Professional Documents
Culture Documents
Contents
1 Introduction 2
3 Purified water 14
8 Glossary of terms 23
Further reading 26
1 Introduction
In todays pharmaceutical facilities granular activated carbon (GAC). reaches a peak in winter, and falls Dissolved organic Measuring impurities in
the availability of purified water This traps the solids and organic to a minimum in summer. Ground
is essential. While the domestic matter. Finally chlorine is added waters are much less affected by compounds potable water
consumer considers tap water to be to kill remaining bacteria. A small the seasons. Organic impurities in water arise In order to design or select a water
pure, the pharmaceutical end-user residual of chlorine is left to maintain from the decay of vegetable matter, purification system it is necessary to
The quality and characteristics of
regards it as grossly contaminated. low bacterial levels. An extra principally humic and fulvic acids, have information on the composition
the potable water supply have an
ultrafiltration stage is sometimes and from farming, paper making and of the feedwater, usually local potable
Within the pharmaceutical industry, important bearing on the purification
used to remove cryptosporidium. domestic and industrial waste. These water. Average data can often
water is most commonly used in regime required to produce purified
include detergents, fats, oils, solvents be obtained from the local water
liquid form, not only as an ingredient water.
and residues from pesticides and supplier, however, an analysis of the
in many formulations but also as a Impurities herbicides. In addition, water-borne water gives the information directly.
cleaning agent. Production of Purified Suspended particles
Water, Highly Purified Water, Pyrogen in potable water Suspended matter in water includes
organics may include compounds
leached from pipework, tanks and
The filter-blocking potential of
Free Water and WFI to international the water can be estimated using
silt, pipework debris and colloids. purification media.
pharmaceutical standards is widely The unique ability of water to a fouling index (FI) test or, less
Colloidal particles, which can be
dissolve, to some extent, virtually reliably, turbidity. A wide range
recognised as a critical process.
every chemical compound and
organic or inorganic, give rise to haze Micro-organisms of methods are available for
or turbidity in the water.
support practically every form of life The chief micro-organisms of concern determining inorganic components.
The production means that potable water supplies Suspended particles can foul for water purification systems are Ion chromatographic, ICP-mass
bacteria. A typical bacterial level for a
of potable water contain many substances in solution
or suspension.
reverse osmosis membranes and
electrodeonisation stacks, as well as potable pharmaceutical water supply
spectrometric or spectrophotometric
methods are often used. Electrical
interfere with the operation of valves is ten colony forming units per one conductivity provides a guide
Purified water used in pharma
processes is usually produced in-situ
Variations in and meters. hundred milliliter (10 CFU/100ml) or to potential problems. Organic
from local potable water which has raw water quality less. Bacteria are usually kept at these compounds can be determined
been produced by the treatment of Unlike other raw materials, potable
Dissolved inorganic low levels by the use of residual levels individually, e.g. chromatographically,
natural water sources. water varies significantly in purity compounds of chlorine or other disinfectants.
Once the disinfectants are removed
or an overall indication of organic
content can be provided by a total
For potable water the overall both from one geographical region Inorganic substances are the major during purification, bacteria have the organic carbon (TOC) measurement.
requirement is to produce drinking to another and from season to impurities in water. They include: chance to proliferate. Total viable bacterial counts as well
season. Water derived from an
water that conforms to regulations Calcium and magnesium salts as those of individual species can be
and that has acceptable clarity, upland surface source, for instance,
which cause temporary or Dissolved gases measured by filtration or inoculation
taste and odour. Natural water is usually has a low content of
permanent hardness Potable water is in equilibrium with and incubation in a suitable growth
taken from upland sources, such dissolved salts and is relatively soft,
but has a high concentration of Carbon dioxide, which dissolves in the air and so contains dissolved medium.
as reservoirs, from rivers or from water to give weakly acidic oxygen and carbon dioxide. Carbon
underground aquifers and potable organic contamination, much of it Total dissolved solids (TDS) is the
carbonic acid dioxide behaves as a weak acid and
water is produced by a series of steps colloidal. By contrast, water from an residue in ppm obtained by the
uses the capacity of anion exchange
which vary with the water source, underground source generally has a Sodium salts resins. Dissolved oxygen is usually
traditional method of evaporating
local and national regulations and the high level of salts and hardness but a a water sample to dryness and
low organic content. River sources are Silicates leached from sandy only an issue where bubble formation
heating at 180C. By far the greatest
choice of technologies. One approach river beds is a problem. In applications where
is outlined here. intermediate in quality but also often proportion of the filtered residue
the purified water is used in open
contain products from industrial, Ferrous and ferric iron compounds containers it will rapidly re-equilibrate
is inorganic salts and TDS is used
After passing through a series of agricultural and domestic activities. derived from minerals and rusty as an indicator of the total level of
screens to remove debris, the water with the gases in the air.
iron pipes inorganic compounds present. It can
is mixed with ozone in contact tanks Seasonal variations in water quality
be measured directly or estimated by
to oxidise pesticides and herbicides are most apparent in surface waters. Chlorides from saline intrusion multiplying the conductivity of the
and kill bacteria and algae. Excess During the autumn and winter
months, dead leaves and decaying Aluminum from dosing chemicals water in S/cm at 25C by 0.7.
ozone is destroyed. Water is then and minerals
clarified to remove suspended solids, plants release large quantities of
which are collected as a sludge cake. organic matter into streams, lakes Phosphates from detergents
and reservoirs. As a result, organic
A flocculent such as poly-aluminium
contamination in surface waters
Nitrates from fertilisers
chloride may be added to help this
process. A sand gravity filter and/or
further ozonation may also be used
before the final filtration stage with
T h e P h a r m a Pu re Wat e r G u i d e
Due to its exceptional purifying flows on the other. The small pore Ion exchange (IX) Positively charged ions (e.g. calcium, Reverse osmosis permeate passes Veolia Water Solutions &
efficiency, reverse osmosis is a very size and hydrophobic property of magnesium) are removed by the through one or more chambers Technologies pharmaceutical CEDI
Beds of ion exchange resins can
cost-effective technology for the the membrane prevents water cation resin by exchanging hydrogen filled with ion exchange resins held process utilizes cation beads in the
efficiently remove ionised species
removal of the great majority of from passing through the pore. The ions for the heavier more highly between cation or anion selective concentrate stream and layered beds
from water by exchanging them
impurities. Reverse osmosis protects membrane acts as a support that charged cations. Once exhausted membranes. Ions that become bound of cation and anion resins in
for H+ and OH- ions. Ion exchange
the system from colloids and organic allows the gas and water to come the cation resin is regenerated by to the ion exchange resins migrate dilute stream.
resins are sub-1 mm porous beads
fouling. It is often followed by ion into contact with each other across exposing the resin to an excess of from the dilute chamber to a separate
made of highly cross-linked insoluble The resins are housed in wide cells
exchange or electrodeionisation. the pore. By controlling the pressure strong acid, usually hydrochloric (HCl). chamber (concentrate) under the
polymers with large numbers of that provide a flow path for the ions
Reverse osmosis units need periodic and composition of the gas in contact influence of an externally applied
strongly ionic exchange sites. Ions Similarly, negatively charged ions in transit. This offers advantages
cleaning & sanitisation with acid with the water, a driving force can be electric field, which also produces the
in solution migrate into the beads; (e.g.sulphate, chloride) exchange in the flexibility of design and
and alkaline solutions. Specially generated to move dissolved gasses H+ and OH- necessary to maintain
where, as a function of their relative with hydroxyl ions on the anion resin. mechanical simplicity on an industrial
constructed membranes are available from the water phase into the gas the resins in their regenerated state.
charge densities (charge per hydrated Anion resin is regenerated using scale. The ion migration from dilute
for hot water sanitisation at 85C. phase. The membrane contactor Ions in the concentrate chamber are
volume), they compete for the strong sodium hydroxide solution to concentrate is enhanced by the
works under the same basic principles recirculated to a break tank or flushed
Degassing that vacuum degassifiers or forced
exchange sites. Beads are either (NaOH).
to waste.
layered resin bed in the dilute.
cationic or anionic. Strong cation
Membrane (DG) draft deareators operate under.
resins are usually polysulfonic acid
The very large surface areas of ion
The ion exchange beds in continuous
Reverse osmosis (and sometimes
However, the membrane-based exchange resins makes them a membrane degassing) is typically
A membrane contactor is a derivatives of polystyrene cross-linked electrodeionisaton (CEDI) systems
technology offers a cleaner, smaller potential breeding place for micro- used before CEDI to ensure that the
hydrophobic membrane device that with divinylbenzene. Strong anion are regenerated continuously, so they
and more stable operating system organisms and can lead to the release CEDI stack is not overloaded with
allows water and a gas to come resins are benzyltrimethyl quaternary do not exhaust in the manner of ion
than the conventional degasification of fines and soluble components. For high levels of salts. The small volume
into direct contact with each other ammonium hydroxide (Type 1) or exchange beds that are operated
tower design. The pore size of the these reasons, good quality resins of resins in the stack results in low
without mixing. Water flows on benzyldimethlyethyl quaternary in batch mode (with chemical
membrane is in the order of 0.03 should be used and bed volumes kept bleed of organic molecules. Typically,
one side of a membrane and a gas ammonium hydroxide (Type 2) regeneration). CEDI beds are typically
microns, so air-borne contamination as small as reasonably possible. Filters
derivatives of polysytrene cross-linked also smaller and remain in service for
will not pass through the pore and are typically installed after the beds
with divinylbenzene. much longer periods.
enter the water stream. Membrane to trap fines and other particulate
degassing is frequently used when Beds of ion exchange resins are matter. Bacterial build up can be CEDI is preferred for many purified
treating feed water that has a high available either in cartridges or minimised by frequent recirculation water generation applications in
level of dissolved CO2 (>10-15 ppm). cylinders, which are replaced of the water and by regular cartridge Pharma, because of its clean non-
Carbon dioxide will freely pass /removed from site for remote replacement. chemical nature and constant high
through an RO membrane. As it regeneration, or as an arrangement quality water produced.
Modern ion exchange plant
passes through an RO membrane of tanks, vessels, valves and pumps,
design uses relatively small resin The resins used in CEDI systems
it will dissociate and raise the which allows on site regeneration
beds and frequent regeneration can either be separate chambers of
conductivity of water. Membrane of the ion exchange resins.
this minimises the opportunity for anion or cation beads, layers of each
degassing effectively removes the
microbial growth. type within a single chamber or an
dissolved CO2, and maintains a low
intimate mixture of cation and anion
conductivity, which is important With suitable choice of resin,
beads.
for subsequent treatment steps, pretreatment and system design, ion
particularly continuous electro- exchange enables the lowest levels of
deionisation (CEDI). ionic contamination to be achieved.
Continuous electrodeionis
ation(CEDI)
Continuous electrodeionisation is a
technology combining ion exchange
resins and ion-selective membranes
with direct current to remove ionised
species from water. It was developed
to overcome the limitations of ion
exchange resin beds, notably the
release of ions as the beds exhaust
and the associated need to change or
regenerate the resins.
T h e P h a r m a Pu re Wat e r G u i d e
Current CEDI stacks development Stills are sensitive to chlorine and should be protected with activated carbon or and UF has reduction of endotoxin To assure filter performance prior Uses the same principles and is
allow the user to carry out hot water sodium bisulfate injection. (pyrogens) from 2 log 10 to 4 log10. UF to use closely related to Pressure Decay.
is capable of consistent production of
sanitisation at 85C, for a period of
Microporous Filters water meeting the USP WFI endotoxin
To meet regulatory requirements 4. Water Intrusion Test (WIT)
1 to 4 hours.
Microporous filters provide a physical barrier to the passage of particles and limit of 0.25 Eu/ml. FDA Only used to test hydrophobic
Distillation micro-organisms in purified water systems. Cartridge filters, characterised by UF membranes can be sanitised with cGMP guidelines to achieve Best PTFE membrane filters used for gas
sterilisation.
absolute particle size ratings, have uniform molecular structures, which, like a a variety of chemical agents such Practice
The pharmaceutical still chemically
sieve, retain all particles larger than the controlled pore size on their surface. as sodium hypochlorite, hydrogen
and microbiologically purifies water Prevention of batch loss/
peroxide, peracetic acid and with hot reprocessing
by phase change and entrainment Cartridge filters (0.05 to 0.22 m) are typically used before the purified water
water and / or steam.
separation. In this process, water is distribution tank to trap micro-organisms and fine particulates.
evaporated producing steam. The
Trapped particulates, including micro-organisms or their metabolic products,
steam disengages from the water
and soluble matter, can be leached from filters and suitable maintenance
leaving behind dissolved solids, non-
(regular sanitisation and periodic replacement) is necessary to maintain desired
Technologies used to control Micro-organisms
volatiles, and high molecular weight
levels of performance. Newly installed filters usually require rinsing before use to Microporous Ultra Reverse Ultra-
impurities. However, low molecular filter filter osmosis violet
remove extractable contaminants.
weight impurities are carried with light
water mist/droplets, which are A microporous filter membrane is generally considered to be indispensable in a Micro-organisms
entrained in steam. A separator water purification system, unless it is replaced by an ultraviolet generator
Endotoxins
removes fine mist and entrained or ultrafilter.
impurities, including endotoxins. Key bacterial challenge test organism
The purified steam is condensed Liquid Filter Clean Liquid Excellent removal Brevundimonas diminuta trapped on a
into water for injection. Distillation membrane
Good removal
systems are available to provide Partial removal
a minimum of 3 log10 reduction
in contaminants such as micro-
organisms and endotoxins. Three
designs are available including single
10 T h e P h a r m a Pu re Wat e r G u i d e 11
Ultraviolet light System design Storage tank and distribution are provide maintenance contracts. These The validation documentation
potential sources of contamination, types of maintenance contracts focus package should follow the various
Ultraviolet light is used as a bactericide and to break down and photo-oxidise
The different technologies described particularly from bacteria. Good on maintaining the system in a state regimes, protocols and guidelines laid
organic contaminants to polar or ionised species for subsequent removal by ion
on the previous pages can be design and proper maintenance as close to that at which it operated out by the regulatory authorities and
exchange. The UV sources in pharmaceutical water purification systems are low
combined in a variety of ways to regimes are needed to minimise at commissioning. All parameters are the industry bodies, typically:
or medium pressure mercury vapour lamps.
achieve the desired degree of problems. The choice of materials of recorded during the contract visit and
Radiation with a wavelength of 240-260 nm has the greatest bactericidal construction is also critical. Metals, adjusted accordingly with all changes
water purification.
action with a peak at 265nm.It damages DNA and RNA polymerase at low doses other than stainless steel, should recorded. Cleaning, repairs and
preventing replication. For most Pharma applications, UV chambers and lamps Each system will require some
be avoided. There are many high preventative maintenance operations
need to be designed to provide a sufficient dosage of UV to achieve a 6 log10 pretreatment based on the particular
purity plastics available but care are recorded within the report sheets.
reduction of typical pathogenic contaminants. feedwater to remove particulates,
needs to be taken to avoid those The final report will also give details
chlorine or chloramines, calcium
Radiation at shorter wavelengths (185 nm) is effective for the oxidation with fillers and additives which could of any recommended and necessary
and magnesium. This is preferably
of organics. The UV breaks large organic molecules into smaller ionised contaminate the water. Storage actions.
followed by reverse osmosis to
components, which can then be removed by a downstream continuous tanks should be protected from
remove virtually all colloids, particles
electrodeionisation. 185 nm UV is also used to destroy excess chlorine or ozone. ingress of contaminants with suitable
and high molecular weight organic
UV radiation at 185 nm is a highly effective photo-oxidant and a key component vent filters. The purified water is
compounds and over 90% of ions. The
in producing purified water with the lowest levels of organic contaminants. recirculated continuously
resultant deionised water will contain
and cooled down to maintain purity.
some organic compounds, some ions,
Germicidal lamp output verses germicidal effectiveness some bacteria and cell debris and all
UV disinfection is often used to
maintain microbial purity in the
the dissolved carbon dioxide The water standards in the
distribution loop.
and oxygen. pharmacopoeias
The water is next treated by one Maintenance of the water USP United States Pharmacopoeia
or more techniques depending on purification system Ph Eur European Pharmacopoeia
the required purity - ion exchange
or second stage reverse osmosis or
In order to ensure that once JP Japanese Pharmacopoeia
qualified, the facility remains in a Good Manufacturing Practice (GMP)
CEDI to remove ions, UV light to kill
state of qualification, a preventative
bacteria and/or to oxidise residual
maintenance programme must Validation and trend FDA Code of Federal Regulations
organic compounds and ultrafiltration
to remove endotoxin, protease and
be developed. In order to enable monitoring 21CFR210 & 21CFR211
Documentation list
Abbreviation / Full Title What it is for Abbreviation / Full Title What it is for
Document Document
URS User Requirement To tell the supplier what the customer requires, what specification that DQ Design Qualification The design qualification or enhanced design review is carried out to
Specification needs to be adhered to, how much water is needed, what the water system ensure that the designed equipment, using the design documents,
is to do etc. Document created by the client or his engineer. meets the user requirements. The review is documented and created by
the supplier.
VMP Validation Master Plan This documents the clients approach to validation on site and in particular
to the current site project. It identifies the scope of the validation exercise SDS Software Design Specification To describe the control panel software function and design
allowing the validation on site to be suitably managed. Created by the client
or his engineer. STS Software Test Specification To test the functions described in the SDS
QPP Quality & Project Plan This document defines how the supplier will fulfil the user and suppliers HDS Hardware Design To describe the control panel hardware function and design
quality requirements on the project. It also provides details of the project Specification
management on the contract. This may include a Gantt chart for the project
management of the contract. This is the suppliers response to the VMP. HTS Hardware Test Specification To test the functions described in the HDS
Document created by the supplier.
GAMP Good Automated To categorise configurable instruments. This gives information on how
QIP Quality Inspection Plan This document gives details of how and when the equipment that is to Categorisation Manufacturing Practice to record configuration and validation process that should be used
be supplied is inspected at the suppliers works. This details the type Categorisation
of inspection and who will inspect, also giving options as to when it is
suggested that the client inspects. The document is created by the supplier. MFAT Mechanical Factory To test the equipment at the suppliers factory without running water
Acceptance Test through the system. The system does not have to be fully assembled for
FDS Functional Design To describe the components of the equipment, how it will be connected this. Checks include ensuring the correct equipment is available
Specification together and how the system functions. This is the suppliers response to the
clients URS. Document created by the supplier. FAT Factory Acceptance Test To test the equipment operationally in the factory with water. This tests
all the equipment functionality.
P&ID Process & Instrument Drawing of the system, that shows all valves, instruments, and equipment.
Diagram This is the principal design document created by the supplier. SAT Site Acceptance Test This document tests the equipment on site. The SAT can be a
combination of the IQ, Commissioning and OQ documents, depending
Valve Schedule Valve Schedule Lists all the valves and the valve specification. Created by the supplier. on each clients understanding. The supplier creates the SAT document.
Instrument Schedule Instrument Schedule Lists all the instruments and the instrument specification. Created by the IQ Installation Qualification To document that the equipment is correctly installed on site as
supplier. intended. The supplier normally creates this document.
Equipment Schedule Equipment Schedule Lists all the equipment and the equipment specification. Created by the Commissioning Commissioning To document that the system is correctly set up and that the system is
supplier. Protocol made ready for full functional operation. This document records all the
start up data. The supplier creates this document.
Utilities Schedule Utilities Schedule Lists all the utilities and the utility specification, such as water, drains,
electricity, steam, air, chemicals etc. Created by the supplier. OQ Operation Qualification To document that the system functions and operates as described in the
FDS. The supplier normally creates this document.
GA Drawing General Arrangement Equipment layout drawing, showing information as to the connections to
Drawing the equipment and their locations. PQ Performance Qualification To record that the system produces good quality water and that the
quality is consistent when the system is on line. The user creates this
document.
14 T h e P h a r m a Pu re Wat e r G u i d e 15
Organic Carbon represented the first test methods which could be used temperature dependent, but at an acknowledgement that samples are adversely contaminated when collected detected. A wide range of TOC
for equipment verification, on-line process control, and release of water to a higher conductivity than of the and transported for off-line measurement. This is not an indictment of off-line analyzers exist and can be broadly
production for the first time in the pharmaceutical industry. In addition, the USP. The Ph Eur has also retained measurement methods, but it is an affirmation that high purity water samples divided into those which oxidise all
USP specifications set standards for the measuring instrumentation used testing for nitrate, heavy metals, and are easily contaminated, and they are well-suited to on-line measurements. the carbon to carbon dioxide and
for TOC and conductivity measurements, such as system suitability, limit of aluminum (when used for dialysis measure the CO2 selectively and
Historically, the pharmacopoeia had no monographs for steam quality
detection, instrument resolution, and calibration requirements for sensor and solutions), though there is discussion those that either partially oxidise
requirements. A survey of the industry revealed that there are many descriptions
transmitter. Concurrently, all of the USP wet chemistry tests for bulk waters within the Ph Eur to eliminate the the organic compounds, to acids
for steam and its uses and quality attributes, but there was no single recognised
were deleted, with the exception of micro-organisms and endotoxins (for WFI heavy metals testing. for example, or fully oxidise all
authoritative body which defined steam for use in high purity applications
only). The Stage 1 conductivity test has a conductivity limit that is temperature species present and measure the
In July 2004, the Ph Eur also revised (not plant steam). The industry has often turned to a British Health Technical
dependent, thereby allowing the user to measure uncompensated conductivity change in conductivity due to all the
the requirements for calibrating Memorandum HTM 2010 which described the requirements for the production
and temperature on-line, in real-time, and release water to production oxidised species. The latter reading
the sensors and transmitter. The of steam and other agents used for sterilisation, but not the chemical attributes.
continuously and without having to wait hours or longer for a test result from will include, for example, nitric and
requirement for the meter tolerance Industry requested some input from the USP, and in 2006 the USP added a new
the lab. This temperature dependent limit remains in place today. The TOC limit sulphuric acids from the oxidation of
will be 3% + 0.1 S/cm and the sensor monograph Pure Steam. Pure Steam can be qualitatively described as steam
is approximately 500 ppb. N and S atoms. The former are usually
tolerance will be 2%, which is the that meets all the requirements of WFI, after condensation. There are no physical
used off-line to show compliance
In 2000, the European Pharmacopoeia (Ph Eur) deleted most of its wet chemistry same as the current USP requirement. tests for limits on non-condensable gasses or % saturation, as there is in HTM
with TOC specifications. The latter
tests and replaced them with TOC and conductivity testing for bulk Aqua The differences in the details of 2010. The USP monograph specifically notes the physical requirements are not
are used for in-line monitoring. Due
Purificata and bulk Aqua ad Injectabilia, while retaining testing for Heavy conductivity calibration requirements stated, but adds The level of steam saturation or dryness, and the amount of
to the risks of contamination, in line
Metals and Nitrates. The Ph Eur TOC test, listed as 2.2.44, is nearly identical to between Ph Eur and USP are minor. noncondensable gases are to be determined by the Pure Steam application.
measurements are essential for TOC
the USP <643> method in terms of limits and methods, though there is a subtle This puts the burden on the user to determine appropriate physical properties
Until 2006, the JP relied on the same levels <25 ppb and recommended at
difference in the limit, and it is widely considered harmonized. However, while depending on the use of the steam.
types of wet chemistry tests for <50 ppb.
conductivity was also adopted by the Ph Eur, the calibration methods and the
control of pharmaceutical waters, Last, the most significant change in the water testing across the pharmacopoeia
test methods and test limits were substantially different than the USP. The main role of TOC is for monitoring
but 2006 new tests were adopted. is the subtle endorsements of on-line, real-time testing. The JP is promoting the
The Ph Eur method called for a limit of 4.3 S/cm at 20C for PW and 1.1 S/ and trending. In most waters TOC
Developed in cooperation with use of real-time measurement tools, where appropriate. This has been discussed
cm at 20C for WFI. While the replacement of the Ph Eur wet chemistry tests cannot be related directly to the
the USP Pharmaceutical Water in an FDA training session and at seminars. The science is very simple. Whether
represented an advancement for the pharmaceutical industry in terms of testing, concentration of organic molecules in
Expert Committee, conductivity you produce water that is 0.055 S/cm or 0.8 S/cm (14x greater), the resulting
it was not harmonized. the water as the amount of carbon is
and TOC testing has been adopted. water will be ~1 S/cm when exposed to the atmosphere due to the immediate
different in different molecules. For
Continued industry requests and pharmacopoeial efforts for more uniform The JP conductivity test is written infusion of CO2. Likewise, exposure of water with 5 ppb TOC or 50 ppb TOC to
example, 100 ng/g (ppb) of carbon is
global testing renewed the harmonization efforts between the U.S., European identically to the USP <645>, with an the environment is easily contaminated by air-borne impurities and particulates,
present in a solution of 131 ng/g (ppb)
and Japanese (JP) pharmacopoeias. In July 2004, the Ph Eur conductivity uncompensated conductivity limit perfumes, container residue or soaps, and other matter. For water conductivity
phenol or 990 ng/g (ppb) chloroform,
requirements were modified and are given by two tables, one each for PW and that is temperature dependent. The and TOC, the original purity of the water is obscured by external contamination,
because phenol contains 76% by
WFI, showing conductivity limits as a function of temperature. The Ph Eurs same JP conductivity limits are in thereby hiding the true quality of the water. On-line, real time testing gives a
weight of carbon and chloroform
Stage 1 conductivity specification for WFI is identical to the USP conductivity place for PW and WFI like the USP, and more accurate representation of the quality of the water used in Production.
contains 10% by weight of carbon. The
specification for both PW and WFI. However, the Ph Eur limit for PW is also in contradiction to the Ph Eur which
Article printed with the authorization of DR. ANTHONY C. BEVILACQUA, Mettler-Toledo Thornton, Inc. requirements for TOC monitoring are
has higher limits for PW.
a very rapid response and continuous
Variations of resistivity The TOC requirement in the JP Total Organic Carbon (TOC) availability, with sufficient sensitivity
specifically references methods in and precision.
with temperature USP <643> and Ph Eur 2.2.44, but the
Due to the potential variety and complexity of organic compounds present in
purified water it is not practical to measure them all routinely. An indicator of
Temperature Resistivity of Resistivity of JP is also recommending lower TOC overall organic contamination is needed. The most useful has proved to be TOC.
(C) pure water 20.7 ng/g NaCl in limits of 400 ppb when measured
(M-cm) water (M-cm) Organic substances in a water sample are and the resultant oxidation products
off-line and 300 ppb when measured
0 86.19 28.21
on-line. These limits are based on a
5 60.48 22.66
survey of the industry in Japan, and
10 43.43 18.30
15 31.87 14.87 Typical Values of Typical Values
20 23.85 12.15 Conductivity at 25C of TOC ppb
25 18.18 10.00 S/cm Mains water 500 - 5000*
30 14.09 8.28 1 mg/l NaCl 2.2 RO permeate 25 100
35 11.09 6.90 10 mg/l NaCl 22.0 DI water 50 500
40 8.85 5.79 100 mg/l NaCl 220.0 RO + CEDI 5 30
45 7.15 4.89 1 mg/l HCl 8.0 * (typically 1000 3000)
50 5.85 4.15 10 mg/l CO2 4.0
18 T h e P h a r m a Pu re Wat e r G u i d e 19
5W
ater purity standards
Purified water is used in most
Pharmacopoeia requirements for purified water Three Stage Philosophy Table 1
Pharmaceutical manufacturing
Stage 1
processes all around the world. Properties Ph Eur USP
Temperature not less than 25C Stage 1: Temperature/Conductivity Requirements (for USP)
Therefore, international and national Conductivity <4.3 S/cm at 20C <1.3 S/cm at 25C*
and conductivity not greater than (for non-temperature compensated conductivity measurements)
authorities have established water TOC <500 g/l C** <500 ppb
quality standards for purified and 1.3 S/cm Temperature Conductivity Temperature Conductivity
Bacteria (guideline) <100 CFU/ml <100 CFU/ml
C S/cm C S/cm
SAMPLE PASSES TEST
0 0
other regulated grades of water. Nitrates <0.2 ppm -
Key authorities include: 0 0.6 55 2.1
Heavy metals <0.1 ppm - If measured on-line the conductivity 5 0.8 60 2.2
The United States meter must be calibrated and non
10 0.9 65 2.4
Pharmacopoeia (USP) temperature compensated, the
Temperature/Conductivity Requirements (for Ph Eur) temperature must be measured
15 1.0 70 2.5
The European (for non-temperature compensated conductivity measurements) 20 1.1 75 2.7
Pharmacopoeia (Ph Eur) independently by an adjacently
25 1.3 80 2.7
Temperature Conductivity Temperature Conductivity installed calibrated temperature
The Japanese Pharmacopoeia (JP) 0
C S/cm 0
C S/cm meter. If the temperature is less 30 1.4 85 2.7
The standards in this section are a 0 2.4 60 8.1 than 25C or the conductivity greater 35 1.5 90 2.7
summary and correct at the time of than 1.3 S/cm then the conductivity 40 1.7 95 2.9
10 3.6 70 9.1
going to press. Standards are regularly measured must be checked against 45 1.8 100 3.1
20 4.3 75 9.7
reviewed and updated and users the Temperature/Conductivity 50 1.9 - -
25 5.1 80 9.7
should refer to the latest version of chart table 1.
30 5.4 90 9.7
the full standards.
40 6.5 100 10.3 Stage 2 Table 2
Pharmacopoeia standards 50 7.1
The temperature adjusted to 25C
Separate pharmacopoeia are when change in conductivity is less Stage 3: Conductivity Requirements (for USP) as a Function of pH
produced by a number of authorities, Pharmacopoeia requirements for than a net 0.1 S/cm per 5 minutes
pH S/cm pH S/cm
take a conductivity reading:
notably in the USA, Europe and Japan. water for injection & highly purified water 5.0 4.7 6.1 2.4
Each specifies materials, including
Properties Ph Eur USP
If it is not greater than 2.1 S/cm 5.1 4.1 6.2 2.5
water, to be used in pharmaceutical then it meets the requirements
Conductivity <1.1 S/cm at 20C*** <1.3 S/cm at 25C* 5.2 3.6 6.3 2.4
work. The standards for purified If it is greater than 2.1 S/cm then
TOC <500 g/l C** <500 ppb 5.3 3.3 6.4 2.3
water are similar in each case. Extra go to stage 3
Bacteria (guideline) <10 CFU/100ml <10 CFU/100ml 5.4 3.0 6.5 2.2
criteria are set for water required for
Endotoxins <0.25 IU/ml <0.25 EU/ml Stage 3
sterile applications. The standards for 5.5 2.8 6.6 2.1
purified water given in the European Nitrates <0.2 ppm - Temperature @ 25C 5.6 2.6 6.7 2.6
Pharmacopoeia (Ph Eur) and in the US Heavy metals <0.1 ppm - Determine pH 5.7 2.5 6.8 3.1
Pharmacopoeia (USP) are summarized If conductivity reading in stage 2 5.8 2.4 6.9 3.8
below. Water for injection has * Offline conductivity measurements possible. If in-line conductivity exceeds values
is not greater than conductivity 5.9 2.4 7.0 4.6
then refer to USP tables in section 645 (Table 1). If value exceeds that in table 1, refer
stringent bacterial/pyrogen criteria reference for given pH (table 2) it 6.0 2.4 - -
to Three Stage Philosophy.
and methods of preparation are meets the requirements. If the pH
** Or pass oxidisable substances test
specified. is outside the range 5.0 7.0 the
*** If in-line conductivity exceeds values then refer to the European
Pharmacopoeia (Ph Eur) water does not meet requirements.
Filtration A purification process in Microorganism Any organism PPB Parts per billion is a unit equal Sanitisation Chemical and/or Turbidity The degree of cloudiness
which the passage of fluid through a that is too small to be viewed by the to microgramme per kilogram of physical processes used to kill micro of water caused by the presence
porous material results in the removal unaided eye, such as bacteria, viruses, water. Numerically ppb are equivalent organisms and reduce contamination of suspended particles or colloidal
of impurities. molds, yeast, protozoa, and some to microgramme per litre in dilute from microorganisms. material. Turbidity reduces the
fungi and algae. aqueous solutions. transmission of light and is measured
Fines Particulates released from a Service Deionisation(SDI)
in Nephelometric Turbidity Units
bed of material such as ion exchange Nuclear Grade Resin A high purity PPM Parts per million is a unit equal Deionisation service provided by
(NTU).
resins. (analytical) grade of ion exchange to milligramme per kilogram of water. exchanging cylinders containing
resin originally developed for the Numerically ppm are equivalent ion exchange resins, which have Ultrafiltration A process in which
Fouling Index see Silt Density Index.
nuclear energy industry. to milligrammes per litre in dilute been regenerated or replaced at a water is filtered through a polymeric
GAMP Good Automated aqueous solutions. regeneration station. membrane having a very fine pore
Offline In water monitoring
Manufacturing Practice. structure.
systems, referring to measurement PPT Parts per trillion is a unit equal Silt Density Index Also called the
Gramnegative refers to bacteria devices that are not directly coupled to nanogramme per kilogram of Fouling Index (FI) is a test used to Ultraviolet (Photochemical)
that do not absorb a violet stain to the water stream. water. estimate the potential of the water to Oxidation A process using short
originally described by Gram. block filters, derived from the rate of wavelength light to kill micro
Online In water monitoring PSG Pure Steam Generator.
blockage of a 0.45 micronfilter under organisms and cleave or oxidise
Grampositive Refers to bacteria systems, referring to measurement
Pyrogen A category of substances, standard conditions. organic molecules.
that absorb a violet stain originally devices directly coupled to the water
including bacterial endotoxins, which
described by Gram. stream. SJP (JP) The Society of Japanese USP United States Pharmacopoeia
may cause a fever when injected or
Pharmacopoeia (SJP) is a nonprofit The United States Pharmacopoeia
Hardness The scaleforming Ozone Ozone is used in the infused.
foundation authorised by the Ministry (USP) is the official public standards
and latherinhibiting qualities of pharmaceutical industry as a
Qualification The act of establishing of Health, Labour and Welfare setting authority for all prescription
some water supplies, caused by sanitizing agent. O3 is a very strong
with documented evidence that the (MHLW). and overthecounter medicines,
high concentrations of calcium and oxidising agent, kill bacteria and
process, equipment, and/or materials dietary supplements, and other
magnesium. Temporary hardness, reduce TOC in water. It was established mainly to promote
are designed, installed, operated and healthcare products manufactured
caused by the presence of magnesium dissemination of the Japanese
Particulates Discrete quantities of perform according to the pre and sold in the United States. USP
or calcium bicarbonate, is so called Pharmacopoeia (JP) for the purpose
solid matter dispersed in water. determined specifications. sets standards for the quality of these
because it may be removed by boiling of maintenance and improvement
products and works with healthcare
the water to convert the bicarbonates Permeate The purified solution Regeneration The method by which in the efficacy, safety and quality of
providers to help them reach the
to the insoluble carbonates. Calcium which has been produced by passage exhausted ion exchange resins are pharmaceutical drugs.
standards. USPs standards are also
and magnesium sulfates and through a semipermeable reverse reactivated by treatment with strong
Softening A water treatment recognised and used in more than 130
chlorides cause permanent hardness. osmosis membrane. acid or alkali.
process whereby cations, notably countries.
HPW Highly Purified Water. pH A measure of the acidity or Resistivity The electrical resistance hardnessforming calcium and
Validation Confirmation, through
alkalinity of a solution equal between opposite faces of a one magnesium ions, are exchanged for
Ion Any nonaggregated particle the provision of objective evidence,
to log (H+). centimetre cube of a given material sodium using cation exchange resins
of less than colloidal size possessing that requirements for a specific
at a specified temperature. Resistivity in the sodium form.
either a positive or a negative electric PhEur European Pharmacopoeia. intended use or application have been
is the reciprocal of conductivity.
charge. Stagnation State of a liquid without fulfilled.
Photooxidation see Ultra Violet For water analysis, resistivity is
current or circulation.
Ion Exchange (IX) The process (Photochemical) Oxidation. usually reported in megohm Verification Confirmation, through
of purifying water by removing centimetres(Mcm). Sterilisation Destruction or removal the provision of objective evidence,
Planktonic Used to describe aquatic
ionized salts from solution, by of all living microorganisms. that specified requirements have
microorganisms that float. Storage Tank In water purification
replacing hydrogen ions for cation been fulfilled.
systems, a container holding Total Dissolved Solids (TDS) A
impurities and hydroxyl ions for anion Point of Use A dispense point from
quantities of purified water. measure of the total of organic and WFI Water For Injection.
impurities. a purified water system from which
inorganic salts dissolved in water,
water can be taken. Reverse Osmosis (RO) A process
LAL Limulus Amoebocyte Lysate, obtained by drying residue at 180C.
in which water is forced under
an extract from the horseshoe crab Polishing The final treatment
pressure through a semipermeable Total organic carbon (TOC) Total
which forms a gel in the presence stage(s) of a water purification
membrane leaving behind dissolved concentration of carbon present in
of sufficient endotoxin. Used as the system.
organic, dissolved ionic, and organic compounds.
basis for the LAL test for endotoxins.
Potable Water Water which meets suspended impurities.
Line Cell An electrode assembly regulations as suitable for ingestion
inserted into a water stream by by humans.
which the conductivity or resistivity is
measured.
26 T h e P h a r m a Pu re Wat e r G u i d e 27
Further reading Handbook of Water Purification, edited by Walter Lorch, The single source Specific
published by McGraw Hill.
There are several books in English focusing specifically on
solution solutions
Water Treatment Handbook Degrmont, published
purified water for pharmaceutical industry. by Lavoisier. Veolia Water Solutions & Veolia Water Solutions &
The ISPE notforprofit professional society has issued Many of the ASTM standards in volumes 11.01 and Technologies (VWS), a subsidiary Technologies unparalleled
several Baseline guides, Volume 4 Water and steam 11.02 are relevant to purified water. (www.astm.org). of Veolia Water. VWS is one of technological experience delivers
systems (2001), Volume 5 Commissioning and the worlds major designers complete solutions that meet and
Qualification (2001). Information on water treatment can be found at of technological solutions and exceed these standards through
www.veoliawater.com and www.veoliawaterst.com constructor of facilities for water compliance with:
The Ultrapure Water journal (Tall Oaks Publishing)
Every effort has been made to ensure that the information treatment. With over 6,500
contains articles of interest as do two books by T.H.
employees, the company has
latest USP and Ph Eur standards
Melltzer from the same publisher: High Purity Water in this publication is correct. Veolia Water Solutions &
Technologies cannot be held responsible for any errors or operations in more than 50 countries. cGMP requirements
Preparation for the semiconductor, pharmaceutical
omissions due to changes in technology or standards that VWS recorded revenue of 1.6 billion
and power industries (1993) and Pharmaceutical water
in 2005.
GAMP validation control systems
systems(1996). have occurred since publication date.
VWS Pharmaceutical Group
FDA requirements
specialises in providing ISPE Engineering Guide
pharmaceutical water treatment
CE marking
technology solutions and services.
Veolia Water Solutions &
Within the pharmaceutical industry, Technologies services to the
water is most commonly used in pharmaceutical industry range from
liquid form, not only as an ingredient technical assistance to complete
in many formulations but also as a water cycle management.
cleaning agent. Production of Purified
Water, Highly Purified Water, Pyrogen Visit our website at
Free Water and WFI to international www.veoliawaterst.com
pharmaceutical standards is widely Email us on
recognised as a critical process. pharma-info@veoliawater.com
Primary Filtration Hardness Removal Oxidizer Removal Prefiltration Bacteria Reduction Primary Treatment Polishing Bacteria Reduction Pyrogen Removal
Activated Carbon
Filters Cartridge
Continuous Electro-
deionization (CEDI)
Ultraviolet (UV)
20-5 Micron
Cartridge Filter Single Pass Reverse
Multimedia Filter (MM) Softeners (1x) Granular AC (GAC)
Feed water Osmosis (RO) Ultra Filtration
Organic Scavenger (OS) Non & Backwashable
Ultraviolet (UV) Ceramic Membrane
Sand Filter (SF) Hot Water or Steam
In-Situ Mixed Bed Hollow Fiber Membrane
Sanitizable
Deionizer (MB) Chemical Sanitizable
Hot Water or Steam
+ 1-5 Micron Cartridge Filter Sanitizable
+ Sub-Micron Cartridge
Twin Pass Reverse Filter (0.22)
Sulfite Injection Osmosis (RORO)
Antiscalant Injection
Off Site Regenerable
Ultra Filtration (UF)
Mixed Bed Deionizer
Ultraviolet (UV) (SDI)
Purified Water Storage & Distribution WFI Generation & Storage / Distribution Pharmaceutical Facility Waste Water
Chemical
Purified Ozone
Hot Water (85C)
Water Tank Over Heated (121C)
Steam
North America
Vandalia, OH
Tel: +1 937 890 4075
Fax: +1 937 890 9925
biopharm.info@veoliawater.com
Puerto Rico
Caguas
Toll free: 1-800-564-3157
Tel: +1 787 747 9439
Fax: +1 787 747 0380
Local Office