If you’re responsible for sourcing a new purified water system or are responsible for an existing system, it’s important that you understand what a purified water system does and how the different components work together. This article will provide you with an overview of the most common variations of reverse osmosis (RO) based water purification systems for pharmaceutical applications.

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General Process Flow

The US Pharmacopeia (and others) specify that purified water must be produced from potable water. For simplification, we will assume here that the purified water system is fed from a municipal potable water source.

Pharmaceutical Purified Water Production System Diagrams

The diagrams below illustrate the typical major components of pharmaceutical purified water production and distribution systems. Keep reading for a detailed explanation of each unit operation.

Typical Purified Water Distribution Loop

Reverse Osmosis – The Heart of the System

At the heart of almost all modern purified water systems is a reverse osmosis (RO) machine. Reverse osmosis is a process for removing dissolved impurities from water by forcing water through a semipermeable membrane. The water is stripped of most of its contaminants as it passes through (permeates) the membrane. This purified water is commonly called RO permeate.

Not all the water passes through the membrane, though. Some water remains on the “dirty” side of the membrane and helps to flush contaminants away from the membrane’s surface. In order to prevent the membrane clogging, two conditions must be met:

1. The contaminants must be kept in solution; and
2. The contaminants must be swept away by the water, meaning that the “cross-flow” must be maintained to promote appropriate turbulence and velocities at the membrane surface.

A reverse osmosis system typically sends about 25% of its feed water to drain. This means that 4 gallons of feed water are needed to produce 3 gallons of RO permeate. This 3:4 ratio means that the system is operating at 75% recovery. System recovery rates are limited by RO design choices and operating conditions.

Pre-Treatment: Keeping the Heart Beating

The performance of RO machines degrades under the following conditions:

1. Inorganic fouling of the membrane surface, also known as scale;
2. Organic fouling of the membrane surface;
3. Biological fouling of the membrane surface and flow channels;
4. Membrane oxidation;
5. Obstruction of flow by sediment or other suspended solids; and
6. The scale prevention step prevents inorganic fouling, which is typically caused by hardness or metals. These contaminants precipitate when their concentrations exceed solubility limits, covering portions of the membrane with scale.

The scale prevention step prevents inorganic fouling, which is typically caused by hardness or metals. These contaminants precipitate when their concentrations exceed solubility limits, covering portions of the membrane with scale.

Organic fouling is caused by the presence of organic compounds in the feed water. It is sometimes prevented by a separate organic removal pre-treatment step and other times handled by carrying out periodic high pH cleanings of the RO system. Adequate cross-flow and lower membrane flux rates can also contribute to mitigation when operating the system in adverse conditions.

Biological fouling occurs when bacteria cover a significant portion of the membrane surface with biofilm. This growth inhibits flow through the membrane as well as inhibiting the very important cross-flow that keeps the membrane surface clean, a double whammy that negatively impacts the quantity of water produced as well as its quality. Biological fouling can be slowed by upstream disinfection and by maintaining some dissolved oxygen in the feed water. Pharmaceutical RO systems are typically designed to be sanitized chemically or with hot water on a regular basis in order to limit bacterial growth.

Membrane oxidation is fast, irreversible and is caused by the presence of oxidants in the feed water, such as chlorine, chloramines or ozone. Most purified water systems include a dechlorination step as most municipal water supplies provide water with either a chlorine or chloramine residual. Aging and chemical exposure have a similar but much slower effect.

Sediment and other suspended solids physically “plug up” the RO membranes in a system. This leads to reduced and uneven flow through the membrane elements, increasing the rate of fouling, decreasing water production and eventually decreasing purified water quality.

Polishing

In most cases, the permeate from an RO machine is not quite pure enough to meet pharmacopoeia standards, most notably with respect to dissolved solids. The polishing step further removes dissolved ions and organics so as to reliably meet conductivity and total organic carbon (TOC) limits. This is typically achieved with ion exchange but can sometimes be achieved with a second RO purification step.

Heat sterilizable EDI system installed on a purified water production system

Distribution

Purified water does not stay pure for very long. After all, water is the universal solvent as well as the basis of life as we know it! Purified water distribution systems are most often designed as loops where the purified water is stored in a sanitary tank and is pumped around a loop with one or more on-demand usage points.

Link to ShekeSaisi

While distribution loop designs vary, it is widely accepted that they should maintain a minimum water velocity and contain no dead volumes – areas where water can stagnate outside the main flow.

Water flowing through the distribution loop sometimes flows back through the polishing step so as to keep it purified since the air in the storage tank causes an increase in conductivity as CO2 dissolves into the water.

Sterilization

The final step in producing purified water is sterilization. This step is generally integrated into the distribution loop. While many approaches exist, almost all systems include a final filtration step with 0.2 or 0.1 micron cartridge filters providing a final physical barrier against bacteria.

Additionally, many systems include an ozonation system to maintain low levels of ozone in the distribution tank and, sometimes, to allow for a periodic ozone sterilization of the distribution loop itself.

Finally, ultraviolet (UV) sterilization units are often used for sterilization and, sometimes, for TOC reduction. It is generally recommended that these units be installed upstream of the final filter so that any dead or deactivated bacteria will be caught by the filter. UV is also used to break down ozone since compendial waters must not contain ozone at the point of use.

Conclusion

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WATER SYSTEM IN PHARMACEUTICAL INDUSTRY

1. PREFILTRATION: – The purpose of prefiltration—also referred to as initial, coarse, particulate, or depth filtration—is to remove solid contaminants from the incoming source water supply and protect downstream system components from particulates that can inhibit equipment performance and shorten their effective life.

• This coarse filtration technology primarily uses sieving effects for particle capture and a depth of filtration medium that has a high “dirt load” capacity.
• Removal efficiencies and capacities differ significantly, from granular bed filters such as multimedia or sand for larger water systems, to depth cartridges for smaller water systems.
• Unit and system configurations vary widely in the type of filtering media and the location in the process.
• Granular or cartridge prefilters are often situated at the beginning of the water purification system prior to unit operations designed to remove the source water disinfectants.
• Cartridge-type coarse filters may also be used to capture fines released from granular beds such as activated carbon and deionization beds.
• Design and operational issues that may impact the performance of depth filters include:-

1. Channeling of the filtering media,
2. Blockage from silt, microbial growth, and
3. Filtering-media loss during improper backwashing.

• An important design concern is sizing of the filter to prevent channeling or media loss resulting from inappropriate water flow rates as well as proper sizing to minimize excessively frequent or infrequent backwashing or cartridge filter replacement.

2. ACTIVATED CARBON:- Activated carbon beds, depending on the type and placement, are used to adsorb low-molecular weight organic material, bacterial endotoxins, and oxidizing additives such as chlorine and chloramine compounds, removing them from the water.

• They are used to achieve certain quality attributes and to protect against reactions with downstream unit operations, stainless steel surfaces, resins, and membranes.
• The chief operating concerns regarding activated carbon beds include the propensity to support bacterial growth, the potential for hydraulic channeling, the organic adsorption capacity, and insufficient contact time.
• Operation deficiencies may result in the release of bacteria, endotoxins, organic chemicals, and fine carbon particles.
• Control measures may involve monitoring water flow rates and differential pressures, sanitizing with hot water or steam, backwashing, testing for adsorption capacity, and frequent replacement of the carbon bed.
• Monitoring of carbon bed unit operation may also include microbial loading, disinfectant chemical reduction, and TOC if used for TOC reduction.
• The use of hot water or steam for carbon bed sanitization is ineffective if there is channeling rather than even permeation through the bed.
• Channeling can be mitigated through design and proper flow rates during sanitization.
• Microbial biofilm development on the surface of the granular carbon particles can cause adjacent bed granules to agglomerate. This may result in ineffective removal of trapped debris and fragile biofilm during backwashing, and ineffective sanitization.

3. ADDITIVES:- Chemical additives are used in water systems:-

1) To control microorganisms by use of sanitizing agents, such as chlorine compounds and ozone;
2) To enhance the removal of suspended solids by use of flocculating agents;
3) To remove chlorine compounds;
4) To avoid scaling on reverse osmosis membranes; and
5) To adjust pH for more effective removal of carbonate and ammonia compounds by reverse osmosis.
These additives do not constitute “added substances” as long as they are either removed by subsequent processing steps or are otherwise absent from the finished water. Control of additives to ensure a continuously effective concentration and subsequent monitoring to ensure their removal should be designed into the system and included in the monitoring program.

4. ORGANIC SCAVENGERS:- Organic scavenging devices use macroreticular, weakly basic anion-exchange resins capable of removing negatively charged organic material and endotoxins from the water.

• Organic scavenger resins can be regenerated with appropriate biocidal caustic brine solutions. Operating concerns are associated with organic scavenging capacity; particulate, chemical, and microbiological fouling of the reactive resin surface; flow rate; regeneration frequency; and shedding of fines from the fragile resins.
• Control measures include TOC testing of influent and effluent, backwashing, monitoring hydraulic performance, and using downstream filters to remove resin fines.

5. SOFTENERS:- Water softeners may be located either upstream or downstream of disinfectant removal units. They utilize sodium-based cation- exchange resins to remove water-hardness ions, such as calcium and magnesium that could foul or interfere with the performance of downstream processing equipment such as reverse osmosis membranes, deionization devices, and distillation units.

• Water softeners can also be used to remove other lower affinity cations, such as the ammonium ion, that may be released from chloramine disinfectants commonly used in drinking water. If ammonium removal is one of its purposes, the softener must be located downstream of the disinfectant removal operation.
• Water softener resin beds are regenerated with concentrated sodium chloride solution (brine).
• If a softener is used for ammonium removal from chloramine- containing source water, then the capacity, contact time, resin surface fouling, pH, and regeneration frequency are very important.

6. DEIONIZATION:- Deionization (DI) and continuous electrodeionization (CEDI) are effective methods of improving the chemical quality attributes of water by removing cations and anions.

• DI systems have charged resins that require periodic regeneration with an acid and base.
• Typically, cation resins are regenerated with either hydrochloric or sulfuric acid, which replace the captured positive ions with hydrogen ions.
• Anion resins are regenerated with sodium hydroxide or potassium hydroxide, which replace captured negative ions with hydroxide ions. Because free endotoxin is negatively charged, some removal of endotoxin is achieved by the anion resin.
• The system can be designed so that the cation and anion resins are in separate or “twin” beds, or they can be blended together to form a “mixed” bed.
• The CEDI system uses a combination of ion-exchange materials such as resins or grafted material, selectively permeable membranes, and an electric charge, providing continuous flow (of product and waste concentrate) and continuous regeneration.
• Water enters both the resin section and the waste (concentrate) section. The resin acts as a conductor, enabling the electrical potential to drive the captured cations and anions through the resin and appropriate membranes for concentration and removal in the waste water stream. As the water passes through the resin, it is deionized to become product water.
• The electrical potential also separates the water in the resin (product) section into hydrogen and hydroxide ions. This permits continuous regeneration of the resin without the need for regenerant additives.
• However, unlike conventional deionization, CEDI units must start with water that is already partially purified because they generally cannot achieve the conductivity attribute of Purified Water when starting with the heavier ion load of source water.
• Internal distributor and regeneration piping for DI bed units should be configured to ensure that regeneration chemicals contact all internal bed and piping surfaces and resins.
• Rechargeable canisters can be the source of contamination and should be carefully monitored. Full knowledge of previous resin use, minimum storage time between regeneration and use, and appropriate sanitizing procedures are critical factors for ensuring proper performance.

7. REVERSE OSMOSIS:- Reverse osmosis (RO) units use semipermeable membranes. The “pores” of RO membranes are intersegmental spaces among the polymer molecules. They are big enough for permeation of water molecules, but they limit the passage of hydrated chemical ions, organic compounds, and microorganisms.

• RO membranes can achieve chemical, microbial, and endotoxin quality improvement. Many factors, including pH, temperature, source water hardness, permeate and reject flow rate, and differential pressure across the membrane, affect the selectivity and effectiveness of this permeation.
• The process streams consist of supply water, product water (permeate), and waste water (reject). Depending on the source water, pretreatment and system configuration variations and chemical additives may be necessary to achieve the desired performance and reliability.
• For most source waters, a single stage of RO filtration is usually not enough to meet Purified Water conductivity specifications. A second pass of this permeate water through another RO stage usually achieves the necessary permeate purity if other factors such as pH and temperature have been appropriately adjusted and the ammonia from source water that has been previously treated with chloramines is removed.
• RO units can be used alone or in combination with DI and CEDI units, as well as ultrafiltration, for operational and quality enhancements.

8. ULTRAFILTRATION:- Ultrafiltration is a technology that is often used near the end of a pharmaceutical water purification system for removing endotoxins from a water stream though upstream uses are possible. Ultrafiltration can use semipermeable membranes, but unlike RO, these typically use polysulfone membranes with intersegmental “pores” that have been purposefully enlarged.

• Membranes with differing molecular weight “cutoffs” can be created to preferentially reject molecules with molecular weights above these ratings.
• Ceramic ultrafilters are another molecular sieving technology. Ceramic ultrafilters are self-supporting and extremely durable; they can be backwashed, chemically cleaned, and steam sterilized. However, they may require higher operating pressures than do membrane-type ultrafilters.
• All ultrafiltration devices work primarily by a molecular sieving principle. Ultrafilters with molecular weight cutoff ratings in the range of 10,000–20,000 Da are typically used in water systems for removing endotoxins. This technology may be appropriate as an intermediate or final purification step. As with RO, successful performance is dependent upon pretreatment of the water by upstream unit operations.

9. MICROBIAL-RETENTIVE FILTRATION:- Microbial-retentive membrane filters have a larger effective “pore size” than ultrafilters and are intended to prevent the passage of microorganisms and similarly sized particles without unduly restricting flow. This type of filtration is widely employed within water systems for filtering the bacteria out of both water and compressed gases as well as for vent filters on tanks and stills and other unit operations.

• The following factors interact to create the retention phenomena for water system microorganisms:

1. The variability in the range and average pore sizes created by the various membrane fabrication processes;
2. The variability of the surface chemistry and three-dimensional structure related to the different polymers used in these filter matrices; and
3. The size and surface properties of the microorganism intended to be retained by the filters.

• The typical challenge organism for these filters, Brevundimonas diminuta, may not be the best challenge microorganism for demonstrating bacterial retention by 0.2- to 0.22-mm rated filters for use in water systems because this challenge microorganism appears to be more easily retained by these filters than some other water system bacteria.
• Nevertheless, microbial retention success in water systems has been reported with the use of filters rated as 0.2 or 0.1 mm.
• There is general agreement that, for a given manufacturer, their 0.1-mm rated filters are tighter than their 0.2- to 0.22-mm rated filters.
• It should be noted that filters with a 0.1-mm rating may result in a lower flow rate compared to 0.2- to 0.22-mm filters, so whatever filters are chosen for a water system application, the user must verify that they are suitable for their intended application, use period, and use process, including flow rate.
• In water applications, microbial retentive filters may be used downstream of unit operations that tend to release microorganisms or upstream of unit operations that are sensitive to microorganisms. Microbial retentive filters may also be used to filter water feeding the distribution system.
• It should be noted that regulatory authorities allow the use of microbial retentive filters within distribution systems or even at use points if they have been properly validated and are appropriately maintained.
• A point-of-use filter should only be intended to “polish” the microbial quality of an otherwise well-maintained system and not to serve as the primary microbial control device. The efficacy of system microbial control measures can only be assessed by sampling the water upstream of the filters.
• As an added measure of protection, in-line UV lamps, appropriately sized for the flow rate, may be used just upstream of microbial retentive filters to inactivate microorganisms prior to their capture by the filter. This tandem approach tends to greatly delay potential microbial penetration phenomena and can substantially extend filter service life.

10. ULTRAVIOLET LIGHT:- The use of low-pressure UV lights that emit a 254-nm wavelength is used for microbial control.

• This 254-nm wavelength is also useful in the destruction of ozone.
• At wavelengths around 185 nm (as well as at 254 nm), medium-pressure UV lights have demonstrated utility in the destruction of the chlorine-containing disinfectants used in source water as well as for interim stages of water pretreatment.
• High intensities of 254 nm or in combination with other oxidizing sanitants, such as hydrogen peroxide, have been used to lower TOC levels in recirculating distribution systems.
• The organics are typically converted to carbon dioxide, which equilibrates to bicarbonate, and incompletely oxidized carboxylic acids, both of which can easily be removed by polishing ion exchange resins.

11. DISTILLATION:- Distillation units provide chemical and microbial purification via thermal vaporization, mist elimination, and water vapor condensation. A variety of designs is available, including single effect, multiple effect, and vapor compression. The latter two configurations are normally used in larger systems because of their generating capacity and efficiency.

• Source water controls must provide for the removal of hardness and silica impurities that may foul or corrode the heat transfer surfaces, as well as the removal of those impurities that could volatize and condense along with the water vapor. In spite of general perceptions, even the best distillation process does not ensure absolute removal of contaminating ions, organics, and endotoxins.
• Most stills are recognized as being able to accomplish at least a 3–4 log reduction in these impurity concentrations. They are highly effective in sterilizing the feed water.
• Areas of concern include carry-over of volatile organic impurities such as trihalomethanes and gaseous impurities such as ammonia and carbon dioxide, faulty mist elimination, evaporator flooding, inadequate blow down, stagnant water in condensers and evaporators, pump and compressor seal design, pinhole evaporator and condenser leaks, and conductivity (quality) variations during start-up and operation.
• Methods of control may involve the following:

1. preliminary steps to remove both dissolved carbon dioxide and other volatile or noncondensable impurities;
2. reliable mist elimination to minimize feed water droplet entrainment;
3. visual or automated highwater- level indication to detect boiler flooding and boil over; use of sanitary pumps and compressors to minimize microbial and lubricant contamination of feed water and condensate;
4. proper drainage during inactive periods to minimize microbial growth and accumulation of associated endotoxin in boiler water;
5. blow down control to limit the impurity concentration effect in the boiler to manageable levels;
6. on-line conductivity sensing with automated diversion to waste to prevent unacceptable water upon still startup or still malfunction from getting into the finished water distribution system; and
7. Periodic testing for pinhole leaks to routinely ensure that condensate is not compromised by nonvolatized source water contaminants.

12. STORAGE TANKS:- Storage tanks are included in water distribution systems to optimize processing equipment capacity.

• Storage also allows for routine maintenance within the purification system while maintaining continuous supply to meet manufacturing needs.
• Design and operation considerations are needed to prevent or minimize the development of biofilm, to minimize corrosion, to aid in the use of chemical sanitization of the tanks, and to safeguard mechanical integrity.
• Areas of concern include microbial growth or corrosion due to irregular or incomplete sanitization and microbial contamination from unalarmed rupture disk failures caused by condensate-occluded vent filters.
• Control considerations may include using closed tanks with smooth interiors, the ability to spray the tank headspace using sprayballs on recirculating loop returns, and the use of heated, jacketed/insulated tanks. This minimizes corrosion and biofilm development and aids in thermal or chemical sanitization.
• Storage tanks require venting to compensate for the dynamics of changing water levels. This can be accomplished with a properly oriented and heat-traced filter housing fitted with a hydrophobic microbial retentive membrane filter affixed to an atmospheric vent. Alternatively, an automatic membrane-filtered compressed gas blanketing system may be used. In both cases, rupture disks equipped with a rupture alarm device should be used as a further safeguard for the mechanical integrity of the tank.

13. DISTRIBUTION SYSTEMS:- Distribution system configuration should allow for the continuous flow of water in the piping by means of recirculation.

• Use of no recirculating, dead-end, or one-way systems or system segments should be avoided whenever possible. If not possible, these systems should be flushed periodically and monitored more closely.
• Pumps should be designed to deliver fully turbulent flow conditions to facilitate thorough heat distribution (for hot-water sanitized systems) as well as thorough chemical sanitant distribution. Turbulent flow also appears to either retard the development of biofilms or reduce the tendency of those biofilms to shed bacteria into the water.
• Components and distribution lines should be sloped and fitted with drain points so that the system can be completely drained.
• In distribution systems, dead legs and low-flow conditions should be avoided, and valved tie-in points should have length-to-diameter ratios of six or less.
• In systems that operate at self-sanitizing temperatures, precautions should be taken to avoid cool points where biofilm development could occur. If drainage of components or distribution lines is intended as a microbial control strategy, they should also be configured to be dried completely using dry compressed gas because drained but still moist surfaces will still support microbial proliferation.
• The distribution design should include the placement of sampling valves in the storage tank and at other locations, such as in the return line of the recirculating water system.
• Direct connections to processes or auxiliary equipment should be designed to prevent reverse flow into the controlled water system.
• Hoses and heat exchangers that are attached to points of use to deliver water must not chemically or microbiologically degrade the water quality.

FIND MORE AT…
Reference links
http://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPWatePharmaceuticalUseTRS970Annex2.pdf
https://www.pharmatutor.org/articles/quality-of-water-for-pharmaceutical-use-an-overview?page=2

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