SUMMARY

The requirement for water quality varies from industry to industry so does the treatment methods. Available water treatment systems in pharmaceutical industries have been discussed briefly along with the system components to give information about water purification leading to USP grade purified water. Pharmaceutical industries make use of the advanced technology to generate maintain and monitor water quality conforming to the international standards. Water may be contaminated in various ways with different pollutants. Water systems also monitor for a number of contaminants that are currently not regulated. This monitoring data provides the basis for identifying contaminants to be regulated in the future. The amount and type of treatment varies with the source type and quality. Many ground water systems can satisfy all requirements without applying any treatment, while others need additional treatment. Water suppliers use a variety of treatment processes to remove contaminants from drinking water. The most commonly used processes include filtration, flocculation and sedimentation, and disinfections for surface water. Some treatment trains also include ion exchange and adsorption. Water utilities select a combination of treatment processes most appropriate to treat the contaminants found in the raw water used by the system. The purpose of this report is to provide information on water purification systems ( generation of water ) regarding their use in the Pharmaceutical industries concerning water quality requirement specified by USP and regulatory bodies for pharmaceutical process and other applications.

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Introduction
Within the pharmaceutical industry, water is most commonly used in liquid form, not only as an ingredient in many formulations but also as a cleaning agent. Production of Purified Water, Highly Purified Water, Pyrogen Free Water and WFI to international pharmaceutical standards is widely recognized as a critical process. Water is a very important element in our everyday life. Ranging from household to industry; water is utilized for various purposes. However, water is contaminated with different pollutants from its source in many ways including microorganisms. By using different water treatment methods, water can be purified as per specific requirement. Water quality requirement for a pharmaceutical industry is of utmost importance to formulate quality medicines having no adverse health effects.

Water sources
Water is generally classified into two groups: Surface Water and Ground Water. Surface water is found in a river, lake or other surface impoundment. This water is usually not very high in mineral content, and many times is called "soft water" even though it usually is not. Surface water is exposed to many different contaminants, such as animal wastes, pesticides, insecticides, industrial wastes, algae and many other organic materials. Even surface water found in a pristine mountain stream possibly contains Giardia or Coliform Bacteria from the feces of wild animals, and should be boiled or disinfected by some means prior to drinking. Ground Water is that which is trapped beneath the ground. Rain that soaks into the ground, rivers that disappear beneath the earth, melting snow are but a few of the sources that recharge the supply of underground water. Because of the many sources of recharge, ground water may contain any or all of the contaminants found in surface water as well as the dissolved minerals it picks up during it's long stay underground. Waters that contains dissolved minerals, such as calcium and magnesium above certain levels are considered "hard water" Because water is considered a "solvent", i.e., over time it can break down the ionic bonds that hold most substances together, it tends to dissolve and 'gather up' small amounts of whatever it comes in contact with. For instance, in areas of the world where rock such

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as limestone, gypsum, fluorspar, magnetite, pyrite and magnesite are common, well water is usually very high in calcium content, and therefore considered "hard".

Necessity of water Treatment

Following are the reasons for water treatment: To eliminate possible health and environmental hazards To get safe potable and domestic use water for humans To get soft water for industrial machinery such as boiler, generator To get de-mineralized or purified water for manufacturing process To produce water as per specific requirement

1. Raw Water Treatment Processes

The amount and type of treatment varies with the source type and quality. Many ground water systems can satisfy all requirements without applying any treatment, while others need to add chlorine or additional treatment. Because surface water systems are exposed to direct wet weather runoff and to the atmosphere and are therefore more easily contaminated, these water should be treated. Water suppliers use a variety of treatment processes to remove contaminants from drinking water. These individual processes may be arranged in a "treatment train" (a series of processes applied in sequence). The most commonly used processes include filtration, flocculation and sedimentation, and disinfection for surface water. Some treatment trains also include ion exchange and adsorption. Water utilities select a combination of treatment processes most appropriate to treat the contaminants found in the raw water used by the system.

2. Water for Pharmaceutical Process

Pharmaceutical process water should meet the USP requirement for purified water. Purified Water is described in the USP 23 monograph as follows: "Purified Water is water obtained by distillation, ion-exchange treatment, reverse osmosis, or other suitable process. It is prepared from water complying with the regulations of the U.S. Environmental Protection Agency (EPA) with respect to drinking water. It contains no added substances." Page 3 of 14

Purified water should have the following microbial quality as well as chemical quality 2.1. Microbial Quality Regarding the bacteriological purity of PW, the monograph states only that PW must comply with the EPA regulations for drinking water. The EPA regulations only specify limits for coliform bacteria. In the informational section of the USP 23, which deals with action guidelines for the microbial control of ingredient water, it says: "A total microbial (aerobic) count that may be used for source drinking water is 500 colony-forming units (cfu) per mL. A general guideline for Purified Water may be 100 cfu/mL." These numbers for cfu/mL are only advisory guidelines that represent recommended alert/action limits, not reject levels. The informational section also suggests that the microbial action limits for PW should be based on the intended use of the water and the nature of the product being made. It recognizes that microbial limits for PW require being defined on a case-by-case basis. USP23 Supplement 5, effective since November 1996, specifies the method for total bacteria counts. It states "Heterotrophic Plate Count of a 1-mL sample, using Plate Count Agar at an incubation temperature of 30 to 35 degrees Celsius for a 48-hour period (minimum)." There is some controversy (Collentro 1996) because this method will underestimate "starved" bacteria in high-purity water. 2.2. Chemical Quality Effective November 15, 1996, the former inorganic chemistry tests (for calcium, sulfate, chloride, ammonia, and carbon dioxide) were replaced with a three stage conductivity test. The conductivity limit is pH dependent, but for example, at pH 7.0, conductivity should be less than 5.8 microSiemens/cm. The former test for oxidizable substances was replaced with a Total Organic Carbon (TOC) limit of 0.05 mg/L. TOC is an indirect measure of organic molecules present in water measured as carbon. The new tests allow continuous in-line monitoring of water using instrumentation rather than lab work.

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3. Water For Injection (WFI)

The USP 23 monograph states: "Water for Injection (WFI) is water purified by distillation or reverse osmosis." WFI is produced by either distillation or 2-stage RO. It is usually stored and distributed hot (at 80 degrees C) in order to meet microbial quality requirements.

3.1. Microbial Quality The USP monograph makes no references to bacteria limits for WFI. It does not need to be sterile; however, the monograph specifies that WFI not contain more than 0.25 USP endotoxin units (EU) per mL. Endotoxins are a class of pyrogens that are components of the cell wall of Gram-negative bacteria (the most common type of bacteria in water). They are shed during bacterial cell growth and from dead bacteria. Indirectly, the water must be of a very high microbial quality in order to have a low endotoxin concentration. The USP informational section recommends an action limit of 10 cfu/100 mL. The recommended method of testing is membrane filtration of a 100-mL sample and plate count agar at an incubation temperature of 30 to 35 degrees Celsius for a 48-hour period. 3.2. Chemical Quality The chemical purity requirements of WFI are the same as PW (purified water).

4. Modern Water Treatment Processes in Pharmaceutical Industries

In Pharmaceutical Industries, raw water is treated in different stages to meet criteria specified for various applications. Process water should meet USP specification for purified water. Besides soft water is used for boiler feed water and generator cooling tower. Pre-treated water is used for drinking, sanitary, washing applications etc. Water treatment system consists of the following four plants: Iron Removal Plant Pre-Treatment Plant Softened Water Plant Page 5 of 14

Purified Water Plant

A block diagram showing all the plants is given below:

Figure 01: Block Diagram of water treatment plants

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4.1 Iron Removal Plant Bore hole water is passed through Deep tube well to Iron Removal Plant. Iron is removed here with the help of Sand filter. Alum is dosed to the raw water prior to entrance to the sand filter. Required Iron concentration is less than 0.1 ppm.

4.2 Pre-Treatment Plant This plant consists of tank, pumps, sand filters, activated carbon filters and dosing systems. Raw water pump takes water from the tank and forces through the filtration media of the Omnifiltration system. Flocculant such as alum is dosed to destabilize the colloidal particles and to give rise to insoluble compounds before entry to the filtration media. Omnifiltration system consists of two filters installed in series and controlled by diaphragm valves. Water passes downwards through the filtering layers in the two units and flows out of system free of particulate material or undesirable elements. Sodium hypochlorite is dosed for oxidization as well as for minimizing microbiological contamination. Activated carbon filters remove color, odor and free chlorine. 4.3 Softened Water Plant Hardness in a water supply can result in scale formation, which is a deposit of minerals left over after the water has been removed or evaporated. This can be foundin reverse osmosis systems, clean steam generators and distillation systems. The most common technology used for removing scale formed by calcium and magnesium ions is ion exchange water softening. A water softener has four major components, a resin tank, resin, a brine tank and valves or controller. When hard water is passed through the resin, calcium, magnesium, and other multivalent ions such as iron adheres to the resin, releasing the sodium ions until equilibrium is reached. A regeneration is needed to exchange the hardness ions for sodium ions by passing a sodium chloride (NaCl) solution (called brine) through the resin. Acidification/Degasification can be used as a softening process but it has numerous disadvantages, such as handling chemical (sulphuric acid, anti-scalant) and instrumentation for two Ph adjustments. Nanofiltration is sometimes referred to as a softening membrane process and will remove anions and cations. The feedwater

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requirement for a nanofiltration system is about the same as for a reverse osmosis system and feed water should be pre-treated prior to going to the membranes. 4.4 Purified Water Plant Purified Water is generated by Reverse Osmosis (RO) and continuous De-ionization (CDI). Softened water is passed through a packaged water treatment unit called Ionpro plus that consists of Reverse Osmosis and continuous di-ionization system. This unit runs continuously to fill the purified water storage tank of capacity 10000 liters. The treated water from the unit passes through a UV sterilizer to control microbial contamination. The purified water from the storage tank is pumped through the ring main via heating and cooling exchangers to different user points. Vessel and pipe work are constructed from SS316L. The plant has a PW capacity of 550 lts/hr. The USP grade of Purified Water are PH=5.7, TOC< 500 ppb, Microbial Content 100 cfu/ml and conductivity < 1.3s/cm. 4.4.1. Reverse Osmosis stage RO membranes are used to remove contaminants that are less than 1 nm nominal diameter. Reverse osmosis typically removes 90% to 99% of ionic contamination, most organic contamination, and nearly all particulate contamination from water. RO removal of non-ionic contaminants with molecular weights <100 Dalton can be low. It increases at higher molecular weights and, in theory, removal will be complete for molecules with molecular weights of >300 Dalton and for particles, including colloids and micro-organisms. Dissolved gases are not removed (eg. CO2). During reverse osmosis, pretreated water is pumped past the input surface of an RO membrane under pressure (typically 4-15 bar, 60-220 psi) in cross-flow fashion. RO membranes are typically thin film composite (polyamide). They are stable over a wide pH range, but can be damaged by oxidizing agents such as chlorine, present in municipal water. Pretreatment of the feedwater with microporous depth filters, softener and activated carbon is usually required to protect the membrane from large particulates, hardness and free chlorine. Typically 75%-90% of the feedwater passes through the membrane as permeate and the rest exits the membrane as concentrate, that contains most of the salts, organics, and essentially all of the particulates. The ratio of the volume of permeate to the volume of feedwater is referred to as the "recovery". Operating an RO system with a low recovery will reduce membrane fouling, especially that due to precipitation of low solubility salts. Page 8 of 14

However, recoveries of up to 90% are possible, depending on the quality of the feedwater and the use of filtration and softening pretreatment. The performance of the RO component of a water purification system is typically monitored by measuring the percent ionic rejection, which is the difference between the conductivities of the feed and permeate divided by the feed conductivity, calculated as a %. The "ionic rejection" and "recovery" will vary with the feedwater, the inlet pressure, the water temperature and the condition of the RO membrane. Due to its exceptional purifying efficiency, reverse osmosis is a very cost-effective technology for the removal of the great majority of impurities. Reverse osmosis protects the system from colloids and organic fouling. It is often followed by ion exchange or electrodeionisation. Reverse osmosis units need periodic cleaning & sanitisation with acid and alkaline solutions. Specially constructed membranes are available for hot water sanitisation at 85C. RO technology involves using a high pressure pump to force a portion of feed water through a semi-permeable membrane. The amount of permeate product water produced varies directly with the feed water pressure and temperature. Since the bulk of the product water contaminants are left on the feed water upstream side of the membrane and could foul the membrane, a portion of feed water is directed to drain. This stream is called reject water. An internal pump boosts the feed water to 20 bar causing water to be foced through the membrane. This results in the removal of greater than 99% of all micro-organisms, pyrogens, particles, colloids and organics greater than 200 molecular weight. The ionpro plus unit is supplied with 4 RO membranes which will deliver upto 550 liters per hour at 20 C. After the RO stage, the permeate is fed to the CDI stage. 4.4.2. Continuous Electro deionization Continuous electrodeionization is a technology combining ion exchange resins and ion-selective membranes with direct current to remove ionised species from water. It was developed to overcome the limitations of ion exchange resin beds, notably the release of ions as the beds exhaust and the associated need to change or regenerate the resins. Reverse osmosis permeate passes through one or more chambers filled with ion exchange resins held between cation or anion selective membranes. Ions that become bound to the ion exchange resins migrate from the dilute chamber to a Page 9 of 14

separate chamber (concentrate) under the influence of an externally applied electric field, which also produces the H+ and OH- necessary to maintain the resins in their regenerated state. Ions in the concentrate chamber are recirculated to a break tank or flushed to waste. The ion exchange beds in continuous electrodeionisaton (CEDI) systems are regenerated continuously, so they do not exhaust in the manner of ion exchange beds that are operated in batch mode (with chemical regeneration). CEDI beds are typically also smaller and remain in service for much longer periods. CEDI is preferred for many purified water generation applications in Pharma, because of its "clean" non-chemical nature and constant high quality water produced. The resins used in CEDI systems can either be separate chambers of anion or cation beads, layers of each type within a single chamber or an intimate mixture of cation and anion beads. Veolia Water Solutions & Technologies' pharmaceutical CEDI process utilizes cation beads in the concentrate stream and layered beds of cation and anion resins in dilute stream. The resins are housed in wide cells that provide a flow path for the ions in transit. This offers advantages in the flexibility of design and mechanical simplicity on an industrial scale. The ion migration from dilute to concentrate is enhanced by the layered resin bed in the dilute. Reverse osmosis (and sometimes membrane degassing) is typically used before CEDI to ensure that the CEDI "stack" is not overloaded with high levels of salts. The small volume of resins in the stack results in low bleed of organic molecules. Typically, RO removes about 95% of ions; CEDI will remove 99% of the remaining ions as well as carbon dioxide, organics and silica. 5. Water for Injection (WFI) Plant Water for injection is generated by means of multistage (3 rd effect) thermal distillation with a capacity of 600 liters/hour at atmospheric pressure. Purified water enters to the first column through a preheating unit. Industrial steam is supplied to the 1st effect column to generate steam from purified water, which is passed to the second effect column. Steam from 2nd effect column is passed through the 3rd effect column to produce purified steam which is condensed and stored in a 4000 liter storage tank as water for injection. Page 10 of 14

The design of these units allows producing sterile and pyrogen free water as defined by the European pharmacopeia and USP standard. WFI is maintained at temperature between 80-900C in the storage tank and in the ring main. Periodic Sterilization of the WFI tank and ring main is performed by raising the temperature to 1210C and maintaining the temperature for 30 minutes. The storage tank, pump and ring main have been constructed from Stainless Steel 316L

Figure 02: Flow diagram of purified water and WFI generation 5.1 Key criteria for Purified water (PW) & Water for injection (WFI) Loops No stagnant conditions and areas of low flow rate

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Temperature control Continuous and turbulent flow at all points in the distribution loop Proper slope of the pipeline to ensure drainability Stainless steel surface finish with appropriate roughness in order to avoid nutrient and biofilm accumulation

Air breaks System fully drainable No deadlegs according 6D rule (CFR 212) Periodic sanitisation or sterilisation of the storage tank and loop Storage tank protected with 0.2 micron hydrophobic vent filter PW & WFI distribution designed as loop configuration Sufficient instrumentation and monitoring equipments. Critical ones will be commissioned and qualified

Conclusion
Latest technological experience delivers complete solutions that meet and exceed these standards through compliance with: Latest USP and Ph. European standards cGMP requirements GMP validation control systems FDA requirements ISPE Engineering Guide IPCC environmental requirements

Whatever our needs - Pre-treatment, Purification, Storage and Distribution of water - latest Technologies uses the latest technologies available to improve manufacturing efficiency and reduce costs, without compromising process security and product quality. All aspects of our product development, project management and service offerings are managed to a high quality standard to ensure that our dedicated team of experts is in tune with the market needs.

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Referencess
1. Edstrom Industries (www.edstrorm.com) 2. Water Quality Association (WQA) 1998 3. www.veoliawaterst.com 4. www.microbix.com/products/WFI.html 5. www.honeyman.co.uk 6. www.labx.com 7. www.tka.de 8. www.wfiglobal.com/news/pr/2003-12-29-china.asp

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Probable questions on Water Treatment

1.What are the necessities of water treatment? 2.What are the monographs of purified water? 3.Diagramatically represent the modern water treatment processes used in pharmaceutical industries. 4.Describe the reverse osmosis process for purified water 5.Depict the flow diagram of purified water and WFI generation. 6.What are key criteria for purified water and water for injection (WFI) 7.What are the quality requirements for WFI? 8.What do you know about softened Water Plant?

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