Pharmaceutical Water System Fundamentals.
William V. Collentro
]
Impurities in Raw Water
William V. Collentro
Welcome to “Pharmaceutical Water System
Fundamentals.” This feature discusses technical justification, design considerations, operation, maintenance,
compliance, and validation for pharmaceutical water
systems. It is the intention of this column to be a useful resource for daily work applications. The primary
objective of this column is to provide a basic summary
of the function, selection, design consideration, proper
operation, preventative maintenance, and regulatory
expectations associated with the individual unit operations employed in pharmaceutical water systems.
Pharmaceutical water systems are considered to be
a “black box” by many organizations. In fact, these
systems consist of multiple complex unit operations
including, but not limited to, pretreatment systems, ion
exchange units, reverse osmosis systems, membrane
filtration, distillation units, distribution loops, and storage systems. Unfortunately, expanded use of instrumentation and controls has decreased “owner” understanding of systems. Frequently, the performance of
individual components is not “controlled,” ultimately
resulting in an unacceptable excursion. Core principles
for manufacturing, operation, compliance, validation,
and regulatory disciplines require, as a minimum, a
basic understanding of every major component. These
principles are frequently neglected for pharmaceutical
water systems.
Topics associated with pharmaceutical water systems
are complex and often require an understanding of scientific, engineering, and technical principles. This situation is complicated when the numerous components
employed in a pharmaceutical water system are not
understood to be associated with individual unit opera-
For more Author
information,
go to
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tions. By presenting the fundamentals for each unit
operation it is possible to transform myriad individual
components into a series of operations configured to
provide and deliver an “ingredient,” pharmaceutical
water, meeting compendial requirements in a fully controlled manner. Because personnel with limited background and experience may find themselves involved
with technology used in pharmaceutical water systems,
the unit operation approach is a logical method to
achieve this objective. Further, the technical language,
mathematics, and engineering drawings with symbols
may be esoteric and incomprehensible for those not
trained in the field. It is our intention to present topics
clearly and in a meaningful way so that readers will be
able to understand and apply the principles discussed in
daily work situations.
Reader comments, questions, and suggestions are
needed to help us fulfill our objective for this column.
Please send your comments and suggestions to column
coordinator William V. Collentro at wcsi38@aol.com
or to journal coordinating editor Susan Haigney at
shaigney@advanstar.com.
KEY POINTS
The following key points are discussed in this article:
•Selection of individual unit operations for a pharmaceutical water system providing bulk compendial
water should be based on a thorough analysis of
chemical, microbial, and physical parameters of the
feed water supply. Without a basic understanding of
the characteristics, impurities, municipal treatment
techniques, and seasonal and climatic effects on a
feed water supply, it is impossible to understand the
[
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ABOUT THE AUTHOR
William V. Collentro is a senior consultant and founder of Water Consulting Specialists, Inc. (www.
waterconsultingspecialists.com) in Doylestown, PA. He has more than 40 years of experience in water
purification. He may be reached by e-mail at wcsi38@aol.com.
Journal
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Pharmaceutical Water System Fundamentals.
basis for the design, operation, and maintenance of
a compendial water system.
•Impurities in raw water may include particulate matter, dissolved and ionized inorganic matter, gases that
are either non-reactive or reactive with water, organic
matter, disinfection by-products, residual disinfecting
agents, microorganisms, bacterial endotoxins, and
colloidal material.
•Reliance on municipal or private treatment sources for
compliance with requirements should be evaluated.
Test data should be available. Testing frequency should
be adequate to monitor seasonal or other variation,
and test results should be representative of feed water
received by the manufacturing site.
•Three case histories are described in which impurity levels changed, resulting in system excursions.
Ongoing monitoring of water system impurities,
process or equipment modifications, or other subtle
changes must be the norm to prevent these types of
problems.
INTRODUCTION
Selection of individual unit operations for a pharmaceutical water system providing bulk compendial water should
be based on a thorough analysis of chemical, microbial,
and physical parameters of the feed water supply. In addition to the water system design requirements, the United
States Pharmacopeia (USP) USP32 Official Monographs (1)
for both water for injection and purified water states, “It
is prepared from water complying with the United States
Environmental Protection Agency National Primary Drinking Water Regulation or with the drinking water regulations
of the European Union, Japan, or with the World Health
Organization’s Guidelines for Drinking Water Quality.” Without a basic understanding of the characteristics, impurities,
municipal treatment techniques, and seasonal and climatic
effects on a feed water supply, it is impossible to understand
the basis for the design, operation, and maintenance of a
compendial water system.
Impurities in raw water may be categorized as follows:
•Particulate matter
•Dissolved and ionized inorganic matter
•Gases (non reactive with water)
•Gases (reactive with water)
•Organic material
•Disinfection by-products
•Residual disinfecting agent
•Microorganisms
•Bacterial endotoxins
•Colloidal material.
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Each of these impurities is briefly discussed in this article, and case studies are described in which impurity levels
changed resulting in system excursions. Ongoing vigilance
must be provided to prevent these types of problems.
Particulate Matter
Particulate matter is material that is not dissolved in
water. Particulate matter could include silt, sand, and
debris, as well as corrosion products of iron or other
materials used in the distribution piping to a facility.
It is important to understand that the concentration of
particulate matter measured at a treatment facility may be
significantly less than that observed in the feed water to a
facility because of corrosion in distribution piping. This
is often noted when distribution piping failure occurs.
Particulate matter can interfere with the long term successful operation of unit operation used in USP water for
injection and purified water systems. Particulate matter
is generally considered as undissolved material with a
size larger than 10 microns. It is interesting to note that
the human eye cannot detect particles in water with a
size less than approximately 40 microns.
Dissolved And Ionized Inorganic Matter
Most impurities in raw water will dissolve and fully or
partially ionize in water. Materials such as common
table salt will dissolve and ionize in water producing a
positively-charged ion (cation) and negatively-charged ion
(anion). The net negative and positive charges are equal.
The ionized material contributes to the conductivity of
water. The concentration of ionized material may also be
expressed as total dissolved solids, which is a bit misleading
since material must be both dissolved and ionized. Most
ions exhibit about the same “equivalent conductance” or
“mobility” with the exception of the hydronium (hydrogen)
ion associated with acidic solutions and the hydroxyl ion
associated with basic solutions. Many materials may dissolve in water but not fully ionize. These materials are very
important to water purification operations because ionic
removal techniques require that the equilibrium associated
with these compounds be considered. Both USP purified water and water for injection use conductivity as the
indicator for inorganic contamination with specification
referenced in the Official Monographs to USP “Physical
Tests” Section <645> (2).
Gases (Non Reactive With Water)
Gases such as oxygen and nitrogen are present in water.
These gases dissolve but do not react with water to produce
ions. The concentration of oxygen and nitrogen in water
increases with decreasing temperature and is generally in
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William V. Collentro.
the range of 5 to 20 mg/l. With the exception of oxidation
of stainless steel surfaces in high temperature applications,
reactive gasses do not effect long term operation of water
purification components.
Gases (Reactive With Water)
Some gases react with water. The two most important
reactions are associated with carbon dioxide and ammonia. Carbon dioxide reacts with water in an equilibrium
reaction producing the hydronium ion and the bicarbonate
ion as follows:
CO2 + 2H2O ↔ HCO3- + H3O+
Ammonia (gas) reacts with water producing the hydroxyl
ion and the ammonium ion as follows:
NH3 + H2O ↔ NH4+ + OHBoth of these reactions are extremely important to
systems using reverse osmosis for ion removal, because
ammonia and carbon dioxide gases will pass through
the membrane and reestablish equilibrium in the product
water, increasing water conductivity. Subsequently, reactive gases can have a significant effect on the operation
and performance of USP water for injection and purified
water systems.
Organic Material
Organic material may be present in water supplies, particularly if the source water is from a “surface” source (e.g., river,
lake, stream, etc.) or a ground water source “influenced”
by surface water. The organic material is generally associated with a complex heavy molecular weight fraction
referred to as humic acid and a lighter molecular weight
less complex fraction, fulvic acid, both of which are products of rotting vegetation and associated material in the
“recharge source” to the supply water. Both fractions are
referenced as naturally occurring organic material (NOM)
and react with disinfecting agents to produce highly undesirable disinfection byproducts. Organic material will
foul anion exchange resin, impact the design criteria for
activated carbon units, foul reverse osmosis membranes,
and inhibit the ability of a water purification system to
meet the USP Official Monograph specification for Total
Organic Carbon (TOC) set forth in USP “Physical Tests”
Section <643> (3).
Disinfection Byproducts
As indicated previously, disinfection byproducts are produced by the reaction of bacteria destroying disinfecting
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agents and heavy molecular weight NOM for surface water
supplies or ground water supplies influenced by surface
water supplies. The US Environmental Protection Agency
(EPA) identifies bromate, chlorite, haloacetic acids (HHA5),
and total trihalomethanes (TTHMs) as regulated disinfection byproducts (4). Chlorite can potentially affect the
nervous system of infants, young children, and fetuses of
pregnant women. All of the other indicated disinfection
byproducts are associated with increased risk of cancer.
The EPA Surface Water Treatment Rule (SWTR) (5) outlines
specific criteria for control of disinfection byproducts. Trihalomethane compounds, and to a lesser degree extend
HAA5 compounds, can significantly affect the performance of USP water for injection and purified water systems. Chloroform, a chlorinated volatile compound, is
the most prevalent THM compound. It is not completely
effectively removed by water purification unit operations.
Chloroform is generally present (at reduced levels of the
feed water concentration) in USP purified water and water
for injection systems with a feed water supply from a surface source or ground water source influenced by a surface
water source.
Residual Disinfecting Agent
Historically, the US has employed chlorine for disinfection of source water. However, control of carcinogenic
disinfection byproducts by the EPA SWTR has significantly changed municipal water disinfection techniques.
While “primary disinfection” of source water is generally
conducted with chlorine, alternative compounds such as
ozone and chlorine dioxide appear to present positive alternatives to control production of disinfection byproducts.
For “secondary disinfection” (introduction of disinfection
agent prior to distribution to control bacteria), ammonia
is injected with chlorine to produce chloramines for an
increasing number of municipal systems using source
water from a surface water supply or ground water supply
influenced by a surface water supply. The “family” of chloramine compounds provides effective microbial control
when employed in water at pH values > 8. Unfortunately,
chloramines provide significant challenges to the short
and long term performance of USP water for injection and
purified water systems. Specifically, chloramines are much
more difficult to remove than chlorine (hypochlorous and
hypochlorite ion).
Microorganisms
The EPA National Primary Drinking Water Regulation
(NPDWR) (6) provides specific limits for Total coliform, Fecal
coliform and E.coli, Giardia lamblia, Legionella, viruses, and
Cryptosporidium. Turbidity is listed as an indicator of the
Journal
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Pharmaceutical Water System Fundamentals.
Figure 1: Case history #1, original system.
TO VAPOR
COMPRESSION
DISTILLATION UNIT
MUNICIPAL
WATER
Cartridge
Filtration
Multimedia
Filtration Unit
Activated
Carbon Unit
Dual Water
Softening
Units
presence of microorganisms with a SWTR limit. Further,
SWTR provides a heterotrophic plate count (HPC) limit
for total viable bacteria of 500 cfu/ml, consistent with the
recommended “Action Limit” in USP “General Information” Section <1231> (7). Microbial control from feed
water to compendial product water is obviously critical
in USP water for injection and purified water systems.
Bacteria are generally detected in samples of water in the
feed to a facility.
Bacterial Endotoxins
Bacterial endotoxins will be present in feed water. The
concentration of bacterial endotoxins will be related to
the amount of Gram-negative bacteria in the source water.
Bacterial endotoxin levels > 100 IU/ml have been noted
for feed waters from a surface source. Bacteria endotoxin
levels in feed water may be a concern for USP water for
injection systems, particularly if a membrane process is
not used for feed water to a distillation unit.
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Impurity Summary
The EPA NPDWR can be obtained at http://www.epa.
gov/safewater/. It is suggested that many validated USP
water for injection and purified water systems rely on
data from a municipal (or private) treatment source for
compliance with requirements set forth in the Official
Monographs. Are results for all indicated parameters in
the NPDWR available? Are records being maintained
to indicate the required testing? What is the frequency
of the testing? Is the testing frequency increased with
seasonal and climatic changes? Are test results from the
treatment facility representative of the feed water to a
facility particularly with regard to residual disinfecting
agent concentration and microbial levels?
The following three case histories are provided to demonstrate the importance of the understanding, monitoring, and control of feed water impurities on production
of USP purified water and water for injection.
Colloidal Material
CASE HISTORY # 1: CHANGE IN
MUNICIPAL TREATMENT PROCESS
A fraction of certain elements may exist in a colloidal
form. Colloids exhibit a slight negative charge and are
very small particles. The primary colloids of concern are
associated with silica, aluminum, and iron. Colloids are
removed by reverse osmosis and ultrafiltration. Some
municipal treatment facilities will introduce a treatment
chemical to convert iron to a colloidal state to minimize
staining of bathroom and kitchen accessories. Unfortunately, the colloidal form of iron is much more difficult
to remove and may foul reverse osmosis membranes in
USP purified water systems and pretreatment systems to
distillation units in USP water for injection systems.
Figure 1 provides a flow diagram of a USP water for injection pretreatment system. The system consists of multimedia filtration, water softening, and activated carbon
adsorption, providing pretreated water to a vapor compression distillation unit. Historically, the municipal treatment
facility employed chlorine for microbial control. Soon
after implementation of the Disinfection Byproducts Rule,
the municipality began injecting ammonia to treated water
prior to distribution, producing chloramines, to minimize
production of TTHMs. While the facility was notified of
the treatment change, personnel were not familiar with
the consequences of this change.
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Validation T echnology [Winter 2010]
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William V. Collentro.
Figure 2: Case history #1, enhanced system.
MUNICIPAL
WATER
Recirculation
Pump
Multimedia
Filtration Unit
Activated
Carbon Unit
Inline
Ultraviolet
Sanitization
Unit
Dual Water Softening Units
(Series Operation)
TO VAPOR COMPRESSION
DISTILLATION UNIT AND PURE
STEAM GENERATOR
Reverse Osmosis
System
Continuous
Electrodeionization
System
Inline
Ultraviolet
Sanitization
Unit
Final 0.1
Micron
Filtration
System
Break Tank
Upon change of disinfecting agent the conductivity of
USP water for injection began to increase and within a
day exceeded the criteria set forth in USP “Physical Tests”
Section <645>. An investigation was conducted.
Chlorine is removed by activated carbon by forming a
surface oxide depicted by the following equation:
C* + H2O + HOCl- → CO* + H3O + ClIn this equation, C* indicates the activated carbon surface while CO* represents the surface oxide on the activated
carbon media. The removal of monochloramine, the predomanent chloramine species for disinfection, by activated
carbon is associated with the following reactions:
NH2Cl + 2 H2O + C* → NH3 + H3O+ + Cl- + CO*
NH2Cl + H2O + CO* → N2 + C* + 2H3O+ + 2 ClNote that the first equation yields ammonia, a gas that
reacts with water, to produce the ammonium ion (equilibrium equation). The ammonia enters the distillation unit
and passes through, as a gas, which reacts with distilled
product water to produce the ammonium and hydroxyl
ions, increasing the conductivity. The immediate action to
reduce conductivity of USP water for injection was to install
(under “Change Control”) rechargeable cation and anion
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canisters downstream of the activated carbon unit. Ultimately, the pretreatment system was enhanced to include
reverse osmosis and continuous electrodeionization as
depicted in Figure 2.
About 12 production days were lost as a result of the
change of disinfecting agent to chloramines by the municipality and the inability to proactively modify the water
purification system to respond to the change. The facility
had been informed of the change a number of months
prior to implementation. Consequences of the change
in disinfecting agent were not realized by individuals
receiving notification. However, every compendial water
system requires stringent control. While the technical
ramifications of the change may have been unknown,
the regulatory aspects of the change should have dictated
a thorough evaluation prior to the date of implementation
by the municipality.
CASE HISTORY #2: LONG-TERM EFFECTS OF
FEED WATER PARAMETER CHANGE
Figure 3 provides a flow diagram of a USP purified water
system. The system consists of multimedia filtration, activated carbon, mixed resin deionization units, and final
filtration proving water to a USP purified water storage
and distribution system. The municipal treatment facility
had switched from chlorine to chloramines for microbial
control about 18 months prior to the problem described
Journal
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Validation T echnology [Winter 2010]
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Pharmaceutical Water System Fundamentals.
Figure 3: Flow diagram of USP purified water system.
MUNICIPAL
WATER
Resin Trap
Filter
Multimedia
Filtration
Unit
Activated
Carbon Unit
Dual Mixed Bed
Deionization Units
FROM LOOP
TO LOOP
USP Purified
Water Storage
Tank
Distribution
Pump
Inline
Ultraviolet
Sanitization
Unit
Final 0.2
Micron
Filtration
System
herein. Activated carbon media was replaced every two
years. System sanitization was performed using hot water.
The frequency of hot water sanitization was based on pointof-use bacteria values or annually. Point-of-use total viable
bacteria was determined by membrane filtration of a 1.0
milliliter sample and 99 milliliters of “sterile water” through
a 0.45 micron filter disc, PCA culture media, 30-35°C incubation temperature and 48-hour incubation time period.
Point-of-use total viable bacteria results for the indicated
18-month period were all <1cfu/ml below internal alert
and action limits of 10 and 25 cfu/milliliter, respectively.
Bacteria were detected in the product. A thorough investigation of ingredients, processing technique, point-of-use
hose sanitization program, and environmental contamination was conducted. The source of bacteria could not
be identified. A review of the USP purified water system
was initiated. The yearly hot water sanitization did not
appear adequate to provide the required microbial control. Samples were shipped to a contract microbiology
lab. The testing volume was increased to 100 milliliters.
The results indicated < 1 cfu/100 milliliters, unbelievable
for the conditions.
Samples were collected from points of use and analyzed for chloramines. The chloramine concentration was
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Journal
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Validation T echnology [Winter 2010]
0.5 to 1.0 mg/l at all points-of-use. Activated carbon unit
design, operating conditions, replacement frequency, and
media selection were all inadequate to provide chloramine
removal. Temporary large-volume activated carbon canisters were employed for chloramine removal. Subsequent
to installation of the temporary large activated carbon
units point-of-use total viable bacteria levels were “Too
Numerous to Count.” Long-term system enhancement
included installation of a properly-sized activated carbon
unit, replacement of the mixed bed deionization units with
reverse osmosis unit with continuous electrodeionization
polishing, and installation of ozone generation for microbial control with daily loop sanitization.
This case history demonstrates the long term affects of
changing facility feed water parameters and the inability
to recognize the affects for approximately an 18-month
period. The sanitization frequency was totally incapable
of supporting the reported total viable bacteria levels. An
evaluation of microbiology laboratory procedures may have
exposed the issue well before it became a crisis. USP purified water samples will occasionally indicate the presence
of bacteria from environmental or sample collection.
CASE HISTORY #3: SURFACE WATER
AFFECTING GROUND WATER SUPPLY
Figure 4 provides a flow diagram of a USP purified water
system. The feed water to the facility was from a ground
water source (multiple wells). The location of the wells
was physically in a valley, close to a river. As part of a USP
purified water system enhancement program, membrane
filtration with periodic chemical storage and distribution loop chemical sanitization for microbial control was
replaced with an ozone system. The enhanced system was
not capable of meeting the conductivity criteria set forth
in USP “Physical Tests” Section <645>. Analysis indicated
the presence of TTHMs in the feed water at a concentration
of about 70 ppb. While not classified as a ground water
supply influenced by a surface water supply by EPA, the
supply was obviously influenced by the river.
The system pretreatment was enhanced to include new
activated carbon units with custom selected media for
TTHM removal. The program provided long-term USP
purified water conductivity control by removal of TTHMs,
principally chloroform, which react with ozone to produce
carbon dioxide and, subsequently, the bicarbonate ion and
highly “mobile” hydronium ion.
The nature of the feed water supply to the facility was
incorrectly classified. Water from ground source water
should be sampled and analyzed to verify the possibility
of surface water contamination. The evaluation should
include all EPA-regulated inorganic, organic, physical, and
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William V. Collentro.
Figure 4: Flow diagram of a USP purified water system.
MUNICIPAL
WATER
Resin Trap
Filter
Multimedia
Filtration
Unit
Break Tank
Repressurization
Pump
Dual Water
Softening Units
Chlorine
Destruct
Ultraviolet
Unit
Reverse Osmosis
System
Continuous
Electrodeionization System
Inline
Ultraviolet
Sanitization
Unit
Final 0.1
Micron
Filtration
System
FROM
DISTRIBUTION
LOOP
Electrolytic
Ozone Generator
USP Purified
Water Storage
Tank
TO
DISTRIBUTION
LOOP
Distribution
Pump
Dissolved Ozone
Destruct Inline
Ultraviolet Unit
microbial impurities. These data should confirm information provided from the treatment facility, many of which
were operated under “contract” for municipalities.
CONCLUSIONS
Knowledge of raw water impurities, municipal water
treatment techniques, and the potential consequences of
changes to treatment techniques are critical to the design,
operation, maintenance, and validation of USP purified
water and water for injection systems.
REFERENCES
1.USP, “Official Monographs,” USP 32-NF 27, United States
Pharmacopeia, 2009.
2.USP, “Physical Tests Section <645>,” USP 32-NF 27, United
States Pharmacopeia, 2008.
3.USP, “Physical Tests Section <643>,” USP 32-NF 27, United
States Pharmacopeia, 2008.
4. EPA, “Disinfectants and Disinfection Byproducts, Final Rule,
“Federal Register, 71:2:388.
5.EPA, “Long Term 2 Enhanced Surface Water Treatment Rule,”
Federal Register 71:3:654.
6.EPA, National Primary Drinking Water Regulation, 40 CFR
191, EPA 816-F-09-0004, May 2009.
7. USP, “General Information” <1231>,” USP 32-NF 27, United
States Pharmacopeia, 2008.
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GENERAL REFERENCE
Collentro, William V., Pharmaceutical Water, System Design, Operation, and Validation, Interpharm Press, Buffalo Grove, IL,
1999. JVT
ARTICLE ACRONYM LISTING
EPAEnvironmental Protection Agency
HHA5Haloacetic Acids
HPCHeterotrophic Plate Count
NOMNaturally Occurring Organic Material
NPDWR National Primary Drinking Water Regulation
PCAPlate Count Agar (Tryptone Glucose Yeast Agar)
SWTRSurface Water Treatment Rule
TOCTotal Organic Carbon
TTHMs Total Trihalomethanes
USPUnited States Pharmacopeia
Journal
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