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Review Article THE PRODUCTION AND BLOW FILL SEAL TECHNOLOGY OF

WATER FOR INJECTION

Article · October 2015

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THE PRODUCTION AND BLOW FILL SEAL TECHNOLOGY

OF WATER FOR INJECTION

ARCHANA ZALA1*
1
Central University of Gujarat, School of Chemical Sciences, Industrial Chemistry, Sector 30, Gandhinagar –
382030, India.

AUTHOR’S CONTRIBUTION
The sole author designed, analyzed and interpreted and prepared the manuscript.

Review Article
__________________________________________________________________________________

ABSTRACT

The aim of this article is to investigate production and production technology of water for injection (WFI).
Water for injection is a worldwide commercial product. Water for Injection is used in production of parenteral
drugs and other preparations where endotoxin content of product must be controlled. Pharmaceutical
applications of WFI are Raw material for manufacturing, Cell culture, Chromatography, Process validation,
Device processing, Purification buffers, DNA/RNA purification, a diluents drugs or medicine production,
cleaning of certain equipment and parenteral product-contact components. There is a large market for medical
and pharmaceutical world. The Pre-filtration, Additives, Softeners, Deionization, Reverse Osmosis, Distillation
and filtration are stages of conversation well water to RO water. Unit process and unit operations are discussed
for production of water for injection. Blow Fill Seal Technology (BFS Technology) is widely use for final
product. The process is constantly undergoing research and development to optimize the process technology and
its components, ultimately producing better quality end products.

Keywords: Water for injection; blow fill seal technology; the production of water for injection; unit operations.

1. INTRODUCTION minimum quantity limit of source of raw water for

production of WFI [2].
Water for Injection [1, 2] is water of extra high
quality, which is used for production of parenterals (e. This source water may be pre-treated so it suitable for
g. infusion solution for intravenous therapy or distillation and water process. The finished water
solution for injection) and water-based ophthalmic must meet all of the chemical requirements for
products according to Pharmacopoeia. Purified Water as well as an additional bacterial
endotoxin specification. Since endotoxins [3] are
Water for Injection [1, 2] is used in the production of produced by microorganisms which are prone to
parenteral products and other preparations where inhabit water. The equipment and procedures must be
product endotoxin content must be controlled, and in designed to minimize or prevent microbial
other pharmaceutical applications, such as cleaning of contamination and it must be remove endotoxin [3]
certain equipment and parenteral product-contact from row water. Row water is use by the system to
components. As per WHO, The drinking water is purify, store, and distribute Water for Injection [1, 2].

_____________________________________________________________________________________________________

*Corresponding author: Email: [email protected];

 
 
 Zala; JACSI, X(X): xxx-xxx, 20YY

Water for Injection [1, 2] systems must be use 2.3 Additives

validate method and produce. The intermediate 2.4 Organic Scavengers
product is submitted to Quality department to test the 2.5 Softeners
quality of water. The Water for Injection monograph 2.6 Deionization
allows it to be packed in bulk for commercial use. 2.7 Reverse Osmosis
[4,5] The final product required specifications include 2.8 Ultra-filtration
the test for Bacterial endotoxins, and those of the 2.9 Charge-Modified Filtration
packaged water Sterile Purified Water,[6] except for 2.10 Microbial Retentive Filtration
Labeling.[7,8]. 2.11 Ultraviolet Light
2.12 Distillation
1.1 Flow Chart of Production 2.13 Storage Tanks
2.14 Distribution Systems
Well Water and plastic granule is raw material. The
well water is treated for conversation of Well water to 2.1 Pre-filtration
RO water then WFI water. Then WFI water is store in
storage tank in aseptic conditions and then water was Pre-filtration is initial process. Filtration is use to
supply to instrument which using BFS technology. remove solid contaminants down to a size of 7 to 10
Instrument has two input one contain plastic and μm from the source of raw water and It is also protect
second contain water. BFS technology gives output downstream system components from particulates
product as WFI. [4,5]. which can inhibit equipment performance and It can
shorten their effective life.
Output of BFS technology product is goes for
capping. Product goes for autoclaving and clarity & This coarse filtration technology utilizes primarily
leak test, QC testing, QC-QA Approval and then it sieve effects for particles capture and a depth of
goes for packaging unit and market. [4,5]. filtration medium that has a higher “dirt load”
capacity. Some filtration units are available in a
2. WELL WATER TO RO WATER (UNIT different range of designs and Designs are use for
OPERATIONS CONCERNS) different applications. It is most applicable unit
process. Removals efficiencies and capacities differ
The step of unit operation for conversation of well significantly, from granular bed filters like
water to RO water: multimedia or sand for large water system, to depth
cartridge for smaller water system.
2.1 Pre-filtration
2.2 Activated Carbon

Fig. 1. Flow chart of production

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Unit and systems configurations are much type of Control of additives is ensuring a continuously
filtration media and locations in the process. Granular effective concentration of product and subsequent
or cartridge pre-filters are some time situating at or monitoring is ensuring their removal. Instrument
near the head of the water pretreatment system should be designed into the system and included in
priorities to unit operations designed to remove the the monitoring program. [8, 10].
source water disinfectant. This location doesn't
preclude the need for periodical microbial controls 2.4 Organic Scavengers
because bio-films can still proliferate; it is slower rate
in the presence of sources water disinfectant. Organic scavenging devices base on basic anion-
exchange resins. It is capable of removing organic
Designs and operation process may impact material and endotoxins [3] from the water. The
performance of depth filters includes channeling of process is use weakly as per protocol. This can
the filtration media, blockages from silt, microbial regenerate by biocidal caustic brine solutions.
growths, and filtration media loss during improperly Operation process are associated with organic
back wash. Control measure involves pressure and scavenging capacity, particulate, chemical and
flow monitors during use and back wash, sanitation, microbiological fouling of the reactive resin surface,
and replacing filtration media. An important design flow rate, regeneration frequency, and shedding of
concern is sizing of the filters to prevent channeling resin fragments. [8]
or media loss resulting from inappropriate water flow
rate as well as proper sizing to minimize excessively 2.5 Softeners
frequent or infrequent back wash or cartridge filter
replacement. [8] Water softeners are used as a disinfectant or
disinfectant removal units it may possible either
2.2 Activated Carbon upstream or downstream of disinfectant. Softeners
utilize sodium-based cation-exchange resins to
Granular activated carbon can absorb low molecular remove water-hardness ions, like calcium and
weight organic material and some oxidizing additives, magnesium that could interfere with the performance
like chlorine and chloramine compounds. Activated of downstream processing equipment, like reverse
carbon must use for removing from the water. They osmosis membranes, deionization devices, and
are used to maintain quality attributes and it give distillation units. [8]
protections against reaction with downstream stainless
steel surface, resin, and membrane. [9] 2.6 Deionization
The activated carbon beds are effective for bacteria Deionization (DI) and continuous electrode ionization
growth, hydraulic channeling, the organic adsorption (CEDI) are effective methods of improving the
capacity, inability to be regenerated in situ, shedding chemical quality attributes of water by removing
of bacteria, endotoxins, [3] organic chemicals, and cations and anions. DI systems are containing charged
fine carbon particles. Control measures may required resins which require periodically regeneration with an
monitoring water flow rates, pressures, sanitizing with acid and base. Cationic resins are regenerated with
hot water or steam, backwashing, testing for either hydrochloric or sulfuric acid that also replace
adsorption capacity, and the most recent requirements the captured positive ions with hydrogen ions.
is to replacement of the carbon bed.[8,9] Anionic resins are regenerated with sodium or
potassium hydroxides, which also replace captured
2.3 Additives negative ions with hydroxide ions. Because free
endotoxin is negatively charged, there is some
The aim of chemical additives are described below (1) removal of endotoxin achieve by the anionic resin.
to control microorganisms e.g. sanitants such as Both regenerant chemicals are biocidal and offer a
chlorine compounds and ozone, (2) to enhance the measure of microbial control. The system can be
removal of suspended solids e.g. flocculating agents, designed so that the cation and anion resins are in
(3) to remove chlorine compounds, (4) to avoid separate or “twin” beds or they can be mixed together
scaling on reverse osmosis membranes, and (5) to to form a mixed bed. Twin beds are easily regenerated
adjust pH [11] for more effective removal of but deionize water less efficiently than mixed beds,
carbonate and ammonia compounds by reverse which have a considerably more complex
osmosis. These additives do not constitute as an regeneration process. Rechargeable resin canisters can
“added substances” and at the end of process it must also be used for this purpose.
be removed by subsequent processing steps. The
additives are absent from the finished water. [10]

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The CEDI system uses a combination of mixed resin, pressure across the membrane affect the selectivity of
selectively permeable membranes, and an electric this permeation. With the proper controls, RO
charge, providing continuous flow (product and waste membranes can achieve chemical, microbial, and
concentrate) and continuous regeneration. Water endotoxin quality improvement. [12]
enters both the resin section and the waste
(concentrate) section. As it passes through the resin, it The process streams consist of supply water, product
is deionized to become product water. The resin acts water (permeate), and waste water (reject). Depending
as a conductor enabling the electrical potential to on source water, pretreatment and system
drive the captured cations and anions through the configuration variations and chemical additives may
resin and appropriate membranes for concentration be necessary to achieve desired performance and
and removal in the waste water stream. The electrical reliability. A major factor affecting RO performance
potential also separates the water in the resin is the permeate recovery rate, that is, the amount of
(product) section into hydrogen and hydroxide ions. the water passing through the membrane compared to
This permits continuous regeneration of the resin the amount rejected. This is influenced by the several
without the need for regenerant additives. factors, but most significantly by the pump pressure.
Recoveries of 75% are typical, and can accomplish a
However, unlike conventional deionization, CEDI 1 to 2 log purification of most impurities. For most
units must start with water that is already partially feed waters, this is usually not enough to meet
purified because they generally cannot produce Purified Water conductivity specifications. [13]
Purified Water quality when starting with the heavier
ion load of unpurified source water. Concerns for all A second pass of this permeate water through another
forms of deionization units include microbial and RO stage usually achieves the necessary permeate
endotoxin control, chemical additive impact on resins purity if other factors such as pH [11] and temperature
and membranes, and loss, degradation, and fouling of have been appropriately adjusted and the ammonia
resin. Issues of concern specific to DI units include from chloraminated source water has been previously
regeneration frequency and completeness, channeling, removed. Increasing recoveries with higher pressures
caused by biofilm agglomeration of resin particles, in order to reduce the volume of reject water will lead
organic leaching from new resins, complete resin to reduced permeate purity. If increased pressures are
separation for mixed bed regeneration, and mixing air needed over time to achieve the same permeate flow,
contamination (mixed beds). this is an indication of partial membrane blockage that
needs to be corrected before it becomes irreversibly
Control measures vary but typically include fouled, and expensive membrane replacement is the
recirculation loops, effluent microbial control by UV only option. Other concerns associated with the
light, conductivity monitoring, resin testing, and design and operation of RO units include membrane
micro porous filtration of mixing air, microbial materials that are extremely sensitive to sanitizing
monitoring, and frequent regeneration to minimize agents and to particulate, chemical, and microbial
and control microorganism growth, sizing the membrane fouling; membrane and seal integrity; the
equipment for suitable water flow and contact time, passage of dissolved gases, such as carbon dioxide
and use of elevated temperatures. Internal distributor and ammonia; and the volume of waste water,
and regeneration piping for mixed bed units should be particularly where water discharge is tightly regulated
configured to ensure that regeneration chemicals by local authorities. [12]
contact all internal bed and piping surfaces and resins.
Rechargeable canisters can be the source of Failure of membrane or seal integrity will result in
contamination and should be carefully monitored. Full product water contamination. Methods of control
knowledge of previous resin use, minimum storage involve suitable pretreatment of the influent water
time between regeneration and use, and appropriate stream, appropriate membrane material selection,
sanitizing procedures are critical factors ensuring integrity challenges, membrane design and heat
proper performance. [8] tolerance, periodic sanitization, and monitoring of
differential pressures, conductivity, microbial levels,
2.7 Reverse Osmosis
and TOC. The development of RO units that can
tolerate sanitizing water temperatures as well as
Reverse osmosis (RO) units employ semi permeable
operate efficiently and continuously at elevated
membranes. The “pores” of RO membranes are
temperatures has added greatly to their microbial
actually intersegmental spaces among the polymer
control and to the avoidance of bio fouling. RO units
molecules. They are big enough for permeation of
can be used alone or in combination with DI and
water molecules, but too small to permit passage of
CEDI units as well as ultra filtration for operational
hydrated chemical ions. However, many factors
and quality enhancements. [8]
including pH, [11] temperature, and differential

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 Zala; JACSI, X(X): xxx-xxx, 20YY

2.8 Ultra Filtration feature of these membranes is their electrostatic

surface charge.
Ultra filtration is a technology most often employed in
pharmaceutical water systems for removing Such charged filters can reduce endotoxin [3] levels in
endotoxins [3] from a water stream. It can also use the fluids passing through them by their adsorption
semi permeable membranes, but unlike RO, these (owing to endotoxin's negative charge) onto the
typically use polysulfone membranes whose inter membrane surfaces. Though ultra filters are more
segmental “pores” have been purposefully often employed as a unit operation for endotoxin
exaggerated during their manufacture by preventing removal in water systems, charge-modified filters
the polymer molecules from reaching their smaller may also have a place in endotoxin removal
equilibrium proximities to each other. particularly where available upstream pressures are
not sufficient for ultrafiltration and for a single,
Depending on the level of equilibrium control during relatively short term use. Charge-modified filters may
their fabrication, membranes with differing molecular be difficult to validate for long-term or large-volume
weight “cutoffs” can be created such that molecules endotoxin retention.
with molecular weights above these cutoffs ratings are
rejected and cannot penetrate the filtration matrix. Even though their purified standard endotoxin [3]
Ceramic ultra filters are another molecular sieving retention can be well characterized, their retention
technology. Ceramic ultra filters are self supporting capacity for “natural” endotoxins is difficult to gauge.
and extremely durable, back washable, chemically Nevertheless, utility could be demonstrated and
cleanable, and steam sterilizable. However, they may validated as short-term, single-use filters at points of
require higher operating pressures than membrane use in water systems that are not designed for
type ultrafilters. endotoxin control or where only an endotoxin
“polishing” (removal of only slight or occasional
All ultra filtration devices work primarily by a endotoxin levels) is needed. Control and validation
molecular sieving principle. Ultra filters with concerns include volume and duration of use, flow
molecular weight cutoff ratings in the range of 10,000 rate, water conductivity [13] and purity, and
to 20,000 Da are typically used in water systems for constancy and concentration of endotoxin levels being
removing endotoxins. [3] This technology may be removed. All of these factors may have to be
appropriate as an intermediate or final purification evaluated and challenged prior to using this approach,
step. Similar to RO, successful performance is making this a difficult-to-validate application. Even
dependent upon pretreatment of the water by so, there may still be a possible need for additional
upstream unit operations. backup endotoxin testing both upstream and
downstream of the filter. [8]
Issues of concern for ultra filters include compatibility
of membrane material with heat and sanitizing agents, 2.10 Microbial-Retentive Filtration
membrane integrity, fouling by particles and
microorganisms, and seal integrity. Control measures Microbial-retentive membrane filters have
involve filtration medium selection, sanitization, flow experienced an evolution of understanding in the past
design (dead end vs. tangential), integrity challenges, decade that has caused previously held theoretical
regular cartridge changes, elevated feed water retention mechanisms to be reconsidered. These filters
temperature, and monitoring TOC and differential have a larger effective “pore size” than ultra filters
pressure. Additional flexibility in operation is possible and are intended to prevent the passage of
based on the way ultra filtration units are arranged microorganisms and similarly sized particles without
such as in a parallel or series configurations. Care unduly restricting flow. This type of filtration is
should be taken to avoid stagnant water conditions widely employed within water systems for filtering
that could promote microorganism growth in back-up the bacteria out of both water and compressed gases
or standby units. [8] as well as for vent filters on tanks and stills and other
unit operations. However, the properties of the water
2.9 Charge-Modified Filtration system microorganisms seem to challenge a filter's
microbial retention from water with phenomena
Charge-modified filters are usually microbially absent from other aseptic filtration applications, such
retentive filters that are treated during their as filter sterilizing of pharmaceutical formulations
manufacture to have a positive charge on their prior to packaging. In the latter application, sterilizing
surfaces. Microbial retentive filtration will be grade filters are generally considered to have an
described in a subsequent section, but the significant assigned rating of 0.2 or 0.22 μm. This rather arbitrary
rating is associated with filters that have the ability to

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retain a high level challenge of a specially prepared mechanism, 0.2 to 0.22 μm rated membranes may not
inoculum of Brevundimonas (formerly Pseudomonas) be the best choice for some water system uses. [14]
diminuta. This is a small microorganism originally
isolated decades ago from a product that had been Microbial retention success in water systems has been
“filter sterilized” using a 0.45-μm rated filter. Further reported with the use of some manufacturers' filters
study revealed that a percentage of cells of this arbitrarily rated as 0.1 μm. There is general agreement
microorganism could reproducibly penetrate the 0.45- that for a given manufacturer, their 0.1 μm rated
μm sterilizing filters. Through historic correlation of filters are tighter than their 0.2 to 0.22 μm rated
B.diminuta retaining tighter filters, thought to be filters. However, comparably rated filters from
twice as good as 0.45 μm filter, assigned ratings of 0.2 different manufacturers in water filtration applications
or 0.22 μm with their successful use in product may not perform equivalently owing to the different
solution filter sterilization, both this filter rating and filter fabrication processes and the non standardized
the associated high level B. diminuta challenge have microbial retention challenge processes currently used
become the current benchmarks for sterilizing for defining the 0.1 μm filter rating. It should be noted
filtration. New evidence now suggests that for that use of 0.1 μm rated membranes generally results
microbial-retentive filters used for pharmaceutical in a sacrifice in flow rate compared to 0.2 to 0.22 μm
water, B. diminuta may not be the best model membranes, so whatever membranes are chosen for a
microorganism. [14, 15] water system application, the user must verify that the
membranes are suitable for their intended application,
An archaic understanding of microbial retentive use period, and use process, including flow rate. For
filtration would lead one to equate a filter's rating with microbial retentive gas filtrations, the same sieving
the false impression of a simple sieve or screen that and adsorptive retention phenomena are at work as in
absolutely retains particles sized at or above the liquid filtration, but the adsorptive phenomenon is
filter's rating. A current understanding of the enhanced by additional electrostatic interactions
mechanisms involved in microbial retention and the between particles and filter matrix. These electrostatic
variables that can affect those mechanisms has interactions are so strong that particle retention for a
yielded a far more complex interaction of phenomena given filter rating is significantly more efficient in gas
than previously understood. A combination of simple filtration than in water or product solution filtrations.
sieve retention and surface adsorption are now known These additional adsorptive interactions render filters
to contribute to microbial retention. [14, 15] rated at 0.2 to 0.22 μm unquestionably suitable for
microbial retentive gas filtrations. When microbially
The following all interact to create some unusual and retentive filters are used in these applications, the
surprising retention phenomena for water system membrane surface is typically hydrophobic (non-
microorganisms: the variability in the range and wettable by water). A significant area of concern for
average pore sizes created by the various membrane gas filtration is blockage of tank vents by condensed
fabrication processes, the variability of the surface water vapor, which can cause mechanical damage to
chemistry and three-dimensional structure related to the tank. Control measures include electrical or steam
the different polymers used in these filter matrices, tracing and a self-draining orientation of vent filter
and the size and surface properties of the housings to prevent accumulation of vapor
microorganism intended to be retained by the filters. condensate. However, a continuously high filter
B. diminuta may not the best challenge temperature will take an oxidative toll on
microorganisms for demonstrating bacterial retention polypropylene components of the filter, so
for 0.2 to 0.22 μm rated filters for use in water sterilization of the unit prior to initial use, and
systems because it appears to be more easily retained periodically thereafter, as well as regular visual
by these filters than some water system flora. The inspections, integrity tests, and changes are
well-documented appearance of water system recommended control methods. In water applications,
microorganisms on the downstream sides of some 0.2 microbial retentive filters may be used downstream of
to 0.22 μm rated filters after a relatively short period unit operations that tend to release microorganisms or
of use seems to support that some penetration upstream of unit operations that are sensitive to
phenomena are at work. Unknown for certain is if this microorganisms. Microbial retentive filters may also
downstream appearance is caused by a “blow- be used to filter water feeding the distribution system.
through” or some other pass-through phenomenon as It should be noted that regulatory authorities allow the
a result of tiny cells or less cell “stickiness”, or by a use of microbial retentive filters within distribution
“growth through” phenomenon as a result of cells systems or even at use points if they have been
hypothetically replicating their way through the pores properly validated and are appropriately maintained.
to the downstream side. Whatever is the penetration A point-of-use filter should only be intended to
“polish” the microbial quality of an otherwise well-

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 Zala; JACSI, X(X): xxx-xxx, 20YY

maintained system and not to serve as the primary because of their generating capacity and efficiency.
microbial control device. The efficacy of system Distilled water systems require different feed water
microbial control measures can only be assessed by controls than required by membrane systems. For
sampling the water upstream of the filters. As an distillation, due consideration must be given to prior
added measure of protection, in-line UV lamps, removal of hardness and silica impurities that may
appropriately sized for the flow rate (see Sanitization), foul or corrode the heat transfer surfaces as well as
may be used just upstream of microbial retentive prior removal of those impurities that could volatize
filters to inactivate microorganisms prior to their and condense along with the water vapor. [14, 15]
capture by the filter. This tandem approach tends to
greatly delay potential microbial penetration In spite of general perceptions, even the best
phenomena and can substantially extend filter service distillation process cannot afford absolute removal of
life. [8, 14 & 15] contaminating ions and endotoxin. Most stills are
recognized as being able to accomplish at least a 3 to
2.11 Ultraviolet Light 4 log reduction in these impurity concentrations.
Areas of concern include carryover of volatile organic
The use of low-pressure UV lights that emit a 254 nm impurities such as trihalomethanes (see Source and
wavelength for microbial control is discussed under Feed Water Considerations) and gaseous impurities
Sanitization, but the application of UV light in such as ammonia and carbon dioxide, faulty mist
chemical purification is also emerging. This 254 nm elimination, evaporator flooding, inadequate blow
wavelength is also useful in the destruction of ozone. down, stagnant water in condensers and evaporators,
With intense emissions at wavelengths around 185 nm pump and compressor seal design, pinhole evaporator
(as well as at 254 nm), medium pressure UV lights and condenser leaks, and conductivity (quality)
have demonstrated utility in the destruction of the variations during start-up and operation. Methods of
chlorine containing disinfectants used in source water control may involve preliminary de carbonation steps
as well as for interim stages of water pretreatment. to remove both dissolved carbon dioxide and other
High intensities of this wavelength alone or in volatile or non condensable impurities; reliable mist
combination with other oxidizing sanitants, such as elimination to minimize feed water droplet
hydrogen peroxide, have been used to lower TOC entrainment; visual or automated high water level
levels in re-circulating distribution systems. indication to detect boiler flooding and boil over; use
of sanitary pumps and compressors to minimize
The organics are typically converted to carbon microbial and lubricant contamination of feed water
dioxide, which equilibrates to bicarbonate, and and condensate; proper drainage during inactive
incompletely oxidized carboxylic acids, both of which periods to minimize microbial growth and
can easily be removed by polishing ion exchange accumulation of associated endotoxin in boiler water;
resins. Areas of concern include adequate UV blow down control to limit the impurity concentration
intensity and residence time, gradual loss of UV effect in the boiler to manageable levels; on-line
emissivity with bulb age, gradual formation of UV- conductivity sensing with automated diversion to
absorbing film at the water contact surface, waste to prevent unacceptable water upon still startup
incomplete photo degradation during unforeseen or still malfunction from getting into the finished
source water hyper chlorination, and release of water distribute system; and periodic integrity testing
ammonia from chloramines photo degradation, for pinhole leaks to routinely assure condensate is not
unapparent UV bulb failure, and conductivity compromised by non volatized source water
degradation in distribution systems using 185 nm UV contaminants. [14-16 & 8]
lights. Control measures include regular inspection or
emissivity alarms to detect bulb failures or film
2.13 Storage Tanks
occlusions, regular UV bulb sleeve cleaning and
wiping, downstream chlorine detectors, downstream
polishing deionizers, and regular (approximately Storage tanks are included in water distribution
yearly) bulb replacement. [8] systems to optimize processing equipment capacity.
Storage also allows for routine maintenance within
2.12 Distillation the pretreatment train while maintaining continuous
supply to meet manufacturing needs.
Distillation units provide chemical and microbial
purification via thermal vaporization, mist Design and operation considerations are needed to
elimination, and water vapor condensation. A variety prevent or minimize the development of biofilm, to
of designs is available including single effect, minimize corrosion, to aid in the use of chemical
multiple effect, and vapor compression. The latter two sanitization of the tanks, and to safeguard mechanical
configurations are normally used in larger systems integrity. These considerations may include using

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 Zala; JACSI, X(X): xxx-xxx, 20YY

closed tanks with smooth interiors, the ability to spray distribution systems, particular care should be
the tank headspace using spray balls on recirculating exercised to avoid or minimize dead leg ratios of any
loop returns, and the use of heated, jacketed/insulated size and provide for complete drainage. If the system
tanks. [14, 15] is intended to be steam sanitized, careful sloping and
low-point drainage is crucial to condensate removal
This minimizes corrosion and bio-film development and sanitization success. If drainage of components or
and aids in thermal and chemical sanitization. Storage distribution lines is intended as a microbial control
tanks require venting to compensate for the dynamics strategy, they should also be configured to be
of changing water levels. This can be accomplished completely dried using dry compressed air (or
with a properly oriented and heat-traced filter housing nitrogen if appropriate employee safety measures are
fitted with a hydrophobic microbial retentive used). Drained but still moist surfaces will still
membrane filter affixed to an atmospheric vent. support microbial proliferation. Water exiting from
Alternatively, an automatic membrane-filtered the distribution system should not be returned to the
compressed gas blanketing system may be used. In system without first passing through all or a portion of
both cases, rupture disks equipped with a rupture the purification train.
alarm device should be used as a further safeguard for
the mechanical integrity of the tank. [15] The distribution design should include the placement
of sampling valves in the storage tank and at other
Areas of concern include microbial growth or locations, such as in the return line of the recirculating
corrosion due to irregular or incomplete sanitization water system. Where feasible, the primary sampling
and microbial contamination from unalarmed rupture sites for water should be the valves that deliver water
disk failures caused by condensate-occluded vent to the points of use. Direct connections to processes or
filters. [8, 14 & 15] auxiliary equipment should be designed to prevent
reverse flow into the controlled water system. Hoses
2.14 Distribution Systems and heat exchangers that are attached to points of use
in order to deliver water for a particular use must not
Distribution system configuration should allow for the chemically or microbiologically degrade the water
continuous flow of water in the piping by means of quality. The distribution system should permit
recirculation. sanitization for microorganism control. The system
may be continuously operated at sanitizing conditions
Use of non-recirculating, dead-end, or one-way or sanitized periodically. [8, 14 & 15]
systems or system segments should be avoided
whenever possible. If not possible, these systems 3. BLOW-FILL-SEAL TECHNOLOGY
should be periodically flushed and more closely
monitored. Experience has shown that continuously Aseptic blow-fill-seal (BFS) technology is the process
recirculated systems are easier to maintain. Pumps by plastic granules are comes under applicable heat
should be designed to deliver fully turbulent flow which provides different size and shape, at a time
conditions to facilitate thorough heat distribution (for products filled with fillers, sterile [6] filtered product
hot water sanitized systems) as well as thorough are seals in sequence of operations within the
chemical sanitant distribution. controlled sterile [6] environment of a single
instrument of production. The blow-fill-seal process is
Turbulent flow also appears to either retard the aseptic processing technology, which is accepted by
development of biofilms or reduce the tendency of worldwide in the allowed for the industrial
those biofilms to shed bacteria into the water. If engineering aseptic production. Blow-fill-seal systems
redundant pumps are used, they should be configured are providing too much flexibility for packaging and
and used to avoid microbial contamination of the different - different design of product, low economical
system. Components and distribution lines should be cost and a high sterility assurance. [17]. Due to
sloped and fitted with drain points so that the system instruments, minimum number of operating personnel
can be completely drained. In stainless steel and small space can produce the large number of the
distribution systems where the water is circulated at a production. A variety of polymers may be used in the
high temperature, dead legs and low-flow conditions process, low and high-density polyethylene and
should be avoided, and valved tie-in points should polypropylene being the most popular. Low and high-
have length-to-diameter ratios of six or less. [14, 15] density polymer are use in difference types of
packaging. The inner sides of packages (which
If constructed of heat tolerant plastic, this ratio should interact with product) are made up of low density
be even less to avoid cool points where bio-film polymer and outer side is made up of high density
development could occur. In ambient temperature polymers. [18, 19]

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Fig. 2.A process flow diagram for Production of WFI

3.1 Production by BFS Technology

3.1.5 Mould opening
3.1.1 Extruding
With the opening of the blow mould, the container
The plastic parison, extruded from polymer, is exits from the machine and the cycle repeats itself.
accepted by the opened blow mould and cut below the Transfer for further processing is achieved by means
die of the parison head. [4, 5] Plastic polymer is of conveying. The cycle is then repeated to produce
convert liquid phase to solid phase, which is suitable another filled container. The filled containers are
for input polymer in blow mould and stop the flow of tested and checked to ensure that they meet the very
polymer. strict specifications laid down for such products. The
duration of the complete cycle is between 10-18
3.1.2 Moulding seconds, depending on the container design and the
amount of liquid to be filled. [4, 5 & 20-24]
The main mould closes and simultaneously seals the
bottom. The special mandrel unit settles onto the neck 4. WATER-FOR-INJECTION (WFI)
area and forms the parison into a container, using QUALITY WATER
compressed air. Small containers are formed by
vacuum. [4, 5] 4.1 Water for Injection (WFI)
3.1.3 Filling Water for injection is produced highly purified water,
free of any contamination. This water is ideal for
By way of the special mandrel unit, the product, many applications in the research and Industry or
precisely measured by the dosing unit, is filled into Institute. This advanced process incorporates
the container. [4, 5] innovative techniques at every stage of the process to
reduce bio burden and techniques are also maintain
3.1.4 Sealing low endotoxin levels. Our WFI product is based on
standard USP testing requirements for Water for
After the special mandrel unit retracts, the head mould Injection.[1, 2]
closes and forms the required seal by vacuum. [4, 5]

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Fig. 3. BFS Technology

Table 1. Product Specifications [27]

Oxidizable Substances [28] Solution remains faintly pink

Plating Efficiency (Cell line: LM) Pass
Endotoxin [29] ≤ 0.025 EU/mL
Sterility by USP [17 & 30] Pass
Random Contamination Pass
Total Organic Carbon [25] < 500 ppb
Water Conductivity [13] Meets USP requirements
Particulate Matter USP ≤ 25 particles/mL that are ≥ 10μm in size
≤ 3 particles/mL that are ≥ 3μm in size
Other “For IVD, Manufacturing and Research Uses Only”,
“Sterile” [6]
Mycoplasma Tested negative
Water conductivity, (before packaging) Meets USP temperature and conductivity requirements
USP<645> [13]

The following tests are mention by USP conductivity, • Raw material for manufacturing, Cell culture,
oxidizable substances, endotoxin, particulate, total Process validation, Device processing,
organic carbon (TOC), [25] and sterility. [17] The Purification buffers, Chromatography [26,27]
endotoxin specification is 10 times more sensitive 5. CONCLUSIONS
than the USP requirement. Test results for
conductivity prior to packaging also as per USP WFI is one of the best parenteral and most frequently
testing requirements for WFI quality water. [22-24] used in medical center and scientific institution.
Suitable rang of test result are mention in table of Blow–fill seal technology is advance aseptic
production Specification. processing technology for liquid pharmaceutical
products. It provides far higher levels of quality
4.2 Applications assurance, together with definite cost advantages,
compared with traditional aseptic filling techniques.
Worldwide acceptance in the market has confirmed

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 Zala; JACSI, X(X): xxx-xxx, 20YY

the particular suitability of this form packaging for Seeds, J. Agric. Food Chem., 57 (15), pp
ophthalmic applications BFS technology has great 7022–7029.
potential in the field of bio-pharmaceutics because of 11. US Pharmacopoeia: PH, Chapter791,
reduced human intervention. Water for injection is http://www.pharmacopeia.cn/v29240/usp29nf2
produced highly purified water, free of any added 4s0_c791.html
components. It's making averness to unit operations 12. Seymour S. Kremen (1975) Reverse osmosis
and technology. This water is ideal for many makes high quality water now, Environ. Sci.
applications in the research and biopharmaceutical Technol., 9 (4), pp 314–318.
industry. This advanced process incorporates 13. US Pharmacopoeia: Water conductivity,
innovative techniques at every stage of the process to Chapter 645,
reduce bioburden and maintain low endotoxin levels. http://www.pharmacopeia.cn/v29240/usp29nf2
4s0_c645.html
COMPETING INTERESTS 14. US Pharmacopoeia: Microbiological
procedures for absence of specified
Authors have declared that no competing interests Microorganisms—nutritional and dietary
exist. supplements, Chapter2022,
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REFERENCES 4s0_c2022.html
15. US Pharmacopoeia: Microbiological evaluation
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practices for bulk pharmaceutical excipients, Tallentire. (1991) Airborne Microbial
Chapter 1078, Challenges of Blow/Fill/Seal Equipment, J.
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Inhibitor from Acacia victoriae Bentham

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26. US Pharmacopoeia: Chromatography, Chapter FDA (December 1987), “Validation of the

621, Limulus Amebocyte Lysate Test as an End
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29. Chromogenic-Kinectic LAL Assay using
guidelines outlined by the manufacturer and
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