Inline ultraviolet sanitization units emitting radiation at a wavelength of 253.7 nanometers (nm) have been used for several years in compendial water systems. Use of 253.7 nm radiation does not destroy bacteria but inhibits replication by modifying deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Radiation at 184.9 nm at much higher ultraviolet radiation intensity is also used. Oxidizing 184.9 nm ultraviolet radiation oxidizing UV radiation at 184.9 nm wavelength destroys bacteria by production of ozone and the hydroxyl radical. Further, the highly oxidative environment results in oxidation (partial and complete) of organic material. Residual ozone will attack culture media used during enumeration of bacteria. Ultraviolet oxidation at 184.9 nm involves several different chemical reactions. There are several regulatory and operational considerations associated with the use of terminal 184.9 nm ultraviolet radiation. Case histories describing various ultraviolet radition systems are described. It is suggested that a properly sized 253.7 nm ultraviolet unit may be positioned downstream of the 184.9 nm unit to remove dissolved ozone.
Comependial water systems have used inline ultraviolet sntization units emitting radioation at a wavelength of 253.7 nanometers (nm) for several years. These units inactivate bacteria by modifying DNA/RNA such that organisms will not replicate (1). Some concerns associated with “sub-lethal” inactivation have been expressed by regulatory personnel (2). Regulatory concerns have been documented associated with the ability of the technology to inactivate bacteria by several logs (3). Furthemore, the literature indicates that photo-reactivation of certain organisms may be a concern (4, 5). Personal experience indicates that control of bacteria may be achieved in various water purification sections of a compendial water system, such as after an activated carbon unit. Complete bacteria inactivation is not achieved but levels are reduced below an established alert/action level, thereby extending the time between sanitization of components such as reverse osmosis pretreatment equipment.
The use of inline ultraviolet units in compendial water systems is not uncommon, thus the use of physically similar inline units using 184.9 nm radiation at much higher ultraviolet radiation intensity was accepted as “benign”. In fact, there is a significant difference in the two technologies. Semiconductor applications have used the oxidizing units producing 184.9 nm radiation for several years. The units provide oxidation of trace amounts of organic material to carbon dioxide at the required extremely low ppb or ppt levels for ultrapure water used in semiconductor manufacturing. An example of ultrahigh purity semiconductor grade water is presented in the Table. It should be noted that semiconductor grade water chemical requirements are much more restrictive than USP/EP Purified Water and Water for Injection chemical requirements.
Oxidizing 184.9 nm inline ultraviolet units may also be used to remove disinfecting agent from raw water (7). Complete removal of chlorine (hypochlorous acid and hypochlorite ion) is generally much easier than removal of monochloramine. The technology may be used prior to reverse osmosis units with non-chlorine tolerant reverse osmosis membranes (e.g., thin-film composite polyamide material) in lieu of activated carbon or injection of reducing agent for certain applications (8).
Oxidizing 184.9 nm inline ultraviolet units are being used within USP/EP Purified Water distribution systems or as one of the terminal operations in make-up water to both USP/EP Purified Water or USP water for injection storage systems. As discussed below, 184.9 nm ultraviolet radiation will not only oxidize organic material and destroy bacteria, but also provide an ozone residual. The presence of ozone, an antimicrobial agent, in either Purified Water or Water for Injection is not acceptable (9. 10). In addition, the presence of an antimicrobial agent will attack culture media used during enumeration of bacteria (11). Finally, organic material may not be fully oxidized to carbon dioxide in the 184.9 nm ultraviolet unit. The resulting lighter molecular weight of organic fragments are technically “added substances” as defined in the USP Official Monographs for USP/EP Purified Water and Water for Injection.
Table: Electronics and Semiconductor Industries - Type E-1 Water Requirements.
OXIDIZING ULTRAVIOLET RADIATION BASIC THEORY
Ultraviolet radiation, at a wave length of 253.7 nm, has historically been used in pharmaceutical water purification applications for bacteria control. However, 253.7 nm ultraviolet radiation does not destroy bacteria but inhibits replication by modifying deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) (12, 13). On the other hand, oxidizing ultraviolet (UV) radiation at 184.9 nm wavelength destroys bacteria through production of ozone and the hydroxyl radical, both extremely powerful oxidizing agents (14, 15). Furthermore, the highly oxidative environment results in oxidation (partial and complete) of organic material.
Ultraviolet oxidation at 184.9 nm involves several different chemical reactions. The reactions include the following:
- Reaction with dissolved oxygen, present in water, to produce ozone. Ozone will subsequently oxidize any organic material in water and destroy bacteria within the inline ultraviolet unit stainless steel “oxidizing” chamber. Further, ozone will continue to oxidize organic material and destroy bacteria in the distribution system.
- Generation of the hydroxyl radical by “splitting” of the water molecule. Rapid oxidation of organic material and destruction of bacteria by the hydroxyl radical will occur within the stainless steel oxidizing chamber of the unit. However, the half-life of the hydroxyl radical is less than one second. Measureable amounts of the hydroxyl radical in oxidizing ultraviolet unit product water will generally not be detected.
- Production of hydrogen peroxide by reaction with water and dissolved ozone. Additional production of the hydroxyl radical by the reaction of hydrogen peroxide with 253.7 nm ultraviolet radiation, a portion of the UV spectrum in the oxidizing ultraviolet unit, may occur.
- Potential numerous parallel reactions involving inorganic, organic, and/or colloidal material in water, bacterial endotoxins, and even the stainless steel walls of the oxidizing ultraviolet unit and distribution loop components.
As indicated, the hydroxyl radical, while an extremely powerful oxidizing agent with significant absorption rate to target compounds and bacteria, has a very short half-life of less than one second. Subsequently, oxidation associated with the hydroxyl radical is essentially limited to the stainless steel chamber of the inline UV unit. On the other hand, dissolved ozone will be present in the oxidizing ultraviolet unit product water and continue to oxidize material including bacteria. Ozone decomposes to oxygen with a half-life as long as about 165 minutes in ultrahigh purity water (16). It should be noted that the actual “effective” half-life of ozone increases in high purity water as the concentration of impurities (inorganic, organic, and microbial) decrease (17).
Additional Information—184.9 nm Radiation
Additional important information regarding 184.9 nm ultraviolet radiation is presented as follows:
- Low pressure mercury lamps omit ultraviolet radiation with “peaks” in wave length at 184.9 and 253.7 nm. Ultraviolet radiation at 253.7 nm, with proper intensity, will destroy ozone, converting it to oxygen. Subsequently, a portion of the ozone produced within the oxidizing chamber of a 184.9 nm ultraviolet unit will be destroyed. However, in a recirculating system with storage tank, multiple passes through the 184.9 nm ultraviolet unit could result in an increase of loop dissolved ozone concentration depending upon specific parameters. These include the concentration of ozone in ultraviolet unit product water, actual half-life of ozone in the system, point-of-use volumetric demand, volume of water in the storage and distribution system, and temperature of water.
- Fused quartz sleeves allow transmission of 184.9 nm ultraviolet radiation from the lamp to water in the oxidizing chamber. Metallic oxides added to quartz can eliminate transmission of 184.9 nm ultraviolet radiation to water in the oxidizing chamber. Glass and quartz containing a high concentration of silica will also decrease 184.9 nm ultraviolet radiation transmission (18).
- Ultraviolet radiation at proper intensity and a wave length of 184.9 nm is capable of “breaking” single carbon-to-carbon bonds, double carbon-to-carbon bonds, single carbon-to-chloride bonds, single carbon-to-nitrogen bonds, and double carbon-to-nitrogen bonds. It will not destroy double carbon-to-oxygen bonds in organic material (19).
- In general, the solubility of ozone in water is greater than 10 times the solubility of oxygen in water at the same temperature.
The intensity of ultraviolet radiation required for effective organic material and bacteria destruction at 184.9 nm wave length is 2.5 to eight times the 30-35 mJ/cm2 value required for conventional 253.7 nm disinfecting units. Furthermore, 184.9 nm ultraviolet radiation has a limited “penetration” length through water, when compared with 253.7 nm ultraviolet radiation. Smaller diameter highly polished interior stainless steel cylinder oxidizing chambers with longer lamps are recommended.
While information in the literature is limited, toxic organic compounds associated with incomplete oxidation of organic material may be a concern (20). It is suggested that the lower total organic carbon levels and lower conductivity from water produced by a system including reverse osmosis and continuous electrodeionization will limit or eliminate production of toxic compounds. Specifically, reverse osmosis should remove all organic material with a molecular weight > 150-250 Daltons the 184.9 nm ultraviolet radiation should oxidize the majority of the lighter molecular weight non-volatile organic compounds to carbon dioxide.
REGULATORY AND OPERATIONAL CONSIDERATIONS
There are several regulatory and operational considerations associated with the use of “terminal” 184.9 nm ultraviolet radiation. Potential areas of concern include the following (21):
- USP General Notices Section 4.10, “Monographs”, states:
“Because monographs may not provide standards for all relevant characteristics, some official substances may conform to the USP or NF standard but differ with regard to nonstandardized properties that are relevant to their use in specific preparation.”
- USP General Notices Section 5.20, “Added Substances” states:
“Added substances are presumed to be unsuitable for inclusion in an official monograph and therefore prohibited if: (1) They exceed the minimum quantity required for providing their intended effect; (2) their presence impairs the bioavailability, the therapeutic efficacy, or safety of the official article; they interfere with the assay and the tests prescribed for determining compliance with the compendial standards.”
- USP General Notices Section 5.60, “Impurities and Foreign Substances” states:
“Tests for the presence of impurities and foreign substances are provided to limit such substances to amounts that are unobjectionable under conditions in which the article is customarily employed.
Non-monograph tests and acceptance criteria suitable for detecting and controlling impurities that may result from a change in processing methods or that may be introduced from external sources should be employed in addition to the tests provided in the individual monograph, where the presence of the impurity in inconsistent with applicable good manufacturing practices or good pharmaceutical practices.”
- USP General Information Section <1231>, “Water for Pharmaceutical Purposes”, states:
“High intensities of this wave length alone 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. …Areas of concern include …conductivity degradation in distribution systems using 185 nm UV lights.”
Each of the quoted section from USP should be considered when using 184.9 nm ultraviolet radiations for “polishing” application, particularly in recirculating loops, for pharmaceutical waters. The presence of ozone can impact detection of bacteria by attack of culture media. Sample collection should include sodium thiosulfate “tablet(s)” if even trace amounts of an antimicrobial agent are present (22). Water used for preparation of culture media should be free of antimicrobial agents or treated with sodium sulfite or sodium thiosulfite (23).
Incomplete oxidation of organic material to carbon dioxide requires tests for identification of the spectrum of fragmented organic compounds that are generated. Product testing is required to verify that all identified fragmented organic compounds do not interfere with final product.
If mixed ion exchange resin is used for removal of carbon dioxide as the bicarbonate or carbonate ions, oxidation of the resin may occur (24, 25, 26). The ion exchange resin decomposition products present another source of trace organic contaminants that must be identified as indicated above.
It would be inappropriate to suggest that the use of 184.9 nm ultraviolet radiation should carefully be evaluated without providing information from operating systems supporting the concerns. The following three case histories provide a broad overview to support concerns.
Case History #1
Figure 1: Case history #1.
A USP Purified Water system is depicted in Figure 1. A municipal supply with surface water source provides feed water to the system. Primary and secondary disinfection by the municipality includes chlorine (hypochlorous acid and hypochlorite ion) without ammonia. The water purification system includes cartridge filtration, rechargeable activated carbon adsorption canister, rechargeable mixed ion exchange resin canisters, inline ultraviolet sanitization unit (254.7 nm), and one micron resin fine “trap” cartridge filtration. The system is not provided with recirculation provisions but diverts water to drain prior to feeding the downstream tank. Product water from the water purification system feeds a stainless steel USP Purified Water storage tank. Purified water flows through a 184.9 nm ultraviolet unit directly to a stainless steel loop with eight points-of-use. Recirculated water from the loop returns to the storage tank.
The system is never sanitized, chemically or thermally. About every two weeks, the rechargeable activated carbon canister is changed when the rechargeable mixed ion exchange resin canisters are changed. Samples from the effluent of the rechargeable activated carbon canister immediately before change indicate <0.01 mg/l free and total chlorine. Total viable bacteria samples from individual points of use, collected daily on a rotating basis, indicate <1cfu/100 ml (membrane filtration using plate count agar (PCA), 72 hour incubation time period, and 30-35˚C incubation temperature). Online loop conductivity and TOC measurement are within the criteria set forth in USP Physical Tests Sections <645> and <643> respectively.
System design is reviewed as part of a system expansion to add two additional points-of-use. A third party questions the point-of-use total viable bacteria levels and sanitization provisions as part of the review process. Ultimately, tests for dissolved ozone are performed from a sample collected at the final point-of-use in the recirculating loop. Results indicate 0.02 – 0.03 mg/l of ozone.
The presence of dissolved ozone in water explains the total viable bacteria data as well as the associated lack of system sanitization. While ultimate resolution of the issue is unknown, the water does not meet USP Purified Water requirements.
Case History #2
Figure 2: Case history #2.
A USP Purified Water system is depicted in Figure 2. The system consists of a pretreatment section, reverse osmosis/continuous electrodeionization loop, and storage and distribution. Water from the loop feeds 15 USP purified water points-of-use. One point-of-use feeds a multiple effect distillation unit feed water tank with pump while another point-of-use feeds a pure steam generator feed water tank (and pump).
A municipal water supply with surface source feeds water to the facility. The municipal system’s primary disinfection uses chlorine while ammonia is injected at the distribution point resulting in monochloramine as a secondary disinfecting agent. The literature discusses issues associated with monochloramine removal (27, 28, 29).
The pretreatment system includes backwashable multimedia filtration, water softening, activated carbon adsorption, and carbon fine cartridge filtration system. The reverse osmosis/continuous electrodeionization “loop” includes a conical bottom unpigmented polypropylene break tank, reverse osmosis unit, continuous electrodeionization unit, inline ultraviolet sanitization unit (253.7 nm) and final 0.2 micron filtration system. Water recirculates back to the break tank or is directed to the downstream USP Purified Water Storage Tank based on tank level. USP Purified Water flows to a sanitary stainless steel pump, 184.9 nm ultraviolet unit and directly to the distribution loop.
About four months after initial system start-up, the online conductivity of USP purified water begins to steadily increase. A less dramatic increase in total organic carbon (TOC) is also noted. Ultimately, conductivity exceeds the criteria set forth in USP Physical Tests Section <645> and eventually increases to a value exceeding both the multiple effect distillation unit and pure steam generator manufacturers’ suggested maximum feed water value. Point-of-use total viable bacteria levels were all <1 cfu/100ml (membrane filtration of a 100 ml. sample, R2A culture media, 120 hour incubation time period, and 30-35˚C incubation temperature). A review of reverse osmosis system product water conductivity indicated a slight increase during the time period. Continuous electrodeionization unit conductivity had also increased slightly, from 0.60 µS/cm to 0.85 µS/cm at 25–30˚C.
USP Purified Water use was terminated except for pure steam generator and multiple effect distillation system feed. However, polishing mixed ion exchange resin canisters were positioned between the point-of-use valves for each unit and the feed water tank using flexible hoses. Over an additional four week period, the conductivity of the recirculating USP Purified Water Loop exceeded 10 µS/cm at 25˚C. TOC levels had increased from 0.020 mg/l to >0.200 mg/l.
A thorough review of the system was conducted. As part of system review, total chlorine was detected in the product water from the activated carbon unit. Subsequently, total chlorine was measured and detected in product water from the reverse osmosis unit, continuous electrode ionization unit, and post sanitizing inline ultraviolet unit (253.7 nm) final filtration system. However, undetectable or only trace concentration of total chlorine was detected in the USP Purified Water distribution loop.
Obviously, monochloramine was not being completely removed by the activated carbon unit. Monochloramine is not effectively removed by either reverse osmosis or continuous electrodeionization. In fact, the literature indicates that monochloramine will oxidize both ion exchange resin and ion exchange membranes in continuous electrodeionization units. This may release ion exchange resin oxidation decomposition products. The 184.9 nm ultraviolet system was oxidizing the monochloramine. Analysis of USP Purified Water loop samples indicated the presence of the chloride ion. The 184.9 nm ultraviolet unit was replaced with a 253.7 nm ultraviolet sanitization unit and final 0.001 micron ultrafiltration system. The activated carbon media was changed to acid washed and rinsed custom selected media. Upon restart of the system conductivity in the USP Purified Water distribution loop decreased to a value of about 0.6 µS/cm at 23˚C while TOC decreased to about 0.015 mg/l. Periodic loop hot water sanitization was performed every six months. Ultrafiltration unit chemical cleaning/sanitization was also performed once every six months, prior to hot water sanitization of the storage and distribution system. Point-of-use total viable bacteria levels were <1cfu/100 ml.
In this situation 184.9 nm ultraviolet radiation was oxidizing an organic impurity, monochloramine, which was not being removed by the upstream water purification system. The increase in conductivity demonstrates the strong oxidizing capability of 184.9 nm ultraviolet radiation. It is suggested that the observed increase in TOC is attributed to the fact that lighter molecular weight “fragmented” organic material may be oxidized by conventional TOC monitors more rapidly than heavy molecular weight organic material. Further, the presence of chloride ion can also provide an enhance TOC value at low concentrations since the “measurement” technique for a TOC unit is generally conductivity or “differential” conductivity. While the initial total viable bacteria levels were all <1cfu/100 ml, it is difficult to speculate whether monochloramine, dissolved ozone, or a combination of both disinfecting agents was suppressing the true total viable bacteria level by attacking culture media during enumeration. This case history provides additional information associated with the use of 184.9 nm ultraviolet radiation for USP Purified Water “loop” reduction in TOC levels.
Case History #3
Figure 3: Case history #3.
A USP Purified Water system is depicted in Figure 3. The system consists of a pretreatment section, reverse osmosis/rechargeable mixed resin canister section, and unpigmented polypropylene construction storage and distribution. Water from the loop feeds 6 USP Purified Water points-of-use.
A municipal water supply from a surface source feeds water into the facility. The municipal system’s primary and secondary disinfecting agent is chlorine.
The pretreatment system includes cartridge filtration, water softening, and activated carbon adsorption. The reverse osmosis/rechargeable mixed resin “system” includes a reverse osmosis unit, rechargeable mixed resin canisters, inline ultraviolet sanitization unit (253.7 nm) and final 0.2 micron filtration system. Water is not continuously recirculated through the reverse osmosis/rechargeable mixed bed resin system. It is rinsed to drain every four hours if there is no demand and rinsed to drain for 10 minutes prior to being directed to the downstream conical bottom unpigmented USP Purified Water Storage Tank based on tank level. USP Purified Water flows to a multistage centrifugal non sanitary distribution pump, 184.9 nm ultraviolet unit, polishing rechargeable mixed resin canisters and socket welded unpigmented polypropylene distribution loop, returning to the conical bottom USP Purified Water storage tank.
Total viable bacteria levels at point-of-use are consistently <1 cfu/100 ml. Chemical sanitization of the storage and distribution system is never performed. The rechargeable mixed resin canisters downstream of the reverse osmosis unit are changed upon an increase in conductivity, about once every two to three months. The rechargeable mixed resin canisters downstream of the 184.9 nm ultraviolet unit are changed once every three months with “virgin” mixed bed resin. A new quality assurance director joins the organization and questions the lack of USP Purified Water storage and distribution loop sanitization.
As part of system evaluation for the quality assurance director total viable bacteria samples are collected using sterile containers with a sodium thiosulfate tablet. Bacteria enumeration is conducted using membrane filtration of a 100 ml sample, R2A culture media, 30-35˚C incubation temperature, and 120 hour incubation time period. Results indicate ~ 2000 cfu/100 ml. Bacteria enumeration using membrane filtration of a one ml USP Purified Water sample in 99 ml of sterile water, R2A culture media, 30-35˚C incubation temperature, and 120 hour incubation time period indicates 46 cfu/ml. The total viable bacteria action limit for the system is 50 cfu/100 ml.
The USP Purified Water storage and distribution system contain dissolved ozone that suppresses the total viable bacteria results. It is suggested that the “virgin” resin in the USP Purified Water dstribution loop mixed bed canister removes a portion of the dissolved ozone from the upstream 184.9 nm ultraviolet unit, oxidizing the resin and introducing decomposition products to delivered USP purified water.
The 184.9 nm ultraviolet unit and “virgin” rechargeable mixed bed polishing system were removed from the USP Purified Water distribution loop and replaced with an ultrafiltration system with about 2-3% waste stream (non-bacteria retentive filtration). An intensive storage and distribution loop sanitization was conducted using a 1% solution of hydrogen peroxide and peracidic acid (30). Point-of-use valves were replaced with “zero dead leg”-type valves. A three month chemical sanitization cycle for the USP Purified Water storage and distribution system was initiated. Ultrafiltration unit cleaning/sanitization was also conducted once every three months. Point-of-use total viable bacteria levels were routinely <1cfu/100 ml.
The use of 184.9 nm ultraviolet radiation in USP Purified Water distribution loops will yield dissolved ozone. The dissolved ozone provides an antimicrobial agent, prohibited for bulk compendial waters. Bacteria and biofilm may be present because dissolved ozone in “delivered” water samples attacks culture media. Further, incomplete oxidation of organic material or downstream ion exchange resin may introduce “added substances” as defined in USP. It is suggested that a properly sized 253.7 nm ultraviolet unit may be positioned downstream of the 184.9 nm unit to remove dissolved ozone, similar to technology used in USP Purified Water systems with gaseous or electrolytic ozone generation for microbial control.
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