cleaning and
sanitizing RO.
Times for specialized periodic sanitization methods such as regeneration, replacement of media, and
drainage will depend on the equipment piece and specific design.
All sanitization methods (frequency and length of sanitization) will be system and sanitizing agent dependent, and must be validated.
b) Pressurized Carbon Dioxide
Periodic microbial growth inhibition coupled with shutdown is sometimes practiced where the high cost of
electricity and water favors shutdown of pretreatment and RO systems during normal non-work periods
such as third shift or weekends. During the shutdown, rather that maintaining water flow to drain to inhibit
microbial growth, the cartridge filters and RO are deadheaded and pressurized with carbon dioxide to 24 bar. This lowers the pH to <5.5 which inhibits microbial growth in the stagnant water as well as dissolving scaling chemicals such as carbonate from the RO. Before start-up, the acidic water and carbonate
salts are flushed to drain. The advantages include savings on energy and water consumption coupled
with microbial inhibition and de-scaling during a normal shutdown period. In addition, this technology has
the potential advantage of eliminating the need for a softener before the RO if there is a match between
shutdown frequency and fouling frequency of the RO without a softener present in pretreatment.
c) Ultraviolet Light (UV)
Treatment with UV light is a popular form of microbial control and disinfecting due to ease of use. Water
is exposed, at a controlled rate, between ultraviolet light waves. The UV light de-activates DNA in the
microbes preventing duplication and hence leading to bacteria reduction. See section on UV light systems in Chapter 8, Storage and Distribution Systems for additional information. In pretreatment systems,
UV is used when chlorine/chloramine and heat are not available or possible. The feed water to a UV
needs to be free of suspended solids, which can “shadow” bacteria, preventing adequate UV contact. UV
is typically used in controlling feed water to an RO unit that cannot accept chlorine or heat, and in
controlling non-chlorinated water re-circulation during system idle time. The UV system does not leave a
residual in the treated water, and therefore is only effective if there is direct UV light contact with microbes.
d) Chlorine
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Municipalities frequently use chlorine to disinfect the water before and during, distribution. Chlorine is fed
into the system to kill bacteria at typical dosage levels of 0.2 to 2.0 ppm. In order to maintain the “kill
potential,” an excess of chlorine is fed into the supply to maintain a chlorine residual. The chlorine level at
outlying distribution points is targeted at about 0.2 to 0.5 ppm; however, if the water supply is heavily
contaminated with organics, the chlorine may react and form certain chlorinated hydrocarbons
(trihalomethanes or THM’s). In other cases, chlorine can dissipate and no residual level is maintained at
outlying points in a municipal distribution system. Chlorine concentration should be monitored in the feed
water and in parts of the pretreatment system prior to its removal.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Molecular chlorine can have adverse effects on the components in a water purification system. It will
cause oxidative deterioration of the membranes, particularly polyamides, used in ultrafiltration and RO. It
also will cause degradation, embrittlement, and loss of capacity in de-ionization resins (oxidation rate
varies with resin type) although the amount is low to moderate at chlorine concentrations usually found in
drinking water. It also will cause corrosion of stainless steel, particularly at elevated temperatures and
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171
APPENDIX
may carryover into the product in a distillation system. Therefore, in most systems making purified water,
the chlorine is removed at some point.
Advantages:
low capital cost; common treatment; compliments municipal water treatment; maintains
a residual; easy to test and maintain levels
Disadvantages: can create THMs; does not affect all organics; residual chlorine is not acceptable in
many final treatment systems
The two principal methods of chlorine removal are activated carbon and reduction, often with sulfite.
Activated Carbon
Activated carbon removes the chlorine by adsorbing it onto the carbon particles in a carbon bed. There is
also some reduction of chlorine to chloride. Removal efficiency depends on bed depth, face velocity and
adsorptive capacity of the carbon. Design is based on rate of adsorption with adsorption rates typically
being more rapid for chlorine than organics if this is done in the same operation. Design based on chlorine removal will occur with bed depths of as little as 2-3 feet (0.61-0.91 m) and hydraulic rates of 2-4
gpm/ft3 (270-540 l/min/m3) of empty bed volume. Carbon bed volume is a balance between total adsorptive capacity and the frequency of replacement of the carbon bed.
Use of carbon to remove chlorine provides the perfect conditions for microbiological growth: slow flow
rates in a warm media with lots of nutrient present. Hence a program to periodically sanitize the carbon
bed is required. Heat (either steam [plant steam can be used, but often is not] or hot water at 190°F) is
effective with sanitization frequency varying from daily to a couple of times a week or less. With a proper
sanitization program, microbial growth in carbon beds can be controlled. Following the sanitization the
carbon bed is usually rinsed to remove fines before being put back in service.
Advantages:
removes low molecular weight organics; removes color; removes chlorine effectively;
technically not complex; relatively low cost
Disadvantages: high potential for increase in bioburden; medium to high capital cost; shedding of fines
requires downstream filtration; periodic replacement of the spent carbon
Reduction
The addition of a reducing agent will reduce the chlorine to chloride. Sulfite, usually as sodium bisulfite, is
generally the reducing agent of choice. The chemistry is:
SO3- + Cl2 + H2O ----> 2Cl- + 2H+ + SO4=
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The addition of sulfite, also may require an accompanying pH adjustment step. The chloride and sulfate
that are formed may be removed by a subsequent de-ionization step or RO.
Mr. Shlomo Sackstein
Herzlia,
Disadvantages: technically more
complex,
chemical handling
including sodium bisulfite and acid/base
ID
number:
216389
Advantages:
effectively removes chlorine; lower capital cost than carbon filters that can be heat sanitized; no regeneration or replacement required; low operating cost
for pH adjustment; potential for microbial growth in sulfite feed tank requires frequent (<5
days) preparation of sulfite solution; higher capital cost for feed systems and monitors;
higher cost than disposable carbon.
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172
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APPENDIX
e) Chloramines
Chloramines are formed by the reaction of chlorine and ammonia. Municipalities add ammonia (nearly
25% in 1990, principally in the southeast and Midwest US) to form a longer acting disinfectant than
chlorine and to reduce the formation of trihalomethanes during the chlorination of municipal water. Chloramines are three compounds: monochloramine (NH2Cl), dichloramine (NHCl2), and trichloramine (NCl3).
Dichloramine is a particularly strong biocide.
Chloramines present problems since the removal is typically not a single step. The methods for chloramine removal are:
•
activated carbon
•
reduction (sulfite injection)
Activated Carbon
Chloramines, like chlorine, can be removed by carbon; however, the absorption is much slower than for
chlorine or organics. Chloramine adsorption will require hydraulic rates as much as 3-6X less than chlorine and empty bed contact times of 3-6X those required for chlorine.
The removal of chloramines by activated carbon results in dissociation of some of the chloramines to
ammonium ion and ammonia. The ratio is dependent on pH and temperature. The ammonium ion can be
removed by cation exchange (water softening). Thus, if chloramines are present in the feed water, it may
be desirable to locate the carbon bed for removal of microbial control agent prior to the water softening
operation in the pretreatment system design.
The advantages and disadvantages of carbon are similar to those for chlorine. The potential dissociation
of chloramines to form ammonia is a disadvantage and can cause problems in final treatment. See
Section 4.9.
Reduction
Reduction with sulfite will convert chloramines to ammonium ion and chloride ion. These are removed by
an ion exchange operation or the ion removal process in final treatment. Again, if chloramine is present,
it may be desirable to locate the microbial agent removal prior to the water softening operation in the
pretreatment design. The advantages and disadvantages of sulfite reduction are similar to those for
chlorine.
11.4.5
pH and Carbon Dioxide
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pH, the negative log of the hydrogen ion concentration, is a measure of the concentration of hydrogen ions
(H+) in a water-based solution. The more hydrogen ions that are present, the lower the pH and the more acidic
the solution.
Mr. Shlomo Sackstein
The concentration of H ions (pH) is very important
because it affects the chemistry of the water. For inHerzlia,
stance, the pH of the water, along with other parameters, can tell us if the water will corrode piping or if certain
contaminants (carbonates) are likelyID
to precipitate
and cause
scaling.
number:
216389
+
In water or aqueous solutions, a certain ratio of water molecules, H2O, separates (or “dissociates”) into ions,
H+ and OH-.
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H2O <----> H+ + OH-
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173
APPENDIX
Because of the properties of water, when the concentrations of hydrogen (H+) and hydroxyl (OH-) present in
any water-based solution are multiplied together, the value is always the same. This number is the “equilibrium ion product”, Kw, which has been determined to have the value shown below:
Kw =
[H+] x [OH-] = 1.01 x 10-14 at 25°C
Where [H+] = Concentration of H+ (moles/liter)
[OH-] = Concentration of OH- (moles/liter)
Free carbon dioxide in water is produced by the decay of organic matter, dissolution of carbon dioxide from
underground sources, and solution from the atmosphere. Since the carbon dioxide content of the atmosphere is quite low (less than 0.04%), this is not a major source of carbon dioxide in the water and surface
waters normally are relatively low in free carbon dioxide; however, well waters usually contain an appreciable
quantity of free carbon dioxide.
Free carbon dioxide is the term used to designate carbon dioxide gas dissolved in water. The designation
“free” carbon dioxide differentiates a solution of carbon dioxide gas from combined carbon dioxide present in
the form of bicarbonate and carbonate ions. In the case of high purity water, low levels of carbon dioxide from
the atmosphere can cause the pH to drop from 7.0 to 5.5 and the conductivity to increase from 0.1 µS to 1 µS.
Low levels of CO2 also can prevent a water purification system such as two-pass RO from producing water
with a conductivity of <1 µS.
The pH of the water causes the equilibrium between free carbon dioxide (gas) and bicarbonate alkalinity
(dissolved ion) to shift to more or less carbon dioxide. The determination of the level of CO2 present in the
water as it proceeds through the treatment process is important to understand because it can affect the final
water quality or it can cause premature exhaustion of ion exchange systems.
The approach to pH in the pretreatment system affects the equilibrium between carbonate, bicarbonate, and
carbon dioxide. As the pH is lowered the equilibrium is shifted toward carbon dioxide which is a neutral
species dissolved in the water with the ionic charge being maintained with anions from the added acid and
the net formation of water. As the pH is increased, the equilibrium is shifted toward bicarbonate and then
carbonate with the ionic charge being maintained by the addition with cations from the added base and the
net formation of water.
11.4.6
Importance of Feed Water pH
EPA drinking water standards require that the pH of the water be within a range of 6.5-8.5; however, the range
of most water is much narrower due to the corrosive nature of water with an acidic pH and a scaling potential
at a high pH. The feed water pH is very important when designing the pretreatment for a purified water
system. Also, the pH is an important parameter is designing a RO system or an ion exchange system.
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If the pH of the feed water is less than 8.3, the feed water will have to be analyzed for the amount of CO2
present in the water. The lower the pH from a pH of 8.3, the higher the potential capacity for dissolved CO2.
The CO2 will directly pass through pretreatment and an RO membrane and depress the conductivity and pH,
making it difficult to meet the USP conductivity requirements. If the system has an ion exchange system
following the RO, high levels of CO2 will produce a high ionic loading on the system. High CO2 may require the
use of a degasifier to remove the CO2. See Section 11.4.3.1.
Mr. Shlomo Sackstein
Herzlia,
If the feed water pH is between 6-10,ID
the RO
system has the216389
potential to incur hardness scaling. Adding acid
number:
to the feed water controls the deposition of scale, but this converts carbonates to CO2 that will pass through
both the RO and distillation final treatment processes. On the other hand, the addition of base converts the
bicarbonate to carbonate, and carbon dioxide (CO2) to bicarbonate. These ions will be removed by an RO
unit, but also will cause scaling. Most pharmaceutical companies incorporate the use of ion exchange softening in order to prevent scaling from occurring in the RO membrane.
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174
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APPENDIX
Chloramine in the feed water can result in ammonia or ammonium. The pH as well as temperature affects the
equilibrium between ammonia and ammonium. Acidic conditions are required to maintain the ionic species
for removal in an RO unit. In final treatment ammonia will pass through an RO unit. In distillation, the higher
temperatures shift the equilibrium from, ammonium towards ammonia. Ammonia will affect conductivity and
pH, making it difficult to meet the USP conductivity requirements.
Based on these situations, some water systems will include the capability to add either acid or a base to the
water in order to optimize the performance of the system. The most common acid used for pH adjustment is
sulfuric acid because it is readily available and less corrosive than hydrochloric acid. The most common base
used for pH adjustment is sodium hydroxide (caustic soda) because it is readily available, and the final
treatment process will remove sodium ions.
11.5
FINAL TREATMENT FOR NON-COMPENDIAL AND COMPENDIAL PURIFIED WATER
SYSTEMS
11.5.1
Ion Exchange for Purified Water Applications
11.5.1.1
Ion Exchange Use in USP Systems
The primary purpose of ion exchange equipment in USP high purity water systems is to satisfy the ionic
quality portion of the specification. Ion exchange systems can effectively reduce organics in many applications with proper ion exchange resin selection and maintenance. Ion exchange systems may not meet USP
TOC requirements without additional membrane processes in certain applications where high feed water
TOC levels exist. For most water supplies, both two-bed and mixed-bed units in series can be utilized to meet
the USP water specifications.
Ion exchange systems require pretreatment to remove undissolved solids from the water stream and to avoid
resin fouling or degradation. Although dechlorination also is recommended to avoid resin degradation by
oxidation, the low levels of residual chlorine commonly found in potable water supplies, in worst cases,
demonstrate only long-term effects on most ion exchange resins. Typical pretreatment for an ion exchange
system includes a filter and/or carbon filter for removal of undissolved solids and chlorine.
11.5.1.2
Functionality
With the exception of one-time use (virgin) resins (which are not regenerated), cation and anion exchange
resins are regenerated with acid and caustic solutions, respectively. As water passes through the ion exchange bed, the exchange of ions in the water stream for the hydrogen and hydroxide ions held by the resin
occurs readily and is driven by concentration gradient. Similarly, the regeneration process is driven by excess
chemical.
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Cation Exchange: Cation exchange is the exchange of cations (Ca, Mg, Na, etc.) in water for hydrogen ion
(H+). Hydrogen cycle operation of cation exchangers is the term used when regeneration is accomplished
with dilute acid (generally sulfuric (H2SO4) or hydrochloric (HCl). All salts are converted to corresponding
acids following the cation exchange process.
Mr. Shlomo Sackstein
Herzlia,
Anion Exchange: Anion Exchange is the exchange of anions (SO , HCO , Cl , etc.) in water for hydroxide
ions (OH ). This exchange following cation
exchange completely
demineralizes water when carried to compleID number:
216389
4
=
3
-
-
tion. The anion exchange resin is typically regenerated with sodium hydroxide (NaOH).
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Ion exchange resins are available in “strongly” and “weakly” ionized versions. Strongly ionized resins have a
greater affinity for all ionized constituents in water and are capable of removing even weakly ionized constituents such as acetates and silica with practical exchange capacities of 18 and 14 kgs as CaCO3 per ft3 of resin
(0.5 and 0.4 kgs/m3) for cation and anion resins respectively. Weakly ionized resins are ineffective at remov-
For individual use only. © Copyright ISPE 2001. All rights reserved.
175
APPENDIX
ing weakly ionized constituents; however, their exchange capacities are two to three times that of strongly
ionized resins and can be regenerated more efficiently.
Ion exchange resins have a higher affinity for polyvalent ions. A result, common divalent ions such as calcium, magnesium, sulfate, etc., are removed first as water passes through the resin bed. Monovalent ions
such as sodium, potassium, and chloride can be displaced by divalent ions in the exhaustion cycle and will
leak into the product stream first. RO product streams are generally comprised of monovalent ions and
present a more difficult challenge to ion exchange units than a typical raw water. Mixed bed ion exchange
units were developed to provide superior removal of monovalent ions.
Two bed (also called separate bed) deionizers use two separate columns for the cation and anion resin.
Regeneration of a two-bed unit is relatively simple since chemicals are easily introduced and rinsed. No resin
separation or mixing is required as with the alternative mixed bed deionizer.
Mixed bed (also called mono-bed) deionizers utilize one column with both cation and anion resins intimately
mixed for the service mode. Regeneration is more complex than two-bed regeneration as resin separation
and mixing steps are required.
Mixed bed ion exchangers function as an infinite series of two-bed ion exchangers since the resin bed is
comprised of both cation and anion resins thoroughly mixed. Therefore, residual ions that may leak through a
two-bed exchange system are eventually removed by the mixed bed exchanger to achieve optimum ionic
purity.
Among two bed systems, there are two types: co-current and counter-current regeneration units. In cocurrent regeneration systems, the regeneration fluid flows in the same direction of the process water stream.
In a counter-current system, these fluids flow in opposite directions. The practical results of counter-current
regeneration are higher quality product water and approximately 50% reduction in chemical usage.
11.5.1.3
Operating Parameters
From a process standpoint, ion exchange systems require consideration of three basic parameters: flow rate,
ionic loading, and product water quality.
There are many parameters to consider on a practical level including cost of operation, capital cost, space
requirements, chemical handling issues, etc. However, for the purpose of sizing equipment and defining the
basic needs of an ion exchange system, these parameters are most important.
Deionizer Type
Two Bed
Two Bed
Mixed-Bed
Co-Current
Regeneration
Counter Current
Regeneration
2.0-10.0
0.2-2.0
0.055-1.0
4
6-8
0.067
0.1-0.133
5-15
5-25
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Product Water Quality (µS/cm)
Mr. Shlomo Sackstein
6-8
Herzlia,
Kgs of Acid/Caustic per liter resin (100% Basis)
0.1-0.133
ID number: 216389
Lbs of Acid/Caustic per ft3 resin (100% Basis)
Process Flow Rate (gpm/ft2 of bed area)
5-10
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4:16 AM
12.21-24.42
12.21-36.63
Process Flow Rate (m3/hr/m2) of bed area)
Typical Operating Temperature Range in °F (°C)
176
40-140 (4-60)
40-140 (4-60)
For individual use only. © Copyright ISPE 2001. All rights reserved.
12.21-61.05
40-140 (4-60)
APPENDIX
The table above lists basic operation information for ion exchange systems. Process flows should be maintained within these ranges to avoid problems such as channeling and high pressure drops. Process flow rates
that are too low may result in channeling through the ion exchange bed. Channeling is typically recognized by
significantly shorter run times between regeneration. Excessive flow rates can significantly increase system
pressure loss and potentially affect product water quality.
11.5.1.4
Component Description
An ion exchange system is comprised of a tank(s), ion exchange resin, a piping and valve system, water/
chemical distributors internal to the tank(s), a regeneration system, and a conductivity or resistivity meter and
cell. Typically, other instrumentation may include a flow meter and pressure gauges. Ion exchange systems
are available in both on-site regenerable and off-site regenerable (rechargeable) versions. In both versions,
tanks may be constructed from fiberglass, stainless steel or carbon steel with an inert interior lining such as
vulcanized rubber or PVC. Off-site regenerated or rechargeable systems are typically transported off site to
a facility that is equipped to either regenerate or replace the resin. For this reason, these units are typically
supplied with fiberglass or light gauge stainless steel tanks in sizes ranging from less than 1 ft3 (0.03 m3)-50
ft3 (1.4 m3) per tank. Larger, off-site regenerated systems are recharged with new resins on-site, and the
exhausted resin is returned to an off-site regeneration facility.
On-site regenerated units are designed with a much more complicated valve and piping system to accommodate on-site chemical regeneration and rinsing. These systems are selected when larger volumes of water
are required on a continuous basis, thus justifying the higher capital investment.
11.5.1.5
Tanks
For pharmaceutical applications, given the typical quantity of water utilized, ion exchange tanks rarely need
to be more than 3-4 feet (.91 m-1.22 m) in diameter. Typically, tank straight shells are 6-8 feet (1.82 m-2.44 m).
Steel tanks are welded and typically manufactured and designed in accordance with the ASME Code for
operating pressures between 100 and 150 psig (7 and 10.5 kgs/cm2 gauge). ASME Code stamping is not
necessarily required for this type of equipment; however, local regulations and end user safety concerns
should govern this decision.
11.5.1.6
Distributors
Each ion exchange tank includes distributors at all pipe to tank interfaces. Distributors are required to ensure
that resin does not escape from the tank while water is flowing through the system and to provide adequate
distribution of flow through the vessel. Distributors are typically supplied in stainless steel, PVC, CPVC,
polypropylene or PVDF. Structural integrity of a distributor system is a key element in any design since a
ruptured distributor can cause a significant loss of resin and may require significant time for repair.
11.5.1.7
This Document is licensed to
Piping and Valves
The selection of a piping and valve system depends upon several factors including budget, product water
quality (in terms of chemical analysis), and preferred methods of sterilization. Most ion exchange systems
are provided with schedule 80 PVC or CPVC piping and valves. The advantages of these materials include
low cost, ease of assembly, and high corrosion resistance. Specialty plastics such as polypropylene and
PVDF also have been utilized in DI systems to a great extent. These materials are more expensive than either
PVC or CPVC; however, these materials are superior in terms of the lower level of organic leachables into the
process water. Furthermore, these materials are available in a piping design that more closely resembles the
orbital welding in sanitary stainless piping systems.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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Stainless steel piping systems offer greater structural integrity than plastic piping systems and the ability to
sanitize using hot water or steam. On the other hand, stainless steel is much more vulnerable to corrosion
and more expensive than PVC and CPVC.
For individual use only. © Copyright ISPE 2001. All rights reserved.
177
APPENDIX
11.5.1.8
Regeneration System
On-site regenerated ion exchange systems require a regeneration system that includes chemical pumps
and/or eductors, chemical tanks, piping and valves, and related instrumentation. The cost critical component
in any regeneration system is the chemical pump. Pumps better suited for this application require inert materials of construction and the capability to closely meter or regulate the chemical dosage. Positive displacement pumps driven by either electric motors or compressed air are ideally suited for this application.
Chemical eductors offer another option to deliver chemicals to an ion exchange system; however, chemical
dosing may be inconsistent based on variable dilution water pressure and flow.
11.5.1.9
Microbiological Concerns, Cleaning, and Sanitization
Although ion exchange resins beds, due to the hydrogen ion and hydroxide ion exchange sites, have pH
values at the extreme ends of the range, microbiological activity remains a concern. The regeneration of both
the cation and anion exchange resin beds effectively sanitizes the system; however, as the system processes
water, the resin becomes exhausted and the pH approaches neutral. Organic matter, which may be deposited on or absorbed by the resins, particularly the anion resin, and the laminar flow of water through the bed
foster bacteria growth in ion exchange beds. For this reason, regeneration frequency is more important to ion
exchange systems that are not designed with auxiliary microbiological control components such as UV lights.
Polishing ion exchange systems are typically positioned in a system with bacterial control elements such as
sub-micron filters and ultraviolet sterilizers, and may operate for several weeks without requiring regeneration.
11.5.1.10
Advantages and Disadvantages
Ion exchange based WFI and purified water systems have an extensive installed based and lengthy history.
Major advantages are the considerable flexibility in flow rate of ion exchange systems, lack of sophisticated
maintenance requirements, consistent production of Stage 1 conductivity, and the ability to use the chemical
regeneration of ion exchange resins as a means of microbial control. The major disadvantages include the
necessity to store and handle acid and caustic, the requirements to neutralize waste chemicals (for on-site
regenerated systems only), and the reduced ability of ion exchange resins to reduce dissolved organics
relative to membrane based systems.
11.5.2
Reverse Osmosis (RO) for High Purity Water Applications
11.5.2.1
Description
RO is a pressure driven process utilizing a semi-permeable membrane capable of removing dissolved organic and inorganic contaminants from water. A semi-permeable membrane is permeable to some substances such as water, while being impermeable to other substances such as many salts, acids, bases,
colloids, bacteria, and endotoxin.
This Document is licensed to
RO membranes are produced commercially for water purification in spiral wound and hollow fiber configurations. Spiral wound elements are much more forgiving in pretreatment protection against fouling. Membranes
are available in two basic materials: cellulose acetate and thin film composite (polyamide). All of the membrane types have advantages and disadvantages. Cellulose acetate membranes are the oldest commercially.
Cellulose acetate has the advantages of being the lowest initial cost membrane and is chlorine tolerant. The
primary disadvantages of cellulose acetate membranes are: the fastest loss of rejection among membrane
types; the necessity to operate in a pH range of 5 to 6 to minimize hydrolysis; and the necessity to keep free
chlorine in the feed stream to control bacterial consumption of the base membrane material. Cellulose acetate membranes also are more resistant to some types of fouling than alternative membranes. Cellulose
acetate membranes are relatively intensive in energy considerations since the membranes normally operate
at a high pressure (300-500 psig or 21-35 kgs/cm2 gauge) and commonly operate at elevated feed water
temperatures (60-80°F) (15-27°C).
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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178
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APPENDIX
Thin film composite RO membranes offer the highest rejection of contaminants of all membrane types in
current production. Thin film composite membranes operate effectively at low water temperatures (40°F
(4°C) and higher) and low pressure (150 psig (10.5 kgs/cm2 gauge) and higher). The initial capital cost of thin
film composite membranes may be higher than the capital cost of cellulose acetate membranes, but offer the
higher rejection and expected longer life. The primary negative aspect of thin film composite membranes is
the intolerance for chlorine in the feed water.
Thin film composite membranes are degraded rapidly in the presence of chlorine at municipal drinking water
levels. The dechlorination of the feed water does allow the opportunity for some bacterial growth to occur and
more sanitization efforts are required with thin film composite membranes than with chlorine tolerant types.
Both thin film composite and cellulose membrane can be appropriate for use in pharmaceutical water systems. The optimum membrane selection is based upon an analysis of capital cost, operating cost, membrane
life, rejection, and bacterial control. The majority of pharmaceutical systems utilize thin film composite membranes.
Most spiral wound RO membranes incorporate a brine seal at the leading end of the RO element. This seal is
designed to expand between the membrane and the pressure vessel that contains the RO membrane. The
purpose of the seal is to prevent passage of water between the membrane and the pressure vessel and to
divert the flow of water across the RO membrane surface. The brine seal can cause bacterial problems since
a stagnant water condition is inherently created by the presence of the seal. Some membranes are produced
today without a brine seal on the leading end. These membranes are commonly referred to as loose wrap or
full fit and are configured in several different ways with the same goal of allowing modest controlled flow
between the RO membrane and the pressure vessel. This type of membrane is superior for use in pharmaceutical RO units as bacterial contamination is minimized.
RO membranes can vary in configuration. They are designed in arrays such that turbulence is reasonably
maintained to minimize scale precipitation and fouling. Greater turbulence also decreases the boundary layer
and reduces the salt level at the membrane surface improving permeate quality. As permeate (product) is
formed, the feed water stream concentrates in contaminants. Typical arrays frequently reduce the number of
membrane pressure vessels in parallel as the feed water flow is reduced. Recycle of the reject concentrate is
sometimes employed to maintain the higher turbulence without using more feed water. This must be designed
such that the resultant concentrated feed stream does not precipitate downstream.
11.5.2.2
Application
RO can be successfully implemented in pharmaceutical systems several ways. RO units can be utilized
upstream of deionizers to reduce regenerant acid and caustic consumption or to minimize resin costs. Product staged RO units (two sets of RO membranes in series) are generally capable of producing water that
meets the requirements of the USP for TOC and conductivity. Some installations produce water that meets
the Stage 1 conductivity level allowing on-line measurement while others produce water that passes Stage 2
or 3 levels requiring laboratory testing. Each installation must be carefully analyzed to assess the probable
product water quality relative to consistent conductivity levels.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
Even small changes in feed pH can have a very dramatic effect on final system conductivity and this parameter should be monitored and controlled
pH control is a216389
part of the system) utilizing a very accurate pH
ID (ifnumber:
11.5.2.3
Instrumentation and Control
meter with a feedback loop for any chemical feed pump. Using a simple on/off signal for chemical feed pump
control is not recommended.
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The product quality from the RO system is directly related to the feed quality. As a result, monitoring the feed
quality can provide a method for notifying an operator of an impending issue before the product quality from
the RO system degrades. The feed and permeate conductivity can be directly compared to provide on-line
For individual use only. © Copyright ISPE 2001. All rights reserved.
179
APPENDIX
monitoring of RO ionic rejection. Permeate flow, waste flow, and feed temperature are typically monitored as
well as pressure for feed, concentrate, and permeate. These parameters should be measured using calibrated, NIST traceable instruments. Some RO units also monitor additional parameters such as membrane
inter-stage pressure and conductivity. Scale will tend to form on downstream membranes and pressure drop
can be an indicator. Chlorine or Oxidation Reduction Potential (ORP) monitoring is sometimes utilized to
protect chlorine intolerant membranes against oxidation.
Most RO units incorporate some level of automation. Protective devices are typically included to protect:
pumps against low suction pressure and membranes against high pressure and high temperature. Most
valves on RO units are manually adjusted. Automatic valves are utilized in many units to accomplish product
side flushing and system sanitization. Membrane cleaning is performed manually in most systems, but can
be automated.
11.5.2.4
Limitations
RO cannot remove 100% of contaminants from water and has very low to no removal capability for some
extremely low molecular weight dissolved organics. RO also quantitatively reduces bacteria, endotoxin, colloids, and other macro molecules from water. RO cannot purify 100% of a feed water system. A concentrate
flow is always necessary to remove the contaminants that are rejected by the membrane.
Recovery is defined as the percentage of feed water that becomes purified product water. Most RO units
operate in the range of 75% recovery. Some small units operate at lower recoveries, while large systems may
have recoveries as high as 85% if water consumption is critical. Many users of RO utilize the waste stream
from the RO unit for cooling tower make-up water, compressor cooling water, etc. The determination of
recovery must be a balance of life cycle costs, water, waste, and maintenance factors. A high recovery unit
may have less waste to achieve the desired output rate, but it tends to have high maintenance costs due to
effects of the concentrate.
Carbon dioxide passes directly through the RO membrane and, for design purposes, the CO2 will be in the
RO product stream at the same level that is present in the feed water stream. Excess carbon dioxide in the
RO product stream may cause product water quality problems directly or may increase the load on the anion
resin in deionizers which follow the RO unit to raise the RO permeate to a higher quality level.
Water quality produced by an RO system is dependent upon a number of factors, including, but not limited to:
membrane type, operating pressure, and feed water quality. Since RO membranes remove a percentage of
the contaminants in the feed water, as the feed water quality degrades so will the product quality. As a result,
it is conceivable that the feed water quality could change enough so that the product quality from the RO
system may no longer meet USP quality.
Present RO technology requires ambient RO operation with occasional chemical or hot water sanitization.
Operating at ambient temperatures can result in the possibility of biological growth. The ability for RO systems to continuously operate at high temperature (80°C) should alleviate this; however, to date, this may be
the most significant factor in why RO use in a WFI application is rather limited.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Since RO membranes remove a percentage of the constituents in the feed water as the feed water quality
deteriorates or the membranes degrade, it may become more challenging for the RO system to meet USP
WFI product quality. As a result, the RO-based USP WFI system may require more regularly scheduled
monitoring than a distillation system.
The performance of an RO system also is dependent upon potentially numerous “o” rings between the membrane elements and between the membrane elements and the membrane element housings. O-ring slippage
may result in poor water quality. This would normally result in high conductivity (low resistivity), providing a
means of monitoring for unacceptable water quality.
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180
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APPENDIX
11.5.2.5
Scaling
RO scale formation in waste streams is predicted by a calculation that utilizes the concentrate stream water
levels of calcium, alkalinity, total dissolved solids, and temperature. The proper pH to operate a RO unit at
(without the use of an antiscalant agent) is a minimum of 0.5 pH units below the pH calculated to produce
scale.
Scale control through acidification of feed stream to lower the pH is very effective. The principal negative
aspect of this method of scale control is in the formation of free carbon dioxide from bicarbonate that is
present in the feed water as the pH is lowered.
Antiscalant chemicals also are available for injection into the RO feed water stream. The antiscalant agents
are very effective in minimizing scale formation through a sequestering action that increases the time necessary for crystal formation of the precipitate.
The various membrane types have different maximum operating temperatures. Many RO systems utilize feed
water preheating to optimize the membrane area and to minimize the pumping energy required to operate the
RO system. It is prudent to have high temperature protection for the membranes when utilizing feed water
preheating.
11.5.2.6
Cleaning and Sanitization
Virtually all RO units need periodic cleaning. Acid based cleaners are used to remove accumulated metals
and salts from the membranes. Alkaline detergent cleaners are used to remove silt and organic foulants from
the membranes. Sequential acid and alkaline cleanings are frequently done to assure a thorough cleaning.
Cleaning frequency should not be more than four times per year if the pretreatment system is designed and
working properly. Cleaning need is based upon a loss of rejection, an increase in the feed to waste membrane
pressure drop, or a loss of product flow.
Chlorine tolerant membranes can be sanitized with chlorine solutions. Non-chlorine tolerant membranes can
be effectively sanitized with a peracetic acid/hydrogen peroxide solution. Some membranes are sufficiently
heat resistant to allow thermal sanitization at 80°C.
11.5.2.7
Purification Capability and Efficiency
A single stage of RO elements commonly reduces the level of raw water salts by 90 to 99%. Other raw water
contaminants such as colloids, bacteria, and endotoxin also are reduced by 1-3 logs. Passage of water
through a single pass of RO membrane may frequently not purify the water to a level that meets the current
requirements for USP Purified Water.
This Document is licensed to
Repurification of the water through a second set of RO membranes will raise the quality of water to levels that
can exceed the requirements of USP Purified Water or Water For Injection in most applications. RO systems
that utilize two sets of RO membranes in series are commonly called two-pass or product staged RO units.
Product staged RO units can produce water from the municipal drinking water supplies to produce product
water which will normally have a resistivity of 0.5 Mohm/cm or greater.
Mr. Shlomo Sackstein
Herzlia,
Almost all product staged RO units can produce product water that passes the USP tests for conductivity and
TOC; however, product staged ROID
product
water may not
necessarily pass the conductivity test in rare
number:
216389
applications.
11.5.2.8
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Performance
RO unit must incorporate sufficient membrane area for reliable operation. All membrane manufacturers offer
recommendations for membrane area required as function of the feed water quality. One of the most impor-
For individual use only. © Copyright ISPE 2001. All rights reserved.
181
APPENDIX
tant factors for optimization of membrane area is the understanding of fouling and scaling potential. The Silt
Density Index (SDI) reading offers an indication of the tendency of the feed water to foul membranes as a
result of salt, colloids, or bio-burden. Most membrane manufacturers recommend an SDI reading of three or
less with an upper limit for proper membrane operation. In general, the higher the membrane area for a fixed
product water flow rate, the lower the rate of membrane fouling will be. This is not entirely true since the
percent recovery may differ, and therefore might be a factor. A high recovery for the same flow and membrane
area will tend to foul more. It is obvious that an increase in membrane area will cause an increase in the
capital cost of the equipment due to the increased requirement for membranes and pressure vessels. An
intelligent RO design will optimize the membrane area versus the maintenance and cleaning requirements of
the RO system.
Advantages:
RO is utilized to reduce or eliminate chemical handling. This can be a significant advantage
for RO when compared with regenerable deionization systems. RO generally has better
TOC reduction that ion exchange alone.
Disadvantages: Water consumption due to the relatively high waste flow if wastewater reuse is not employed.
RO is utilized in many new purified water systems due to the low chemical handling requirement and the membrane barrier to bacteria, endotoxin, organics, and salts. Additionally, if
the RO pretreatment is not designed to properly handle raw water change, RO maintenance
can become expensive.
11.6
DISTILLATION FOR HIGH PURITY WATER SYSTEMS
11.6.1
Thermal Efficiency of Distillation Systems
Heat losses from a distillation system are due to:
•
Radiation
•
Venting
•
Heat exiting with the blowdown and distillate streams which are at higher temperature than the feed
•
Heat exiting with cooling water
Because of these heat losses, it takes more than one pound of plant steam to produce one pound of WFI in
a single effect distiller. For this reason, Multi-Effect distillers are used in order to improve the performance of
the system.
This Document is licensed to
The Performance Ratio (R) of a distiller is defined as the amount of distillate produced in relation to the
amount of steam consumed, and is given by: R = Md/Ms, where
R = Performance Ratio (dimensionless)
Md = distillate produced (lbs)
Ms = steam consumed (lbs)
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Another way to measure the performance of a distiller is often stated in terms of Thermal Economy (E). This
is defined as the amount of distillate produced in relation to the amount of energy input, and can be given by:
E = Md/1000 BTU heat input.
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182
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APPENDIX
A typical single effect distiller, without feedwater pre-heating, has an R of about 0.82 and an E of about 0.89.
Pre-heating of the feedwater in the condenser raises the R to 0.93 and the E to 0.96 respectively.
Feedwater pre-heaters are sometimes used to elevate the temperature of the feedwater prior to entering
each effect in a ME system, and thereby reduce the steam requirements of the distiller.
Typical performance values for a 600-gph VC and 5-effect ME are shown in the table below.
VC
5 ME
Cold
Hot
Cold
Hot
Economy in lbs/1000 BTUs
19.52*
6.8
3.84
3.84
Performance Ratio (lbs of distillate/lb of steam
27.67
7.11
3.39
3.39
* Economy takes into consideration the electrical energy consumption for the VC.
11.6.2
Water Recovery
A portion of the feedwater is continuously discharged to waste in order to limit the total dissolved solids
content of the feedwater within the evaporator. That portion of feedwater not evaporated is termed blowdown,
and is discharged continuously to waste. The total quantity of feedwater (Mf) required is given by the sum of
the distillate produced (Md) and the blowdown (Mb) discharged. The Recovery Ratio (Rc) of a distilling unit is
determined by dividing the product rate (Md) by the feedwater rate (Mf).
Hence the Equations: Mf = Md + Mb and Rc = Md/Mf.
In order to minimize energy consumption and pre-treatment cost, it is desirable to have a high Rc. The Rc is
limited by the scaling potential of the water. At low flow rates, it may be limited by practical considerations.
The higher the Total Dissolved Solids (TDS) of the feed, the lower is the recovery. With deionized feedwater,
the recovery is 90%-95%. With softened feed, the recovery is typically 80%-85%.
11.6.3
Number of Effects or Columns in an ME Design
Increasing the number of effects in an ME system does not result in increased output, but it reduces the
amount of steam and cooling water required to produce the same amount of distillate, compared to a system
with fewer effects.
This Document is licensed to
In order to maintain a temperature difference for heat transfer between the vapor from one effect and the
boiling liquid of the next effect, the pressure within each succeeding effect must be lower than its predecessor. The temperature and pressure are highest in the first effect, and are lowest in the condenser and the last
effect, which are nearly at the same pressure and temperature.
Mr. Shlomo Sackstein
Herzlia,
In order to minimize the heat rejection
of the216389
condenser, it is desirable to operate the system
IDrequirements
number:
over the lowest temperature range possible. Additionally, a lower temperature operation reduces the potential
for scaling and corrosion. If we call the temperature at which the first effect operates the top temperature and
the temperature of the condenser downstream of the last effect the bottom temperature, that constitutes the
temperature range for the multi-effect distiller. In a non-pharmaceutical application, the bottom temperature
Downloaded on: 6/2/10 4:16 AM
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183
APPENDIX
can be below the boiling point at the prevailing atmosphere, i.e., operation is under vacuum. This is not an
acceptable practice for the production of WFI quality water because of the potential for air leak into the
system. In addition, a low temperature, below that considered sanitary, is unacceptable.
The top temperature is dependent on the pressure of the heating steam, normally 100-125 psig, while the
bottom temperature is dependent on the condenser pressure, which is normally 7-10 psig.
The temperature range and equipment cost limit the number of effects that are justifiable. The fixed charges
for additional effects ultimately dissipate the savings in energy. It is important to note that there is a certain
amount of variety in the designs of multiple effect distillers, and that although their geometry may differ, they
are thermodynamically all the same. The larger the output of the system and the higher the cost of steam, the
more economically justifiable it is to increase the number of effects.
Typical ME systems have 3-5 effects, and some have as many as 8 effects.
11.6.4
Non-Condensable, Venting, and Deaeration
Non-condensable gases such as carbon dioxide and oxygen are dissolved within the feedwater and become
liberated as the temperature of the water increases. These gases, if they are not removed, have two detrimental effects on distillation units. Since the gases are non-condensable, they can blanket the heat transfer
surface and inhibit heat transfer in the condenser and evaporator. This translates into reduced output. In
addition, these gases are corrosive and will contribute to the pitting, embrittlement, and cracking of stainless
steel. For these reasons, it is imperative for designers and operators to ensure proper and adequate venting
of the distilling unit.
The steam carries non-condensables that are liberated from the raw water during evaporation. The gases do
not travel alone and will not be vented without the associated steam.
There are two characteristics of non-condensable liberated by ordinary waters which allow designers to
locate and vent these gases from an evaporator or condenser. Oxygen and carbon dioxide are significantly
heavier than the associated steam, and therefore collect mostly at the bottom. Additionally, non-condensable
gases tend to migrate to the coldest surface they can find.
Considering the points above, the gases liberated in each effect are processed through the bottom of each
effect with the distillate and make their way to the final condenser which is vented along its length. Operators
should ensure that a steady stream of steam is exiting the distiller vent at all times. Improper venting and/or
a malfunctioning distillate level control can result in CO2 being pulled into the distillate pump suction and
processed across the conductivity cell, resulting in high conductivity reading.
11.6.4.1
Deaerator (also called Decarbonator)
This Document is licensed to
All feed waters have dissolved gasses the amount of which depends on water temperature, composition, and
pH. The latter is dependent on the type of pretreatment used. Other gasses occur due to the breakdown of
some of the constituents during heating, as is the case of alkalinity.
Mr. Shlomo Sackstein
It is very desirable, whenever practical, to remove
the gasses from the feed waters prior to entry into the
Herzlia,
evaporator in order to minimize corrosion and to improve heat transfer. This is often done in VC distillers,
where a deaerator is installed between
feed heater and 216389
the evaporator. Because of the configuration and
IDthenumber:
relatively high operating pressure of the ME, it is difficult to incorporate a deaerator within the system. A
stand-alone deaerator will be costly, and therefore is not included.
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A typical VC deaerator consists of a cylindrical tower in which stripping steam and feedwater flow counter
current to one another. Prior to entering the deaerator, the feedwater has been pre-heated in the blowdown
cooler, distillate cooler, and feedwater pre-heater. As the temperature of the feedwater increases, the non-
184
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
condensable contained within the feed have a greater tendency to become liberated. Entering the deaerator
at a temperature greater than 93°C, the feedwater is sprayed through a nozzle, which disperses the water in
the shape of a cone to maximize the contact area with the counter current stripping steam. The majority of
gases within the feedwater are liberated at this point, and are vented to atmosphere. The evaporator vent is
the source of the stripping steam which provides additional heating to the feedwater, prior to entering the
evaporator. Deaerators are usually constructed of stainless steel.
11.6.5
Typical Water Analysis
The table below provides typical water analysis of a feed source for a high-purity water distillation system,
and is used to compare pretreatment and operating cost for a 5-effect ME with a VC.
Feedwater Analysis City of Ocala, FL. Plant Effluent
Constituent
mg/l
Constituent
mg/l
Constituent
mg/l
Constituent
mg/l
Calcium
38
Fluoride
0.7
Nitrate
1.1
Zinc
0.026
Chlorine
13
Iron
0.026
Sodium
8.1
Carbon Dioxide
0.2
Magnesium
14.0
Sulfate
111
pH
8.2
Bicarbonate, HCO3 1.2
TDS
157
High Purity Water Production Costs
600 GPH of high purity water at 82°C
Consumables
600 GPH of high purity water at 30°C
5MEF
VC
5MEF
VC
Steam in lbs/hr
1,471
700
1,471
180
Electricity (kw)
1.5
26.5
1.5
26.5
--
17,520
--
17,520
32,143
--
32,143
--
Regenerant in lb/yr
Acid in lb/yr
This Document is licensed to
Caustic in lb/yr
Cooling Water in gpm
30,917
--
30,917
--
18
--
32
--
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Downloaded on: 6/2/10 4:16 AM
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185
APPENDIX
Associated Costs
Steam ($/year)
Electricity ($/year)
5MEF
VC
5MEF
VC
$79,802
$37,975
$79,802
$9,765
$736
$13,000
$736
$13,000
Regenerant ($/year)
$876
$876
Acid ($/year)
$1,928
$1,928
Caustic ($/year)
$4,019
$4,019
Cooling Water ($/year)
$1,513
$2,688
Running Cost ($/year)
$87,998
$51,851
$89,173
$23,641
Running Costs in US$/1000 gallons
$20.95
$12.34
$21.23
$5.63
The above figures are based on 7000 hour per year operation and the following utility and consumables’ costs
in US dollars:
Steam
$7.75 per 1000 lbs
Electricity
$0.07 per kWh
Sodium Hydroxide
$0.13 per lb
Renerant-brine
$0.05 per lb
Hydrochloric Acid
$0.06 per lb
Cooling water
$0.20 per 1000 gal
For costs of consumables, which are different from those used above, calculations can be made by substituting other values.
11.6.5.1
Comparisons
ME can be used as a standby clean steam generator; VC cannot be used because of the lower steam
pressure.
Pretreatment: VC does not require as much pretreatment as ME. See Baseline pretreatment in the main
chapter.
This Document is licensed to
Size Selection: The cost of the VC does not scale down as well as the ME. VC is not offered in less than 100
gph, and equipment cost is most competitive with ME in the 300 gph and above.
Mr. Shlomo Sackstein
For a hot (80°C) system, an 8-effect ME willHerzlia,
approximately match the thermal economy of a VC. For an
ambient system, it takes 24 effects to match the economy of VC. Obviously, such number of effects is not
practical.
ID number: 216389
Chlorine Attack: Although the VC still is much more forgiving because it operates at lower temperature, it
also is subject to stress corrosion cracking caused by the chlorine. However, at very low chlorine levels, the
problems may not appear until after years of operation.
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At the relatively high temperature of the ME, the attack is very rapid, and failure may occur in weeks or
months.
186
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APPENDIX
11.7
CLEAN STEAM - CLEAN STEAM GENERATORS
Pharmaceutical steam systems including the generator are relatively simple in design, construction, and
operation. Yet, many users can benefit from a better knowledge of factors which contribute to an optimum
baseline system.
11.7.1
System Selection and Design Considerations
11.7.1.1
Sizing the System
A generator designed to deliver the maximum output at a relatively high clean steam pressure will deliver
significantly more steam at the lowest pressure and vise versa.
This appears to be an advantage and often is; however, there can be problems if the performance is not well
understood and is taken into consideration at the design stage and later during operation. The following
example best illustrates the performance of the generator and the advantages and disadvantages.
Example
A generator is sized to deliver 2000 lbs/hr (909 kgs/hr) clean steam at 60 psig (4.2 kgs/cm2 gauge), utilizing
plant steam at 120 psig (8.43 kgs/cm2 gauge). Operating at a reduced level of 30 psig (2.1 kgs/cm2 gauge)
clean steam pressure and assuming 5 psi (0.35 kgs/cm2) pressure drop across the steam control valve.
Net steam pressure to evaporator =120 - 5 =115 psig (8.08 kgs/cm2), (347.3°F (175.17°C) saturated temperature)
CS temperature @ 60 psig = 307.63°F (153.13°C)
CS temperature @ 30 psig = 274.46°F (134.7°C)
Temperature difference available for clean steam generation,
∆ T @ 60 psig = 347.3 - 307.63 = 39.67°F (22°C)
∆ T@ 30 psig = 347.3 - 274.6 = 72.7°F (40.5°C)
The amount of steam produced, lbs/hr, W = U x A x ∆ T
Where: U = heat transfer coefficient in Btu/hr/ft2/°F and A = CS evaporator surface area in ft2
Since the heat transfer surface is fixed, and the change in the heat transfer coefficient is negligible, the
amount of clean steam produced is directly proportional to the temperature difference.
The amount of clean steam produced @ 30 psig compared to that produced at 60 psig at the same plant
steam pressure is: lb/hr of CS @30 psig = (72.7/ 39.67) x 2000 = 3,665 lbs/hr (1666 kgs/hr), or 183% of that
at 60 psig (4.2 kgs/cm).
This Document is licensed to
Specific volume of steam @ 60 psig = 5.818 ft3/ lbs.
Mr. Shlomo Sackstein
Total volume of 60 psig steam = 5.818 x 2000Herzlia,
=1,636 ft /hr and specific volume @ 30 psig = 9.403 ft /lbs.
Total volume of steam @ 30 psig = 9.403
* 3665 = 34,462 lbs/hr,
or 296% of that @ 60 psig.
ID number:
216389
3
3
Since the steam passage areas including the separator have not changed, the velocity of steam increases
approximately 300%.
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If this increase is not anticipated and planned for at the design stage, there can be a potential for carryover of
contaminants through the separator due to the higher steam velocity.
For individual use only. © Copyright ISPE 2001. All rights reserved.
187
APPENDIX
See the following table to determine the output change at different plant and CS steam pressures.
To use the table follow the above example.
•
Find the temperature difference for the current and desired operating pressures.
•
Calculate ratio of New/Current and multiply the current output by the ratio. If the current output is not
known, use 100% to obtain the percentage change.
In addition to the high velocity and carryover considerations, operating at a temperature difference above
70°F (21°C) is not recommended without consulting the CS manufacturer.
At high temperature difference, a heat transfer phenomenon called “dry wall condition” can occur. Simply put,
the steam, in this case, is that much hotter than the water on the other side of the heat transfer surface, that
the surface cannot be maintained wet. It is not unlike throwing drops of salty water on a very hot stove. The
water evaporates instantly leaving behind a residue (scale). The problem is more of a concern when the CS
feed water has relatively high TDS, such as with softened water. The example above with 72.7°F (22.6°C)
temperature difference would not be recommended.
The opposite of operating with high pressure/temperature differential is operating with very low differential.
For a CS generator producing 2000 lbs/hr (908 kgs/hr) @ 30 psig (2.1 kgs/cm2 gauge) clean steam and 120
psig (8.4 kgs/cm2 gauge). Plant steam, the output drops to 54.6%, or 1091 lbs/hr (495.3 kgs/hr).
Temperature and Pressure Difference between Plant Steam and CS Steam
Clean Steam
PLANT STEAM PRESSURES AND TEMPERATURES
P
Temp.
50
55
60
65
70
75
80
85
90
95
100
105
110
115
Psig
°F.
298
125
130
25
267.3
30.74 35.70 40.37 44.81 49.03 53.05 56.90 60.60 64.15 67.56 70.86
NR
NR
NR
NR
NR
30
274.5
23.54 28.50 33.17 37.61 41.83 45.85 49.70 53.40 56.95 60.36 63.66 66.84 69.93
NR
NR
NR
NR
35
281.0
16.97 21.93 26.60 31.04 35.26 39.28 43.13 46.83 50.38 53.79 57.09 60.27 63.36 66.34 69.24
NR
NR
40
287.1
10.90 15.86 20.53 24.97 29.19 33.21 37.06 40.76 44.31 47.72 51.02 54.20 57.29 60.27 63.17 65.98 68.72
45
292.7
05.27 10.23 14.90 19.34 23.56 27.58 31.43 35.13 38.68 42.09 45.39 48.57 51.66 54.64 57.54 60.35 63.09
50
298.0
04.96 09.63 14.07 18.29 22.31 26.16 29.86 33.41 36.82 40.12 43.30 46.39 49.37 52.27 55.08 57.82
55
303.0
60
307.6
65
312.1
70
316.3
75
320.3
80
324.2
303 307.6 312.1 316.3 320.3 324.2 327.9 331.4 334.8 338.1 341.3 344.4 347.4 350.3 353.1 355.8
04.67
NR
9.11 13.33 17.35 21.20 24.90 28.45 31.86 35.16 38.34 41.43 44.41 47.31 50.12 52.86
This Document is licensed to
4.44
8.66 12.68 16.53 20.23 23.78 27.19 30.49 33.67 36.76 39.74 42.64 45.45 48.19
4.22
8.24 12.09 15.79 19.34 22.75 26.05 29.23 32.32 35.30 38.20 41.01 43.75
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
4.02
7.87 11.57 15.12 18.53 21.83 25.01 28.10 31.08 33.98 36.79 39.53
3.85
7.55 11.10 14.51 17.81 20.99 24.08 27.06 29.96 32.77 35.51
NOTE: Plant Steam Pressure Is Downstream of Steam Control Valve.
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188
120
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APPENDIX
11.7.1.2
Feed Water Pressure and Pump
The feed pressure is typically 8-10 psi (0.5-0.7 kgs/cm2) above the clean steam pressure, which is typically
30-60 psig (2.1-4.2 kgs/cm2 gauge, a feed pressure range of approximately 40-70 psig (2.8-4.9 kgs/cm2
gauge). Most CS generators have outputs of less than 4,000 lbs/hr (1,816 kgs/hr). Many have outputs of less
than 1,000 lbs/hr (450 kgs/hr). That is a feed rate of slightly more than 2 gpm (7.5 l/min).
The sanitary centrifugal feed pumps favored by the pharmaceutical industry will be operating near shutoff
head at flow rates of less than 10 gpm (38 l/min), particularly with very small generators. Installing pump
circulation loops complicates piping, and under certain scenarios may call for installing a heat exchanger to
address temperature buildup. This adds undue complexity. Consider the possibility of feeding the generator
from an existing source with sufficient pressure. The dedicated pump, even at very low flow rate, is most likely
the next best option.
11.7.1.3
Feed Water Contact Surfaces
It is common that users specify mechanical and electropolish and sanitary clamp connections for piping, heat
exchangers, and vessels in contact with the feed water although such features are not necessary for achieving the desired clean steam quality.
Often, the reason given for such requirements is attributed to having the feed to the CS piped from the WFI or
USP Purified Water loop. Such practices rule out the use of the less costly Simple CS Generator which
otherwise may be acceptable.
Consider the economics of the proposed feed source at the selection stage. If WFI or USP Purified is the
most logical source, consider the possibility of using an atmospheric break or sanitary backflow preventers
so that the CS does not become an extension of the source loop.
11.7.2
Utilities
Plant Steam Flow Rate, lbs/hr: Make provisions for 110-120% of the maximum expected clean steam
production. Generators with feed heaters and low TDS feed water will use closer to the 110% rate, and those
without feed heaters and with high TDS (high blowdown rate) will use closer to the 120% rate.
Plant Steam Pressure should be nominally 50-60 psig (3.5-4.2 kgs/cm2 gauge) above the clean steam
pressure. See (1) above.
Feed Water Rate: With very low TDS, DI, or equal water, the typical feed rate is 105%-110% of the CS
production rate depending on the size of the generator.
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With higher TDS feed water, the blowdown rate is increased to lower the concentration of salts. The feed
varies and often is 115%-120% of CS rate.
Electric Power: Other than controls, the only power requirement is for the feed/booster pump when used.
Since almost all CS generators require relatively small flow rates, the power requirement is mainly dependent
on the boost pressure. Motors will vary from 2-5 horsepower. (1.5-3.75 kW).
Mr. Shlomo Sackstein
Herzlia,
Instrument Air: 80-100 psig (5.6-7.0
kgs/cm
gauge) instrument
air is required for systems with air operated
ID
number:
216389
2
controls.
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189
APPENDIX
11.7.3
Periodic Cleaning and Derouging
It is common for CS generators and other stainless steel equipment used in high purity steam and water
applications, to develop rouge or scale. Some of the cleaning chemicals can be very harsh and may etch the
stainless surface. The extra cost on electropolishing becomes wasted after one harsh cleaning. When contracting an outside service to perform the cleaning and any subsequent passivation, ensure chemicals used
do not cause etching. It is common to avoid passivation with nitric acid if the surface is electropolished, using
citric acid and ammonium citrate.
11.7.4 Conductivity Monitoring
The conductivity of the CS condensate sample on a system with relatively high feed conductivity is an indication of carryover through the separator. Therefore, it serves as a good on-line warning that pyrogens may be
present. When the CS generator is operating on high purity DI feed water, the monitoring of CS sample
conductivity or resistivity is meaningless; especially if the conductivity is lower than the limits set in the USP.
In order to verify that the separator system works as intended, it would have to be challenged. Sodium sulfite
or other non-chloride-based salt can be injected in the feed to determine the corresponding product conductivity. Recommended salt concentration in the feed is 150-200 mg/l. Based on approximately 10% blowdown,
the concentration inside the CS will be 1,500-2,000 mg/l. The test is recommended after fieldwork or cleaning
which may involve the disturbance of the separator system.
11.8
MICROBIAL CONTROL BASICS, TESTING, AND STERILIZATION SANITIZATION
EQUIPMENT DESIGN AND INSTALLATION ISSUES
11.8.1
Bacteria in Pharmaceutical Water Systems
11.8.1.1
Background
Various types of bacteria can be found in the feedwater to purified water systems. Among the ways that these
bacteria can be classified is Gram positive or Gram negative, which is based on their retention of a dye after
a staining and washing procedure. The results of the Gram test are dependent on cell wall structure, and
therefore indicative of many other characteristics.
Most aquatic bacteria are Gram negative, and bacteria commonly found in purified water systems are generally Gram negative because Gram positives cannot thrive on extremely low nutrient levels. Gram negative
bacteria are more heat sensitive than Gram positives, and cannot proliferate at temperatures above 60°C.
However, the possibility of Gram positive organisms in the system cannot be completely ruled out, and the
sanitization and testing procedures should take this into account.
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Bacteria generally range from approximately 0.5 µm to 5 µm. The rod-shaped Pseudomonas diminuta, which
is used for challenging sterilizing filters, has a minimum dimension of approximately 0.3 µm.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
When Gram negative organisms are killed they release endotoxins; lipopolysaccharide molecules which
cause a fever when injected into the bloodstream. Because they cause fever, these substances are termed
“pyrogens,” meaning generating heat. These substances also have been linked to much more serious reactions when introduced into the blood stream, including lethal septic ‘shock’. They are a major concern in
products intended for injection and may be a concern in other non-oral dosage forms such as transdermals.
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Bacteria have a tendency to attach to surfaces and form biofilms. Biofilms form an external polysaccharide
layer. This external film protects the bacteria from antimicrobial agents and makes them much more resistant
to sanitization procedures. In addition, disinfection of the biofilm does not necessarily remove it from the
190
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APPENDIX
surfaces. Since the dead biofilm provides nutrients and attachment points for new biofilm, its removal must be
considered when developing a sanitization strategy. Biofilms are difficult to detect since water samples are
used to measure free floating (planktonic) bacteria, and these bacterial counts do not directly correlate to
biofilm concentration. Prevention or removal of biofilms can be affected by the various continuous and periodic microbial control methods described in this chapter; however, once a biofilm has developed, the severity
and frequency of the microbial control techniques may need to be significantly increased.
11.8.1.2
Microbial Levels in USP Purified Water and Non-Compendial Water
Most techniques for measuring microbial populations in a water sample require a time delay of two to three
days, and they do not yield an exact value. For this reason, the USP monograph for purified water does not
contain a microbial limit. Instead, alert and action level guidelines must be established by the end user. The
USP informational chapter discusses the need to match the microbial quality of the purified water to the end
use. An action level of 100 CFU/ml is suggested in the USP, and the FDA Guide to Inspection of High Purity
Water Systems states that any action level over 100 CFU/ml is unacceptable.
Since actual microbial counts are dependent on the method and technique of counting, the specifications for
alert and action levels should be based on an understanding of the method, including time, temperature, and
media. What may be more important than the total count is a continuous monitoring program that indicates
trends before they become a problem. It also is important to identify the specific contaminants in addition to
the total count. The water system should not add objectionable organisms to the final drug product. Objectionable organisms are defined in the FDA Inspection Guide as “any organisms that can cause infections
when the drug product is used as directed, or any organisms capable of growth in the drug product.”
Alert levels are set according to a statistical review of data to reveal those results that are above the normal
operating range of the system, and are generally used to initiate an investigation with the objective of detecting and resolving problems before the action limit is reached. It should be noted that action levels are not
pass/fail tests. These are levels which indicate that a problem exists and the problem must be investigated
and an appropriate corrective action taken.
11.8.1.3
Microbial Limits in WFI
According to the USP, Water For Injection is “intended for use in the preparation of parenteral solutions.” The
monograph makes no specific reference to a bacterial limit. WFI is generally expected to be free of microorganisms. Since some microbial contamination may be encountered during sampling, an action limit of 10
CFU/100 ml is commonly specified. The presence of any amount of bacteria in a WFI system is cause for
concern and should be investigated.
The bacterial requirement which is explicitly stated on the monograph is for bacterial endotoxin. The USP
endotoxin limit for WFI is 0.25 EU per ml.
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Even bacteria which are destroyed quickly within the storage and distribution system will release endotoxin.
Therefore, it is imperative that the treatment system removes bacteria before they get to the distribution
system, rather than relying on protection measures within the distribution system (such as heat) to remove
bacteria.
Mr. Shlomo Sackstein
Herzlia,
Although bacterial contamination in a WFI system will lead to the proliferation of endotoxin, it may be possible
to pass an endotoxin limit, but not ID
a bacterial
limit so both216389
tests should be performed. An endotoxin level
number:
cannot be directly correlated to a bacteria count.
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11.8.2 Testing and Documentation
Microbial control in high purity water systems relies heavily upon the use of instruments that directly monitor
the control parameters (e.g., temperature indicators, ozone monitors, UV intensity meters). However, microbiological monitoring is necessary to assure that the intended water quality is met at the system use points.
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191
APPENDIX
Microbiological monitoring is performed by removing a sample of the water at designated sample ports in the
system and performing a heterotrophic plate count. For systems in which endotoxin must be controlled (i.e.,
WFI), a Limulus Amebocyte Lysate (LAL) test also is performed. The heterotrophic plate count requires
laboratory manipulation (e.g., filtration/ plating), incubation, and reading, which require several days before
results are available. Identification of bacteria found will take considerably longer. Therefore, a documentation
system needs to be in place so that a correlation can be made between results and the system operating
information at the time of sampling (such as the sanitization logs, flush logs, data from system operation
records, the identification of the sampling technician, etc.)
11.8.2.1
General Testing Considerations
An initial, more intensive sampling program will be undertaken as part of the validation effort, and is discussed in Chapter 10 and in the Commissioning and Qualification Guide. This section focuses on ongoing
microbial sampling and monitoring after the system has been placed in production.
All use points in the distribution loop should be represented in a monitoring regimen. Testing of the water
being supplied to the loop, prior to dilution in the distribution tank, provides important information on the
efficacy of the purification system. For WFI or other water with endotoxin limitations, LAL testing is typically
performed concurrently with the heterotrophic plate count. The water system is typically tested daily with
individual sample ports being rotated through to include each point over a specified period. The specified
period between samples for any given use point must be based on historical data. Sampling each point every
week has generally been found acceptable by the FDA. With smaller systems, this may result in only one
sample from the system on any day. Although it would be more costly, sampling multiple points each day can
provide useful information about the system. For example, if one sample is found to be unacceptable, and
there were no other samples taken on that day, it is difficult to know if the problem is from the use point, or
throughout the system. However, if many samples were taken and only one use point had a problem, the
quality of water from the remaining use points can be defended. The sampling performed should simulate the
production use of that water. For example, water used through a hose should be sampled through the same
hose. The flush performed prior to sampling (if any) should reflect the flush used prior to production use.
Procedures for sampling and testing must adhere to aseptic technique to ensure that contamination is not
introduced.
The quantity of water used for analysis is a minimum of 1 ml for purified and non-compendial, and 100 ml for
WFI, according to the USP. Larger quantities such as 100 ml for purified and 250 ml for WFI are recommended.
11.8.2.2
Testing Documentation
Sampling procedures should be delineated in an approved protocol (SOP). Testing methods also should be
specified in an approved SOP. This would include the equipment and materials to be used, the procedures,
growth promotion testing of the media, and negative controls. Procedures for performing the heterotrophic
plate count are delineated in the latest edition of Standard Methods for the Examination of Water and Wastewater. Note that organisms in pharmaceutical water will have adapted to a low nutrient environment, and a
standard growth media may shock the organisms and result in erroneously low counts. Therefore, a low
nutrient media may be more appropriate for the testing. All testing should follow a validated procedure. All
methods, compendial or otherwise, should be shown to be effective on the particular system being tested.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
For new or modified systems, sampling
testing should be
completed as part of a Performance QualificaIDandnumber:
216389
tion (PQ). The PQ should provide an overview of the system or the modifications and delineate the monitoring
program (the sample ports, frequency of testing, type of testing performed, relevant SOPs, etc.). When completed, the PQ should include testing results, investigations of Out Of Specification (OOS) results, special
study results (such as a sanitization frequency study), a section for any deviations, and a summary report.
The sampling regimen should include samples taken immediately prior to sanitization in order to exhibit worst
case conditions.
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APPENDIX
Following qualification, testing must be performed routinely in order to ensure that microbiological control is
maintained. The documentation system must provide ready access to test results.
11.8.2.3
Analysis of Results
The primary purpose of reviewing test results is to reveal OOS findings to ensure product is not jeopardized
and so that correction can be made. The identification of the organisms found is an important part of the
investigation since this will provide strong evidence of the source of contamination. For example, Staphylococcus is typical of sample handling problems; Bacillus is typical of environmental contamination of the
sample port, and Gram negative rods are typical of water borne contamination. Follow-up sampling performed in reaction to the OOS result would be included in the investigation.
11.8.3
Sterilization/Sanitization Designs
Various designs may be incorporated to facilitate heat sanitization of process water distribution systems.
In this section, two designs for sanitization are considered:
•
Hot Pharmaceutical Water (80°C) System
•
Ambient Pharmaceutical Water System
a) See Section 11.4.4.4 on Pretreatment Processes - Control of Microbiological Growth earlier in this chapter.
The boundaries for this design will be defined for each of the two designs set forth.
The systems described are based on designs that have been found acceptable in a number of installations.
It is recognized that a wide variety of system designs may meet the same objectives and also prove acceptable from a regulatory and operations standpoint.
11.8.4
Hot System Distribution Loop
In this system, the boundaries begin with the storage vessel and include pumps, distribution piping (all drops)
and the return loop that terminates at the storage vessel.
The storage vessel should be a fully jacketed vessel with the capability of heating and cooling. Heating of the
storage vessel is usually achieved with steam. Cooling, when required, is achieved with chilled or cooling
tower water.
It has been found that a hot distillation system has a tendency to build heat when the effluent from the still is
discharging into the tank. The effluent may be as high as 96°C. If the water is too hot, the distribution pump
may cavitate or boiling will occur in the pump. In addition, the system may be more susceptible to “Rouge”
when water is kept at temperatures exceeding 87°C.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
When the system is down for maintenance
or repairs or modification,
ID number:
216389 it will be necessary to sanitize the
A hot system is generally considered to be self sanitizing as long as the temperature of the circulating water
is maintained between 75°C and 85°C.
system to bring down the microbiological load and to reduce the pyrogen burden.
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The method used with hot systems is to flush the system, all sampling points, and all points of use with hot
(80°C) water. The quality of the flush water must be at least as good as the water to be used in the system.
Flushing with two to three volumes of the water in the distribution system should achieve sanitization. If
sanitization is not achieved, then flushing must be continued and the source of the contaminant removed.
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193
APPENDIX
The heating medium may be hot liquid or steam. It should be designed to heat the ambient process water
from 15 to 80°C within a specified period (generally two to four hours).
If the heating and cooling heat exchangers are not directly installed in the return loop, process water should
pass through when not in use for heating, eliminating the possibility of a dead leg.
Most systems can be fully sanitized with 80°C circulating process water within two to three hours once 80°C
process water temperature is achieved.
As a safety note, all exposed piping and storage tank surfaces should be insulated to prevent accidental
burning of personnel in the heat sanitization cycle. In addition, the points of use must be monitored during the
entire sanitization cycle.
11.8.5
Cold System
The boundaries are the same as a hot system. A by-pass line may be provided to recirculate process water
through the pretreatment train to avoid stagnant flow conditions.
Sanitization of a cold system may be accomplished using hot water using two stainless steel double tube
sheet heat exchangers, one for cooling and one for heating.
The heat exchanger used for cooling is typically installed after the distribution pump(s). The heat exchanger
used for heat sanitization is usually installed on the return loop just prior to the return to the storage tank.
One heat exchanger to heat and cool the process water is a viable alternative, but should be designed for the
more extreme temperature range.
The heat exchanger for cooling may be cooled with cooling tower water, chilled, or domestic cold water. The
cool down cycle should be designed to cool 80°C process water to approximately 15°C over a specified
period (based on the operational needs). The initial cooling should be very gradual to prevent thermal shock.
11.8.6
Ozone System
Ozone (O3) is a naturally occurring triatomic form of oxygen. O3 is unstable at atmospheric temperatures and
pressures, and decomposes readily into molecular oxygen (O2).
There are no objectionable by-products or residues when water is disinfected with ozone. The presence of
oxidizable substances will generate trace carbon dioxide and in the absence of oxidizable substances, only
oxygen will be formed.
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Very low concentrations of ozone of the order of 0.1 to 0.2 mg/l have been shown to control microbiological
growth to below 1 CFU/100ml.
Due to the limited half life, ozone must be produced on-site where it is required.
Mr. Shlomo Sackstein
11.8.6.1
Materials of Construction
Herzlia,
Few organic materials are unaffected
contact. Gaskets,
piping, vessels, filters, and ion exchange
IDby ozone
number:
216389
resins may be subject to attack, and therefore all materials that come in contact should be specifically selected.
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PVC will be attacked by ozone, but PVDF and PTFE are not so vulnerable.
Stainless steels that may be pitted by Chlorine resist ozone. Thus, ozone will not damage stainless steel stills
and will be removed in the distillation process.
194
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APPENDIX
11.8.6.2
Comparisons with Chlorine
Chlorine is relatively stable in water and is not described by any half-life characteristic.
Ozone has a relatively short half-life depending on temperature and pH. At neutral pH and 20°C, this can be
two hours in high purity water. Multiple feed points can reinforce the concentration of ozone in a very large
distribution system.
Removal of chlorine and many of its bi-products are comparatively difficult to remove. Absorption by activated
carbon or reaction with bisulfite are the common methods used, each having its own specific problems.
Chlorine may convert many organic substances into derivatives that have been identified with carcinogenicity.
Ozone reverts to oxygen and/or carbon dioxide.
Chlorine requires diffusion through the cell walls of the organism in order to degrade enzymes. Tests indicate
that chlorine required more than 400 hours at a concentration of 0.1 mg/l to destroy 99% of 60,000 CFU of E.
Coli.
Ozone, when added to water using an efficient mixer, kills bacteria in seconds. At an equivalent CFU level to
the chlorine test, ozone will destroy more than 99% in less than one minute.
11.8.6.3
Ozone Generation
There are two commercial methods to manufacture ozone: corona discharge and electrolytic generation.
The corona discharge method uses an air/oxygen feed. It produces acceptable quality ozone for pharmaceutical purposes if the feed stream to the generator is sufficient low in nitrogen and moisture to avoid production
of harmful level of nitric acid. Excessive levels of nitric acid in the ozone effluent can drop the pH and conductivity of the water below acceptable levels and promote corrosion of stainless steel surfaces. Pharmaceutical
design typically employs a dryer and a molecular sieve to reduce nitrogen and moisture from the instrument
air.
The other commercial method of ozone production is electrolytic generation. Low conductivity water is used
as the feed stream to a catalytic generation cell. Electrolytic ozone generators can be operated directly
immersed in a side stream of the water circulating system or can be used to produce a gas first and then be
transferred to the water using a conventional contractor device.
Electrolytic generators typically produce lower contamination levels than corona discharge units, but are
generally more capital cost intensive. Both can be operated successfully when designed and maintained
properly.
This Document is licensed to
11.8.6.4
Ozone System Installation
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
The optimum location for ozone injection is in the loop return, just before it re-enters the storage tank.
To ensure ozone does not contaminate the pharmaceutical product, it may be removed shortly before the first
“point of use.”
Ozone destruction can be accomplished by various technologies including:
•
Catalytic
•
Thermal
•
UV
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195
APPENDIX
•
Chemical
•
Time (half life in solution is 20 to 100 min.)
UV will destroy ozone in solution and catalytic destruct units will destroy the “off gases.” Ozone monitoring is
required as follows:
•
in solution prior to the ozone destruction
•
following the ozone destruction
•
return line to the storage tank
•
return ozone levels from loop piping during sanitation sequences
•
ambient air surrounding the system
Standard germicidal UV units with a high UVC (UV within the wavelengths of 220 to 290 nm) output using
low-pressure mercury lamps are ideal for reducing ozone in pure water.
The combination of ozone and UV is claimed to produce an oxidizing process more powerful than ozone
alone.
11.8.7
UV Light
See Section 11.4.4.4C on Pretreatment Processes - Control of Microbiological Growth - UV Light earlier in
this chapter.
11.8.7.1
Ultraviolet Lights
Flowing water may be exposed, at a controlled rate, to ultraviolet light waves. With proper maintenance, UV
systems are simple and reliable, generating a high reduction in bacteria (99% plus) when operating at 254
nm wavelengths. However, the feedwater to a UV needs to be free of suspended solids which can “shadow”
bacteria, preventing adequate UV contact. Therefore, it is only effective if there is direct light contact with
microbes.
Two different types of mercury vapor arc tubes generate UV light: low pressure and medium pressure. The
pressure designation refers to the amount of gas pressure inside the particular arc tube. Low pressure is near
a vacuum and generates a narrow wavelength band in the 254 nm range. Medium pressure arc tubes, near
1 atmosphere or slightly positive displacement, generate wavelengths ranging from 180 to 365 nm. The peak
germicidal efficiency for UV light is between 254 and 265 nm.
This Document is licensed to
11.8.7.2
Design and Installation of UV Lights
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Water from a storage tank can be recirculated through UV light systems so that the entire system volume of
the tank is treated. This results in multiple passes of the entire tank volume through the UV. This increases the
overall cumulative dose and prevents reinfection in the storage tank. The minimum recycle rate to maintain
disinfection is between 4-6 times per hour.
When specifying or designing a UV unit, temperature conditions of the water must be taken into account.
Conventional UV units have a maximum temperature limitation of 120°F (48.9°C) and require special cooling
arrangements to withstand temperatures up to 150°F(65.6°C). Medium pressure units can withstand much
higher temperatures up to 212°F (100°C) if necessary.
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APPENDIX
Pressure limitations also need to be recognized. Most UV units have a operating pressure limit of 100-120
psi. High pressures require special arrangements, such heavier flanges or an ASME code stamp.
Most UV units are installed in a horizontal position to eliminate air pockets; however, consulting the manufacturer for their recommendations is appropriate.
A log reduction target should be specified when purchasing a unit.
All wetted parts should be similar to the storage and distribution system specifications.
The use of UV units does not negate the need for periodic sanitization of the system.
The specified dosage should be obtained even at the end of lamp life, as all UV lamps degrade and lose
germicidal efficiency over time. The units should be sized so that a safety margin is built in so that even at the
end of the lamp life (EOL), the minimum dose requirement is always exceeded.
11.8.7.3
UV Light Dosage and Sizing Requirements
Proper UV dosage measured in milli-watt seconds per square centimeter at the chamber wall determines the
performance of a UV unit in storage and distribution systems. Each microorganism has been assigned a kill
dose, known as D10 that produces a 1 log, or 90% kill rate. E. Coli, for example, has a D10 of 3 milli-watt
seconds per square centimeter. This gives a 1 log reduction. To achieve a 3 log reduction, a dose of 6 milliwatt seconds is required. Most pharmaceutical water systems require at least a minimum of 30 milli-watt
seconds per square centimeter dosage to maintain germicidal effectiveness.
The following factors are involved in the selection of a UV unit to obtain satisfactory performance in storage
and distribution systems:
•
Flow-rate - The units must be sized to handle the maximum flow possible from the system.
•
Water quality is critical to the success of a UV unit’s performance. Whenever possible, a water sample
should be obtained, and the water checked for UV transmission through a UV spectrophotometer. UV
absorbing compounds such as iron, manganese, dissolved organics, turbidity, or suspended solids all
affect germicidal efficiency. Although in the storage and distribution systems, only the dissolved organics
should be seen.
•
Identification of microorganisms and concentrations also affect sizing. If there is a high concentration or
multiple organisms, this could dictate a larger UV unit.
•
Temperature of the water also affects the choice of UV units. Low pressure units have specific temperature limitations, while medium pressure units do not. In very cold (5-10°C) or hot water systems (above
45°C) the arc tube efficiency is greatly reduced.
•
Whenever possible water in storage tanks or distribution loops should be recirculated through the UV
unit. The ideal rate would be a minimum of four times per hour for the entire volume of the tank or the
entire volume of the loop.
This Document is licensed to
11.8.7.4
Characteristics
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Conventional low-pressure units usually have multiple lamps in a chamber to achieve the proper amount of
UV energy for germicidal energy. Medium pressure units usually employ a single lamp approach due to the
much higher output of the individual lamp. Each lamp type has advantages depending upon the application.
The lamps are enclosed within quartz sleeves which contact the water. All other wetted parts should be
manufactured from an acceptable inert material, generally 316L SS. UV intensity and frequency should be
monitored continuously and recorded.
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197
APPENDIX
11.9
FABRICATION/PROCEDURES FOR DISTRIBUTION SYSTEMS
11.9.1
Introduction
Fabrication of the distribution system must be made with extreme care and precision to ensure a smooth
internal finish that will not allow any crevices that will support or promote bacterial growth, metal corrosion, or
particulate generation.
The chapter provides an understanding of the requirements of fabrication, materials of construction, and
specialized equipment required to fabricate a piping distribution system.
Decisions concerning the material of construction, the orbital welding, the special handling, and the special
environment required must be made and understood by the pharmaceutical manager responsible for the high
purity water distribution piping fabrication and installation.
Unlike the equipment selection, the piping fabrication will require selections of material with specific compositions, welding using inert gas envelopes, and a cleanroom environment.
11.9.2
Materials of Construction
Material selection should be consistent throughout the distribution, storage, and processing systems. The
material should be rigid, capable of withstanding steam sterilizing temperatures (as required), cleaning solutions, passivation solutions (as required), and capable of maintaining a durable and corrosion resistant surface finish.
The material in common use in pharmaceutical water systems is a stainless metal. Based on cost and ease
of fabrication, this material is nickel chromium steel.
Inert non-metallic materials also are available that can withstand steam sterilization (as required). These
materials are used extensively in the electronics industry for ultra-pure water systems where they have
proved themselves capable of containing and preserving the high level of purity used in the semi-conductor
industry.
11.9.3
Types of Stainless Steel
Type 316L is the preferred steel for a high purity water generation and distribution system. The “L” designation
indicates a low level of carbon compared to the non “L” grade.
Alternates to 316L grades are 317L with its higher chromium and molybdenum contents and 304L with its
higher chromium content but lower nickel and molybdenum levels.
11.9.3.1
This Document is licensed to
Corrosive Resistance
Chromium content is the most important alloying element in stainless steel followed by nickel and molybdenum.
Mr. Shlomo Sackstein
Herzlia,
Steels with chromium in excess of 11.5% will form a protective film of chrome oxide on the metal surface. The
presence of nickel in amounts moreID
than 7%
enhances the216389
corrosion resistance over the straight chromium
number:
grade and improves its ductility.
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The performance of stainless steels is governed by the oxidizing characteristics of the environment, similarly
to the oxidization of ordinary steels. Strong oxidizing conditions generate a superior protective coating for the
stainless steel and a powdery rust on ordinary steels which eventually, if left unchecked, will consume all of
the metal.
198
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APPENDIX
11.9.4
Weldability and Polishability
Austenitic stainless steels such as AISI type 316L contain impurities in addition to the major elements described. These include:
•
Sulfur (S)
•
Aluminum (Al)
•
Oxygen (O)
•
Silicon (Si)
•
Manganese (Mn)
•
Phosphorus (P)
•
Titanium (Ti)
•
Calcium (Ca)
The effects of some of these elements are cumulative inasmuch as the oxygen can offset some of the
welding characteristics of low sulfur steels and the weld penetrations experienced with sulfur may be offset
by high levels of aluminum. In addition, the ratio of the trace elements of aluminum to silicon has been shown
to effect slag formation during welding which in turn produces inclusions.
Manganese has been shown to combine with the sulfur and form manganese sulfide (MnS) inclusions on or
in the surface of the metal.
Even the major element chromium, may contribute toward oxide inclusions in the metal surface.
11.9.4.1
The Impact of Sulfur on Welding and Internal Finishing
Small amounts of sulfur improves machinability as well as weldability; however, with the advent of modern
techniques in the steel refining process, the mills are able to produce steels at a cost with very specific
chemical compositions.
Low sulfur AISI 316L steels when based on the specification limit of 0.03% have some advantages to obtaining an unpitted polish, but other impurities such as manganese, silicon, oxygen, aluminum, calcium, titanium,
and chromium can contribute to the oxide inclusions that we are trying to minimize by reducing sulfur content.
This Document is licensed to
A mid-range sulfur content would be ideal for welding but any mismatch in the sulfur content of the mating
parts will easily outweigh the advantages of low or lower sulfur levels.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
An ideal compromise would be a level between 0.005% and 0.02% or a modified maximum limit of 0.02%
since the lower limit will probably not be attained. However, if not all welded parts can be obtained at similar
levels, the exercise produces very little overall advantage.
11.9.4.2
Heat Number and its Impact on Weldabilty
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Weld parameters will remain consistent and orbital welding processors will reproduce similar welds if the
material remains the same. Since the melting point of steel varies over a range depending upon the concentration of each element present in the steel, the amount of heat required to melt and thus attain the liquefaction of the steel will vary from concentration to concentration.
For individual use only. © Copyright ISPE 2001. All rights reserved.
199
APPENDIX
Each “melt” of steel is assigned a “Heat Number” to identify the mix or exact composition of the steel.
316L stainless steel has a wide tolerance of “active” elements such as chromium, molybdenum, nickel, and
carbon which vary as much as 100% and as little as 12%. These variations will change the melting point and
the electrical current input of the welding machine considerably.
While the “Heat Number” can be specified for all tubing purchased for a specific distribution system, the heat
number for connected fittings and valves are more difficult to control.
Where possible, all fittings, valves, tubing, and weldable pieces of the same nominal size (diameter) should
be purchased and manufactured from AISI 316L steel with the same Heat Number in order to standardize the
weld quality for each tubing size.
11.9.5
Corrosion Hazards of Stainless Steels
While being protected by the chrome oxide film, which will guard against most corrosive attacks, there remains five corrosive hazards associated with the successful use of stainless steels.
a) Intergranular Corrosion
Austenitic 300 series stainless steels which do not contain any of the stabilizing elements, titanium, or
columbium are susceptible to intergranular corrosion which can cause early failure or reduced life.
b) Galvanic Corrosion
Occurs when an assembly of dissimilar metals is immersed an any solution which acts as an electrolyte.
Therefore, any transition of drain or condensate piping to a dissimilar metal should use a dielectric union
to prevent electrolysis. It is recommended to maintain drains and condensate from pharmaceutical water
and steam in stainless steel due to corrosivity of fluid.
c) Contact Corrosion
Occurs when small pieces of carbon steel, scale, copper or other foreign material is lodged on the
surface of stainless steel.
d) Pitting or Pinhole Corrosion
Solutions containing chlorides may attack stainless steel in a pitting action. This is usually due to high
concentrations of the chloride ion due to evaporation.
e) Stress Corrosion Cracking
This Document is licensed to
Chloride solutions are the worst offenders in promoting stress cracking. Cracking is most likely to occur
in hot rather than cold solutions. High and low stresses in the same member produce a condition likely to
result in stress corrosion if chlorides are present.
Mr. Shlomo Sackstein
Corrective action is to keep the internal strain
in stainless steels as low as possible by fully annealing or
Herzlia,
utilizing stress relieved versions of stainless steels at 1200°F.
ID number: 216389
Select tubing with good concentricity and close wall thickness tolerance to avoid high and uneven stresses
when tubes are rolled into tube bundle headers etc.
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Avoid joining dissimilar metals and avoid cyclic bending.
200
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
11.9.6
Corrosion Protection of Stainless Steel
Surface protection of chromium nickel stainless steel is inherent when chromium levels are in excess of
11.5%.
A passive or inert surface is established naturally with these steels due to exposure to air, aerated water, and
other oxidizing atmospheres.
Airborne impurities, heating, and other direct contact materials can damage this protective film causing the
metal to be compromised in its ability to ward off the corrosive process.
11.9.6.1
Passivation of Stainless Steels to Restore Protective Film
Passivation is the process that establishes a surface or film on nickel-chrome steels and maximizes the
corrosion resistance.
The passivation process cleans the exposed surfaces of the contaminates, soils, and surface impurities that
cause film damage. The process forms a new strong protective film in areas that have become “active” or
sensitized due to welding.
11.9.6.2
Rouging or Ferric Oxide Discoloration of SS Systems
Rouging is seen in many water systems, but is more prominent in hot, distilled, and clean steam systems.
Rouge can be in the form of dust or a light film that can be wiped off. Rouge also can be in the form of a
bonded multi-layer that requires scraping with a sharp tool to remove.
Rouge is found in many forms:
•
Orange - found in high purity/high temperature systems
•
Light Red - found in high purity/high temperature systems
•
Red - found in high purity/high temperature systems
•
Reddish Brown - found in high purity/high temperature systems
•
Purple - found in clean steam and high temperature water systems
•
Blue - found in clean steam systems
•
Gray - found in clean steam systems
•
Black - found in clean steam systems
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
Castings and Forgings for Vessel Components
ID number: 216389
See appendix section on passivation for more details.
11.9.7
Most castings and forgings are used for components attached to vessels, such as agitator impeller hubs and
instrument housings. Castings typically contain higher levels of ferrite that can cause potential problems with
components in contact with high purity water (rouging). In addition, castings are usually more porous or
grainier, and will not typically take a polish higher than a 4 at best. Forgings are less susceptible to rouging
and can be polished up to a 8 mirror finish.
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201
APPENDIX
11.9.7.1
General: Sanitary Tubing and Piping
•
The piping or tubing and valve ends to be joined by welding must be within the set tolerances as far as
inside diameter and out of roundness is concerned.
•
All the welds should be done with automatic welding machines (orbital welding) with insert gas (Ar)
blanket where possible.
•
If unavoidable, the last weld of an assembly may be done manually by a qualified, certified welder.
•
All welds should be documented and inspected.
•
If orbital welding is done, a video tape (borescope) can be prepared for random welds; however, this is
optional. Also, an isometric or piping drawing should be marked identifying each weld by a unique number, date, and welder ID number.
•
The piping (tubing) installation should be done according to approved piping drawings (orthographic and/
or isometrics).
•
The piping support method and the support spacing should be in accordance with the piping specification and applicable drawings. It is very important that the installing contractor follows the design documents and does not use shortcuts as the piping support spacing is based on calculations to assure the
permitted deflection (sagging) of the pipe between the adjacent supports.
•
As the piping system larger sections are installed, the piping installation contractor shall make up the
latest issue of the piping drawings verifying that the system is installed in accordance with the applicable
drawings, ensuring all valves, fittings, etc., are installed. If there are deviations from the drawing, the
drawing shall be marked up for the preparation of an “as-built” final revision. The “as-built” revision of the
drawing should be approved by the user. The user should have access to the “as-built” drawings. The
qualification protocol completion report should make reference to the “as-built” drawings.
•
The installed piping system should be pressure tested according to the requirements of the piping fabrication specification. During the performance of the pressure test, the pipe slope should be checked and
documented. During the pressure testing, the piping is not insulated, but is full with water - a condition
closest to the operating condition. If there are deviations from the required slopes due to faulty installation
due to a larger than specified pipe support span, the installation needs to be corrected. The main purpose
of the pipe slope is the assurance of self drainage. The results of the pressure test and slope measurements should be documented.
After the piping (tubing) system installation, pressure testing, and pipe slope parameters are satisfied and
accepted, the system is ready for passivation.
This Document is licensed to
11.9.8
Surface Finish of Stainless Steels
Mr. Shlomo Sackstein
Herzlia,
300 series stainless steel “sheet” may be produced with a very fine grain, slightly milky appearance through
to a bright highly reflective finish produced
on mirror polished
rolls.
ID number:
216389
11.9.8.1
Cold Rolled Stainless Steel Finishes
These terms are used by the steel mills without a good method of quantifying the surface quality, roughness,
and texture.
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Mills also relate to the ASTM or AIAI finishes which range from 1 to 8, where 8 is a “mirror finish.” This method
also is subjective and relates to the method used to obtain the finish.
202
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APPENDIX
11.9.8.2
Stainless Steel Polishes and Improved Finishes
A third identification method commonly used to define surface finishes is the “Grit Finish” which is the number
of scratch lines per inch of surface produced by an abrasive wheel or belt.
While this system qualifies the finish and allows acceptance based on measurable criteria, the criteria is not
a true measure of the surface quality as it does not define the depth of the “scratch lines.”
Grit finishes come in grades related to the standard abrasive tools or surfaces:
20 grit = 100+ RMS and 90+ RA
180 - same as a 2B finish - = 80 RMS and 70 RA approximately
240 - between a 2B and a 3A finish - = 15 to 63 RMS and 14 to 57 RA
320 - same as an 8 finish - is 10 to 32 RMS and 9 to 29 RA
500 - same as a 9 finish - is 4 to 16 RMS and 4 to 14 RA
11.9.8.3
Electro-Polishing of Stainless Steel
Mechanical finishing has certain inherent deficiencies, one of which is the tendency to enlarge the exposed
surface area.
Electro-polishing is able to improve the mechanical finish by rounding off the sharp peaks of the “scratch
lines.”
The advantages of electro-polishing are:
•
reduces the surface areas
•
provides a sanitary acceptable surface finish
•
cleans the surface
•
passivates the surface of stainless steel with a chromium layer
•
removes impurities trapped below folded layers of mechanically formed ridges
•
reveals defects that have been hidden by mechanical polishing through smearing effect
This Document is licensed to
Electro-polishing requires a mechanical polish preparation developed with a uniform progressive grit polishing application.
Mr. Shlomo Sackstein
11.9.9
Stainless Steel Distribution Piping
Herzlia,
Stainless steel pipe is available in heavy
gage “schedule” piping,
thin wall solid drawn tubing, and thin wall
ID number:
216389
seamed tubing.
11.9.9.1
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Solid Drawn Thin Wall Tubing
The selected materials are available in solid drawn tube suitable for the type of service expected from a high
purity water distribution system.
For individual use only. © Copyright ISPE 2001. All rights reserved.
203
APPENDIX
This is an acceptable material for a high purity water loop and should conform to ASTM A632.
Tubing should be 16 gauge (.065 in./0.165 cm) for tubing diameters of between 1 and 3 inches (2.54 and 7.62
cm) inclusive and 14 gauge for 4 in. (10.16 cm) diameter.
11.9.9.2
Welded Seam Thin Wall Tubing
Acceptable thin wall tubing is available at a reduced cost with a welded seam produced in an oxygen free
environment. (TIG)
The tubing is available with a uniform smooth surface in accordance with ASTM A269 and may be polished
mechanically and electrically to a suitable surface finish.
0.065 in. (0.165 cm) thick sheet metal is used for the manufacture of seamed tubing between 2 and 3 inches
(5.08 and 7.62 cm) diameter with .083 in. thick for 4 in. (10.16 cm) diameter and progressively larger for 5 in.
(12.7 cm) and above to suit the application and location. The metal is cut and cold rolled to form a round tube.
The tube is clamped so that the two edges make contact. The inside and outside of the tube is blanketed with
Argon gas to expel all oxygen and the seam is welded without filler, producing a consistent smooth and
oxidation free surface inside and out.
11.9.9.3
Material and Installation Certifications
•
mill test certificate of piping/tubing material
•
weld test, spot x-ray of carbon steel piping welds, borescope of stainless steel piping/tubing welds
•
pressure test, slope measurement certificate
•
weld identification on piping drawings
11.9.10
Elbows/Bends In Tubing
While butt joints can be accomplished leaving a smooth surface free of pits, crevices and oxidation, welds are
expensive and should be minimized.
Current practice is to use tight welded elbows for each directional change in the distribution piping. Considering the extent of high purity water distribution piping involving points of use drops from 25 in a small system
to more than 100 in a large one, the total number of elbows is considerable. These can range from 130 to 500
and from 60 to 1000 welds to install them.
This Document is licensed to
The purchase of longer lengths than the standard 20 ft (6 m) lengths (say 40 ft (12 m) lengths) and the
utilization of long sweeping bends, instead of the traditional tight welded elbows can reduce the total number
of welds by up to 60% and the total pipe used by 10%.
Mr. Shlomo Sackstein
Herzlia,
Any reduction in these requirements
due number:
to frictional improvements
of large sweeping bends compared to
ID
216389
High purity water systems, in order to maintain flow at all times without stagnation, water must be pumped
continuously with the associated energy requirements.
tight traditional bends are added to the advantages of the change from elbows to bends.
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Sweeping bends may be accommodated in many areas and with careful design, the advantageous could be
exploited.
Large sweeping bends are preferred in order to reduce the potential of wrinkling and/or damage to the
internal pipe finish.
204
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
11.9.11
Types of Non-Metallic Materials
Few compatible non-metallic piping materials are available that will withstand the rigors of a pharmaceutical
high purity water system, such as:
•
80 to 90°C operation or periodic sanitization
•
121°C steam sterilizing temperatures
•
ozone and or chlorine contact
One such material that will support the above requirements and limit extractable to a minimum level compatible with stainless steel is polyvinylidene fluoride (PVDF).
This material is available in a compatible range of pipe diameters, surface finishes, and automated orbital
welding capability.
11.9.11.1
Corrosive Resistance of PVDF
PVDF is inert and will not exhibit any surface corrosion when in contact with 90°C high purity water or
commonly used oxidizers.
11.9.11.2
Weldability and Polishability of PVDF
The surface finish of PVDF is equivalent to electro-polished stainless steel and the fusion welding equipment
and capabilities are similar to stainless steel orbital welders.
11.9.11.3
PVDF Distribution Piping and Fittings
Weldable fittings, elbows, tees, reducers, adapters, diaphragm valves, zero static valves, flow meters, regulators, etc. are available for PVDF pipe.
11.9.11.4
Pressure Rating of PVDF Piping Systems
Rated pressures for PVDF piping ranges from 230 psi at 68°C to 50 psi at 149°C.
Due to softening at elevated temperatures, continuous support is recommended for systems that are operated at 65°C or above.
11.10
This Document is licensed to
DESIGN OF A WFI/PURIFIED WATER DISTRIBUTION SYSTEM
The layout and general design of a high purity water system (WFI or purified water) should be consistent and
follow good manufacturing guidelines in respect to installation, support, natural drainage, flow rates, dead or
stagnation areas (dead legs), and minimization of areas that may promote micro-organism growth.
11.10.1
Mr. Shlomo Sackstein
Herzlia,
Fittings and Equipment
ID number: 216389
All equipment that, when installed, comes in direct contact with the high purity water should use a suitable
stainless steel or non-metallic material for all contact areas, except for valve diaphragms and tri-clamp gaskets.
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This includes all valves and monitoring sensors.
For individual use only. © Copyright ISPE 2001. All rights reserved.
205
APPENDIX
Valve design should be sanitary diaphragm type, installed at approximately 60°C to the vertical to optimize
drainability. Hash marks or drain dots are provided on many designs to allow precise orientation of the valves
in horizontal installations.
PTFE Teflon faced diaphragms are preferred for hot water applications, covering a temperature range from 30 to 350°F (0 to 177°C).
Connecting flanges for all valves and fittings should be tri-clamp design.
11.10.2
Natural Drainage
Well designed distribution loops should be installed overhead and point of use valves should be located at a
convenient location within the process or user area, below the distribution loop.
Slopes should be verified externally after hanging and before insulation is installed.
Hangers should use steel clamps/fittings with Viton or similar inserts designed for use with the particular
tubing, installed for SS at least on 10 ft (3 m) centers. Support for PVDF piping should be appropriate for the
operating temperatures. Continuous support of plastic pipe should be considered using angle iron or equivalent to prevent slope changes due to expansion and contraction and point stresses from hangers.
Piping distribution from an unavoidable low point in the system, such as the storage tank discharge elbow,
should be designed with a clear low point and a sanitary drain valve installed with a maximum of 6 diameter
dead leg (no less than 6 diameters from the centerline of the main line to the valve center line based on the
main line diameter).
Slope of distribution system process pipe or tubing should be a minimum of 1/16 in./ft (0.52 cm/m).
Location of all drain valves should be totally and easily accessible.
11.11
FABRICATION OF A WFI/PURIFIED WATER DISTRIBUTION SYSTEM
High purity water distribution systems using the material and finishes specified above must be joined using
acceptable welding or other sanitary techniques.
11.11.1
Assurance of Quality Distribution Piping
The distribution piping and storage systems should be installed in accordance with cGMPs and should be
fabricated, manufactured, procured, and installed in strict accordance with explicit operating procedures.
11.11.2
This Document is licensed to
Operating Procedures Should Include the Following:
Purchase of components for the distribution and storage system from a list of selected/preferred vendors.
Procurement of specific components based on preferred part numbers, listed for each vendor where applicable. Procurement of other components, such as valves, pumps, filters, instruments, and tanks etc. using
approved specifications.
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Inspection of all components of the system on receipt for compliance and/or damage. Verification of the bill of
lading using a detailed list of purchased parts.
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The qualification of welding procedures in accordance with a detailed list of set-up parameters for:
206
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
a) Receiving, fabrication, cutting, end facing, and welding to be performed in a clean area devoid of any
equipment previously used on “carbon” steels.
b) Tubing specification, heat lot, diameter to be used for the specific application
•
Check tubing for crushing and confirm the nominal diameter.
•
Examine interior and exterior of tubing for physical damage, scratches (interior) dirt or grease.
•
Clean tubing of grease and dirt using an approved cleaning solvent isopropyl alcohol (IPA) and lint
free cloth. Repeat cleaning until lint free cloth is visually free of grease or dirt.
c) Length of tubing and facing specifications.
Cut tubing to length and finish with a square deburred butt end or as recommended by the fusion welding
equipment supplier.
11.11.2.1
Cleaning
•
Place a lint free cloth in tubing prior to facing and/or deburring.
•
Use only Isopropyl alcohol as a cleaner solvent for SS and other appropriate solvent for PVDF. Use
sparingly and ensure that all traces have evaporated prior to bagging.
•
Use only lint free cloths such as “Texwipe.”
•
Clean both inside and outside of tube ends and do not touch the end area with bare hands or soiled
material.
11.11.2.2
Protection
a) Bag the prepared tubing or the ends of the tubing with clear plastic bags and tape the bag to the tubing if
the tubing is not to be welded within two hours or if the tube is to be welded outside the clean fabrication
area.
b) Weld fittings, elbows, tees, etc. should be examined similar to the tubing and cleaned of all dirt or grease
prior to welding. All weld fittings should be received, sealed in a plastic or other lint free, non-metallic
sealed bag.
c) The fitting should remain in the bag until just prior to welding or for inspection following receipt.
This Document is licensed to
Valves and instruments, etc. should be procured with tri-clamp or suitable sanitary type fittings and mating
fittings should be welded onto the tubing in accordance with the system design. Receipt should be in a totally
enclosed sealed lint free bag, similar to the weld fittings.
Mr. Shlomo Sackstein
Welding of tubing, weld fittings, tri-clamp, or suitable
sanitary type fittings should be performed inside the
Herzlia,
fabrication cleanroom, using TIG orbital welding for SS throughout and PVDF fusion machine for PVDF.
ID number: 216389
Purging of each assembly with Argon Purge gas should be completed for all SS prior to welding. The gas
should be 99.999% pure and contain less than 1ppm of moisture or 2ppm of oxygen.
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The complete removal of all air should be accomplished prior to commencing welding.
For individual use only. © Copyright ISPE 2001. All rights reserved.
207
APPENDIX
Welder qualifications should be performed for all welders and re-qualification at the commencement of each
work-day and/or the change to a different diameter.
11.11.3
Clean Preparation Area
A cleanroom/trailer should be used to ensure that welding, bending, and fabrication of high purity water piping
are not contaminated with metal or non-metallic particulates.
The area should be filtered to control particulates with limited controlled access. The following procedures
should be followed:
•
All cutting and welding equipment should be cleaned of any impurities or particulates.
•
The room should be maintained clean at all times and access should be across sticky floor mats.
•
All piping and fittings should be cleaned prior to and following welding.
•
Assemblies should be bagged following welding and the bags removed just prior to making field welds.
•
Welding and fitting technicians should use overshoes and cleanroom gloves. The gloves are worn to
prevent finger print oils from getting onto the pipe.
The above procedures are currently typical for a high purity piping system for the semi-conductor industry
and is considered advisable for pharmaceutical installations with similar requirements.
Inspection of completed welds is sometimes not possible or practical. Remote borescope inspection is limiting and often not precise. Common practice and the practice recommended is to provide a validated process
for all welds, a precise instrument to make the welds, an inert environment around the weld and a clean
contact surface. These goals may not be accomplished if the environment for storage and the welding process is not controlled. Skin oils and metal particulates will contaminate the surfaces of the mating tubing. The
mating surfaces must be cleaned and maintained clean through the welding process to ensure a contamination free weld and therefore a validated weld.
The use of a clean area and clean area procedures will protect the welds and reduce the defect incidents
associated with contaminates in the welding areas. (This approach has been shown to be cost effective by
the cost sensitive semi-conductor industry.)
Spot checks of the outside and inside surfaces on a percentage or time basis will provide assurance of the
system efficiency.
11.11.4
This Document is licensed to
Joints Using Fusion Butt Welding
Orbital welding is the recommended industry standard for high purity water systems in biotech, pharmaceutical and semi-conductor industries. This is due to the smooth inner weld bead that is characteristic of this
joining process.
11.11.4.1
Orbital Welding
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Orbital welding is a welding method used for joining stainless steel piping and tubing with electric arc in a
welding machine not using any filler (welding rod) under inert atmosphere argon (Ar). Electric power characteristics are displayed on the control panel instruments and, if required, a printout of the welding parameters
can be obtained.
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208
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APPENDIX
11.11.4.2
Borescoping
A borescope is a fiber optic instrument with a monitor (TV screen and optional video tape recorder) used for
inspecting the weld inside the pipe or tubing. The fiber-glass cable is a maximum 20 ft. long with a light and
lens at the end. Borescoping is done for verification of the weld quality.
With the control of the welding process and the processing area, borescope inspection of the inside of the
weld is only considered necessary as a means of control and is recommended as part of the qualifying
process for the weld size and daily restart checks. (See details later in this Section.)
Video recording each weld is considered un-necessary and difficult to justify.
11.11.5
High Tech. Orbital Tube and Pipe Welding for Stainless Steel
Semi-automatic, programmable, orbital, inert gas purged welding equipment for both tube and pipe is available from many manufacturers. The basic principals and techniques are the same for all commercial machines.
The system is an automatic “Heliarc” or “TIG”(Tungsten Inert Gas) process where Inert Argon gas from a
cryogenic or low temperature source is used to protect the molten steel from oxidation during the metal
fusion.
Liquid argon in Dewers is preferred due to its high purity at 99.999%. A gas purifier such as the Nanochem
should be used during purging to bring the contaminants down to the ppb levels which is preferred.
The above equipment will weld stainless steels, nickel based alloys, titanium, and aluminum.
11.11.5.1
Accessories
Welding accessories are available to assist in set-up, alignment of pipe butts, purging, fitting alignment, pretacking fixtures, and finishing of the pipe ends in preparation for welding.
11.11.6
Weld Criteria
•
Weld quality must meet the strictest standards.
•
All welds must be fully penetrated around the entire weld perimeter with no crevices or entrapment sites.
These areas are particularly vulnerable to crevice corrosion.
•
All welds should be smooth, uniform, complete and flat, not concave, on the outside.
•
The weld should have a uniform and complete weld bead width on the inside with little or no convexity.
•
The inner weld bead should contain no concavity.
•
•
This Document is licensed to
Mr. Shlomo Sackstein
There should be no visible signs of oxidation/discoloration
Herzlia, of the inner weld.
The joints should be square facing
properly aligned.
Tubing surfaces should not be offset in any
ID and
number:
216389
plane or direction by more than +/-0.003 in.
•
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The weld width should be nominal 1/8 in. wide.
For individual use only. © Copyright ISPE 2001. All rights reserved.
209
APPENDIX
11.11.6.1
Welder Qualification
There are many types of metals and even more methods of good joining of metal parts by welding.
Each welder performing welding on certain metals must be qualified for this type of metal and welding. The
American Society of Mechanical Engineers (ASME) and the American Welding Society (AWS) have welding
procedures for welder qualifications. Each qualified welder should be formally qualified with a certificate
qualifying him or her for a certain type of weld.
As a general rule, welders and welding procedures are qualified to ASME B 31.3 (chemical plant and petroleum refinery piping), that incorporates ASME Section IX by reference.
11.11.6.2
Common Test Methods for Installed Piping
Test methods on installed piping are: pressure testing, Verification of slope and the last step of passivation
requiring the testing of the final rinse water.
11.11.7
Weld Defects Examples
11.11.7.1
Joint Misalignment
Poor alignment of joint caused by equipment or procedure failure.
Follow GMP welding procedures/use tube alignment gauge.
11.11.7.2
Lack of Penetration
Weld bead does not completely penetrate the ID of tube caused by poor setting of weld program parameters,
material thickness and/or composition did not allow for complete penetration or improper welding amperage
caused by power fluctuations.
Develop proper welding parameters/adjust program to compensate for thickness or material/adjust for amperage fluctuation.
11.11.7.3
Excessive Penetration
Weld bead over penetrates causing excessive concavity or spikes caused by incorrect weld program (too
hot), excessive welding amperage caused by power fluctuations or material thickness and/or composition
which, caused excessive penetration.
This Document is licensed to
Develop proper welding parameters/adjust program/use dedicated circuit.
11.11.7.4
Lack of I.D. Purge
Mr. Shlomo Sackstein
Herzlia,
Sugaring of the weld bead caused by
a lack
of ID purge. 216389
ID
number:
Discoloration/oxidization in the heat effected zone caused by a lack of ID purge or the use of an impure purge
gas.
Monitor the purge-flow at the weld site and ensure the hose is not pinched.
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11.11.7.5
Interrupted Purge
A short segment of discoloration/oxidation and excessive penetration caused by a momentary purge gas
pressure drop commonly caused by a pinched gas line.
210
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
Monitor purge-flow and ensure the gas hose is not pinched.
11.11.7.6
Purge Gas Purity Problems
Coloration/oxidation along the weld area caused by impurities in the weld purge gas or in or on the metal
surface.
Eliminate purge and surface impurities and check for excessive concentrations of oxygen and moisture.
11.11.7.7
Heat Tint/Haze
Light coloration/haze along weld area caused by minor impurities in weld purge gas or metal surface.
Eliminate impurities in weld zone.
11.11.7.8
Oxidation/Discoloration
Discoloration ranging from blue/brown haze to dark blue with black edges caused by oxygen contaminated
purge gas, incomplete sealing, or insufficient pre-purge.
Ensure the complete sealing of the purged line and monitor the purge flow and purity.
11.11.7.9
Insufficient Tie-In
Weld on OD is good, but the ID is incomplete and does not overlap weld start caused by incorrect speed or
time in the weld program. (Uncalibrated weld head.)
Use high quality welding equipment and check for appropriate procedures.
11.11.7.10 Electrical Current Fluctuations
Significant narrowing of ID weld bead width and/or lack of penetration of tube ID in affected areas caused by
electrical power fluctuations (not using a dedicated circuit).
Ensure that a dedicated circuit is used.
11.11.7.11 Inclusions/Dross(non-metallic substance)
Non-metallic formation on ID weld caused by tungsten inclusion.
This Document is licensed to
Use high quality base material for welding rod.
11.11.7.12 Pinholing
Mr. Shlomo Sackstein
Herzlia,
Ramp (feather) the welding amperage properly and provide post purge.
ID number: 216389
Small holes in the weld bead caused by the weld puddle being cooled to rapidly.
11.11.7.13 Porosity
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Metallic or non-metallic impurities trapped in the weld bead (tungsten or slag) caused by the introduction of
impurities from outside or from the weld material.
Eliminate impurities from outside or from the metal.
For individual use only. © Copyright ISPE 2001. All rights reserved.
211
APPENDIX
11.11.7.14 Cracking
Cracks in either the surface of the weld caused by brittle metal or use of a very hot weld program with rapid
cooling.
Use only good quality materials and acceptable welding programs. Do not quench or cool the weld.
11.11.8
High Tech. Orbital Tube and Pipe Welding for PVDF Piping
Semi automatic fusion welding machines are available for orbital welding of PVDF piping.
An elastic pressure element backs up the inside of the fusion zone, totally avoiding an inner bead.
A controlled pressure thermoplastic melt optimizes the homogeneous joint between the plastic parts, producing a consistent joint quality.
11.11.9
Remedial Action for Defective Welds - SS or PVDF Piping
Rewelding or weld repairs are not acceptable.
Weld Replacements
The following is a procedure for replacing defective welds:
a) Cut out rejected weld using a band or cut-off saw.
b) Where possible, retain section for further inspection.
c) Prepare faces of tubing and check for signs of discoloration.
d) Ensure that all traces of any heat effected areas are removed.
e) Cut and shape pipe ends using proprietary facing equipment.
f)
Debur and reweld.
g) Assign a “R” suffix to weld number.
11.11.10
Joints Using Sanitary Clamps
This Document is licensed to
The sanitary clamp system of quick disconnect fittings are designed to provide a smooth non-contacting or
non-corrosive environment.
The sanitary joints may be cleaned in place, provide leak tight connections and may be adapted to other
forms of piping.
Mr. Shlomo Sackstein
Herzlia,
These joints should be used for all distribution pipe connections to valves, sensor housings, and fittings not
adaptable to orbital fusion welding. ID number: 216389
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212
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
11.12
ABBREVIATIONS AND DEFINITIONS
11.12.1
Definitions
ABS - A plastic material used to make pipe; based on combinations of acrylonitrile, butadiene and styrene;
ABS is a relative inert material and contributes little in the way of contamination to pharmaceutical water.
Absorption - Assimilation of molecules or other substances into the physical structure of a liquid or solid
without chemical reaction.
Aerobic Bacteria - Bacteria capable of growing in the presence of oxygen.
Anaerobic Bacteria - Bacteria capable of growing in the absence of oxygen.
As-Built Drawings (Record Drawings) - Construction drawings and specifications that represent the physical condition of the plant or system at turnover from the designer or installer at satisfactory operation. These
documents supplement and compliment the system manuals and protocols.
Backwash - The process of flowing water in the opposite direction from normal service flow through a filter
bed or ion exchange bed. The purpose of backwashing a sand filter is to clean it by washing away all the
material it has collected during its service cycle. The purpose of backwashing a carbon filter is also to clean
it, but primarily to eliminate flow channels that might have formed and to expose new absorption sites.
Bacteria - Single-celled microorganisms measured in high purity water by several means: culturing, high
power microscope, or Scanning Electron Microscope (SEM). The value is reported as Colony Forming Units
(CFU), or colonies per milliliter or per liter. The bacteria in the water act as particle contamination on the
surface of the product, or as a source of detrimental by-products. See Pyrogen.
Blowdown - The withdrawal of water from an evaporating water system to maintain a solids balance within
specified limits of concentration of those solids.
BOD - Biological oxygen demand of water. This is the oxygen required by bacteria for oxidation of the soluble
organic matter under controlled test conditions.
Breakthrough - Passage of a substance through a bed, filter, or process designed to eliminate it. For ion
exchange processes, the first signs are leakage of ions (in mixed beds, usually silica) and the resultant
increase in conductivity. For organic removal beds, usually small, volatile compounds (THMs are common in
activated carbon).
Calibration - A comparison of a measurement standard or instrument of unknown accuracy to detect, correlate, report, or eliminate by adjustment of any variation in the accuracy of the unknown standard or instrument.
This Document is licensed to
Cation Exchange Resin - An ion exchange resin which removes positively charged ions.
Mr. Shlomo Sackstein
Certified Vendor Drawings - Drawings prepared
by vendors for the fabrication of equipment, specialty
Herzlia,
components, and skid mounted systems. These are certified as fabricated by the vendor and become the
official document for the equipment ID
involved.
number: 216389
Commissioning - A prescribed number of activities designed to take equipment and systems from a static,
substantially complete state to an operable state.
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Conductivity - A measure of flow of electrical current through water. This conductance is high with high Total
Dissolved Solids (TDS) water and very low with ultrapure deionized water. Conductivity is the reciprocal of
resistivity (C=1/R) and is measured in micromho/cm (µmho/cm) or microsiemens/cm (µS/cm).
For individual use only. © Copyright ISPE 2001. All rights reserved.
213
APPENDIX
Contaminant - Any foreign component present in another substance. For example, anything in water that is
not H2O is a contaminant.
Critical Instrument - These are the instruments used to measure critical parameters.
Critical Parameter - These are the measured values that would determine process compliance and cause a
system to revert to a fail-safe mode.
Drinking Water - EPA primary drinking water or comparable regulations of the European Union or Japan.
Endotoxins - Pyrogens from certain Gram negative bacteria. Generally highly toxic Lipopolysaccharideprotein complexes (fat, linked sugars, and protein) from cell walls. A marker for these bacteria with a reputation for persistent contamination because they tend to adhere to surfaces. See Pyrogen.
Enhanced Documentation - Collection of Engineering, Quality Control and Regulatory Affairs documents
which will be required for the operation, validation, maintenance, and regulatory compliance of a pharmaceutical plant.
EPA - Environmental Protection Agency.
Extractable - Trace material from piping and/or equipment which have been extracted by the processed fluid.
FDA - US Food and Drug Administration.
General Arrangement - A more specific version of a general layout which includes the system interface
points, space requirements, ergonomics, construction issues, manufacturing flow of materials and operators,
maintenance requirements, and future expansion or alterations.
General Equipment Layout - A diagram that relates the unit operations of the system to one another. Its
development should depend on production requirements, product matrix, and possibilities for future expansion.
Good Engineering Practices (GEP) - Standards, specifications, codes, regulatory and industrial guidelines
and accepted engineering and design methods to design, erect, operate, and maintain a pharmaceutical
facilities taking into account not only regulatory compliance, but also safety, economics, environment protection, and operability. Standards and specifications are provided by recognized sources such as established
engineering contractors and pharmaceutical companies. Codes are provided by local, state or federal jurisdictions, or insurance companies. Guidelines are issued by professional societies, industrial organizations, or
regulatory agencies. Engineering design methods have been established in the engineering educational
system.
This Document is licensed to
Grains Per Gallon - A unit of concentration. 1 grain/gal = 17.1 mg/l.
Gram Negative Bacteria - A basic classification of bacterial type, along with “Gram positive.” These organisms resist straining by the Gram technique. Sometimes considered “bad” bacteria when discussing pollution
or contamination; however, this is an artificial and quite broad classification.
Mr. Shlomo Sackstein
Herzlia,
Halogens - Atoms of the chlorine family
also include216389
fluorine, bromine, and iodine.
ID which
number:
Hardness - The concentration of calcium and magnesium salts in water. Hardness is a term originally referring to the soap-consuming power of water; as such it is sometimes also taken to include iron and manganese. “Permanent hardness” is the excess of hardness over alkalinity. “Temporary hardness” is hardness
equal to or less than the alkalinity. These also are referred to as “non-carbonated” or “carbonate” hardness,
respectively.
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214
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
High Purity Water - Water conforming to USP Monographs or equivalent.
Heavy Metals - High molecular weight metal ions, such as lead. Known for their interference with many
processes, and “poisoning” of catalysts, membranes, and resins.
Humic Acid - The classical method for fractionating the humic colloids that disperse in the sodium hydroxide
extract is to acidify the suspension with sulphuric or hydrochloric acid, which causes a part of the dispersed
organic matter to precipitate. The part that stays in solution is known as fulvic acid, that which precipitates out
as humic acid, and that part of the organic matter which does not disperse in the alkali but remains in the soil
as humin.
Hydrocarbons - Organic compounds containing only carbon and hydrogen. Sometimes broadened to include compounds or mixtures of compounds with small amounts of oxygen also.
Hydrophilic - Having an affinity for water. Its opposite, non-water-wettable, is hydrophobic.
Inorganics - Chemical compounds which are not organic in nature. Inorganics that are soluble in water
generally split into negative and positive ions, allowing their removal by deionization.
Instrument List - A list of instrumentation which includes the instrument tag number, instrument name,
manufacturer name, model and serial number, P&ID reference, critical or non-critical, and local or panel
mounted.
Ion - An atom or radical in solution carrying an integral electric charge, either positive (cation) or negative
(anion).
Ion Exchange (IX) - One of the processes used to further reduce the concentration of ions in water supplies
referred to as total dissolved solids removal. The process uses anion and cation exchange resin to chemically
react with and remove the remaining ions or TDS in the water. This process results in water with virtually no
TDS.
Ion Exchange Regeneration - The process by which ion exchange resin that can no longer effectively
remove ions from the water is recharged. This recharging or regeneration is performed by adding an excess
of caustic (NaOH) to the anion resin and an excess of either hydrochloric acid (HCl) or sulfuric acid (H2SO4)
to the anion resin. These regenerant solutions are allowed to flow through the resin beds at specific flow rates
for specific periods of time depending on the type of resin, the ionic load, and the final purity desired. The
regenerant solutions react with the ion exchange resin releasing the removed cations and anions which are
then carried away to drain by the flow of the regenerant chemicals. The excess chemical is rinsed from the ion
exchange resin with purified water when the bed is ready for another service cycle.
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Ion Exchange Resin - A styrene-divinylbenzene or acrylic copolymer formed into small, spherical, and
highly porous beads about the size of a pinhead. These inert beads are chemically treated so that they
perform as if they were chemical compounds.
Mr. Shlomo Sackstein
Herzlia,
Membrane - A barrier, usually thin, that
the passage216389
only of particles up to a certain size or of special
IDpermits
number:
Langelier Index - A means of expressing the degree of saturation of a water as related to calcium carbonate
solubility.
nature.
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Micron - The same as a micrometer or 1000th of a millimeter. The typical particle size of importance in
deionized water is less than 0.2 µm.
For individual use only. © Copyright ISPE 2001. All rights reserved.
215
APPENDIX
Microorganism - Organisms (microbes) observable only through a microscope. Larger, visible types are
called organisms.
Milligrams Per Liter (mg/l) - A term used to report chemical analyses. Milligrams per liter refers to the
milligrams of the compound or element present in 1 liter (1000 milliliters) of water. Another term often used is
parts per million (ppm) which is the same for substances in water. 1 mg/l = 1000 ug/l = 1 ppm.
Mixed Bed Ion Exchange - The use of both cation and anion exchange resin mixed together in one tank.
MSDS (Material Safety Data Sheet) - Document produced by the manufacturer that contains the chemical
and physical properties of a substance that are pertinent to safe handling and storage.
NPDES Permit - The National Pollution Discharge Elimination System permit required by and issued by EPA.
Organics - Short for organic chemicals; those compounds that contain carbon to hydrogen bonds and are
not carbonate related.
Orifice - An opening through which a fluid can pass; a restriction placed in a pipe to provide a means of
measuring flow.
Osmosis - The passage of water through a permeable membrane separating two solutions of different concentrations; the water passes into the more concentrated solution.
Oxidizer - A chemical which readily oxidizes more reduced substances. Examples of strong oxidizers are
ozone, hydrogen peroxide, chloride, persulfates, and oxygen itself.
Ozone - Ozone is a very strong gaseous oxidizing agent. It is used in deionized water systems to kill bacteria
and to reduce, by oxidation, the amount of TOC in the water. Ozone is O3 and due to reaction with other things
rapidly becomes oxygen (O2). Therefore, it has a short but effective oxidizing potential. It can be destructive to
ion exchange using membrane filters and other plastic materials in the system.
Particles - A physically measurable contaminant in deionized water. Particles can be bacteria, colloidal material or any other insoluble material. Particle counts are reported as number of particles per liter of a particular size measured in micrometers (microns).
Passivation - The means of obtaining the loss of chemical reactivity exhibited by certain metals under special environmental conditions. More specifically, the state in which a stainless steel exhibits a very low corrosion rate. Passivation generates an oxide film that covers and protects the surface of the metal.
Pasteurization - A process for killing pathogenic organisms by heat applied for a critical period of time.
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Pathogens - Disease-producing microbes.
Permeability - The ability of a body to pass a fluid under pressure.
Mr. Shlomo Sackstein
Piping A cylindrical device used for the conveyance
of fluid that is sized by nominal outer diameter dimenHerzlia,
sion.
ID number: 216389
pH - pH, the negative log of the hydrogen ion concentration, is a measure of the concentration of hydrogen
ions (H+) in a water-based solution. The more hydrogen ions that are present, the lower the pH and the more
acidic the solution.
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Photo Oxidation - The mechanism by which ultraviolet light reduces Total Organic Carbon (TOC) to Carbon
Dioxide. If halogenated organics are present, both CO2 and mineral acids can be formed.
216
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
Polypropylene (Polypro) - A plastic material used to make pipe; thermoplastic member of polyolefin family
of plastics; lightest plastic known; polypro is a relatively inert material and contributes little in the way of
contamination to pharmaceutical water.
Polyvinyl Chloride (PVC) - A plastic material used to make pipe that is used extensively with water. Prone to
produce extractables during start-up in high purity water.
Polyvinylidene Fluoride (PVDF) - A plastic material which is used to make pipe for the distribution of pharmaceutical waters. PVDF is a relatively inert material and contributes little in the way of contamination to
pharmaceutical water.
Precipitate - An insoluble reaction product; in an aqueous chemical reaction, usually a crystalline compound
that grows in size to become settleable.
P&ID (Process and Instrument Diagram) - This diagram illustrates schematically, the detailed piping, electrical, and control requirements of the system.
Process Flow Diagram (PFD) - A schematic of the system which utilizes graphic symbols and text to illustrate the steps of an operation in proper sequence. A PFD should present a detailed, accurate, and ordered
flow of raw material or ingredient through each manufacturing phase.
Purified Water - USP Purified Water prepared from water complying with the quality attributes of “Drinking
Water” with conductivity in accordance with stage 1, 2 and 3 tests and the following tables. Total Organic
Carbon at 0.5 mg/l. Less than 100 CFU/ml (10,000 CFU/100 ml) for FDA microbiological acceptability.
Pyrogen - Trace organics which are used as markers of bacterial growth or contamination. Produced by
various bacteria and fungi. Critical pharmaceutical and biotechnological processes have restrictions on contamination by these substances, usually at levels near the limit of detection. Primarily polysaccharide (made
of linked sugars) in nature. Fever producing substances when administered parenterally to man and certain
animals.
Resistivity - The measure of the resistance to the flow of electrical current through high purity water. This is
measured in millions of ohms-cm or Megohm-cm (Mohm-cm). Resistivity is the reciprocal of Conductivity
(R=1/C, 1 Mohm-cm = 1 µS/cm). This provides an easy means of continuously measuring the purity of very
low TDS water or ionic concentration.
Reverse Osmosis - A process that reverses (by the application of pressure) the flow of water in the natural
process of osmosis so that it passes from the more concentrated to the more dilute solution. This is one of the
processes used to reduce the ionic TDS, TOC, and suspended materials of feed water through a semipermeable membrane leaving dissolved and suspended materials behind. These are swept away in a waste stream
to drain.
This Document is licensed to
Rouge - Rouging is a form of surface corrosion that occurs in some stainless steel water systems.
Mr. Shlomo Sackstein
Herzlia,
Salt - Neutral compound formed of two or more ions. The salt disassociates into cations and anions when
dissolved in water.
ID number: 216389
Salinity - The presence of soluble minerals in water.
Sanitary Design - A system of design that meets standard, specification, codes, regulatory and industrial
guidelines, and acceptable engineering design methods to reach a degree of sanitation required by food,
pharmaceutical, and cosmetics processing.
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Saturation Index - The relating of calcium carbonate to the pH, alkalinity, and hardness of a water to determine its scale-forming tendency.
For individual use only. © Copyright ISPE 2001. All rights reserved.
217
APPENDIX
Scale - The precipitate that forms on surfaces in contact with water as the result of a physical of chemical
change.
Sedimentation - Gravitational settling of solid particles in a liquid system.
Silica - Silicon dioxide (SiO2) and it hydrated forms, classed as reactive and non-reactive. Generally, reactive
silica is removed by the anion exchange resin. Reactive silica is only slightly ionized and is held lightly by the
anion resin. It is for this reason that silica is the first thing to break through when the resin nears exhaustion.
Non-reactive silica is generally considered to be particulate (colloidal) in nature.
Soda Ash - A common water-treatment chemical, sodium carbonate.
Softening - The removal of hardness (calcium and magnesium) from water. This is a PRETREATMENT
process which used cation exchange resin to remove the hardness elements from the water. The hardness
elements are calcium and magnesium. The cation resin is regenerated with sodium chloride and during the
exchange process, the calcium and magnesium are removed from the water and replaces with sodium ions
(Na+). The resulting sodium salts are much more soluble than the salts of calcium and magnesium and do not
precipitate which provides better feed water to the RO system.
Soluble Silica - The silica present in the water that has actually dissolved in the water.
Stability Index - An empirical modification of the saturation index used to predict scaling or corrosive tendencies in water systems.
Stainless Steel - Steel to which a significant amount of chromium and nickel has been added to inhibit
corrosion.
Start-Up - The initial operation of equipment to prove that it is installed properly and operates as intended.
Start-up is considered complete when the selected equipment will adequately process water as specified.
Sterilization - Refers to the killing of microorganisms in the distribution system. This is normally done periodically by flushing a sterilizing solution, such as hydrogen peroxide or ozone, through the distribution piping
system. In some systems, ozone is continuously injected at low levels for continuous sterilization.
Surface Water - Surface water is any water where the sources is above ground. This can be rivers, lakes, or
reservoirs. Surface waters are usually higher in suspended matter and organic material and lower in dissolved minerals than well water.
Thermal Fusion - The joining of two materials (usually metal or plastic) by use of heat only, without any
additional material. Usually done by the use of automatic TIG welding in alloy steel tubing welding or with
specially designed melting equipment for plastics.
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Total Dissolved Solids (TDS) - The term used to describe inorganic ions in the water. Usually measured by
measuring the electrical conductance of the water corrected to 25°C.
Mr. Shlomo Sackstein
Total Organic Carbon (TOC) - Measure of organics
in water by their Carbon content. This is one of the
Herzlia,
parameters used to determine the purity of Semiconductor Grade water. Feed water will have TOC measured
in parts per million. UPW will have TOC
in parts 216389
per billion (ppb).
IDmeasured
number:
Trihalomethanes (THM) - Compounds present in the feed water that are formed by the reaction of chlorine
and the organic material in the water. The most common THM found in water is chloroform which is quite
difficult to remove. Activated carbon and degasification can serve to reduce THMs.
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218
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
Tubing - A cylindrical device used for the conveyance of fluid that is sized by its inside diameter dimension.
Turbidity - A suspension of fine particles that obscures light rays, but requires many days for sedimentation
because of the small particle size.
Ultrafiltration - Filter technology similar to reverse osmosis that is capable of filtering colloids and large
molecular weight organics out of the water. The filter capability of ultrafiltration filters to 0.005 µm particle size.
Ultrafiltration also will remove organic material down to about 1,000 - 10, 000 molecular weight.
Ultraviolet Sterilizer (UV) - Ultraviolet lamps used to kill microorganisms in water. These can be placed
anywhere in the water system. The wavelength used for control is 254 nanometers (nm).
Ultraviolet TOC Reduction - A UV source which partially oxidized organic compounds to ionic species
which can be removed. Relies on 185 nm radiation from “ozone producing” mercury lamps (along with 254
nm germicidal radiation). Generally has a longer contact time than for sterilization alone.
USP Purified Water - See Purified Water.
Vacuum Degasification - The process of removing dissolved and entrained gases from the reverse osmosis
product water by creating a vacuum in a tower through which the RO product water flows. The degasifier may
be located before the reverse osmosis system, but the majority of the time it will be located after. The most
prevalent gas present is carbon dioxide which may be have been generated during pH adjustment of the
reverse osmosis feed water. Carbon dioxide can be removed by the anion exchange resin, but that load can
be reduced by using the vacuum degasifier. The other gas of concern is the water is oxygen which also is
removed by a vacuum degasifier.
WFI - USP Water for Injection. Prepared from water complying with the quality attributes of “Drinking Water.”
Prepared using Distillation or Double pass reverse osmosis. Conductivity in accordance with Stage 1, 2, and
3 tests and conductivity tables. Total Organic Carbon at 0.5 mg/l. Less than 0.1 CFU/ml (10 CFU/100ml) for
FDA acceptability. Less than 0.25 USP EU/ml.
11.11.2
Acronyms and Abbreviations
AC - Alternating Current
ACS - American Chemical Society
ANSI - American National Standards Institute
API - Active Pharmaceutical Ingredient (also known as Bulk Pharmaceuticals)
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ASME - American Society of Mechanical Engineers
ASTM - American Society for Testing and Materials
Mr. Shlomo Sackstein
Ar - Argon
Herzlia,
BOD - Biological Oxygen Demand ID number: 216389
BPC - Bulk Pharmaceutical Chemicals
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Btu - British Thermal Units
CDI - Electrodeionization Deionization (US Filter)
For individual use only. © Copyright ISPE 2001. All rights reserved.
219
APPENDIX
CFU - Colony Forming Units, i.e., viable bacteria
cGMPs - Current Good Manufacturing Practices
CIP - Clean-In-Place (system)
CO2 - Carbon dioxide
CS - Clean Steam
DCS - Distributed Control System
DNA - Deoxyribose Nucleic Acid
DI - Deionized, Deionizing, Deionization
EDR - Electrodialysis Reversal (Osmonics)
EDI - Electrodeionization (Osmonics and Generic)
EPA - Environmental Protection Agency
EPDM - Ethylene Propylene Diemer
EU/ml - Endotoxin Units per milliliter
FDA - US Food and Drug Administration
gpd - Gallons per day
gph - Gallons per hour
H+ - Hydrogen
HCl - Hydrochloric acid
H2CO3 - Carbonic acid
H2O2 - Hydrogen Peroxide
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H3O+ - Hydroxonium (Hydronium) Ion
HCO3- - Bicarbonate Ion
H2SO4 - Sulfuric acid
KHz - Kilohertz
kW - Kilowatt
KWh - Kilowatt-hour
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Downloaded on: 6/2/10 4:16 AM
l - Liter
220
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
l/min - Liters per minute
LAL - Limulus Amebocyte Lysate
lb - Pound
LSI - Langelier Saturation Index (or Langelier Stability Index)
LVPs - Large Volume Parenterals
m - Meter
m/sec (m/s) - Meters per second
Mb - Megabyte or Distillate blowdown discharged
Md - Mass of Distillate produced
Ms - Mass of steam consumed
MF - Microfiltration or Micro-filter
Mf - Distillate feedwater required
ME - Multi-effect (still)
µ - Micro (one millionth)
µm - Micrometer (micron)
MF - Microfiltration
mg/l - Milligrams per liter
ml - Milliliter
mm - Millimeter
MM - Multimedia Filter
This Document is licensed to
MSDS - Material Safety Data Sheet
MTR - Mill Test Reports
Mr. Shlomo Sackstein
Herzlia,
NDR - Nondispersive Infrared Analysis
ID number: 216389
NIST - National Institute of Standards & Technology
NF - National Formulary (or nanofiltration)
nm - Nanometer
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NTU - Nephelometric Turbidity Units
For individual use only. © Copyright ISPE 2001. All rights reserved.
221
APPENDIX
O3 - Ozone
OSHA - Occupational Safety & Health Administration
p/ml - Particles per milliliter
P&ID - Process and Instrument Diagram
PFD - Process Flow Diagram
PLC - Programmable Logic Controller
PMA - Pharmaceutical Manufacturers Association
PP - Polypropylene
ppb - Parts per billion
ppm - Parts per million
psig - Pounds per square inch gauge
PTFE - Polytetrafluoroethylene
PVDF - Polyvinylidene
R - Performance ratio of a Distiller
Rc - Recovery ration for a still
RA - Average RMS of surface (Roughness Averager)
RO - Reverse Osmosis
rpm - Revolutions per minute
SOP - Standard Operating Procedure
SPC - Statistical Process Control
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SS - Stainless Steel
SVP - Small Volume Parenterals
TC - Total Carbon
TDS - Total Dissolved Solids
THM - Trihalomethanes
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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TOC - Total Organic Carbon
TOX - Total Organic Halogens
222
For individual use only. © Copyright ISPE 2001. All rights reserved.
APPENDIX
US EPA - United States Environmental Protection Agency
UF - Ultrafiltration or Ultra-filter
µmho - Micromho
µmho/cm - Micromho per centimeter
µS - Microsiemens
µS/cm - Microsiemens per centimeter
USP - United States Pharmacopoeia
UV - Ultraviolet Light
VC - Vapor Compression (still)
WFI - Water for Injection
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Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
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223
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Downloaded on: 6/2/10 4:16 AM
For individual use only. © Copyright ISPE 2001. All rights reserved.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Downloaded on: 6/2/10 4:16 AM
For individual use only. © Copyright ISPE 2001. All rights reserved.
This Document is licensed to
Mr. Shlomo Sackstein
Herzlia,
ID number: 216389
Downloaded on: 6/2/10 4:16 AM