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Pure Water Guide LR 2021 v08-US
Pure Water Guide LR 2021 v08-US
WATER TECHNOLOGIES
PHARMACEUTICAL PURE WATER GUIDE
04 Introduction
17 Purified water
27 Glossary of terms
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PHARMACEUTICAL PURE WATER GUIDE
INTRODUCTION
POTABLE WATER contrast, water from an underground Colloidal particles, which can be
source generally has a high level organic or inorganic, give rise to haze
Purified water used in pharmaceutical of salts and hardness but a low or turbidity in the water.
processes is usually produced in-situ organic content. River sources are
from local potable water which has intermediate in quality but also often Suspended particles can foul
been produced by the treatment of contain products from industrial, reverse osmosis membranes and
natural water sources. agricultural and domestic activities. electrodeionization stacks, as well as
Seasonal variations in water quality interfere with the operation of valves
The unique ability of water to are most apparent in surface waters. and meters.
dissolve, to some extent, virtually During the autumn and winter
every chemical compound and months, dead leaves and decaying Dissolved inorganic
support practically every form of life plants release large quantities of compounds
means that potable water supplies organic matter into streams, lakes Inorganic substances are the major
contain many substances in solution and reservoirs. As a result, organic impurities in water. They include:
or suspension. contamination in surface waters � Calcium and magnesium salts
season. Water derived from an bearing on the purification regime � Silicates leached from sandy river
upland surface source, for instance, required to produce purified water. beds
usually has a low content of dissolved � Ferrous and ferric iron compounds
salts and is relatively soft, but has Suspended particles derived from minerals and rusty
a high concentration of organic Suspended matter in water includes iron pipes
contamination, much of it colloidal. By silt, pipework debris and colloids. � Chlorides from saline intrusion
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PHARMACEUTICAL PURE WATER GUIDE
� A
luminium from dosing chemicals Measuring impurities in
and minerals potable water
� P
hosphates from detergents In order to design or select a water
� N
itrates from fertilisers purification system it is necessary to
have information on the composition
Dissolved organic compounds of the feedwater, usually local potable
Organic impurities in water arise water. Average data can often be
from the decay of vegetable matter, obtained from the local water
principally humic and fulvic acids, supplier, however, an analysis of the
and from farming, paper making and water gives the information directly.
domestic and industrial waste. These
include detergents, fats, oils, solvents The filter-blocking potential of
and residues from pesticides and the water can be estimated using
herbicides. In addition, water-borne a fouling index (FI) test or, less
organics may include compounds reliably, turbidity. A wide range
leached from pipework, tanks and of methods are available for
purification media. determining inorganic components.
Ion chromatographic, ICP-mass
Microorganisms spectrometric or spectrophotometric
The chief microorganisms of concern methods are often used. Electrical
for water purification systems are conductivity provides a guide
bacteria. A typical bacterial level for a to potential problems. Organic
potable pharmaceutical water supply compounds can be determined
is ten colony forming units per one individually, e.g. chromatographically,
hundred milliliter (10 CFU/100ml) or or an overall indication of organic
less. Bacteria are usually kept at these content can be provided by a total
low levels by the use of residual levels organic carbon (TOC) measurement.
of chlorine or other disinfectants. Total viable bacterial counts as well
Once the disinfectants are removed as those of individual species can be
during purification, bacteria have the measured by filtration or inoculation
chance to proliferate. and incubation in a suitable growth
medium.
Dissolved gases
Potable water is in equilibrium with Total dissolved solids (TDS) is the
the air and so contains dissolved residue in ppm obtained by the
oxygen and carbon dioxide. Carbon traditional method of evaporating
dioxide behaves as a weak acid and a water sample to dryness and
uses the capacity of anion exchange heating at 180°C. By far the greatest
resins. Dissolved oxygen is usually proportion of the filtered residue
only an issue where bubble formation is inorganic salts and TDS is used
is a problem. In applications where as an indicator of the total level of
the purified water is used in open inorganic compounds present. It can
containers it will rapidly re-equilibrate be measured directly or estimated by
with the gases in the air. multiplying the conductivity of the
water in μS/cm at 25°C by 0.7.
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PHARMACEUTICAL PURE WATER GUIDE
Purifying potable water sufficiently primarily effective in killing planktonic solids and to protect downstream
for use in the pharmaceutical (free-floating) microorganisms. purification technologies from
industry usually requires a series Sloughing biofilm and byproducts fouling and clogging. They are
of purification stages. The overall of microorganism growth and replaced periodically.
objective is to remove the impurities metabolism (e.g. endotoxins) are always
in the feedwater while minimising potential contaminants of water.
additional contamination from the
components of the purification The challenges for a purified water
system and from bacterial growth. generation system are to:
System design and component � Meet all of the requirements
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PHARMACEUTICAL PURE WATER GUIDE
very rapid and small carbon filters The large surface area and high system is about the same as for a
can effectively remove chlorine from porosity of activated carbons along reverse osmosis system and feed
water. The breakdown of chloramines with material they trap, make them water should be pre-treated prior to
by carbon is a relatively slow catalytic a breeding place for microorganisms. going to the membranes.
reaction producing ammonia, nitrogen Activated carbon beds need to be
and chloride therefore larger volumes periodically sanitised or changed MAJOR PURIFICATION
of carbon are needed to handle regularly to minimise bacterial TECHNOLOGIES
these. Organic fouling can reduce build-up.
the effectiveness of the carbon and is Reverse osmosis (RO)
dependent on the local water supply. Water softening (SO) RO membranes are used to remove
This should be considered when Hardness in a water supply can result contaminants that are less than
sizing its carbon units. in scale formation, which is a deposit 1 nm nominal diameter. Reverse
of minerals left over after the water osmosis typically removes 90% to
The second application of activated has been removed or evaporated. 99% of ionic contamination, most
carbon is in the removal of organic This can be found in reverse osmosis organic contamination, and nearly
compounds from potable water. systems, clean steam generators and all particulate contamination from
Activated carbon takes up water distillation systems. water. RO removal of non-ionic
contaminants by virtue of ionic, polar contaminants with molecular
and Van der Waals forces, and by The most common technology weights <100 Dalton can be low.
surface-active attraction. Activated used for removing scale formed by It increases at higher molecular
carbon beds are prone to releasing calcium and magnesium ions is ion weights and, in theory, removal will
fines and soluble components into exchange water softening. A water be complete for molecules with
the water stream and do not remove softener has four major components: molecular weights of >300 Dalton
all dissolved organic contaminants, a resin tank, resin, a brine tank and and for particles, including colloids
but their use can produce a significant valves or controller. When hard and microorganisms. Dissolved gases
reduction in TOC. A purer form of water is passed through the resin, are not removed (eg. CO2).
activated carbon made from polymer calcium, magnesium, and other
beads is sometimes used for this multivalent ions such as iron adheres During reverse osmosis, pretreated
application. to the resin, releasing the sodium water is pumped past the input
ions until equilibrium is reached. A surface of an RO membrane
regeneration is needed to exchange under pressure (typically 4–15 bar,
the hardness ions for sodium ions 60–220 psi) in cross-flow fashion.
by passing a sodium chloride (NaCl) RO membranes are typically thin
solution (called brine) through the film composite (polyamide). They
resin. Acidification/Degasification are stable over a wide pH range,
can be used as a softening process but can be damaged by oxidising
but it has numerous disadvantages, agents such as chlorine, present in
such as handling chemical municipal water. Pretreatment of the
(sulphuric acid, antiscalant) and feedwater with microporous depth
instrumentation for two pH filters, softener and activated carbon
adjustments. Nanofiltration is is usually required to protect the
sometimes referred to as a softening membrane from large particulates,
membrane process and will remove hardness and free chlorine. Typically
anions and cations. The feedwater 75%-90% of the feedwater passes
requirement for a nanofiltration through the membrane as permeate
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PHARMACEUTICAL PURE WATER GUIDE
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PHARMACEUTICAL PURE WATER GUIDE
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PHARMACEUTICAL PURE WATER GUIDE
its “clean” non-chemical nature high levels of salts. The small volume
and constant high quality water of resins in the stack results in low
produced. bleed of organic molecules. Typically,
RO removes about 95% of ions; CEDI
The resins used in CEDI systems can will remove 99% of the remaining
either be separate chambers of anion ions as well as carbon dioxide,
or cation beads, layers of each type organics and silica.
within a single chamber or an intimate
mixture of cation and anion beads. Compared to DI only the combination
of RO and CEDI has been the prefered
Veolia Water Technologies’ process technology as the RO
pharmaceutical CEDI process utilizes provides a very good membrane
cation beads in the concentrate barrier for removing bacteria thus
stream and layered beds of cation greatly reducing the risk of microbial
CEDI Lx Module
and anion resins in dilute stream. contamination. CEDI will polish the RO
permeate to the required conductivity
The resins are housed in wide cells levels required in this market.
Reverse osmosis permeate passes that provide a flow path for the ions in
through one or more chambers filled transit. This offers advantages in the Typically, CEDI product water has a
with ion exchange resins held between flexibility of design and mechanical resistivity of 1 to 18.2 MΩ-cm (at 25°C)
cation or anion selective membranes. simplicity on an industrial scale. and a total organic carbon content
Ions that become bound to the ion The ion migration from dilute to below 20 ppb. Bacterial levels are
exchange resins migrate from the concentrate is enhanced by the minimised because the electrical
dilute chamber to a separate chamber layered resin bed in the dilute. conditions within the system inhibit
(concentrate) under the influence of the growth of microorganisms.
an externally applied electric field, Reverse osmosis (and sometimes
which also produces the H+ and OH- membrane degassing) is typically Modern CEDI stacks allow the user
necessary to maintain the resins in used before CEDI to ensure that the to carry out hot water sanitisation at
their regenerated state. Ions in the CEDI stack is not overloaded with 85°C, for a period of one to four hours.
concentrate chamber are recirculated
to a break tank or flushed to waste. Feed Water Inlet
CONCENTRATE INLET
The ion exchange beds in continuous
electrodeionisaton (CEDI) systems
are regenerated continuously, so they
do not exhaust in the manner of ion
exchange beds that are operated
in batch mode (with chemical
regeneration). CEDI beds are typically Anode Cathode
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PHARMACEUTICAL PURE WATER GUIDE
11
Thinking of Cold WFI Production?
THink ORION
USP/Ph Eur WFI endotoxin limit of ► FDA Only used to test hydrophobic PTFE
► cGMP guidelines to achieve best membrane filters used for gas
practices sterilisation.
► Prevention of batch loss/
reprocessing
Integrity testing
� By proving the link between
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PHARMACEUTICAL PURE WATER GUIDE
80
Germicidal Effectiveness and high molecular weight organic
70 Curve with Peak at 265 nm
compounds and over 90% of ions.
60
The resultant deionised water will
50
185 nm Output Line contain some organic compounds,
40
Other Germicidal Lamp some ions, some bacteria and cell
30 Output Lines
debris and all the dissolved carbon
20
dioxide and oxygen.
10
0
The water is next treated by one
180 210 240 270 300 330 360 390 420
Wavelength in Nanometers (nm) or more techniques depending on
the required purity - ion exchange
or second stage reverse osmosis
Ultraviolet light continuous electrodeionisation. or CEDI to remove ions, UV light
Ultraviolet light is used as a 185nm UV is also used to destroy to kill bacteria and/or to oxidise
bactericide and to break down and excess chlorine or ozone. UV residual organic compounds and
photo-oxidise organic contaminants radiation at 185nm is a highly ultrafiltration to remove endotoxin,
to polar or ionised species for effective photo-oxidant and a key protease and nuclease. Any or all of
subsequent removal by ion exchange. component in producing purified these stages can be combined in the
water with the lowest levels of same unit as the reverse osmosis or
The UV sources in pharmaceutical organic contaminants. separately in a polisher.
water purification systems are low
or medium pressure mercury vapour System design Storage tanks and distribution are
lamps. Radiation with a wavelength The different technologies described potential sources of contamination,
of 240-260nm has the greatest on the previous pages can be combined particularly from bacteria. Good
bactericidal action with a peak at in a variety of ways to achieve the design and proper maintenance
265nm. It damages DNA and RNA desired degree of water purification. regimes are needed to minimise
polymerase at low doses preventing problems. The choice of materials of
replication. For most pharmaceutical Each system will require some construction is also critical. Metals,
applications, UV chambers and pretreatment based on the particular other than stainless steel, should
lamps need to be designed to
provide a sufficient dosage of UV to
achieve a 6 log10 reduction of typical
pathogenic contaminants.
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PHARMACEUTICAL PURE WATER GUIDE
which provides a high degree of � JP – Japanese Pharmacopoeia ‘GAMP 5’ – a guideline for the
assurance that a specific process will ‘Good Manufacturing Practice’ validation of automated systems
consistently produce a product (GMP)
meeting its predetermined � FDA Code of Federal Regulations ISO 9001 – Quality Management
specifications and quality attributes”1. 21CFR210 and 21CFR211 System approval
� The Rules Governing Medicinal
Validation is the process of Products in the European Union The documents created for a validated
documenting the design, installation, Volume 4 water treatment system may vary
operation and performance of an from site to site; however, the
operating system. Periodically all water ISPE ‘Baseline® Guide’ standard documents are generally
treatment systems may be inspected � Volume 4 – Water and Steam covered in the following list of
by the local or international inspecting Systems documents.
authorities to ensure that the
pharmaceutical facility complies with
the local or international regulations.
Ultimately the user is responsible for
validating the water system to make
sure that it meets the requirements of
the inspectors; however, the supplier
will need to provide most of the
test documentation for the water
treatment plant.
1
uidelines on general principles of
G
14 process validation - FDA May 1987.
PHARMACEUTICAL PURE WATER GUIDE
DOCUMENTATION LIST
This document defines how the supplier will fulfil the user and
supplier’s quality requirements on the project. It also provides
details of the project management on the contract. This may
QPP Quality & Project Plan
include a Gantt chart for the project management of the
contract. This is the supplier’s response to the VMP. Document
created by the supplier.
Lists all the valves and the valve specification. Created by the
VALVE SCHEDULE Valve Schedule
supplier.
Lists all the utilities and the utility specification, such as water,
UTILITIES SCHEDULE Utilities Schedule drains, electricity, steam, air, chemicals, etc. Created by the
supplier.
SDS Software Design Specification To describe the control panel software function and design.
STS Software Test Specification To test the functions described in the SDS.
HDS Hardware Design Specification To describe the control panel hardware function and design.
HTS Hardware Test Specification To test the functions described in the HDS.
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PHARMACEUTICAL PURE WATER GUIDE
DOCUMENTATION LIST
Change Control is the most variable component of a water system is carried out on a
Key to the validation effort is the a water system and so regular and regular basis, determined by the
control and evaluation of change detailed monitoring is required. monitoring of bacteria in the system.
both during the time scale of the This monitoring will aid the The method used for sanitisation
project and in subsequent ongoing determination of when the system depends on a number of factors
use. Inspectors mandate change should be sanitised. such as the materials of construction
control for processes, equipment and the design intent. If the system
and control systems. The aim of Sanitisation is made of plastic materials then
any change control is to provide an Sanitisation of the water purification a chemical sanitisation method is
auditable trail and to ensure a state and distribution system is critical to used, as most plastics cannot accept
of control. ensure that microbial contamination high temperatures. Per-acetic acid
is controlled within specifications. and hydrogen peroxide are often
Performance Sanitisation frequency must be used as chemical sanitants. Where
The ongoing performance of the adequate to maintain the purity the materials of construction are
plant is monitored regularly by specifications and is established metal or plastics suitable for high
the user. The user needs to be in based on system usage, regular temperature then heat is frequently
control of the quality of water quality control trend data, and used. Hot water (85°C), overheated
produced by the system. Typically the system manufacturer’s water (121°C), steam or ozone are
the bacteria content of the water recommendation. Sanitisation of frequently used for sanitisation.
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PHARMACEUTICAL PURE WATER GUIDE
PURIFIED WATER
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PHARMACEUTICAL PURE WATER GUIDE
2
USP monogram.
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PHARMACEUTICAL PURE WATER GUIDE
20 23.85 12.15
Conductivity/Resistivity
25 18.18 10.00
The chemical attributes of purified
30 14.09 8.28
Water and Water for Injection (WFI)
were in effect prior to USP23 were 35 11.09 6.90
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PHARMACEUTICAL PURE WATER GUIDE
20
PHARMACEUTICAL PURE WATER GUIDE
� T
he Japanese Pharmacopoeia (JP) 0 2.4
10 3.6
20 4.3
The standards in this section are a
25 5.1
summary and correct at the time
30 5.4
of going to press3. Standards are
regularly reviewed and updated 40 6.5
70 9.7
Pharmacopoeia standards 80 9.7
Separate pharmacopoeia are 90 9.7
produced by a number of authorities, 100 10.3
notably in the USA, Europe and Japan.
Each specifies materials, including
water, to be used in pharmaceutical PHARMACOPOEIA REQUIREMENTS FOR WATER FOR INJECTION AND HIGHLY
work. The standards for purified PURIFIED WATER
water are similar in each case. Extra PROPERTIES Ph Eur USP
criteria are set for water required for CONDUCTIVITY <1.1 µS/cm at 20°C*** <1.3 µS/cm at 25°C*
sterile applications. The standards for
TOC <500 µg/l C** <500 ppb
purified water given in the European
BACTERIA (guideline) <10 CFU/100ml <10 CFU/100ml
Pharmacopoeia (Ph Eur) and in the
ENDOTOXINS <0.25 IU/ml <0.25 EU/ml
United States Pharmacopoeia (USP)
NITRATES <0.2 ppm -
are summarized below. Water for
HEAVY METALS <0.1 ppm -
injection has stringent bacterial/
pyrogen criteria and methods of * Offline conductivity measurements possible. If in-line conductivity exceeds values then refer to USP
tables in section 645 (Table 1). If value exceeds that in table 1, refer to Three Stage Philosophy.
preparation are specified.
** Or pass oxidisable substances test.
*** If in-line conductivity exceeds values then refer to the European Pharmacopoeia (Ph Eur).
3
as of going to print 2020.
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PHARMACEUTICAL PURE WATER GUIDE
Three Stage Philosophy As well as defining the absolute USP and JP allow the use of other
Stage 1 water quality standards, the technologies, such as reverse osmosis
� Temperature not less than 25°C pharmacopoeia monographs give and ultrafiltration, for the production
and conductivity not greater than guidance on appropriate treatment of WFI. Since April 2017 EP has
1.3 μS/cm processes for producing the various fallen in line and will accept a twin
� SAMPLE PASSES TEST types of regulated water. These membrane system for cold WFI water
are generally non-prescriptive. production.
If measured on-line the conductivity
meter must be calibrated and non
temperature compensated, the
temperature must be measured TABLE 1 TABLE 2
independently by an adjacently STAGE 1: TEMPERATURE/CONDUCTIVITY STAGE 3: CONDUCTIVITY
installed calibrated temperature meter. REQUIREMENTS (FOR USP) REQUIREMENTS (FOR USP)
If the temperature is less than 25°C or (for non-temperature compensated AS A FUNCTION OF PH
conductivity measurements)
the conductivity greater than 1.3 μS/cm
TEMPERATURE °C CONDUCTIVITY µS/cm pH µS/cm
then the conductivity measured must
be checked against the Temperature/ 0 0.6 5.0 4.7
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PHARMACEUTICAL PURE WATER GUIDE
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PHARMACEUTICAL PURE WATER GUIDE
Buffer and media preparation direct steam heating, injection and provides the CIP make up and rinse
The grade of pure water required in autoclaves and sterilisers. Most water. Different water types are
for reagent make-up or dilution steam generators benefit from used to suit different manufacturing
will depend on the sensitivity of pretreatment of the water supply processes. Purified water is most
the intended application. For many to avoid build-up or precipitation commonly used.
general pharmaceutical applications of contaminants and so reduce
where sensitivity is not the primary maintenance, improve performance Microbiological Analysis
factor, purified water is sufficiently and enhance hygiene levels. Steam Routine microbiological analysis
pure. It has the added advantage of generators can use purified water requires purified water. This
not only having high purity in ionic with conductivity of <1 μS/cm (> will be largely free of bacterial
terms, but, by also incorporating UV 1.0 MΩ-cm resistivity). It is typically contamination and have low levels
and filtration, can also ensure low produced by reverse osmosis coupled of ionic, organic and particulate
levels of organic contaminants and with electrodeionisation after impurities. Typical values are a
microorganisms. suitable pretreatment. resistivity of <1 μS/cm, TOC <50 ppb
and <100 CFU/ml bacteria count.
Feed to Ultra-pure water Glassware washing or rinsing
systems Glassware washing is an everyday Qualitative Analysis
The production of ultra-pure water practice in most Pharmaceutical The water required for most
(18.2 Mohm-cm resistivity, <5ppb laboratories and the grade of water qualitative analysis methods for
TOC) from tap water or its equivalent required for the task will depend major or minor constituents is
is usually carried out in two stages: on the nature of the intended general grade purified water with
pretreatment and polishing. Ideally, application. To minimise costs, most resistivity <1 μS/cm, TOC less than
pretreatment reduces all the major general-purpose glassware can be 50 ppb and low particulates and
types of impurities - inorganic, washed with purified water. bacterial counts.
organic, microbiological and For more sensitive analytical or
particulate - by over 95%. This can genetic techniques, Water for Water analysis
be achieved most effectively using Injection or highly purified water Water analyses are carried out
reverse osmosis or reverse osmosis grade can be used. Conductivity for many different reasons.
combined with CEDI. should be <0.05 μS/cm, TOC less Requirements include ensuring
than 10 ppb and bacterial counts potable water meets current
Feed to stills <10 CFU/100ml. standards, checking purification
A long-established method for water processes have been successfully
purification, distillation is most Cleaning in place carried out and environmental
effectively performed with pretreated Cleaning in place (CIP) is an testing of feed sources such as
water to minimise the build up of everyday practice in pharmaceutical lakes and rivers. Water analysis
precipitates and the carry over of manufacturing. CIP involves requires purified water for the
impurities. It is common practice periodically cleaning reactors, pumps, preparation of samples, standards
to feed a still with purified water, heat exchangers, distribution loops and blanks. This water must be of
particularly where multi-effect stills and process filling machines. Some a known purity that is sufficiently
are used. processes are cleaned between high so as not to interfere with the
each batch. The sporadic nature of analytical techniques. Water analysis
Pure Steam Generators (PSG) CIP means that demand flow rate applications are usually performed
Steam generators are used in a range can vary widely, and this has to be with water with resistivity of
of applications including clean room factored into the design of the water <0.2 μS/cm, TOC <50 ppb and a
humidification, moisturisation, generation and storage system that bacterial count below 1 CFU/ml.
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PHARMACEUTICAL PURE WATER GUIDE
APPLICATIONS AT A GLANCE
Analytical and General Applications
CONDUCTIVITY TOC FILTER BACTERIA ENDOTOXIN GRADE OF
TECHNIQUE SENSITIVITY
μS/cm ppb μm CFU/ml IU/ml PURE WATER
Feed to Ultra-pure
General <1 <50 NA <1 NA WFI HPW
water systems
Microbiological
General <1 <50 <0.2 <100 NA Purified water
analysis
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PHARMACEUTICAL PURE WATER GUIDE
1 Stored purified water must be 6 Appropriate pipework, fittings 11 CEDI technology modules must
continuously recirculated and quality and finishing must be be fed with reverse osmosis
the equipment periodically used in order to avoid dead–legs, quality water. Hardness,
sanitised. crevices, etc. particules, organics, oxidising
agents, iron and manganese
2 Temperature should be actively 7 The 0.22μm cartridge filter and must be removed before the
controlled in the system by vent filter should be changed module.
means of either heating or regularly; typically at least
cooling heat exchangers, or every six months, to minimise 12 For chemical or hot water
by periodic purging to avoid the build–up of bacterial sanitization of the CEDI module,
overheating. contamination. the module must be able to
bear chemical agents, such as
3 The microbiological purity of 8 At least 5 to 10 minutes of purified peracetic acid and hydrogen
the water in a water treatment water should be run to drain peroxide or hot water at >85°C
system can only be maintained after a period of inactivity, e.g. for a minimum of one hour. This
by recirculating the water before feeding the purified water should be checked before initial
through the various purification tank or during the weekend. sanitisation.
processes via the break tank. The
break tank should be of sanitary 9 To ensure efficient operation of 13 For pretreatment UV,
design and construction. the resistivity meter, a qualified proper pre-filtration should
individual should clean the be implemented to keep
4 Regular sanitisation is essential electrodes of the line cell and particulate from shielding
to prevent build–up of calibrate the resistivity meter organisms from UV light.
biofilm. Heat is the preferred every 12 months.
sanitisation method although 14 UV lamps should be replaced at
hydrogen peroxide and ozone 10 To prolong the life of a reverse appropriate intervals (4,000–
can also be effective. Ozone osmosis membrane, it should be 10,000 hours depending on
and hot water sanitisation are regularly flushed and cleaned. type) and the quartz thimble/
suitable for the storage and Flushing removes particulate sleeve should be cleaned at the
distribution loop. matter or precipitated solids same time.
from the membrane surface.
5 To prevent algal growth, use of
translucent tanks and pipework
should be avoided and storage
vessels should not be installed
close to direct sunlight or
sources of heat.
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PHARMACEUTICAL PURE WATER GUIDE
GLOSSARY OF TERMS
Biofilm – A layer of microorganisms Color change resin – A resin that is Deionisation (DI) – Removal of
enclosed in a glycoprotein dyed with a pH indicator so that it impurity ions from water. Usually
polysaccharide matrix which are changes color upon exhaustion to used to refer to ion exchange – see
adherent to each other and/or to indicate when the cartridge needs ion exchange.
surfaces. replacing.
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PHARMACEUTICAL PURE WATER GUIDE
Deionisation service – see service GAMP – Good Automated Line Cell – An electrode assembly
deionisation. Manufacturing Practice. inserted into a water stream by
which the conductivity or resistivity
Distillation – A purification process Gram-negative – refers to bacteria is measured.
that takes advantage of changing that do not absorb a violet stain
the phase of a substance from liquid originally described by Gram. Microorganism – Any organism
to vapour and back to liquid usually that is too small to be viewed by
at the boiling temperature of the Gram-positive – Refers to bacteria the unaided eye, such as bacteria,
substance, in order to separate it that absorb a violet stain originally viruses, molds, yeast, protozoa, and
from other substances with higher or described by Gram. some fungi and algae.
lower boiling points.
Hardness – The scale–forming Nuclear grade resin – A high purity
Endotoxin – A thermally stable and lather–inhibiting qualities of (analytical) grade of ion exchange
lipopolysaccharide component from some water supplies, caused by resin originally developed for the
the cell wall of viable or nonviable high concentrations of calcium nuclear energy industry.
Gram–negative microorganisms. Can and magnesium. Temporary
act as a pyrogen. hardness, caused by the presence of Offline – In water monitoring
magnesium or calcium bicarbonate, systems, referring to measurement
Endotoxin Units (IU/ml or EU/ is so called because it may be devices that are not directly coupled
ml) – A quantification of endotoxin removed by boiling the water to to the water stream.
levels relative to a specific quantity convert the bicarbonates to the
of reference endotoxin. 1 IU/ml is insoluble carbonates. Calcium and Online – In water monitoring
approximately equal to 0.1 ng/ml. magnesium sulfates and chlorides systems, referring to measurement
cause permanent hardness. devices directly coupled to the water
Exotoxin – A toxic substance stream.
secreted by a bacterium, often HPW – Highly purified water.
causing disease, which can also act Oxidation – A process using
as a pyrogen. Ion – Any non–aggregated particle short wavelength light to kill
of less than colloidal size possessing microorganisms and cleave or oxidise
FDA – United States Food and Drug either a positive or a negative electric organic molecules.
Administration. charge.
Ozone – Ozone is used in the
Feedwater – The water that is Ion exchange (IX) – The process of pharmaceutical industry as a
introduced into a purification process. purifying water by removing ionised sanitising agent. O3 is a very strong
salts from solution, by replacing oxidising agent that kills bacteria
Filtration – A purification process in hydrogen ions for cation impurities and reduces TOC in water.
which the passage of fluid through and hydroxyl ions for anion
a porous material results in the impurities. Particulates – Discrete quantities of
removal of impurities. solid matter dispersed in water.
LAL – Limulus Amoebocyte Lysate,
Fines – Particulates released from a an extract from the horseshoe crab Permeate – The purified solution
bed of material such as ion exchange which forms a gel in the presence which has been produced by passage
resins. of sufficient endotoxin. Used as the through a semi–permeable reverse
basis for the LAL test for endotoxins. osmosis membrane.
Fouling Index – see Silt Density Index.
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PHARMACEUTICAL PURE WATER GUIDE
pH – A measure of the acidity or Qualification – The act of establishing SJP (JP) – The Society of Japanese
alkalinity of a solution equal to –log with documented evidence that the Pharmacopoeia (SJP) is a non–
(H+). process, equipment, and/or materials profit foundation authorised by
are designed, installed, operated the Ministry of Health, Labour and
PhEur – European Pharmacopoeia. and perform according to the pre– Welfare (MHLW). It was established
determined specifications. mainly to promote dissemination
Photo–oxidation – see ultra violet of the Japanese Pharmacopoeia (JP)
(Photochemical) oxidation. Regeneration – The method by which for the purpose of maintenance
exhausted ion exchange resins are and improvement in the efficacy,
Planktonic – Used to describe aquatic reactivated by treatment with strong safety and quality of pharmaceutical
microorganisms that float. acid or alkali. drugs.
Point of use – A dispense point from Resistivity – The electrical resistance Softening – A water treatment
a purified water system from which between opposite faces of a one– process whereby cations, notably
water can be taken. centimetre cube of a given material at hardness–forming calcium and
a specified temperature. Resistivity is magnesium ions, are exchanged for
Polishing – The final treatment stage(s) the reciprocal of conductivity. For water sodium using cation exchange resins
of a water purification system. analysis, resistivity is usually reported in the sodium form.
in megohm–centimetres (MΩ–cm).
Potable water – Water which meets Stagnation – State of a liquid
regulations as suitable for ingestion Reverse osmosis (RO) – A process in without current or circulation.
by humans. which water is forced under pressure
through a semipermeable membrane Sterilisation – Destruction or removal
PPB – Parts per billion is a unit equal leaving behind dissolved organic, of all living microorganisms.
to one microgramme per kilogram dissolved ionic, and suspended
of water. Numerically ppb are impurities. Storage tank – In water purification
equivalent to one microgramme per systems, a container holding
litre in dilute aqueous solutions. Sanitisation – Chemical and/ quantities of purified water.
or physical processes used to
PPM – Parts per million is a unit kill microorganisms and reduce Total dissolved solids (TDS) – A
equal to one milligramme per contamination from microorganisms. measure of the total of organic and
kilogram of water. Numerically ppm inorganic salts dissolved in water,
are equivalent to one milligrammes Service deionisation(SDI) – obtained by drying residue at 180°C.
per litre in dilute aqueous solutions. Deionisation service provided by
exchanging cylinders containing Total organic carbon (TOC) – Total
PPT – Parts per trillion is a unit equal to ion exchange resins, which have concentration of carbon present in
nanogramme per kilogram of water. been regenerated or replaced at a organic compounds.
regeneration station.
PSG – Pure steam generator (CSG – Turbidity – The degree of cloudiness
clean steam generator) Silt Density Index – Also called the of water caused by the presence
Fouling Index (FI) is a test used to of suspended particles or colloidal
Pyrogen – A category of substances, estimate the potential of the water material. Turbidity reduces the
including bacterial endotoxins, which to block filters, derived from the rate transmission of light and is
may cause a fever when injected or of blockage of a 0.45 micron–filter measured in Nephelometric Turbidity
infused. under standard conditions. Units (NTU).
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PHARMACEUTICAL PURE WATER GUIDE
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PHARMACEUTICAL PURE WATER GUIDE
Maximise availability
31
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PHARMACEUTICAL PURE WATER GUIDE
PRETREATMENT
Activated Carbon
Filters Cartridge
20-5 Micron
Cartridge Filter
Multimedia Filter (MM) Softeners (1x) Granular AC (GAC)
Feed water
Organic Scavenger (OS) Non & Backwashable
Sand Filter (SF) Hot Water or Steam
Sanitizable
PURIFIED WATER STORAGE & DISTRIBUTION WFI GENERATION & STORAGE / DISTRIBUTION
Cooler
Heater
Still Generator WFI Storage Distribution
Chemical
Ozone
PURIFIED Hot Water (85°C)
WATER TANK Over Heated (121°C)
Steam
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PHARMACEUTICAL PURE WATER GUIDE
GENERATION TREATMENT
Continuous Electro-
deionization (CEDI)
Ultraviolet (UV)
Treated Water
& Solids
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PHARMACEUTICAL PURE WATER GUIDE
34
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This guide has been written by the experts of Veolia Water Technologies.
Contacts: ranj.rihal@veolia.com,
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