ISO 22519 2023 (En)

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INTERNATIONAL ISO
STANDARD 22519
Second edition
2023-04
Membrane-based generation of water

for injection (WFI)
Production d'eau pour préparations injectables (EPPI) utilisant des
membranes
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ISO 22519:2023(E)
© ISO 2023
Licensed to NPK MEDIANA-FILTER / Vladimir Smirnov (smirnov@mediana-filter.ru)
ISO 22519:2023(E)
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© ISO 2023
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ii © ISO 2023 – All rights reserved

ISO 22519:2023(E)
Contents Page
Foreword......................................................................................................................................................................................................................................... iv
Introduction..................................................................................................................................................................................................................................v
1 Scope.................................................................................................................................................................................................................................. 1
2 Normative references...................................................................................................................................................................................... 1
3 Terms, definitions and abbreviated terms............................................................................................................................... 1
3.1 Terms and definitions....................................................................................................................................................................... 1
3.2 Abbreviated terms............................................................................................................................................................................... 2
4 System boundaries............................................................................................................................................................................................. 3
5 Feed water................................................................................................................................................................................................................... 3
6 Process design for membrane-based WFI generation systems.......................................................................... 3
6.1 General............................................................................................................................................................................................................ 3
6.2 Design conditions.................................................................................................................................................................................. 4
6.3 Important design factors................................................................................................................................................................ 4
6.4 Examples of possible configurations of water technology stages in WFI generation
systems........................................................................................................................................................................................................... 4
6.5 Primary microbial reduction unit operations............................................................................................................. 4
6.6 Instrumentation..................................................................................................................................................................................... 5
7 Sanitization................................................................................................................................................................................................................. 5
7.1 General............................................................................................................................................................................................................ 5
7.2 Sanitization types................................................................................................................................................................................. 5
8 Construction.............................................................................................................................................................................................................. 6
9 Demonstrating performance of critical quality attributes .................................................................................... 6
10 Sampling........................................................................................................................................................................................................................ 6
11 System operation.................................................................................................................................................................................................. 7
12 System maintenance......................................................................................................................................................................................... 7
13 Control............................................................................................................................................................................................................................. 7
14 Other considerations........................................................................................................................................................................................ 8
Bibliography................................................................................................................................................................................................................................. 9
© ISO 2023 – All rights reserved iii

ISO 22519:2023(E)
Foreword
ISO (the International Organization for Standardization) is a worldwide federation of national standards
bodies (ISO member bodies). The work of preparing International Standards is normally carried out
through ISO technical committees. Each member body interested in a subject for which a technical
committee has been established has the right to be represented on that committee. International
organizations, governmental and non-governmental, in liaison with ISO, also take part in the work.
ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of
electrotechnical standardization.
The procedures used to develop this document and those intended for its further maintenance are
described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the
different types of ISO documents should be noted. This document was drafted in accordance with the
editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).
Attention is drawn to the possibility that some of the elements of this document may be the subject of
patent rights. ISO shall not be held responsible for identifying any or all such patent rights. Details of
any patent rights identified during the development of the document will be in the Introduction and/or
on the ISO list of patent declarations received (see www.iso.org/patents).
Any trade name used in this document is information given for the convenience of users and does not
constitute an endorsement.
For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and
expressions related to conformity assessment, as well as information about ISO's adherence to
the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see
www.iso.org/iso/foreword.html.
This document was prepared by Technical Committee ISO/TC 282, Water reuse.
This second edition cancels and replaces the first edition (ISO 22519:2019), which has been technically
revised.
The main changes are as follows:
— title changed;
— PW systems removed from the Scope;
— document structure revised.
Any feedback or questions on this document should be directed to the user’s national standards body. A
complete listing of these bodies can be found at www.iso.org/members.html.
iv © ISO 2023 – All rights reserved

ISO 22519:2023(E)
Introduction
The water quality specifications for water for injection (WFI) are given in national and International
Standards and are well defined and understood.
The WFI generation systems potentially have to be able to cope with fluctuating feed water quality and
be in accordance with the company policy and current good manufacturing practice (cGMP).
Properly engineered, constructed, operated and maintained membrane-based generation systems
can have comparable reliability in meeting WFI quality specifications with low operational costs in
comparison with thermal-based WFI generation. At the time of publication, all major pharmacopoeia
allow non-distillation-based WFI generation, with the exception of the Chinese Pharmacopoeia. The
Chinese Pharmacopoeia has initiated revisions to related standards.
This document has been developed to address the lack of an International Standard concerning
membrane-based WFI generation.
The aim of this document is to:
— set out clear principles needed for reliable membrane-based generation of WFI;
— improve membrane-based generation of WFI process systems and methods;
— combine relevant standards, guidelines and global expert knowledge into one International
Standard;
— consider in-system microbiological aspects of WFI generation;
— standardize expectations for membrane-based WFI generation.
This document provides a global benchmark that can be used by industries that use the WFI generation
system.
© ISO 2023 – All rights reserved v

INTERNATIONAL STANDARD ISO 22519:2023(E)
Membrane-based generation of water for injection (WFI)
1 Scope
This document provides a benchmark for evaluation of the design, operation and performance of water
for injection (WFI) generation systems based on membranes.
This document is applicable to the design of new systems.
This document covers the following topics:
— principles of membrane-based WFI generation systems;
— process design, construction, operation and maintenance of membrane-based WFI generation
systems;
— controlling membrane-based WFI generation system parameters.
This document does not cover the following topics:
— validation;
— distillation.
2 Normative references
The following documents are referred to in the text in such a way that some or all of their content
constitutes requirements of this document. For dated references, only the edition cited applies. For
undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 20670, Water reuse — Vocabulary
3 Terms, definitions and abbreviated terms

For the purposes of this document, the terms and definitions given in ISO 20670 and the following apply.
ISO and IEC maintain terminology databases for use in standardization at the following addresses:
— ISO Online browsing platform: available at https://w ww.iso.org/obp
— IEC Electropedia: available at https://w ww.electropedia.org/
3.1 Terms and definitions

3.1.1
pretreatment
equipment and process stages up to and including the first-pass reverse osmosis (RO) pump or other
membrane-based primary bioburden reduction step
3.1.2
generation system
equipment and process stages after (downstream) reverse osmosis (RO) stage 1 pump
© ISO 2023 – All rights reserved 1

ISO 22519:2023(E)
3.1.3
multimedia filter
MMF
layered filtration media in a pressurized container, used to reduce the level of suspended solids in
incoming feed water
Note 1 to entry: Media layers can consist of anthracite, sand and garnet.
3.1.4
chlorination
dosage or generation of hypochlorite or chlorine to generate controlled free chlorine levels in the
system
3.1.5
activated carbon filter
ACF
activated carbon media for removal of free chlorine, chloramines and total organic carbon (TOC)
Note 1 to entry: The media can be applied as a granular activated carbon (GAC) pressurized container or a
cartridge type. The configuration of the activated carbon filter can depend on, for example, the level of feed
water impurities and system capacity.
3.1.6
ultraviolet
UV
irradiation of water with light in wavelengths ranging from 180 nm to 350 nm for dechlorination
or disinfection purposes at higher wavelengths and total organic carbon (TOC) reduction at lower
wavelengths
3.1.7
molecular weight cut-off
MWCO
molecular weight at which 90 % of the macromolecular solute is rejected by the membrane
3.1.8
electrodeionization
EDI
process for ion removal from water utilizing electricity, ion exchange membranes and resin
3.1.9
continuous electrodeionization
CEDI
process for ion removal from water utilizing electricity, ion exchange membranes and resin
3.1.10
polishing UF
polishing ultrafiltration
membrane-based process for reduction of endotoxin, total organic carbon (TOC) and bacteria post-RO
or post-electrodeionization (EDI) or continuous electrodeionization (CEDI)
3.2 Abbreviated terms
ACF activated carbon filter
CEDI continuous electrodeionization
EDI electrodeionization
EPDM ethylene propylene diene (M-group)
2 © ISO 2023 – All rights reserved

ISO 22519:2023(E)
HWS hot water sanitization
MWCO molecular weight cut-off
MMF multimedia filter
PTFE polytetrafluoroethylene
RO reverse osmosis
SOP standard operating procedure
SS stainless steel
TOC total organic carbon
UF ultrafiltration
UV ultraviolet
WFI water for injection
4 System boundaries
For the purpose of this document, the boundaries for the WFI generation system are as follows:
a) The inlet of potable water to the equipment dedicated to the WFI pretreatment system is the start
of the system.
b) A water treatment system that aims to improve the feed water to potable standards is not part of
the WFI generation system.
c) The WFI generation system end boundary is at the inlet valve (inclusive) of the WFI storage tank or
at the point of use (POU) if a tank is not installed.
d) The WFI storage tank is not included in the WFI generation system boundary.
e) “Industrial” treatment systems upstream of the WFI generation system, including supply to other
plant utilities, for example steam boilers, potable water usage and feed to cooling towers, are not
included in the WFI generation system.
5 Feed water
Incoming feed water should meet the potable water standards of the World Health Organization (WHO)
in Reference [3]. If incoming feed water does not comply with drinking water requirements, additional
systems should be installed to improve the feed water parameters before the membrane-based WFI
generation system.
6 Process design for membrane-based WFI generation systems
6.1 General
This clause gives guidance on proper design of the water treatment system. A risk assessment should
be carried out to improve the final system design by modifying or completing the details in all clauses
accordingly, if applicable.

ISO 22519:2023(E)
6.2 Design conditions

The WFI generation system design should be stable under common worst-case scenarios:
a) changing seasons;
b) feed water microbial load;
c) fluctuation of feed water quality;
d) other fluctuating environmental conditions.
6.3 Important design factors

For designing a membrane-based WFI generation system, the feed water composition should be taken
into account. The following critical parameters may be considered to ensure reliable and effective
operation of primary purification unit operations:
a) scale;
b) TOC;
c) silica;
d) iron;
e) manganese;
f) dissolved solids;
g) suspended solids;
h) dechlorination;
i) microbial.
6.4 Examples of possible configurations of water technology stages in WFI generation

systems
a) Sanitant: dosing of free chlorine or chlorine dioxide.
b) Initial filtration: MMF, cartridge depth filter, UF, screen filters, disk filters.
c) Membrane anti-scaling: softener, electrical scale control, antiscalant.
d) Sanitant removal stage: activated carbon, UV, sodium bisulfite (SBS) or sodium metabisulfite
(SMBS).
e) Production stage: single-pass RO, double-pass RO.
f) CO2 removal: caustic dosing (upstream final-pass RO) or contact degassing membrane (upstream of
final stage).
g) Final stage for further reduction of product conductivity and/or other contaminants (if needed):
CEDI/EDI and/or ultrafiltration.
6.5 Primary microbial reduction unit operations

a) A minimum of two membrane barriers for microbiological and endotoxin removal should be
implemented in accordance with the options listed or in conjunction with extra process steps:
— RO-RO;

ISO 22519:2023(E)
— RO-UF (polishing UF with endotoxin log reduction or minimum MWCO);

— other validatable membrane-based systems.
b) The following additional processes may be implemented as deemed necessary:
— UV irradiation;
— microbial or absolute retentive filters;
— polishing UF;
— other processes.
c) If only one membrane barrier is used then the following risk assessment and implementation may
be drawn up to ensure proper bioburden removal post-membrane:
— institute an independent technological process;
— apply appropriate testing.
6.6 Instrumentation
The minimum instrumentation should be:
a) conductivity instruments after all RO and CEDI/EDI steps;
b) conductivity instruments needed for final product measurement;
c) TOC sample points or TOC online instrumentation for final product monitoring.
7 Sanitization
7.1 General
a) The sanitization performance should be compliant with a contamination control strategy.
b) Sanitization shall be possible throughout the system, from pretreatment to generation included.
c) Sanitization principles and approaches may differ between pretreatment and final treatment
systems.
d) Hot water or other proven sanitization is needed for the final membrane barrier.
e) Hot water temperature or sanitant concentration, time and cycle shall be demonstrated to be
effective in controlling microbiological growth.
f) If ACF is utilized, it should be thermally sanitized.
7.2 Sanitization types

Sanitization types should be as follows:
a) hot water (preferred);
b) chemical;
c) other equivalent processes.

ISO 22519:2023(E)
8 Construction
a) The system shall be hygienically designed and built downstream of final membrane barrier.
b) Consideration should be given to an implementation of hygienic principles in the production system
as necessary based on risk assessment.
c) The components in the pretreatment and generation system should be fabricated from:
— SS304/SS316 (“L” for low carbon content needed if components are welded);
— Polyvinylidene fluoride (PVDF) or other non-corroding, resistant against the intended
sanitization method, for instance HWS, non-particle shedding and non-leaching materials.
d) Gaskets shall be one of the following:
— EPDM encapsulated with PTFE gaskets;
— full EPDM;
— full PTFE;
— silicone;
— fluoroelastomers;
— combinations of inert, resistant against the intended sanitization method, for instance HWS,
non-particle shedding and non-leaching elastomers.
Prior to construction, the system designer should identify certification standards to confirm suitability
of components to the operating parameters in the different parts of the system.
9 Demonstrating performance of critical quality attributes

a) Sampling programmes should include in-system and unit operation sampling to verify control of
system parameters in the system.
b) The minimum microbial parameters that should be monitored are:
— total microbial count;
— endotoxin;
— objectionable organisms.
c) The minimum chemical parameters that should be monitored are:
— conductivity (online);
— TOC;
— other relevant parameters.
NOTE If an online conductivity instrument or TOC analyser is installed and the online conductivity or TOC
analyser has already met regulations for online measurement, there is no need for samples to be taken for off-line
conductivity or TOC testing.
10 Sampling
a) Specific sampling locations and appropriate valve type should be provided to demonstrate control
and to meet the requirements of Clause 9.

ISO 22519:2023(E)
b) The following are the minimum requirements of sampling locations in pretreatment or generation:
1) sample valves upstream and downstream of all unit operations;
2) hygienic sample valves and connection setup shall be used downstream of the final RO stage.
c) Sampling shall be performed in accordance with internal procedures, which shall include a full
flushing of the sample valve in order to prevent contamination of the sample.
11 System operation
a) Proper microbial control shall be demonstrated.
b) The following shall be considered for the microbial control:
1) continuous system operation;
2) flushing;
3) sanitization.
c) Areas of the system that do not have constant flow, as in clean-in-place (CIP) return lines and
bypasses, shall be treated in a manner to avoid microbiological growth. For instance, by draining
between uses.
d) Every time the system has not been in operation for a certain period of time, determined by risk
analysis or testing, a subsequent start-up should be carried out according to an SOP.
12 System maintenance
WFI generation system maintenance should be determined by a risk analysis to determine the activities
needed.
The following actions should be covered by an SOP:
a) inspection;
b) parts replacement;
c) regeneration;
d) sanitization;
e) other applicable actions.
13 Control
The WFI generation control system and other supporting systems should meet the following minimum
requirements:
a) necessary alarms for product quality and system operation;
b) recorded history of critical parameter data;
c) recorded history of critical alarms;
d) programmable logic controller (PLC), distributed control system (DCS) or equivalent with human-
machine interface (HMI).

ISO 22519:2023(E)
14 Other considerations
Depending on the contamination control strategy, risk assessment and risk tolerance, the following
technologies should be considered:
a) supervisory control and data acquisition (SCADA);
b) online TOC;
c) rapid endotoxin testing;
d) rapid microbial testing.

ISO 22519:2023(E)
Bibliography
[1] ASME BPE-2022. Bioprocessing Equipment

[2] ASTM D 6908-03. Standard Practice for Integrity Testing of Water Filtration Membrane Systems
[3] World Health Organization. GMP Water for Pharmaceutical Use, Annex 2, WHO Good Manufacturing
Practices: water for pharmaceutical use. 2021. Available from: https://w ww.who.int/docs/default
-source/medicines/norms-and-standards/g uidelines/production/t rs970-annex2-gmp-wate
-pharmaceutical-use.pdf?sfvrsn=39eb16b8_0
[4] European Medicines Agency. ICH guideline Q10 on pharmaceutical quality system. Committee for
Human Medicinal Products. 2015
[5] European Medicines Agency. Guideline on the Quality of Water for Pharmaceutical Use. 2021
[6] European Medicines Agency. Questions and Answers on Production of Water for Injections by Non-
distillation Methods – Reverse Osmosis and Biofilms and Control Strategies. 2017
[7] ISPE. Baseline Guide Vol 4: Water & Steam Systems. ISPE, 2019
[8] European Commission. EudraLex — The Rules Governing Medicinal Products in the European
Union. Volume 4: Good Manufacturing Practice — Medicinal Products for Human and Veterinary
Use. Annex 11: Computerised Systems. Brussels: EC, 2011
[9] European Directorate for the Quality of Medicines & HealthCare. European Pharmacopoeia (Ph.
Eur.). 10th edition. 2022
[10] Pharmaceuticals and Medical Devices Agency. The Japanese Pharmacopoeia. 18th edition. 2021
[11] USP. United States Pharmacopeia. 2021
[12] FDA. Title 21 CFR Part 11: Electronic Records; Electronic Signatures. 2017

ISO 22519:2023(E)
ICS 13.060.01
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Membrane-based generation of water

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ii ﻿ © ISO 2023 – All rights reserved

© ISO 2023 – All rights reserved ﻿ iii

iv ﻿ © ISO 2023 – All rights reserved

© ISO 2023 – All rights reserved ﻿ v

INTERNATIONAL STANDARD ISO 22519:2023(E)

Membrane-based generation of water for injection (WFI)

3 Terms, definitions and abbreviated terms

3.1 Terms and definitions

© ISO 2023 – All rights reserved ﻿ 1

3.2 Abbreviated terms

ACF activated carbon filter

CEDI continuous electrodeionization

EPDM ethylene propylene diene (M-group)

2 ﻿ © ISO 2023 – All rights reserved

HWS hot water sanitization

MWCO molecular weight cut-off

MMF multimedia filter

SOP standard operating procedure

TOC total organic carbon

WFI water for injection

6 Process design for membrane-based WFI generation systems

© ISO 2023 – All rights reserved ﻿ 3

6.2 Design conditions

6.3 Important design factors

6.4 Examples of possible configurations of water technology stages in WFI generation

6.5 Primary microbial reduction unit operations

4 ﻿ © ISO 2023 – All rights reserved

— RO-UF (polishing UF with endotoxin log reduction or minimum MWCO);

7.2 Sanitization types

© ISO 2023 – All rights reserved ﻿ 5

9 Demonstrating performance of critical quality attributes

6 ﻿ © ISO 2023 – All rights reserved

© ISO 2023 – All rights reserved ﻿ 7

8 ﻿ © ISO 2023 – All rights reserved

[1] ASME BPE-2022. Bioprocessing Equipment

© ISO 2023 – All rights reserved ﻿ 9

© ISO 2023 – All rights reserved ﻿

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