compendial water systems—a 2012 perspective

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Compendial Water Systems—A 2012 Perspective

ABSTRACTCurrent issues potentially affecting pharmaceutical water systems are discussed. These include chlora-mines, trihalomethane, and iron control in municipal water systems; regulatory requirements for methods of production, biofilms, rouging, and system documen-tation. Issues with potential for operational excursions are discussed.

INTRODUCTIONThe content of this discussion addresses current issues and concerns with water systems. Compendial water is a critical utility at any facility. An excursion in sys-tem operation may affect product water quality and facility operation potentially resulting in significant effects on patient and product, and significant loss of revenue. Items discussed are issues with potential for operational excursions.

MUNICIPAL WATER SUPPLIES–CHLORAMINESMunicipal water treatment facilities in the United States have utilized chlorine for destruction of bacte-ria since the early 20th century (1). Chlorine may be introduced in the gaseous form, reacting with water to produce hypochlorous acid and the hypochlorite ions as follows in Equation 1:

Cl2 + 2H2O → HOCl + H3O+ + Cl-

HOCl + H2O → H3O+ + OCl- [Equation 1]

While other disinfecting agents, such as chlorine dioxide or ozone may be used, the vast majority of municipal treatment facilities use chlorine as a “pri-

mary” disinfecting agent (prior to distribution). The hypochlorous acid/hypochlorite ion concentration and contact time required for bacteria destruction is documented in the literature (2). However, hypo-chlorous acid/hypochlorite ion should not be con-sidered for destruction of “large” microorganisms such as Giardia or Cryptosporidium (3, 4). Giardia, for example, is projected to be associated with 100,000-2,500,000 million infections a year in the US and is the most prevalent protozoan parasite in the world (5, 6). In 1993, an estimated 400,000 individuals in Milwaukee, Wisconsin experienced infection from Cryptosporidium with an estimated 120 deaths (7). The 1993 incident resulted in changes to the United States Environmental Protection Agency’s (EPA) “Sur-face Water Treatment Rule.” In 2006, EPA issued the “Long Term 2 Enhanced Surface Water Treatment Rule” (LT2ESWTR) (8). The LT2ESWTR applies to all surface water source water or ground water systems under the direct influence of surface water. The LT2ESWTR targets additional cryptosporidium treatment require-ments for higher risk systems. It includes provisions to reduce risk from uncovered finished water storage facilities to ensure that the systems maintain microbial protection as they take steps to reduce the formation of disinfection byproducts. Disinfection byproducts, such as trihalomethanes, are produced by the reaction of hypochlorous acid/hypochlorite ion with naturally occurring organic material (9). Trihalomethanes, such as chloroform, are known carcinogens.

In an attempt to meet the criteria set forth in the LT2ESWTR, several municipal treatment facilities uti-lize hypochlorous acid/hypochlorite ion for “primary” disinfection and inject ammonia into the treated water

William V. Collentro

ABOUT THE AUTHORWilliam V. Collentro is presently a senior consultant at Concordia-ValSource. He is also an Adjunct Professor at Stevens Institute of Technology, an instructor for PDA’s Training and Research Group, and co-chair of the PDA Pharmaceutical Water Interest Group. He may be reached by e-mail at [email protected].

g x p an dj v t .co m Journal of Validation technology [Winter 2012] 37

W I L L I A M V. C O L L E N T R O

prior to distribution (secondary disinfection). At a pH ≥ 7, ammonia reacts with hypochlorous acid produc-ing monochloramine, as follows in Equation 2 (10):

NH3 + HOCl → H2O + NH2Cl (monochloramine) [Equation 2]

Activated carbon or injection of a reducing agent, such as sodium bisulfite, are both techniques that are used to remove residual disinfecting agent in compen-dial water systems. Removal of hypochlorous acid by activated carbon or reducing agent is demonstrated by the following equations.

Activated Carbon:

C* +2H2O + HOCl → CO* + H3O+ + Cl- [Equation 3]

C* represents the activated carbon surface and CO* represents a surface oxide on the activated carbon surface.

Reducing Agent:

Na2HSO3 + HOCl +H2O→ Na2HSO4 + H3O+ + Cl- [Equation 4]

Removal of monochloramine by activated carbon or reducing agent is demonstrated by the following equations.

Activated Carbon:

C* + NH2Cl + 2H2O →NH3 + H3O+ + Cl- + CO* [Equation 5]

Reducing Agent:

Na2HSO3 + NH2Cl+ 2H2O → Na2HSO4 + H3O+ + H3 +Cl- [Equation 6]

Critical IssuesCritical issues associated with monochloramine in compendial water system feed water (versus hypo-chlorous acid) include the following:

• Conventional activated carbon has limited capacity to remove monochloramine. The use of a “special” media, catalytic activated carbon, is required.

• Sizing (i.e., column diameter and volume of catalytic activated carbon) required for mono-

chloramine removal are much greater than that for hypochlorous acid.

• Catalytic activated carbon operating life prior to “breakthrough” is significantly less for mono-chloramine versus hypochlorous acid.

• Removal of monochloramine by either catalytic activated carbon or a reducing agent results in generation of ammonia that readily dissolves in water. Much like carbon dioxide, ammonia will not be removed by reverse osmosis membranes, increasing product water pH and conductivity. For distillation, ammonia will be present in pure steam and condensed, increasing the pH and conductivity of water for injection (WFI) prod-uct water.

• For purified water systems, if monochlora-mine is not completely removed by activated carbon or reducing agent, it will pass to product water. The presence of the antimicrobial agent is prohibited per the General Notices Section of the United States Pharmacopeia (USP). Of even greater concern is the fact that the presence of monochloramine in product water will “mask” the presence of bacteria by suppressing total viable bacteria results during enumeration. In other words, bacteria and associated biofilm may be present without indication by labora-tory results.

• In WFI systems, monochloramine will thermally decompose, increasing the chloride ion concen-tration, which can result in both chloride stress and pitting attack of 316L stainless steel.

• Monochloramine will oxidize reverse osmosis membranes and ion exchange membranes in continuous electrodeionization units. Oxida-tion of reverse osmosis membranes will result in increased product water total viable bacteria levels, bacterial endotoxin levels, conductivity, and total organic carbon (TOC). Oxidation of ion exchange membranes and ion exchange resin in the continuous electrodeionization “stacks” will result in an increase in the pressure drop through the unit, gradual decrease in product water flow, and gradual increase in conductivity. The indicated negative impact to reverse osmosis membranes and ion exchange membranes and ion exchange resin are irreversible.

As municipal treatment facilities switch to the use of monochloramine as a secondary disinfecting agent, facilities must recognize the challenges associated with its removal. Failure to take respon-sible action can result in significant issues.



MUNICIPAL WATER SUPPLIES— TRIHALOMETHANES (DISINFECTION BYPRODUCTS)For source water from a surface supply or ground water supply influenced by a surface water supply, naturally occurring organic material will react with disinfecting agent, producing disinfection byproducts. For munici-pal treatment facilities using chlorine (hypochlorous acid), trihalomethane (THM) compounds can be a concern in ozonated systems. Trihalomethane include chloroform, bromodichloromethane, dibromochlo-romethane, and bromoform. While the total THMs are regulated at a value generally < 80 ppb, personal observations indicate that values can exceed 100 ppb in the summer months. The feed water source, municipal treatment techniques (i.e., hypochlorous acid concentration and contact time), distribution loop flow rate, and length of distribution loop pip-ing from the municipal treatment facility will affect the THM level.

THMs are poorly removed by water purification unit operations including reverse osmosis and con-tinuous electrodeionization. Custom activated carbon media can provide effective THM removal but the chemi-adsorptive reaction requires significant con-tact time and frequent media replacement (11). For ozonated systems, single digit ppb values of THMs can increase conductivity beyond the Stage 1 value stated in USP Physical Tests Section <645>. For certain systems, the conductivity value may increase beyond the USP specification requiring corrective action. The indicated increase in distribution loop conductivity is generally associated with an increase in distribution loop TOC level.

Seasonal increase in feed water THM levels may also affect WFI systems. While a small increase in loop TOC may be noted, an organic scan of recirculating WFI may indicate the presence of chloroform, the primary THM compound.

MUNICIPAL WATER SUPPLIES—IRON CONTROLThe chemical profile of most ground water supplies is generally different than water from a surface source with higher percent of calcium and magnesium as cat-ions. In addition, the supplies may contain both non-dissolved (particulate) iron oxides and dissolved iron. Municipal treatment facilities may filter water from a ground source to remove particulate matter. This technique may not remove all iron that will ultimately result in red/brown colored “stains” on kitchen, bath-room, and other domestic plumbing fixtures. To avoid

complaints from domestic end users, municipalities may inject one or more proprietary chemical agents. Sequestering agents such as polyphosphates or ortho phosphates keep the iron (particulate or dissolved) in solution, eliminating staining of fixtures. Unfor-tunately, the sequestering process converts iron to the colloidal state, a challenge for compendial water sys-tems. For smaller capacity compendial water systems utilizing rechargeable ion exchange canisters, final 0.2-micron filters may require frequent replacement as a “fine” iron precipitate is noted. It is interesting to note from personal observation that the particle size is less than 2 to 3 microns but greater than 0.1 to 0.2 microns. For systems employing reverse osmosis that generally utilize 1 to 5 micron prefilters, colloi-dal iron fouling of reverse osmosis membrane will occur. This will not only result in a gradual decrease in reverse osmosis unit product water flow rate with time, but also cause difficulty in effective membrane cleaning and increase in product water bacteria levels. Conventional multimedia filters and water softeners have limited capability to remove sequestered iron.

WFI systems with vapor compression distillation units frequently utilize pretreatment consisting of multimedia filtration, water softening, and activated carbon (or injection of a reducing agent). If seques-tered iron is present in municipal feed water, it will be present in the feed water to the vapor compression distillation unit. Iron, sequestered by polyphosphates and orthophosphates, may reappear in the particulate state because of thermal decomposition. The blow-down rate for the vapor compression distillation unit should be adjusted to compensate for precipitation if noted. Multiple effect distillation unit pretreatment systems generally include reverse osmosis, a process that will remove colloidal material.

WATER FOR INJECTION—METHOD OF PRODUCTIONThe current United States Pharmacopeia Official Monograph for WFI (bulk) states that the production method is “…distillation or a purification process that is equivalent or superior to distillation in the removal of chemicals and microorganisms” (12).

The current edition of the European Pharmacopeia (EP) monograph for WFI (bulk) states:

“Water for injection in bulk is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority or purified water by distillation in an appa-ratus of which the parts in contact with water are of neutral glass, quartz, or suitable metal and which is



fitted with an effective device to prevent entrainment of droplets. The correct maintenance is essential. The first portion of distillate obtained when the appara-tus begins to function is discarded and the distillate collected” (13).

While extensive attempts have been made to har-monize the language for WFI production between USP and EP, the “conflict” still exists. Product made in the US for shipment to a country complying with EP criteria must utilize distillation for production of WFI. While the merits of non-distillation based WFI systems versus distillation-based systems is beyond the extent of this article, it is important to indicate the difference in the two pharmacopeias.

BIOFILMBiofilm is a thin layer of material on walls of storage or distribution tubing. It is associated with the pres-ence of Gram-negative bacteria and resulting bacterial endotoxins. Because bacteria control in storage and distribution systems is difficult when an established biofilm is present, the theory, mechanism, and micro-bial control factors are important. Technical focus groups and committees are evaluating these topics at this time.

Biofilm is generally a concern in non-ozonated purified water systems, although it has been noted in both WFI systems and ozonated purified water systems. Biofilm may be associated with the rapid

Table I: Operating data—rapid increase in total viable bacteria levels from biofilm.

Sample Point Number Days After PassivationTotal Viable Bacteriaa

(cfu/ml)Pseudomonas aeruginosa per 100 ml

(present/absent)

1 through 8 1 < 1 absent

1 through 8 2 < 1 absent

1 3 36 absent

2 3 49 absent

3 3 10 absent

4 3 22 absent

5 3 30 absent

6 3 40 absent

7 3 100 absent

8 3 66 absent

1 4 ~480 absent

2 4 ~560 absent

3 4 ~640 absent

4 4 ~400 absent

5 4 ~360 absent

6 4 ~600 absent

7 4 ~720 absent

8 4 ~440 absent

1 5 TNTC absent

2 5 TNTC absent

3 5 TNTC absent

4 5 TNTC absent

5 5 TNTC absent

6 5 TNTC absent

7 5 TNTC absent

8 5 TNTC absent

Note: Total viable bacteria determined by membrane filtration of 1.0 ml of sample and 99 ml of sterile water, R2A agar, 30-35°C incubation temperature, and 72-hour incubation time period.



increase in total viable bacteria levels as exhibited by data in Table I or by sporadic observation of total viable bacteria levels at one or more points-of-use in a distribution system as demonstrated by the data in Table II. A brief discussion of each situation will provide insight to a practical approach for identifica-tion, removal, and control of biofilm.

Figure 1 depicts the USP Purified Water Storage System associated with the data in Table I. Make-up water to the system is from a water purification

system including multimedia filtration, water soft-ening, activated carbon adsorption, and reverse osmosis/continuous electrodeionization “loop” with final 0.1-micron filtration. The storage and distribution loop are hot water sanitized at 90˚C for three hours weekly. Chemical sanitization of the storage and distribution system is performed semi-annually with a 1% solution of hydrogen per-oxide and peracetic acid. As part of facility expan-sion, three points-of-use are added to the system.

Table II: Gradual increase in total viable bacteria from biofilm.

Sample Point No.

TVB ResultsDay 1

(cfu/100ml)

TVB ResultsDay 2

(cfu/100ml)

TVB ResultsDay 3

(cfu/100ml)

TVB ResultsDay 4

(cfu/100ml)

TVB ResultsDay 5

(cfu/100ml)

TVB ResultsDay 6

(cfu/100ml)

TVB ResultsDay 7

(cfu/100ml)

1 <1 <1 3 <1 1 <1 <1

2 <1 <1 <1 <1 <1 <1 <1

3 <1 <1 1 <1 <1 1 <1

4 <1 <1 <1 <1 <1 <1 <1

5 <1 <1 4 4 3 14 53

6 <1 1 1 2 2 4 9

7 <1 2 2 <1 20 1 7

8 1 9 5 10 22 9 55

9 3 9 1 1 54 33 27

10 <1 1 2 1 1 1 <1

11 <1 <1 2 1 <1 1 <1

12 4 6 53 98 71 161 360

13 9 10 31 66 13 15 62

14 1 47 13 51 25 40 260

15 <1 <1 4 6 3 2 23

16 <1 1 1 2 2 7 2

17 1 1 2 3 <1 5 4

18 7 12 5 18 33 52 152

19 <1 3 2 6 9 12 18

20 <1 1 <1 5 <1 1 6

21 <1 2 1 <1 <1 8 2

22 <1 <1 3 <1 1 <1 4

23 <1 <1 <1 <1 <1 <1 <1

24 <1 <1 <1 <1 <1 <1 1

25 <1 <1 1 <1 <1 <1 <1

26 <1 <1 <1 <1 <1 <1 <1

27 <1 <1 <1 <1 1 <1 <1

28 <1 <1 <1 <1 <1 <1 6

Note: Total viable bacteria (TVB) by membrane filtration of a 100-ml sample, R2A culture media, 30-35°C incubation temperature, and 120-hour incubation time period.



Repassivation of the storage system is performed by a contract passivation organization. The con-tract passivation effort does not include the USP purified water storage tank, tubing from the tank to the USP purified water distribution pump, and the distribution pump. The passivation organiza-tion utilizes their tank, pump, hoses, and fittings. Subsequent to passivation and rinse, an extended hot water sanitization cycle is performed (6 hours at 90˚C). As indicated in Table I, the first two days’ data for all points-of-use indicate total viable bac-teria levels < 1 cfu/ml. Bacteria are detected on the third day and rapidly increase to a level that is “too numerous to count.” A Gram stain indicates a Gram-negative organism. Identification by ribo-printer indicates the primary organism as Ralsto-nia pickettii. Chemical sanitization of the storage and distribution system is performed using a 1% solution of peracetic acid and hydrogen peroxide. During chemical sanitization, circulation is main-tained for about one hour with each point-of-use valve opened and flushed until test strips verify the 1% solution. The distribution pump is stopped. The storage and distribution system is stagnant for

approximately 16 hours. After the 16-hour “soak,” the distribution pump is started. Removal of the sanitization solution proceeds using make-up from the USP purified water system through a drain in the distribution loop return tubing. Subsequent to chemical sanitization, all total viable bacteria results from all points-of-use indicated the absence of bacteria in a 1 ml sample.

The observations and sanitization technique pro-vide useful information related to biofilm control as follows:

• Hot water sanitization for a six-hour time period at 90˚C does not remove biofilm

• Ralstonia pickettii appears to be a “marker” Gram-negative organism for the presence of biofilm, first to appear and last to be completely removed

• Penetration of biofilm and removal and destruc-tion of biofilm “components” occurs with a liq-uid chemical sanitization solution in a stagnant condition where diffusion, a process driven by concentration difference, allows equilibration of the sanitizing agent concentration through the biofilm to the tubing, fitting, component, or tank interior wall

Figure 1: Bacteria excursion after passivation-storage and distribution system.



• Attempt to perform effective chemical sanitiza-tion in a dynamic mode does not allow adequate contact between biofilm and the sanitizing agent.

Figure 2 depicts the USP purified water storage sys-tem associated with the data in Table II. As indicated, this is an ozonated system that experienced bacteria contamination at a point-of-use. Colonies of bacteria were identified by riboprinter. In fact, riboprinter results were used to verify the source of distribution loop contamination by “matching” data. Bacteria were identified as Ralstonia pickettii. Extended distribution loop sanitization, in a recirculating mode, was con-ducted with purified water containing 0.5–1.0 mg/l dissolved ozone. Ozone sanitization was performed for approximately eight hours. Point-of-use valves were cycled open/closed during the sanitization cycle. Subsequent to ozone sanitization, total viable bac-teria continued to be noted in 100-ml samples from multiple points-of-use. A liquid chemical sanitization

operation was performed using a procedure similar to that described for the system in Figure 2. Post liquid chemical sanitization results indicated the absence of bacteria in 100-ml samples as routine bacteria control with ozone was reestablished. Additional observa-tions associated with biofilm related to this example suggest the following:

• While ozone is an extremely powerful oxidizing agent, it may not be capable of removing biofilm from a contaminated system because recircula-tion required to compensate for both outgassing and decomposition to oxygen does not allow diffusion to the tubing wall associated with a liquid sanitizing agent in liquid purified water

• The inability of a gaseous sanitizing agent to remove biofilm may explain the poor steam sani-tization attributes observed for activated carbon when compared with much more effective hot water (liquid) sanitization.

Figure 2: Ozonated storage and distribution system with bacteria excursion.



ROUGING OF STAINLESS STEEL STORAGE AND DISTRIBUTION SYSTEMSRouging of stainless steel surfaces for both purified water and WFI can be a major concern. Oxidation of stainless steel surfaces can result in the presence of vis-ible red/brown colored iron oxide material on storage tanks walls and distribution tubing surfaces. Impinge-ment of iron oxidation products is often noted on stor-age tank spray balls and generally on the surface of the first elbow downstream of the distribution pump. Analysis of the impinged material indicates a high iron concentration with lower concentration of chromium and slight concentration of nickel with some molybde-num. Trace concentrations of copper may also be noted. The extent and rate of system rouging appears to vary for similar conditions. For example, a particular WFI storage and distribution system maintaining a water temperature of 80-85˚C may exhibit extensive rouging requiring derouging and repassivation annually while a similar system at another facility may operate for two to four years before rouging is noted.

The theory and mechanism associated with rouging appears to involve several variables and is the subject of ongoing studies and technical articles. It is critical to establish a quantitative program for determining system rouging. Collection and analysis of large vol-umes of water will not provide representative results. An effective quantitative technique is to filter a large volume of water, such as 10-20 gallons and conduct trace metallic analysis for the indicated stainless steel corrosion products. An alternative method is to col-lect swipes or swabs from the interior tank or tubing surfaces. However, this is an intrusive operation to the distibution system. Futher, results are not quantatative because the sample area and rouge removal efficency will vary. The frequency of quantitative filtration-type sampling should be based on the rate of roug-ing increase. Ultimately, the sample and analyses program should verify a “controlled” condition such that “suspended” stainless steel corrosion products, principally iron, do not impact manufacturing opera-tions and product.

SYSTEM DOCUMENTATIONSystem documentation should include several items that may not be included with conventional instal-lation qualification, operation qualification, perfor-mance qualification, and standard operating proce-dures. Items to be considered include, but are not limited to, the following:

• System operating logs should be available. While central facility data accumulation systems may

provide data, completing logs ensures that an indi-vidual familiar with the compendial water system periodically inspects and records critical systems functions. The individual is physically present at the water system during manual data collection. Items such as increased noise from a motor or pump or small leak from a component will not be indicated by a central data collection system. The daily “tour” associated with manual data col-lection detects many issues before they become a major problem. The manual log should focus on critical operating data. The log sheet should con-tain an acceptable range for each parameter that may reflect different conditions such as “normal” make-up operation, “standby,” or “recirculation.”

• A spare parts list should be available for system components. The spare parts list should refer-ence the original manufacturer’s model and serial number. For example, a reverse osmosis system will contain pressure gauges, valves, flow meters, membranes, etc. that are manufactured by various companies, purchased, and used dur-ing assembly of the reverse osmosis unit. The original manufacturer’s information for all com-ponents provides valuable information for insur-ing “like-for-like” replacement of components over the operating life of the system.

• A maintenance manual for the system must address the entire system and not just components. For example, while a reverse osmosis unit or distil-lation unit will be supplied with a manufacturer’s suggested maintenance program, distribution loop components such as valves with diaphragms, sani-tary ferrule gaskets, sanitary pressure and tempera-ture sensors will not contain a periodic proactive maintenance schedule. This program should be established based on individual system operating characteristics such as valve cycling frequency to ensure proper system operation.

• It is imperative that one or more individuals at a facility are familiar with the compendial water system design, operating, and maintenance details. System ownership and responsibility is critical. While service organizations are frequent-ly used to perform maintenance items, the system owner should oversee execution and verify that it has been performed in accordance with estab-lished procedures. It is suggested that a training manual and training sessions, custom-prepared for the system, provide an excellent vehicle for increasing internal knowledge and understand-ing of the system, operation, and maintenance.



SUMMARYCompendial water is a critical utility in any facility. An excursion in system operation may affect product water quality, which in turn may affect patient and product. These effects may cause significant loss of revenue to the organization. Personnel responsible for pharmaceutical water systems operation and oversight must be cognizant of the issues discussed herein and must be proactive in their prevention.

REFERENCES1. McGuire, M. J., “Eight revolutions in the history of U.S.

Drinking Water Disinfection,” Journal of the American Water Works Association, 98(3): 129, 2006.

2. Haas, C.N., and Karra, S.B., “Kinetics of microbial in-activation by chlorine, Part II: Kinetics in the process of chlorine demand,” Water Research, (18):1451, 1984.

3. USEPA, “Drinking Water Contaminants–List of Con-taminants and their MCLs,” Publication: EPA 816-F-09-0004, 2009.

4. Korich, D.G., Mead, J.R., and Madore, M.S., “Effects of ozone, chlorine dioxide, chlorine, and monochloramine on Cryptosporidium parvum oocyst viability,” Applied Environmental Microbiology, 56(1): 423-428, 1990.

5. Furness, B.W., Beach, W.C., and Roberts, J.M., “Giardia surveillance,” Morbidity and Mortality Weekly Report; 49(SS07), Surveillance Summary, Center for Disease Con-trol and Prevention, Atlanta, GA, 1-3, August 11, 2000.

6. Wickramanay, G.B., Rubin, A.J., and Sproul, O.J., “In-activation of Giardia lamblia with ozone,” Applied En-vironmental Microbiology, 1984; 48(1), 671-672.

7. Fox, K.R. and Lytle, D.A., “Milwaukee’s crypto out-break–investigation and recommendations,” Journal of the American Water Works Association, 1996; 88 (9): 87-94.

8. USEPA, “National Primary Drinking Water Regulations: Long Term 2 Enhanced Surface water Treatment Rule,” Final Rule, 40CFRParts 9, 141, and 142, Federal Register 71:2:388, 2006.

9. Reckhow, D.A. and Singer, P.C., “Chlorination byprod-ucts in Drinking Water–from formation potentials to finished water concentrations,” Journal of the American Water Works Association, 82(4), 173-180, 1990.

10. Collentro, W.V., Pharmaceutical Water System Design, Oper-ation, And Validation, second edition, Informa Healthcare, London, U.K., ISBN-13:9781420077827, January 2011.

11. Thompson, K., “Optimizing Activated Carbon for Tri-halomethane Removal,” Water Conditioning and Purifica-tion, May 2002.

12. USP, USP 34-NF 29 through Second Supplement, Water for Injection Monograph, USP34-NF29, 456, No. 2., December 2011.

13. EP, European Pharmacopoeia, Volume 2, 7th Edition, 2010. JVT

ARTICLE ACRONYM LISTINGEPA US Environmental Protection

AgencyEP European PharmacopoeiaLT2ESWTR Long Term 2 Enhanced Surface

Water Treatment RuleTHM Trihalomethane TOC Total Organic CarbonUSP United States PharmacopeiaWFI Water for Injection

compendial water systems—a 2012 perspective

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