Pharmaceutical water system design, operation, and maintenance are selected based on the desired product water chemical and microbial attributes for “delivered” water. The USP and EP Monographs for bulk compendial waters state that feed water must comply with the governing agency’s “Drinking Water” standards. Source water to a municipal treatment facility may be from a surface, ground, or ground source “influenced” by a surface source. During municipal treatment chemical introduction, filtration, disinfection, or other purification processes may be utilized to meet regulatory requirements for Drinking Water, to enhance taste, minimize corrosion of piping, and eliminate precipitation of metallic compounds such as iron on domestic fixtures. However, municipal treatment techniques can impact the successful design, operation, and maintenance of pharmaceutical water systems. Two case histories are presented to demonstrate issues related to common municipal treatment techniques.

 Case History No. 1

Purified Water System with Monochloramine in
Municipal Feed Water

• Feed water characteristics

• Surface source water

• High Naturally Occurring Organic Material (NOM) concentration

• Chlorine used as primary disinfecting agent

• Client population >100,000 people

• Regulated disinfection byproducts (trihalomethanes – THMs and Haloacetic Acids – HAA5) -Table 1, present

• pH adjusted to about 9 by caustic injection to reduce corrosion of domestic lead piping, copper tubing, and lead solder

• Total Dissolved Solid (TDS) level about 70 mg/l

• Total Organic Carbon (TOC) level about 3-4 mg/l

• Ammonia introduced prior to distribution producing monochloramine (Table 2) as secondary disinfecting agent.


• Purified water system design and issues

• System consists of pretreatment, reverse osmosis (RO), continuous electrodeionization (CEDI), storage, “polish” and distribution system as indicated in Figure A.

• Issues noted about 3 months after system commissioning during validation (Performance Qualification)

• Issue – Conductivity in purified water distribution loop exceeds requirements set forth in USP Physical Tests Section <645>. Value increasing with time. Conductivity in distribution loop greater than value from CEDI unit.

• Issue – TOC in purified water distribution loop, while <0.50 mg/l (USP Physical Tests Section <643>) higher than that of CEDI product, averaging about 100 mg/l

• Issue – Pressure drop through CEDI system increasing with time. Increase after 3 months of operation about 5-7 psid.

• Issue – Performance Qualification terminated to resolve issues

• Identification of problems

• The activated carbon unit was not properly sized, operated, or maintained to remove monochloramine. Monochloramine removal by activated carbon is achieved by the following equations (1):

C* + NH2Cl + 2H2O Þ NH3 + H3O+ + Cl- + CO*

Activated Carbon Surface + Monochloramine + Water Þ Ammonia + Hydronium Ion + Chloride Ion + Oxidized Site on the Activated Carbon Surface

2NH2Cl + CO* + H2O Þ N2 + 2H3O+ + 2Cl- + C*

Monochloramine + Oxidized Site on the Activated Carbon Surface + Water Þ Nitrogen + Hydronium Ion + Chloride Ion + Activated Carbon Surface

Removal of monochloramine by activated carbon is much more challenging than removal of chlorine (hypochlorous acid or hypochlorite ion) (2). The literature indicates that about 60-77% of monochloramine present in feed water to an activated carbon unit occurs by the first of the two reactions indicated above (3). Effective removal of monochloramine by activated carbon requires the following:

• Use of catalytic activated carbon

• Activated carbon unit design to produce adequate “Empty Bed Contact Time” (EBCT). The literature indicates that the EBCT for monochloramine removal is 2-4 times that for chlorine removal (4).

• Consideration of feed water temperature as indicated in Table 3.

• Consideration of feed water pH as indicated in Table 4.

• Consideration of feed water TOC concentration since organic material will compete with monochloramine for activated carbon surface “sites”.

• Consideration of activated carbon media mesh size as indicated in Table 5.

• RO and CEDI will not effectively remove monochloramine. Use of the 185 nanometer ultraviolet unit within the Purified Water distribution system results in oxidation and resulting decomposition of monochloramine, increasing both the conductivity and TOC levels.

• Resolution of design, operation, and maintenance problems

• The enhanced system is shown in Figure B.


• The activated carbon unit is improperly sized for the application. The unit was replaced with a larger diameter and higher height unit. Design considered a face velocity of 3 gpm per square foot of cross sectional bed area and volumetric flow of 0.5 gpm per cubic feet of activated carbon media to satisfy the required EBCT.

• Utilize catalytic activated carbon media in new activated carbon unit.

• Reposition the activated carbon unit to a position prior to the water softener system in an attempt to provide removal/reduction of ammonia, as the ammonium ion, generated in the activated carbon unit during monochloramine removal. To enhance ammonia removal, configure the two water softening units for series operation.

• Install a sulfuric acid injection system prior to the activated carbon unit to reduce the feed water pH to a value of 7.2 – 7.5, increasing the ability of the activated carbon unit to remove monochloramine.

• Considering the relatively low alkalinity value of the feed water, eliminate caustic injection prior to the RO unit. To compensate for pre RO pH adjustment direct CEDI wastewater to drain, eliminating “recovery” back to the RO break tank.

• Establish 6 month replacement frequency for the catalytic activated carbon media.

• Remove the 185 nanometer ultraviolet lamps and replace with conventional 254 nanometer lamps.

• Monitor total and free chlorine in a RO feed sample daily

• Establish Certificate of Analysis program for sulfuric acid

• Results

• Successful completion of a Performance Qualification for the enhanced system.

• CEDI product water conductivity < 0.10 µS/cm @ 25?C.

• Purified Water distribution loop conductivity < 0.60 µS/cm @ 25?C.

  Purified Water distribution loop TOC < 10 µg/l


Case History No. 2

Purified Water System with Sequestered Iron and Manganese in Feed Water

• Feed water characteristics

• Ground source water

• High total hardness level

• High total alkalinity level

• Chlorine used for primary and secondary disinfection

• Client population >100,000 people

• pH 7.4 – 7.8 without chemical introduction

• Total Dissolved Solid (TDS) level about 450 mg/l

• Total Organic Carbon (TOC) level <20 µg/l

• High iron and manganese levels required injection of a “blended” phosphate or “ortho/polyphosphate”, a proprietary compound containing monosodium phosphate and sodium acid phosphate. The material sequestered iron and manganese particulate and ionic material to a “suspended” colloidal state. Chemical injection eliminated precipitation of undesirable red colored material on domestic fixtures.


• Purified Water System design and issues

• System consists of pretreatment, reverse osmosis (RO), continuous electrodeionization (CEDI), storage, “polish” and distribution system as indicated in Figure C.

• Issues noted about 6 months after start-up but addressed by extensive maintenance for about 2 years.

• Issue – Extensive RO fouling and scaling was noted. RO membranes were removed and discarded every 4-6 months. Significant red colored “slime” was noted during removal of RO membranes as well as red colored staining on RO membrane surfaces.

• RO conductivity increased with operating time subsequent to RO membrane replacement, exceeding 25 µS/cm @ 25?C after about four months.

• The RO unit transmembrane pressure drop increased continuously with time after new RO membrane installation. RO feed water pressure increased while the RO product water flow rate decreased. The “normalized” RO product water flow rate decreased > 30% after about 4 months of operation with new membranes.

• Used RO membrane autopsy indicated loss of membrane integrity and significant iron fouling was noted.

• As RO product water conductivity increased with time, total viable bacteria levels (TVB) also increased. Undesirable Gram-negative bacteria were also detected.

• CEDI product water conductivity increased as RO product water conductivity increased. Adjustments (increase) to individual CEDI stack voltage/amperage decreased the conductivity but resulted in a CEDI stack life of about 12-18 months.

• The cyclic operating design of the RO/CEDI “system” appeared to accelerated problems indicated above.

• Identification of problems

• “Sequestered” iron and manganese in the feed water were not removed by the multimedia filtration unit or water softening system. A pilot study was conducted on a side stream of RO Unit feed water to determine the effectiveness of different pore size filters to remove iron and manganese. Laboratory testing was “expanded” to assist in detection of colloidal iron, not detected by conventional analysis. Testing indicated that 0.1 to 0.2 micron membrane cartridge filters would remove iron and manganese to an acceptable level.

• Evaluation of alternative methods to remove/destroy the ortho/polyphosphate was unsuccessful. The inability to obtain details of the proprietary agent coupled with concerns associated with production of “foreign substances and impurities” defined in the General Notices Section of USP were both a concern.

• Recirculation of the RO/CEDI “loop” and ability to conduct periodic hot water sanitization for microbial control appeared appropriate.

• Resolution of design, operation, and maintenance problems

• The enhanced system is depicted in Figure D.


• To expedite system enhancements, “stock” oversized RO prefilter housings are purchased. Disposable 0.2 micron filters are installed to remove colloidal iron and manganese. Membrane filter selection is based on the ability to retain colloidal matter and compatibility with periodic hot water sanitization not “extended” bacteria retention.

• Perform extensive enhancements to the RO/CEDI System. Enhancements include the following:

• Conversion of all tubing in contact with RO product water to 316L Stainless Steel, orbitally welded.

n Addition of 316L Stainless Steel RO break tank and full recirculation “loop” containing the RO and CEDI Systems. Break tank includes heating jacket (steam) for periodic hot water sanitization of the entire RO/CEDI loop.

• Conversion of RO waste tubing/valving to allow for high RO Unit recovery (90%) during RO/CEDI loop recirculation.

• Provide a final 0.1 micron sanitary filter system in the recirculating loop.

n Position an inline ultraviolet sanitization unit downstream of the CEDI unit and upstream of the 0.1 micron filtration system to eliminate potential microbial back contamination of the CEDI Unit.

• Install new membrane stacks in CEDI System

• Replace RO 0.2 micron prefilter membranes when differential pressure reaches 25 psid above the new membrane filter pressure drop. Frequency of filter change is 8-14 days.

• Purchase a second set of RO membranes. Remove RO membranes for off-site three step cleaning every six months and replace with clean (“rotated”) RO membranes.

• Conduct hot water sanitization of RO/CEDI loop every 2-4 weeks

• Perform chemical sanitization of the RO/CEDI loop with a 1% peracidic acid and hydrogen peroxide solution annually.

• Change 0.1 micron final membrane filters once every six months

• Install inline ultraviolet sanitization unit downstream of activated carbon unit.

• Perform chemical sanitization of pretreatment system (excluding the activated carbon unit) once every six months. Replace activated carbon media every six months.

• Results

• RO membrane fouling with colloidal iron eliminated.

• CEDI product water conductivity < 0.10 µS/cm @ 25?C.

• Purified Water distribution loop conductivity < 0.60 µS/cm @ 25?C.

• Purified Water distribution loop TOC < 10 µg/l

• RO product water TVB generally < 1 cfu/100 ml

• CEDI and final membrane filter TVB constantly < 1 cfu/100 ml

Rules and regulations for “Drinking Water” coupled with the desire to provide a colorless tasteless “product” that does not corrode piping or stain plumbing fixtures may result in the presence of compounds that affect design, operation, and maintenance of pharmaceutical water systems. An industry trend to “standardize” systems must address the myriad of treatment techniques and chemicals used by municipalities.






(1)        Collentro, W.V., “Pharmaceutical Water – System Design, Operation, and Validation”, Second Edition, Informa Healthcare, ISPN-13:978142007827, London, UK, 2011

(2)        Collentro, W.V., “Monochloramine Removal – Design Operating and Maintenance Issues”, presented at the Ultrapure Water Pharma 2011 Conference, April 11-12, 2011, Philadelphia, PA 2011

(3)        Fairey, J.L., Speitel, G.E. Jr., Katz, L.E., “Monochloramine Destruction by GAC – Effect of Activated Carbon Type and Source Water Characteristics”, Journal of American Water Works Association, 99:7, July 2007, pp 110-120

(4)        Potwora, R., “Chlorine and Chloramine Removal with Activated Carbon”, Water Conditioning & Purification, June, 2009

(5)        United States Environmental Protection Agency, “Drinking Water Contaminants – National Primary Drinking Water Regulations” 2011

(6)        Glaze, W.H., “Chemical Oxidation” Water Quality and Treatment – A Handbook of Community Water Systems, Pontius, F., editor, American Water Works Association, McGraw-Hill, Inc., New York, NY, 1990, pp 747-779

(7)        Calgon Carbon Corporation, “Catalytic Activated Carbon Offers Breakthrough for Dialysis”, published in Dialysis & Transplantation, November 1997. Calgon Carbon Corporation Application Bulletin AB-1063-01/98