Pharmaceutical Water System Fundamentals.

William V. Collentro ]
Pretreatment Unit Operations
William V. Collentro

“Pharmaceutical Water System Fundamentals” dis- magnesium, calcium, and iron from feed water by
cusses technical justification, design considerations, means of ion exchange. Design, operation, main-
operation, maintenance, compliance, and validation tenance, and validation considerations for water
for pharmaceutical water systems. The primary objec- softening units are discussed
tive of this column is to provide a basic summary of • Other pretreatment unit operations or support acces-
the function, selection, design consideration, proper sories include pumps; heat exchangers; chemical
operation, preventative maintenance, and regulatory injection of disinfecting agent, reducing agent, or
expectations associated with the individual unit oper- acid; inline ultraviolet sanitization units; inline ultra-
ations employed in pharmaceutical water systems. violet chlorine/chloramines destruct units; organic
Reader comments, questions, and suggestions are scavengers; storage tanks; and cartridge filtration
needed to help us fulfill our objective for this column. systems.
Please send your comments and suggestions to col-
umn coordinator William V. Collentro at wcsi38@aol. INTRODUCTION
com or to journal coordinating editor Susan Haigney This paper continues a discussion on subject matter first
at [email protected]. presented in “Pharmaceutical Water System Fundamen-
tals: Impurities in Raw Water,” published in the Journal of
KEY POINTS Validation Technology, Volume 16, No. 1, Winter 2010.
The following key points are discussed in this article: Pretreatment components are unit operations
• Pretreatment components are unit operations employed prior to removal of ionic material. Primary
employed prior to removal of ionic material. Pri- types of pretreatment units include multimedia filtra-
mary types of pretreatment units include multi- tion, activated carbon units, and water softening units.
media filtration, activated carbon units, and water A discussion of each component is presented. Design,
softening units operation, maintenance, and validation considerations
• Multimedia filtration removes particulate matter are discussed. Operating data are included as appropriate
from raw water by passing raw water through inert to reinforce critical topics.
material layers of anthracite and sand of decreasing
particle size. Design, operation, maintenance, and MULTIMEDIA FILTRATION
validation considerations for multimedia filtration Multimedia filtration removes particulate matter from
units are discussed raw water. It is generally the first component in a phar-
• Activated carbon removes residual disinfecting agent maceutical water purification system; although, disin-
and reduces the concentration of naturally occurring fecting agent injection or a raw-water break tank may be
organic matter (NOM) from raw water by means positioned upstream.
of surface reaction with activated carbon. Design,
operation, maintenance, and validation consider- Design Considerations
ations for activated carbon units are discussed Multimedia filtration units are vertical cylindrical col-
• Water softening removes multivalent cations such as umns containing two distinct “layers” of material. The

[
For more Author ABOUT THE AUTHOR
information, William V. Collentro is a senior consultant and founder of Water Consulting Specialists, Inc.,
go to Doylestown, PA (www.waterconsultingspecialists.com) and has more than 40 years experience in water
gxpandjvt.com/bios purification. He may be reached at [email protected].

gxpandjv t.com Journal of Validation T echnology [Spring 2010] 37

lower level of material is referred to as “support media,” Column material of construction may be fiberglass
consisting of graduated size gravel. This layer supports reinforced vinyl ester (or polyester) for lower flow appli-
the filter media layer. The filter media also consists of cations. Larger flow rates require steel columns with
graduated levels of material. However, this material is interior lining. The filtration media is very abrasive.
layered in the reverse physical size configuration as the During periodic backwash the filter media will expand.
support media with the coarsest material at the top and During this expansion, the filter media will provide a
finest filter material at the bottom. Layering of the filter “sandpaper-like” action on the interior walls of the filter
media produces the multimedia filtration process that vessel. For steel vessels with simple sprayed- or backed-on
can provide highly effective removal of particulate mat- lining material, erosion will occur. Further, corrosion
ter. As water passes down through the filter layers, larger of the exposed steel surface will provide ongoing iron
particles are removed at the top of the bed with smaller oxidation, introducing particulate matter to the water
particles removed toward the bottom of the media. The in the area of the finest filter material (most abrasive).
course filter media is generally anthracite and the finest Fiberglass reinforced vinyl ester/polyester columns are
filter media is generally sand. “standard” straight side height. Media volume must be
The column diameter for a multimedia filtration unit adjusted to provide the indicated minimum 50% free-
should be selected such that the face velocity through board volume. Distributors for fiberglass reinforced vinyl
the bed is about six gallons per minute (gpm) per square ester/polyester columns are generally of PVC, CPVC, or
foot of cross sectional bed area. Lower face velocities may other plastic material construction. It is suggested that
produce “channeling,” a process associated with non-uni- 316L Stainless Steel distributors be considered for large
form flow over the entire cross section of the filter bed. diameter, lined steel vessels.
Channeling decreases both the ability to remove smaller Multimedia filtration units should be equipped with
particles as well as the physical amount of material that appropriate valves. For fiberglass vinyl ester/polyester
can be removed prior to “breakthrough” of particulate columns, multiport valves may be considered in lieu of
matter into the product water stream. Periodic backwash individual valves. However, top-mounted multiport
is required to remove entrapped particulate matter. The valves with top inlet “riser” tube and top outlet are strong-
backwash flow rate should be about 12-15 gpm per square ly discouraged because desired distribution cannot be
foot of cross sectional bed area. Because feed water tem- achieved. Side mounted multiport valves with top inlet
perature, particularly for water from a surface source, may and bottom outlet provide a technically superior alterna-
vary with seasons, provisions for regulating the backwash tive to top-mounted valves. Individual pneumatically
flow rate must be included. Excessive backwash flow operated diaphragm valves should be considered for
rates are undesirable because impingement of the upper lined-steel column units. The valves should be positive
layers of filter media can occur on the sides and top of acting, air-to-open, spring-to-close. A typical multime-
the filter column resulting in production of “fractured” dia filtration unit with individual valve configuration
material or “fines.” is shown in Figure 1.
There are other design factors that should be considered Other design considerations include the following:
in addition to proper column diameter sizing. The column • Units should be provided with manual inlet and
volume above the support and filter media should be at outlet isolation valves. The use of ball-type valves
least 50% of the combined volume of support and filter is strongly discouraged. Diaphragm valves are
media. This volume, referred to as “freeboard,” allows preferred
room for bed expansion during the backwash operation. • Feed water and product water sampling valves should
Inadequate freeboard will result in impingement of filter be provided. Again, diaphragm-type manual valves
media on column surfaces during backwash. The column are preferred
should be equipped with a lower distribution system that • Feed water and product water pressure gauges should
provides a pressure drop of at least 5-7 psid (pounds per be provided. Liquid-filled gauges with minimum
square inch differential). The pressure drop coupled with three-inch face diameter are desirable. Sanitary pres-
proper distributor physical arrangement will produce sure gauges with custom adapters, shown in Figure
uniform flow distribution over the entire horizontal cross 2, provide desired accuracy and minimum dead leg
section of the filter media layers. The lower distributor pro- for microbial growth. The diaphragm at the base
vides flow distribution. While a simple upper distributor is of a sanitary pressure gauge eliminates the lengthy
suggested, this distributor does not significantly contribute dead leg associated with classical pressure gauges
to the flow characteristics through the filter media. also shown in Figure 2
38 Journal of Validation T echnology [Spring 2010] iv thome.com
 William V. Collentro, Coordinator.

Figure 1: Typical multimedia filtration unit.

• A feed water flow rate meter is required to determine eye has the ability to detect particles of approximately
operating, backwash, and post backwash rinse flow 40 microns and larger. However, removal of particles
rates. Variable area flow rate meters and turbine with a size of one micron and smaller, including heavy
meters are appropriate for this application molecular weight naturally occurring organic material
• The use of a pressure relief valve positioned on the (NOM), NOM complexed with colloidal material, and
top inlet piping of the column should be considered. larger colloidal material can be achieved if the multime-
This eliminates the possibility of column failure on dia filter is operated in a “ripened” condition. Figure 3
high pressure provides a graph demonstrating the ripening process.
• Access manways and “handholes” should be con- While a common practice in municipal applications,
sidered for lined-steel columns. This will facilitate this process is seldom employed for multimedia units for
media removal as well as access to the lower distri- pharmaceutical applications. As particles accumulate in a
bution system multimedia filtration unit after backwash, the entire filter
• The waste line (to drain with air break) from the media “bed” begins to tighten. The entrapped material
multimedia filtration unit should contain a transpar- allows smaller particles to be removed. It may take hours
ent section of tubing or site glass for observation of or even days for the multimedia filtration unit to achieve
entrapped material during the backwash and post this ripened condition after backwash. Obviously it is
backwash rinse-to-drain operations. desirable to delay backwash, operating in the ripened
condition, but avoid breakthrough of particulate matter.
Operating Considerations Experience indicates that breakthrough of particulate
A multimedia filtration unit designed and operated as matter will not occur until the delta P through the unit
discussed previously should be capable of removing par- is 7–11 psid greater than the post backwash delta P. As
ticles with a size of 10 microns and larger. The human indicated, most multimedia filtration units operate in an
gxpandjv t.com Journal of Validation T echnology [Spring 2010] 39
Pharmaceutical Water System Fundamentals.

Figure 2: Sanitary pressure gauge with adapters.

unripened state. As further indicated, the use of accurate filter bed. The duration of this operation is generally
pressure gauges is required to employ this highly desir- approximately 10-15 minutes.
able condition. Proper operation of a multimedia filtration unit should
The duration of the backwash operation should be at be verified by periodic sampling and analysis. Turbid-
least 15-20 minutes. However, the duration should be ity, total suspended solids, and color analyses should be
long enough to allow complete removal of entrapped considered. Sampling prior to backwash, subsequent to
particulate matter. The transparent section of tubing backwash, and during operation is appropriate.
or site glass, discussed earlier, should be used to verify
the absence of particulate matter prior to termination Maintenance
of the backwash cycle. If necessary, the duration of the The following multimedia maintenance items are
backwash cycle should be extended. appropriate:
Subsequent to unit backwash, it is desirable to include • Feed water and product water pressure gauges should
a “settle” time of approximately five minutes between be calibrated once every 6-12 months. Feed water
the end of the backwash cycle and start of the rinse-to- flow indicators should be calibrated annually
drain cycle. This step allows the filter media to settle in • The visible section of the interior of lined-steel col-
desired defined “layers” by gravity. umns should be inspected annually. Further, filter
Subsequent to the settle cycle, a rinse-to-drain cycle media volume (level inside the column) should be
(in the normal operating flow direction) should be per- verified annually
formed. This operation should be executed at the normal • Filter media and support media should be replaced
operating flow rate for the unit. It removes particulate every five years. For fiberglass column units, dis-
matter that may have been introduced by unfiltered back- tributors should be replaced subsequent to old media
wash water as well as “stray” particulate matter from the removal but prior to installation of new media. For
40 Journal of Validation T echnology [Spring 2010] iv thome.com
 William V. Collentro, Coordinator.

Figure 3: Ripening of a multimedia filtration unit.

lined-steel column units lower distributors should be • Operating flow rate—record and verify
thoroughly inspected (and replaced if applicable) • Backwash flow rate—record and verify
• Lined-steel column access port gaskets should be • Backwash duration—record and verify
replaced every time an access port is removed • Settle time duration—record and verify
• Multiport valves should be “rebuilt” every two • Post backwash rinse-to-drain operation flow rate—
years record and verify
• Diaphragms in diaphragm valves should be replaced • Post backwash rinse-to-drain operation duration—
every two years. record and verify
• Valve sequence—operation, backwash, settle,
Validation rinse-to-drain.
The following items should be considered during valida- It should be noted that the suggested validation items
tion of a multimedia filtration unit: apply, as appropriate, to other pretreatment unit opera-
• Support media—certificate of origin tions employing a column and media, such as activated
• Filtration media—certificate of origin and analysis carbon units and water softening units.
• Column data—manufacturer, pressure rating, test
pressure, temperature rating, diameter, straight side ACTIVATED CARBON UNITS
height, overall height, drawing, and materials of Activated carbon can provide two functions within a
construction pretreatment system. Activated carbon removes residual
• Valves—manufacturer, model number, serial number, disinfecting agent present in raw water. It is important
material(s) of construction, size, and type to consider the function of activated carbon for feed
• Pressure gauges—manufacturer, model number, serial water from a ground water source and feed water from
number, materials of construction, accuracy, range, a surface source or ground water source influenced by a
pressure increments, face diameter, material certifica- surface water source. As discussed in Part I of this series
tion, and certificate of calibration of articles, raw water from a surface source or ground
• Relief valve—manufacturer, model number, seri- water source influenced by a surface water source will
al number, size, relief pressure, and materials of contain NOM. One of the functions on an activated
construction carbon unit is to reduce the concentration of NOM. For
• Flow rate meter—manufacturer, type, model number, systems employing downstream reverse osmosis (RO)
serial number, size, range, accuracy, and materials of as a primary ion removal step, NOM, if not removed,
construction will result in fouling of membranes. Fouling can result
gxpandjv t.com Journal of Validation T echnology [Spring 2010] 41
Pharmaceutical Water System Fundamentals.

in loss of RO unit product water flow rate. Perhaps the municipality can demonstrate the ability to meet the
of greater importance, NOM will accumulate on RO indicated EPA DBPR limits. Chlorine is removed from
membrane surfaces directly above a layer on the RO activated carbon, as follows:
membrane surface containing bacteria and bacterial
endotoxins, shown in Figure 4. The organic material C* + 2Cl2 = 2H2O → 4HCl + CO2
provides nutrients for microbial proliferation. This will
result in increased RO product water total viable bacte- C* + H2O + HOCl → CO* + H3O+ + Cl-
ria levels. For the limited number of pharmaceutical
water systems employing ion exchange as a primary ion Note that ammonia gas is not produced by this
removal technique, NOM, if not removed/reduced, will equation.
foul anion (negative ion removal resin) resin. Organic
fouling of anion resin results in a reduction of exchange Design Considerations
capacity. The fouling may be irreversible, requiring An activated carbon unit designed for chlorine removal
replacement of anion resin. with or without the presence of NOM can be selected
A second function of activated carbon is the removal based on a face velocity of approximately 3 gpm per
of residual disinfecting agent. If not removed, residual square foot of column cross sectional bed area and a
disinfecting agent will chemically react with downstream volumetric flow of approximately 1 gpm per cubic foot
reverse osmosis membranes (thin-film composite poly- of activated carbon media. Activated carbon media
amide-type employed for pharmaceutical applications) should be acid rinsed to remove naturally present heavy
resulting in rapid membrane failure. The NOM in raw multivalent cations such as barium, aluminum, and
water from a surface source or ground water influenced strontium. Subsequent to acid rinse by the supplier, the
by a surface water source will react with residual chlo- activated carbon should be treated with a base such that
rine disinfecting agent producing carcinogenic products. pre-shipment product water pH is approximately pH of
Both trihalomethanes (TTHMs) and haloacetic acids 7. Activated carbon media should be replaced annually
(HAA5) are regulated disinfection byproducts by the for feed water that does not contain NOM or every six
US Environmental Protection Agency (EPA) “National months if the feed water contains NOM.
Primary Drinking Water Regulations–Disinfectants and As indicated, the rate of activated carbon removal of
Disinfection Byproducts Rule” (DBPR) (1). To reduce the monochloramine is much slower than that of chlorine.
concentration of undesirable disinfection byproducts, The rate of reaction also decreases with increasing pH and
many municipalities inject ammonia at the point of concentration of NOM (4). Proper activated carbon unit
distribution, producing chloramines. The predominate design for monochloramine removal requires a face veloc-
chloramine compound in raw water is monochloramine ity ≤ 3 gpm per square foot of cross sectional bed area and
(2). Removal of monochloramine by activated carbon a volumetric flow rate ≤ 0.50 - 0.75 gpm per cubic foot
occurs as follows: of media (5). The indicated design conditions assume
that catalytic activated carbon is employed (6). Activated
NH2Cl +C* + 2H2O → NH3 +H3O+ + Cl- + CO* carbon media replacement must be performed every six
months. Activated carbon unit free and total chlorine
2NH2Cl + CO* + H2O → N2 + 2H3O+ + 2Cl- + C* monitoring should be performed frequently to verify that
chloramine “breakthrough” has not occurred.
Where C* indicates the activated carbon surface and Because activated carbon units remove residual dis-
CO* represents a surface oxide on the activated carbon infecting agent and the carbon bed provides a relatively
surface. The rate of the first reaction is greater than that warm, dark, wet area with abundant carbonaceous mate-
of the second reaction (3). The reactions are presented to rial, microbial proliferation will occur within the unit. In
demonstrate the fact that monochloramine is removed in fact, the highest pretreatment system total viable bacteria
a manner different than that of chlorine (hypochlorite levels will be noted in activated carbon unit product
ion); produces ammonia (NH3), which is a “reactive” water samples. Periodic ambient temperature backwash
gas that will pass through a RO membrane; and that is required to reduce product water bacteria levels. The
the kinetics of the reaction are not the same as that for use of periodic hot water sanitization at 80-90°C for a
chlorine removal. two-hour period provides excellent microbial control
Raw water from a ground water source or surface (7). The use of steam for periodic hot water sanitiza-
water source may employ chlorine for disinfection if tion is not suggested. The backwash flow rate should be
42 Journal of Validation T echnology [Spring 2010] iv thome.com
 William V. Collentro, Coordinator.

Figure 4: Layering of material on RO membrane.

about 4.5 to 5.0 gpm per square foot of cross sectional Operating Considerations
bed area. Because feed water temperature, particularly Operating considerations should include the
for water from a surface source, may vary with seasons, following:
provisions for regulating the backwash flow rate must be • An activated carbon unit designed and operated
included. Excessive backwash flow rate is undesirable should be capable of removing all residual disinfect-
because impingement of the relatively fragile activated ing agents and removing greater than 50-60% of
carbon media will occur on the sides and top of the filter NOM from the feed water. Obviously, it is desirable
column resulting in production of “carbon fines.” to periodically backwash units to remove bacteria. It
In addition to proper column diameter sizing, there is suggested that the backwash frequency be limited
are other design factors that should be considered. An to 1-2 times per week. Excessive backwash can result
activated carbon bed depth of 48 inches is suggested, in transfer of denser, activated carbon-containing
particularly for chloramine removal. The column volume residual disinfecting agent and NOM from the top
above the support and filter media should be at least of the bed to the bottom of the bed. This could
75% of the activated carbon volume to allow room for accelerate “breakthrough” of residual disinfecting
bed expansion during the backwash operation. Column agent and/or NOM, requiring frequent activated
selection and distributor design should be similar to that carbon media replacement
for multimedia filtration units. For hot water sanitizable • The duration of the backwash operation should
units, column material of construction must be either be about 15-20 minutes. However, the duration
316L Stainless Steel or preferably high temperature rub- should be long enough to allow complete removal
ber lined, carbon steel. of activated carbon fines. The transparent section of
Hot water sanitizable activated carbon units should tubing or site glass, discussed previously, should be
be equipped with 316L Stainless Steel “face” piping/tub- used to verify the absence of activated carbon fines
ing and diaphragm-type valves. Further, for hot water prior to termination of the backwash cycle
sanitizable units, the use of a dedicated tank, recircula- • Subsequent to unit backwash, it is desirable to allow
tion pump, and heat exchanger should be considered for a five-minute settle time period between the end of
recirculation of hot water, avoiding pressure and tem- the backwash cycle and start of the rinse-to-drain
perature issues associated with heating and expansion cycle. This step allows the media to settle
of a “solid” system containing water. Figure 5 depicts an • Subsequent to the settle cycle, a rinse-to-drain cycle
activated carbon unit with suggested hot water sanitiza- (in the normal operating flow direction) should be
tion accessories. performed. This operation should be executed at
Other design considerations are similar to those pre- the normal operating flow rate for the unit. This
sented for multimedia filtration units. step hydraulically compresses the relatively light
activated carbon media back to the lower section
gxpandjv t.com Journal of Validation T echnology [Spring 2010] 43
Pharmaceutical Water System Fundamentals.

Figure 5: Process flow diagram. Activated carbon unit hot water sanitization components.

of the column. The duration of this operation is For the limited number of pharmaceutical systems
generally approximately 10-15 minutes employing ion exchange resin (two-bed or mixed bed)
• Proper operation of an activated carbon unit should as the primary ion removal process, water softening
be verified by periodic sampling and analysis. Feed should not be employed as a pretreatment technique.
water and product water total organic carbon (TOC), For ion exchange applications, the attraction of ions to
free chlorine, total chlorine, total suspended sol- exchange sites is a function of “charge density,” a func-
ids, and total viable bacteria analysis should be tion of molecular weight and charge. Higher molecular
considered weight ions and ions with multiple electronic charge
• Maintenance items are similar to those for a mul- (valence) have a greater attraction to an ion exchange
timedia filtration unit with the exception of media site than lighter molecular weight monovalent ions.
replacement frequency. Validation considerations, The Table provides a summary of the affinity of vari-
including documentation, are also similar to that ous cations for ion exchange sites (8). A water softener
of a multimedia filtration unit. converts the heavy molecular weight multivalent cations
to monovalent light molecular weight sodium. This is
WATER-SOFTENING UNITS highly undesirable and would adversely affect both the
Water-softening units remove multivalent cations from product water quality and volume of water processed
feed water replacing the ions with sodium. The multiva- between regeneration cycles with acid and caustic for
lent cations, such as magnesium, calcium, and iron will ion exchange units.
form insoluble compounds in the concentrating stages Water softening is an ion exchange process with typi-
of a reverse osmosis unit. The resulting scale will reduce cal reaction, as follows:
RO product water flow and purity. Chemical cleaning
can be used to remove some scalents. However, scales Ca++ + R-Na+ ↔ R-Ca++ + Na+
formed by trace concentrations of aluminum, barium,
and strontium may result in compounds that cannot be Calcium ion present in feed water is attracted to the ion
removed from the RO membranes requiring replacement. exchange resin site and displaces sodium ion from the
The use of water softening as a pretreatment unit opera- resin site. Calcium has a molecular weight of 40 Daltons
tion in a system employing RO for primary ion removal and a +2 charge. Sodium has a molecular weight of 23
is critical to successful system operation. and a +1 charge. Subsequently, the calcium ion has a
44 Journal of Validation T echnology [Spring 2010] iv thome.com
 William V. Collentro, Coordinator.

Table: Relative attraction of various cations to exchange sites.

Lithium (Li+) 0.8

Sodium (Na ) +
2.0

Hydronium (H3O+) 1.0

Potassium (K ) +
3.0

Ammonium (NH4+) 3.0

Magnesium (Mg ) ++
26

Calcium (Ca++) 42
Source: Rohm and Haas, 1965 (9).

much greater attraction to the resin site than sodium. time may be adjusted to obtain the optimum value for
Product water from the softener will contain sodium a specific unit, cation resin, and feed water analytical
as the positive ion (cation) electronically balanced with profile.
negative anions (anions) such as chloride, bicarbonate, The regeneration cycle for common concurrent units
sulfate, etc. employs backwash, salt solution introduction, displace-
Ion exchange would not be a viable process if the resin ment rinse, and fast rinse. The backwash operation is
could not be regenerated. Note that the symbol between performed at a flow rate of approximately 6 gpm per
reactants and products in the equation represents an square foot of cross sectional bed area and time period
equilibrium reaction. During operation, with the major- of 10-20 minutes. As indicated previously, regenerant
ity of resin sites in the sodium form, the equilibrium is salt solution is introduced over a time period of 30-45
strongly driven to the right side of the equation. How- minutes. The displacement rinse (“slow” rinse) is gen-
ever, eventually resin sites are converted to the calcium erally conducted at the same flow rate and time period
(or other multivalent cation) state. The resin will be as the regenerant salt introduction step. Final rinse is
incapable of further multivalent cation removal result- performed at the operating flow rate for a time period of
ing in “breakthrough” of calcium and other multivalent 15-30 minutes, a function of the feed water total hardness
cations. Regeneration is performed with salt, a sodium and regeneration parameters.
chloride solution. During the regeneration process the
sodium ion concentration is orders of magnitude greater Design Considerations
than the concentration of multivalent cations, resulting The column diameter for a water-softening unit should
in the following: be selected such that the face velocity through the bed is
approximately 7 gpm per square foot of cross sectional
Na+ + Cl- + R-Ca++ → Ca++ + R-Na+ + Cl- bed area. The maximum suggested face velocity should
not exceed 10 gpm per square foot of cross sectional
Ion exchange sites are converted back to the sodium bed area. In addition to proper column diameter siz-
form with exchanged calcium removed and diverted to ing there are other design factors that should be con-
waste. Subsequent to regeneration and rinse, the water sidered. The column volume above the support and
softener ion exchange bed is placed in operation and filter media should be at least 50% of the resin volume.
the indicated cycle repeated. The “dose” of salt sug- Other column parameters, including distributor design,
gested for conversation from the calcium form back to are similar to those described for multimedia filtration
the sodium form is 15 pounds per cubic foot of cation units. Column material of construction is similar to the
exchange resin. The salt is introduced over a 30- to 45- description for multimedia filtration units. Hot water
minute regeneration time period at a flow rate of 0.5 to sanitization of water softening units is possible but sel-
3.0 gpm/cubic foot of cation resin and sodium chloride dom employed. The use of stainless steel columns for
concentration of approximately 10%, consistent with the hot water sanitization is discouraged because of chlo-
resin manufacturer’s recommendation. The regeneration ride stress and pitting attack concerns. It is suggested
gxpandjv t.com Journal of Validation T echnology [Spring 2010] 45
Pharmaceutical Water System Fundamentals.

that rubber-lined steel vessels be employed for hot water • Periodic examination of the waste water during the
sanitization application. regeneration steps to verify the absence of cation
Cation resin will become fouled with iron over a peri- resin “fines”
od of time. Iron fouling reduces available resin exchange • Annual or semi-annual collection of cation resin
sites because it is not removed during regeneration with samples for analysis of resin characteristics includ-
salt solution. While use of regenerant salt with an “iron ing iron fouling
removal” additive and iron removal chemical treatment • Verification of the salt volume and weight introduced
techniques are not available, it is suggested that the use during the regeneration cycle
of either technique is inappropriate for pharmaceutical • Proper operation of a water-softening unit should be
water purification applications. Regenerant salt with verified by product and feed water periodic sampling
an “iron removal” additive introduces a “Foreign Sub- and analysis. Total suspended solids, total hardness
stance/Impurity” as defined in the “General Notices” as calcium carbonate, total iron, and total viable
section of the United States Pharmacopeia. Tests necessary bacteria are analyses that should be considered.
to verify removal of the additive are difficult to deter-
mine since the nature and chemical composition are Maintenance
unknown and often proprietary. Chemical cleaning The following water softening unit maintenance items
of cation resin is also inappropriate, because the nature are appropriate:
of the cleaning chemicals is unknown. Further, cation • Feed water and product water pressure gauges should
resin decomposition products, safety issues, and main- be calibrated once every 6-12 months. Feed water
tenance intensive nature of the process are all concerns. flow indicators should be calibrated annually
It is strongly suggested that samples of softener cation • A stainless steel mesh-type resin trap should be posi-
resin be obtained every 6-12 months for analysis. If iron tioned downstream of a water softening unit. The
fouling is indicated, a periodic resin replacement program trap should be inspected frequently to verify that the
should be initiated. Iron can rapidly foul downstream “whole” resin beads are not present. Resin “fines”
RO membranes. The cost of cation resin is inexpensive should be flushed from the trap periodically
compared to the cost of downstream RO membrane • The volume of cation resin in a water softener should
replacement. Finally, iron provides an excellent nutrient be visually determined at least once each year
for several species of pathogens. • Lined steel column access port gaskets should be
The regeneration time period for a water-softening replaced every time an access port is removed
unit is approximately two to three hours, so two units are • Multiport valves should be “rebuilt” every two
generally employed. Because stagnant water provides a years
location for bacteria to replicate, series operation of water • Diaphragms in diaphragm valves should be replaced
softening units should be considered. Generally, this every two years.
mode of operation designates one unit as the “lead” unit
and the other as a “polisher.” The lead unit is regenerated Validation
based on the volume of water processed or indication The following items should be considered during valida-
of product water hardness (online analyzer or “grab” tion of a water-softening unit:
samples). The polishing unit is regenerated based on • Cation exchange resin—certificate of origin
elapsed time. When either unit is being regenerated the • Cation exchange resin—meets US Food and Drug
other unit remains in “service” to provide an uninter- Administration requirements for application
rupted flow of softened water. • Column data—manufacturer, pressure rating, test
Other design considerations are similar to those indi- pressure, temperature rating, diameter, straight side
cated for multimedia filters and activated carbon units. height, overall height, drawing, and materials of
construction
Operating Considerations • Valves—manufacturer, model number, serial num-
Operating consideration should include the following: ber, material(s) of construction, size, and type
• Periodic sanitization and cleaning of the salt stor- • Pressure gauges—manufacturer, model number,
age tank serial number, materials of construction, accuracy,
• Periodic sample collection of the regenerant salt range, pressure increments, face diameter, material
solution concentration to ensure proper conversion certification, and certificate of calibration
of resin back to the sodium form • Relief valve—manufacturer, model number, seri-
46 Journal of Validation T echnology [Spring 2010] iv thome.com
 William V. Collentro, Coordinator.

al number, size, relief pressure, and materials of Heating may be employed for hot water sanitization
construction of activated carbon units and/or water softening units.
• Flow rate meter—manufacturer, type, model num- Heat exchangers of shell and tube type are preferred.
ber, serial number, size, range, accuracy, and materi- Surface in contact with water should be stainless steel
als of construction with non-chemical eluting gaskets.
• Operating flow rate—record and verify
• Backwash flow rate—record and verify Chemical Injection of Disinfecting Agent
• Backwash duration—record and verify Chemical injection of disinfecting agent may be required
• Regenerant salt introduction time—record and if the feed water to a facility has inadequate residual
verify disinfecting agent or elevated total viable bacteria levels
• Regenerant salt concentration—sample, record, and (>500 cfu/ml). Chemical injection of a liquid sanitizing
verify agent such as sodium hypochlorite may be appropriate. A
• Regenerant salt volume—record and verify metering pump for injection with contact baffled cham-
• Regenerant salt purity—record, sample, and verify ber/tank providing approximately 20-minute contact time
• Displacement (slow) rinse time—record and is suggested. Online monitoring for residual disinfecting
verify agent subsequent to storage should be considered.
• Displacement rinse flow rate—record and verify
• Fast rinse time—record and verify Chemical Injection of Reducing Agent
• Fast rinse flow rate—record and verify Chemical injection of reducing agent such as sodium
• Valve sequence—operation, backwash, settle, bisulfite may be employed in lieu of activated carbon
rinse-to-drain. units for ground water supplies not influenced by
a surface water supply and with low TOC concentra-
OTHER PRETREATMENT UNIT OPERATION tion. A positive displacement pump, chemical storage
Other potential pretreatment unit operations or support tank, injection device with mixing capability, and post
accessories for pretreatment equipment are presented. A injection online oxidation-reduction potential (ORP)
brief summary and comments are provided. monitoring system are required. Reducing agents can
introduce significant amounts of bacteria if the system
Pumps is not designed properly or if freshly prepared reducing
Pumps may be used for repressurization of a tank, agent is not used.
increasing raw water pressure to ensure flow through
all pretreatment components, and/or recirculation of Chemical Injection of Acid
water through the pretreatment components to avoid Chemical injection of acid may be required within the
stagnant conditions. While microbial control is a pri- pretreatment system. Injection of acid may be required
mary consideration for recirculation, diffusion of mate- prior to an activated carbon unit to reduce the feed water
rial, by concentration difference, in stagnant activated pH to a value ≤ 8.0. Monochloramine removal at pH
carbon units and water softeners is a concern. Diffusion values > 8.0 requires significant contact time. Many
may result in migration of contaminants to the lower raw feed water supplies for large older cities exhibit pH
regions of an activated carbon unit or water softening values >8.0 in an attempt to eliminate corrosion of lead
unit resulting in premature “breakthrough” of material. pipe or lead soldered copper fittings in residential and
Pumps should be selected such that surfaces in contact commercial property.
with water are stainless steel or non-contaminating mate-
rial. Pump motors should be of a totally enclosed fan Inline Ultraviolet Sanitization Units
cooled (TEFC) type. Variable frequency drives (VFDs) are Inline ultraviolet sanitization units are employed in pre-
recommended for pump motors to allow flow variation treatment systems generally positioned downstream of
for backwash and regeneration operations. activated carbon units. The inline ultraviolet (UV) units
employ UV light at a wave length of 254 nanometers and
Heat Exchangers radiation intensity of about 30,000 to 35,000 microwatt-
Heat exchangers may be used for heating or cooling appli- seconds per square centimeter to control bacteria. It is
cations. Cooling of recirculating pretreated water will very important to indicate that UV deactivates bacteria by
reduce microbial growth particularly for systems with attacking its DNA. However, the bacteria are still meta-
raw water from a surface source during summer months. bolically active and may become reactivated if exposed
gxpandjv t.com Journal of Validation T echnology [Spring 2010] 47
Pharmaceutical Water System Fundamentals.

to light. Inline UV units can provide a one- to two- backwash water and to collect backwash water for
log reduction in bacteria levels if properly selected, gradual discharge to drain.
installed, and maintained.
Cartridge Filtration Systems
Inline Ultraviolet Chlorine And Chloramine Cartridge filtration systems may be employed in pretreat-
Destruct Units ment systems. It is suggested that the number and loca-
Inline ultraviolet chlorine and chloramine destruct tion of the cartridge filtration system be carefully evalu-
units can be used to remove residual disinfecting ated. Systems positioned downstream of an activated
agents. The units operate at a wavelength of 185 nano- carbon unit or in a pretreatment recirculation system
meters and ultraviolet radiation intensity approxi- with activated carbon unit will provide a surface area
mately 5–15 times that used for disinfection. The for accumulation and replication of bacteria.
technology can provide an alternative to activated
carbon for certain applications. It should be indicated
that the TOC level associated with NOM will also be REFERENCES
reduced by 185 nanometer UV. Unfortunately NOM 1. US EPA, “National Primary Drinking Water Regula-
reduction results in a competitive reaction within the tions: Stage 2 Disinfectants and Disinfection Byproducts;
stainless steel chamber containing the UV lamps in Final Rule,” 40 CFR Parts 9, 141, and 142, Federal Register
quartz sleeves. It is strongly suggested that system 71:2:388, 2006.
design and unit selection be performed by the UV 2. Collentro, W. V., Pharmaceutical Water–System Design, Op-
manufacturer. eration, and Validation, informa healthcare, New York, NY,
pg. 38, 1999.
Organic Scavengers 3. Glaze, W.H., Chemical Oxidation, Water Quality and Treat-
Organic scavengers may be used for pretreatment to ment–A Handbook of Community Water Systems, 4th Edition,
both RO units and deionization units if the feed water American Water Works Association, Denver, CO, pp 747-
TOC levels from NOM are excessive. The units con- 779, Publishing Office: McGraw-Hill, Inc., 1990.
sist of a column containing either macroporous sty- 4. Fairey, J.L., Speitel, G.E., and Katz, L.E., “Monochloramine
renic anion resin or gellular acrylic resin. The anion Destruction by GAC – Effect of Activated Carbon Type and
resin will remove NOM that exhibits a slight negative Source Water Characteristics,” Journal of the American Water
charge. Multiple step regeneration using a caustic Works Association, Volume 99, No. 7, July 2007.
brine solution generally followed by hydrochloric 5. Collentro, W. V., Pharmaceutical Water–System Design, Opera-
acid introduction is required. Chemical handling tion, and Validation, Second Edition, informa healthcare,
and safety concerns generally limit the use of this New York, NY, Chapter 3, 2010.
technology. 6. Calgon Carbon Corporation, “Centaur 12x40 Granular
Activated Carbon,” Product Bulletin LC-765-02/98, 1998.
Storage Tanks 7. Collentro, W. V., Pharmaceutical Water–System Design, Op-
Storage tanks may be employed at various points in eration, and Validation, informa healthcare, New York, NY,
a pretreatment system. As indicated earlier, baffled pg. 437, 1999.
tanks may be used with sodium hypochlorite injec- 8. Collentro, W. V., Pharmaceutical Water–System Design, Op-
tion systems to provide contact time for bacteria eration, and Validation, informa healthcare, New York, NY,
destruction. Systems may employ raw water break pg. 139, 1999.
tanks to provide a definitive “air break” between a 9. Rohm & Haas Company, “The Deionization of Water, Part
domestic supply to a facility and the pretreatment I: The Hydrogen Cycle Operation,” Amber-Hi-Lites, No.86,
system. The tank will also provide an excellent point Philadelphia, PA, 1965.
for recirculating pretreated water return flow when
the downstream primary ion removal system does
not require pretreated water. Finally, the feed water GENERAL REFERENCE
piping size to a facility or drain capacity at a facility Collentro, William V., Pharmaceutical Water, System Design,
may not be capable of supporting the backwash flow Operation, and Validation, Interpharm Press, Buffalo Grove,
rate or drain flow rate. Tanks may be used to store IL, 1999. JVT

48 Journal of Validation T echnology [Spring 2010] iv thome.com