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Pharmaceutical Water Treatment

Pharma Water

Pharmaceutical Water Treatment

Pharmaceutical Water Treatment requires removing contaminants from municipal drinking water to meet USP standards. There are two basic types of pharmaceutical water; water for topical use or cleaning (sterile purified water, or PW), or water for injection (WFI) which includes sterile water for irrigation and most sterile water for inhalation.

For PW, USP guidelines require a conductivity limit of 0.6–4.7 µS/cm, a total organic carbon or total oxidizable carbon (TOC) limit of 500 ppb (µg/L), and a bacteria-count limit of 100 cfu/mL.

For WFI, the USP guidelines require a conductivity limit of 0.6–4.7 µS/cm, a TOC limit of 500 ppb (µg/L), an endotoxin limit of 0.25 endotoxin units/mL and a bacteria-count limit of 10 cfu/100 mL.

The main difference between PW and WFI is the amount of bacterial contamination allowed, measured by colony count and by endotoxin level.

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Every Water Treatment Plant is unique, but may include a combination of these Methods:

  • Activated Carbon (AC): AC beds, also known as activated carbon filters, most commonly are used to remove chlorine and chloramine compounds from feed water. This filtration process protects downstream equipment such as RO membranes and IX resin beads from the damaging oxidizing action of chlorine and chloramine compounds.
  • Ion Exchange (IX) units: IX technology exchanges undesirable feed water cations and anions with desirable cations and anions. Cations are positively charged atoms and molecules. Anions are negatively charged atoms and molecules. Cation IX units exchange undesirable feed water cations such as calcium, magnesium, lead, and copper with desirable hydrogen ions. Anion IX units exchange undesirable feed water anions such as chloride, sulfate, phosphate, and nitrate with desirable hydroxide ions. The resulting hydrogen and hydroxide ions then combine to form water.
  • Distillation: Distillation units heat the feed water to its boiling point. Most dissolved and suspended contaminants remain in the water phase. The steam that is produced is condensed and typically meets WFI and PW standards.
  • Reverse Osmosis (R O) Water Treatment: RO water treatment has become the standard at many pharmaceutical water treatment plants. RO technology can be a costeffective replacement for dual cation and anion IX units. RO systems reduce the need to use costly chemicals, especially those that are caustic, and they curtail the ever-increasing cost of regeneration waste disposal. The payback that results from using an RO system can be achieved in less than two years in some situations. An RO membrane system can remove as much as 98–99% or more of all dissolved contaminants and can remove essentially all suspended (particulate) contaminants. However, RO units require pretreatment to prevent scaling, fouling with living and nonliving particulate materials, and chemical attack, commonly by oxidizing agents.
  • Softening: A softener is a type of IX technology that controls scaling in downstream equipment. A softener controls scaling by removing hard scale–forming cations such as calcium and magnesium and exchanging (i.e., replacing) these ions for nonscale- forming sodium ions. An older term, sodium zeolite softening, frequently is used to describe water softening.
  • Cartridge Filtration: Cartridge filtration or other prefiltration technology is used ahead of RO units to protect against fouling from suspended particles in the feed water. RO membrane systems may become fouled if sufficient suspended solids (particulate) removal is not accomplished. Typically, 1–5-µm nominally rated filter cartridges are used.
  • Mixed-Bed IX units usually are positioned after an RO subsystem. The effluent from a mixed-bed IX unit meets USP conductivity limits for PW and WFI.
  • Ultra Violet irradiation may be used for bacterial control.
  • Deionization (D I): DI units in many cases can cost-effectively replace mixed-bed IX units. The resin beads in EDI units do not require chemical regeneration by acid and caustic. EDI units are continuously regenerated electrically.

Water Treatment Systems


Commercial Water Treatment Systems work to remove minerals and pollutants from water. Each water treatment system designed by PWC is custom engineered for the local water chemistry, operating conditions and desired purity. A complete system can include many levels of pretreatment, filtration, polishing and sterilization. We employ all water treatment processes to assure the most economical and environmentally friendly solution.


The United States Pharmacopeia (USP) defines several types of water including: Purified Water, Water for Injection, Sterile Purified Water, Sterile Water for Injection, Sterile Bacteriostatic Water for Injection, Sterile Water for Inhalation, and Sterile Water for Irrigation.  The USP states qualifications for sterility and packaging methods that delineate between the various specific types of water.  However, there are two basic types of water preparation, Water for Injection and Purified Water.  The analytical standards for these two types of water are very similar, differing in the fact that Water for Injection has stricter bacterial count standards and must also pass the bacterial endotoxin test.  Preparation methods are very similar to a point, however, Water for Injection preparation must incorporate distillation or double pass reverse osmosis.  Discussion of the various methodologies used in preparation of USP water applies equally to Purified Water (PW) and Water for Injection (WFI).

The source water supplied to the purification system for preparation of USP water must comply with drinking water standards as defined by the United States Environmental Protection Agency in the National Primary Drinking Water Regulations or equivalent international regulations.  Although the water source must be safe to drink, there is quite a range of problematic contaminants that may be present in the water.  Chlorine is most certainly present in the water and will have to be removed at some point in the purification process.

The analytical standards for USP water have been significantly streamlined.  In the current USP 24, analyses for conductivity, total organic carbon, and bacteria (plus bacterial endotoxin in the case of WFI) are all that is required.  Virtually no water source will meet the conductivity requirement and therefore reduction of ion content of the water is the primary required treatment in USP water preparation systems.  TOC reduction is often accomplished by the same processes employed to reduce ion content.  However, if no membrane technology is utilized in the ion reduction treatment, specific treatment for TOC reduction is likely to be required.  Also, it is fairly common for TOC reduction techniques to be utilized in final storage and distribution systems.  Maintaining low bacteria counts throughout the treatment processes, storage, and distribution system is difficult and therefore bacterial control technology is extremely important in USP water preparation systems.

Considering the required treatment objectives of USP water preparation systems, several categories of treatment warrant examination: dechlorination, ion reduction, bacterial control, and removal of specific impurities.


There are several methods of dechlorinating water.  The most common method is filtration through activated carbon media.  There are also other dechlorination medias including dissimilar metals.  Injection of a reducing agent, most commonly sodium metabisulfite, is also a common dechlorination method.  Recently it has been demonstrated that high dosage exposure to UV light will dechlorinate.

Carbon Filtration

Carbon dechlorinates by chemical reaction with the free chlorine in water, forming hydrochloric acid and carbon monoxide or dioxide.  Carbon is effective on chloramines as well as free chlorine although significant increased contact time is required.  The carbon bed should be sized for an EBCT value of 2 – 5 for free chlorine removal with the volume dependent on chlorine concentration and background water characteristics.  For chloramine removal, EBCT value should be 7.5 – 12.  Carbon filters are also effective for TOC reduction.  The biggest problem with carbon filters is their propensity to become colonized by bacteria.  To combat this colonization, the carbon bed should be hot water or steam sanitizable.  Furthermore, disinfection UV lights should be installed on the inlet and outlet of the carbon filter to prolong the interval between sanitizations.  The quality of the carbon used in carbon filters is also important.  When carbon is used for removal of specific organic compounds the exact characteristics of the carbon are extremely important.  In pharmaceutical dechlorination applications the primary concern is cleanliness of the carbon.  Minimal fines, low ash content, and adequate hardness are desired.  All carbon should be acid washed at the production facility.  Upon installation, the carbon bed must be rinsed to drain until all fines are washed away.  The bed should be periodically backwashed throughout its service life.  Other granular medias have been demonstrated effective at chlorine removal.  Most notable is a dissimilar metal media that is highly effective for free chlorine removal.  This media does not readily promote bacterial growth which is a significant advantage.  However, dissimilar metal medias are expensive and very heavy, prompting significant backwash requirements and for chloramine removal significantly more media is required.

Injection of Reducing Agents

Injection of a reducing agent in the water stream requires very little equipment.  Therefore the capital cost of this dechlorination method is extremely low.  There is an ongoing expense of chemical procurement.  Also, the mixing of reducing agents in water produces hazardous gasses.  Another disadvantage of utilization of reducing agents for dechlorination is the promotion of growth of certain organisms that thrive in a reduced environment.  When utilizing a reducing agent the dose must be kept as low as possible to minimize proliferation of these organisms.  It can be somewhat difficult to maintain an adequate but low dosage of reducing agent in the presence of widely fluctuating chlorine levels.

Ultra Violet UV Light

UV light is widely used in water purification systems for disinfection and TOC reduction.  Use of UV for dechlorination is a relatively new process.  UV light has long been known as a good energy source for breaking chemical bonds.  Use of UV light for destruction of many compounds is proliferating as the proper light dosages are determined and empirically verified.  It has been demonstrated that UV light at a 254 nm wavelength at many times disinfection dosage will destroy free chlorine.  UV light is also capable of destroying chloramine compounds, but the required dosage is significantly increased.  Due to the high dosage required for chloramine destruction, it is sometimes beneficial to use an oxidant in combination with UV for chloramine removal.  The capital cost of UV light for dichlorination of free chlorine is very close to that of a properly designed carbon filtration system.  There is an ongoing electrical cost with UV dechlorination.  However, there is an extreme benefit in elimination of bacterial colonization ground.  Furthermore, the water is given a very strong disinfection dosage that benefits downstream treatment systems.

Ion Removal

There are three basic types of ion reduction processes: membrane processes, ion exchange processes, and distillation processes.  There are many types and combinations of these processes, making the possibilities almost endless.  It is well beyond the scope of this discussion to examine all these possibilities.  However, an overview of the more prevalent and appropriate ion removal systems is relevant.

Membrane Processes

Membranes accomplish a great deal in water purification systems, including: ion removal, particulate removal, removal of organic compounds, and organism removal.  Membranes range dramatically in pore size, molecular weight cut off, and ion rejection.  Ion removal membranes are at the “tight” end of the spectrum and include reverse osmosis (RO) membranes, and nanofiltration membranes.  Actually, membrane chemistry has become so refined that rejection percentage can almost be specified anywhere between 99.9% and 50%, blurring the distinction between nanofiltration, low pressure, standard rejection, and high rejection RO membranes.  A major distinction remains between cellulose based and non-cellulosic membranes.  Cellulosic membranes tolerate exposure to bactericidal oxidizing agents and in fact must operate with a disinfectant present because organisms will eat the membrane material.  Although it may be seen as an advantage to allow a chlorine residual to remain in the water through the reverse osmosis process, the advantages of non-cellulosic membranes far outweigh this advantage.  Non-cellulosic membranes operate at much lower pressures and can tolerate a broad range of pH.  Also, all the advanced formulations are in non-cellulosic membranes.  One of the most important characteristics of ion removal membranes is that they will reject a certain percentage of ions no matter how high in ion concentration the feed stream is (up to maximum osmotic pressure).  This is a significant advantage over ion exchange that must exchange every ion it removes.  It is this characteristic that virtually mandates inclusion of membrane separation in every ion removal system.  It is rarely economically feasible to utilize ion exchange alone for ion removal.  The primary decision in applying membrane separation is whether to use a single pass system or a double pass system.

The conductivity requirements of USP water systems approximate the capability of double pass RO systems.  On many feed waters, double pass RO will consistently produce the required conductivity.  Gas content of the second pass permeate is typically the primary contributor to the on line measured conductivity.  In most waters, carbon dioxide is the primary reactive gas that increases the measured conductivity.  Carbon dioxide content of the second pass permeate can be reduced by increasing the pH of the feed water to the RO system.  This will convert free carbon dioxide gas to bicarbonate ion that can be rejected by membranes.  However, in applications where chloramines are present in the feed water, raising the pH will convert ammonium ions to free ammonia gas that will pass through the membranes and will contribute to the measured conductivity of the water.  Adjusting the pH to be high for one pass and low for another can address the dual gas problem.  Also the use of membrane degasification will eliminate the gas problem.  It should also be noted that the conductivity requirements for USP water do have provisions for qualifying water that is high in on line conductivity readings due to gas content.  Stage two testing is performed at equilibrium with atmospheric gasses.  However, most facilities prefer to qualify conductivity by continuous reading on line instruments.

Proper application of membrane technology requires adherence to proper design criteria and incorporation of proper pretreatment, monitoring, control, and flushing capability.  The primary design criteria in membrane systems is flux.  This is expressed in gallons of water throughput per square foot of membrane area per day (GFD).  The operating flux should generally fall between 10 and 15 GFD for the first pass.  Feed water with higher fouling characteristics toward the low end of the range and better water at the high end of the range.  Feed water to the membrane system must be pretreated to address constituents in the water that may cause fouling or scaling of the membranes.  The specific methods of pretreatment will be discussed as specific contaminant removal.  It is very important to monitor pressure and flow throughout the membrane system, as these determine required maintenance procedures and protective actions.  Feed and product water characteristics must also be monitored.  Quality control consists of acting upon all sensed conditions of the membrane system in the appropriate manner.  Temperature is an important factor in the permeation of water through the membrane.  Often feed water to the RO system is heated to a consistent 77E F, although this is not necessarily an economically sound practice.  Flushing the membranes with permeate water upon shutdown allows the membranes to reside in non fouling/scaling water when the system is not processing, as opposed to feed water.  This is especially important in systems that utilize antiscalants.  Incorporation of automated integral membrane cleaning and sanitization capability in the system enhances system performance and reduces maintenance.

Ion Exchange

Although double pass reverse osmosis may provide adequate ion removal for many pharmaceutical applications, often systems are designed with ion exchange following single or double pass RO.  Ion exchange processes will remove carbon dioxide that can cause two pass RO water to fail on line conductivity requirements.  Furthermore, it is sometimes deemed appropriate in very low flow PW systems to utilize rented portable ion exchange tanks as the sole ion reduction method.  A strong case can be made for ion exchange following reverse osmosis in pharmaceutical systems.  The ion exchange system will provide an additional ion reduction process, generally rendering the water much lower in conductivity than required and providing a back up to the membrane process.  However, there are several problems associated with incorporation of ion exchange in pharmaceutical systems.  Bacterial colonization of ion exchange beds is common, particularly mixed beds which have a neutral pH.  On site regeneration of ion exchange beds involves hazardous chemicals and somewhat elaborate equipment.  Utilizing exchange tanks continually places a “wild card” into the treatment process.  Some of these problems can be mitigated by certain applications of ion exchange technology.  Use of separate beds for cation and anion resins provides extreme pH in the beds that helps retard bacterial growth.  Although a single cation bed followed by a single anion bed does not provide very low conductivity water (primarily due to sodium leakage), adding a second cation bed (cation – anion – cation) greatly reduces conductivity.  On site regeneration, although still requiring hazardous chemicals, is much simpler and less expensive for individual resin beds.  If non regenerating mixed beds are desired, consideration should be given to replacing resin with virgin resin upon each exhaustion.  This is more expensive than utilizing a portable exchange tank from an offsite regeneration supplier, but assures no upset in quality.  Furthermore, with double pass reverse osmosis in front of the mixed bed, resin replacement will be infrequent.  Electrodeionization (EDI) technology provides continuous deionization and continuous regeneration without acid and caustic.  Feedwater to the EDI system must be treated by reverse osmosis.  Depending on raw water quality, a single pass RO may be adequate for EDI pretreatment.  A 0.2 micron or smaller cartridge filtration unit should be installed at the outlet of the final deionization system.  This will prevent resin or other particulate matter from contaminating the deionized water.


Distillation is natures water purification process, consisting of the vaporization and condensation of water.  Distillation equipment is expensive to operate due to the energy cost of vaporizing water.  Typically distillation is used after a primary ion reduction process to reduce the potential for scaling and fouling of the still.  Any contaminant that vaporizes at a lower temperature than water will not be removed in the distillation process, everything else will be removed in a very high percentage (typically >99%).  Use of distillation in pharmaceutical water purification systems is primarily for the preparation of Water for Injection, where it (or double pass reverse osmosis) is required.

Bacterial Control

Bacterial control requires more constant attention than any other aspect of the pharmaceutical water purification system.  Bacterial control includes both equipment and procedures.  Equipment utilized is typically ultraviolet (UV) lights, ozone generation systems, heating systems, and chemical injection/recirculation systems.  Procedures are generally periodic sanitizations and general operational techniques to avoid bacterial intrusion.  Bacterial control is applied to both the water purification system and the storage and distribution system.

UV Light

Ultraviolet light at a wavelength of 254 nm and a dosage of 30,000 microwatt seconds per square centimeter will provide an approximate 6 log kill rate of most bacteria.  It accomplishes this without imparting any chemical residual to the water.  This makes UV light an excellent disinfection device for pharmaceutical water systems.  Placement of UV lights at numerous points in the water purification system is appropriate.  Often UV placement on both the inlet and discharge of a treatment device will significantly prolong the time between periodic sanitizations.  If a UV light is used in a location where significant amounts of hardness ions are present in the water, a sleeve wiper should be incorporated in the UV device or Teflon should be used for the water path.


Ozone is a powerful oxidizing agent, generally created from atmospheric oxygen by an electrical device.  Ozone kills organisms very rapidly by lysing cell walls.  Ozone quickly reverts back to oxygen and is also readily destroyed by UV light.  Ozone is a good sanitizing agent for pharmaceutical systems because it is so powerful and so easily removed from the water.  Because ozone is a powerful oxidizing agent it will harm polyamide membranes, ion exchange resins, and many elastomers.  Ozone is most often used for disinfection in storage and distribution of pharmaceutical water, but can be used in the purification system at any point where materials of construction allow.

Thermal Sanitization

Heat is a reliable method of killing organisms.  It can be used to sanitize cartridge filters, carbon filters, ion exchange beds, membrane systems, piping, tanks, etc.  All systems that are to be heat sanitized require special materials of construction.  This is especially true of membrane systems and ion exchange systems.  The capability of heat sanitization adds significant cost to water treatment devices.  The minimum temperature capable of assured sanitization is 160 F.  Membrane systems and ion exchange systems have difficulty accommodating this extreme temperature and are often sanitized at lower temperatures to prevent damage to system components.  These systems can not tolerate the higher temperatures that are often used in distribution piping and storage tank sanitization.  Typically, system product water that has passed through a steam heat exchanger is used for sanitization.

Chemical Sanitization

A variety of chemical compounds can be used to sanitize various devices in the water purification system.  Because heat sanitizable membrane systems are very expensive, often sanitizing chemicals are periodically circulated through the membrane system.  This is easily accomplished when the membrane system incorporates an integral clean/flush system.  The most important concern with chemical sanitizing agents is the ability to remove them from the system.


Every system must have written procedures to be followed when performing periodic sanitization.  Furthermore, there must be general written procedures for routine maintenance that promote system hygiene, such as requiring disposable gloves and mask be worn during cartridge changes.

Removal of Specific Impurities

Every water source is different and therefore the possibilities of specific problem contaminants are endless.  However, since all water sources supplying USP water purification systems must comply with drinking water standards, the specific problem contaminants are never impurities covered by the primary standards.  The discussion of specific impurities can be further limited to those items that appear most frequently.  Iron, manganese, hydrogen sulfide, hardness ions, particulate matter, high conductivity, and high TOC are all contaminants that occur regularly.

Iron, Manganese, and Hydrogen Sulfide

These contaminants are common in ground water and often occur together.  They will precipitate out of solution when oxidized and the standard method of treating these contaminants is by oxidation and filtration.  Membranes will reject iron and manganese in solution and therefore it is sometimes beneficial to maintain the water in a reduced state and utilize membrane separation for their removal.  Ozone is the preferred oxidant for oxidation/filtration systems, especially if hydrogen sulfide is present.  Chlorine can also be used but requires significant increased contact time and a process to remove residual chlorine.

Softener – Hardness Removal

Hardness ions can be easily removed from water by ion exchange or membrane separation.  Ion exchange systems (softeners) consist of cation resin in the sodium form, regenerated by sodium chloride.  Resin volume required in the softening system is determined by both flow rate and total exchange capacity.  Flow rate must not exceed 5 GPM per cubic foot of resin and is best at approximately 3 GPM per cubic foot.  Flows much less than 2 GPM per cubic foot may promote channeling.  The total exchange capacity of the resin is based on regeneration salt dosage.  This must be compared with the water hardness and flow rate to determine a resin volume that produces an acceptable frequency of regeneration.  Often multiple tanks are used in a softening system to allow the system to remain in service while a tank is regenerating.  Membranes will remove hardness ions, but these ions also tend to precipitate on the surface of the membrane, forming scale.  Injection of acid or antiscalant chemicals into the membrane feed stream can prevent scale formation.  A strong case can be made for both ion exchange softening and membrane removal of hardness ions in pharmaceutical systems.  Typically, the usage of other processes in a system will determine which technique is more appropriate in the overall system design.

Particulate Matter

All water sources contain particulate matter in a wide variation of sizes.  Well water will typically have much lower particle counts than surface water sources.  Municipal water sources will generally be very low in particulate matter at the point of distribution, however, it is not unusual for particulate matter to enter the water stream in distribution piping.  All pharmaceutical systems require particulate removal.  On systems with heavy influent particulate loads a filtration method capable of handling heavy loads must be employed.  A standard approach to this type of filtration is the backwashing multimedia filter (MMF).  MMF’s are capable of removing particles down to a size of approximately 10 microns.  If the particulate load is primarily smaller than this size, the MMF is useless.  Granular carbon filters and ion exchange resins also provide filtration similar to a multimedia filter.  There is a patented filtration process utilizing resin beads coated with a cationic polymer that is capable of removing very small charged particles.  Cartridge filters may be used to remove essentially any particle size.  Often filter cartridge pore size is staged to spread the loading over several banks of cartridges and prolong cartridge life.  The biggest problem with cartridge filters is that they are disposable and filtering to a very small size can be very expensive in ongoing cartridge replacement costs.  Reverse osmosis membranes provide very fine filtration.  However, incoming particulate load is a major factor in membrane fouling.  Water entering an RO membrane must be prefiltered to at least 5 microns.  This retards clogging of the feed channel.  Finer prefiltration can prolong intervals between membrane cleanings.  The use of backwashing micro or ultra filters has become increasingly popular in water purification systems.  These membrane filters can handle very heavy particulate loads with only a course screen as a prefilter.  The membrane filters provide excellent prefiltration for RO membranes, greatly extending cleaning intervals and RO membrane life.  The great benefit of membrane filters is that they remove bacteria.  This is of obvious benefit in pharmaceutical systems, greatly minimizing bacterial colonization of downstream treatment equipment.

High Conductivity

There is not a primary standard for conductivity in drinking water.  Therefore it is possible to have very high levels.  High inlet conductivity will affect the choice of ion reduction processes in the system.  The high inlet conductivity may negate the possibility of complying with USP conductivity limits in a two pass RO or may require a two pass RO in front of EDI, etc.

High TOC

It may be necessary to specifically address high TOC levels in the influent water.  A carbon bed may adequately reduce TOC level.  Another alternative is an anion exchange bed specifically targeted to organic removal.  This would most likely be regenerated with sodium chloride.

For additional detail regarding treatment processes for USP water systems or for a treatment system quotation please contact PWC for further assistance.