A discussion of the pitfalls associated with the design, operation and maintenance of storage and distribution systems in pharmaceutical water applicationsBy William V. Collentro
1. Storage Tank Sizing Make-up and Draw-off Flow Rate Considerations
Most compendial water systems include storage tanks with excessive capacity. The emphasis on capacity appears related to a “safety cushion” in the event of failure of the water purification components in Purified Water (PWS) or Water for Injection (WFI) Systems. It is difficult to justify this concern based on cost savings associated with reduction in water purification system capacity. Storage systems sizing should consider “turnover”. This is a unique function for each system and includes items such as make-up flow rate, maximum daily demand, maximum instantaneous flow rate, time period of each shift requiring water, and number of days per week that water is required. These issues should be addressed in a responsive “Basis of Design”.
The pitfall associated with excessive storage with decreased make-up capacity can produce the following:
- Impact of mechanical heat from recirculation pumps to distribution loop resulting in temperatures that accelerate bacteria growth. - Increase in the time required to recover from a loop microbial or chemical excursion. - Increase in the time required to remove biofilm by chemical sanitization. - Increase in the time period to rinse chemical sanitizing agents. It is suggested that storage capacity should generally not exceed 24-48 hours of compendial water requirements.
2. Storage Tank Design
Tank design should consider operation, and maintenance requirements for the application. It is suggested that 316L stainless steel is appropriate for all applications where ozone, and elevated or cold temperature (<10°C) will be employed (intermittent and/or continuously). Stainless steel tanks should be sanitary design, fabricated and tested in accordance with the ASME criteria for Unfired Pressure Vessels. Vertical cylindrical design should be employed. The use of stainless steel storage increases the operating flexibility of the system. Hot water sanitization, hot water continuous operation, use of ozone for microbial control, and “cold” operation are all possible. However, maintenance of stainless steel storage systems must include periodic passivation and derouging operations.
“Plastic” tanks may be considered for certain PWS applications. Plastic tanks should be of vertical cylindrical type with conical bottom and full diameter gasketed cover. Tanks employing flat bottoms exhibit accelerated microbial proliferation. Plastic tanks with “threaded” small diameter access ports inhibit tank access, often required for mechanical cleaning during chemical sanitization. This is difficult to achieve without complete access to the tank. Finally, exposure to natural and artificial light can produce accelerated microbial growth on the interior of tank walls. Light reflecting material wrapped around the exterior of plastic tanks can reduce the rate of proliferation.
3. Storage Tank Materials of Construction – Mill Certification, Chromium “Shaving”, PWS versus WFI Applications
As indicated earlier, plastic tanks may be employed for PWS application where appropriate. The use of plastic storage and associated plastic distribution systems is generally dictated by system Total Viable Bacteria (TVB) Alert and Action Limits and the ability to periodically chemically sanitize the storage and distribution system. WFI Systems and PWS employing ozone for bacteria control, with very few exceptions, employ 316L stainless steel storage and distribution systems.
Rouging of 316L stainless steel is a concern, particularly for systems treated using ozone or maintained at an elevated temperature. The chromium, nickel, and molybdenum concentration for 316L stainless steel are all critical to control of rouging. Historically, “Mill Certificates” have been accepted as a definitive indication of 316L stainless steel used for tanks, tubing, fixtures, etc. Further, accessory processing operations performed by a “third party”, such as annealing, are not generally controlled through inspection and monitoring of compliance to established standard operating procedures. Specifications for stainless steel components must consider the origin of the material, the validity of the chemical analysis, and the ability of “third party” suppliers to establish and comply with processing techniques.
4. Tank Accessories – Rupture Disc
Rupture discs provide a positive mechanical method of relieving pressure/vacuum for sanitary applications. While PWS or WFI Storage Tanks contain hydrophobic vent filtration systems intended to provide atmospheric pressure conditions in the tanks, transient conditions may occur that result in pressure or vacuum conditions. Rupture discs are generally not employed for plastic storage tanks.
Rupture discs should be provided with an electronic strip that indicates when disc failure has occurred. If not monitored by a continuity device, loss of disc integrity can occur without operator knowledge. This not only inhibits the ability to detect an unacceptable transient condition but produces atmospheric exposure (with bacteria) to the water in the tank. For ozonated tanks, the exhaust from the rupture disc on pressure should be directed through a gaseous ozone destruct system or directly vented to the roof. The suggested pressure rating for the disc should be 50% of the pressure rating for the tank but should not exceed 10-15 psig.
Finally, it is important to recognize that hot and thermally cycled tanks may encounter unacceptable vacuum conditions. While it is acknowledged that the tanks are generally designed in accordance with the ASME Code for a specified positive pressure rating and full vacuum, the use of “compound-type” rupture discs that fail under both positive and negative pressure is strongly recommended. A vacuum condition indicates a design, operational, or maintenance problem. This can produce undesirable results. A WFI Tank at vacuum condition can literally “pull” Pure Steam and condensate through the condenser, vapor-liquid disengaging device, and evaporator of a distillation unit providing make-up. As a result, bacterial endotoxin, ionic material, and organic material could be present in the distilled water due to the incomplete separation of water (liquid) from Pure Steam (gas).
5. Tank Accessories – Hydrophobic Vent Filtration System
PWS and WFI Storage Tanks should be equipped with Hydrophobic Vent Filtration Systems. These systems employ a hydrophobic membrane filter contained in a housing. The systems remove atmospheric bacteria from displacement air during tank drawdown.
One issue of concern relates to membrane filter temperature for tanks containing water at an elevated temperature. As the temperature of water increases, the vapor pressure increases, resulting in water “carryover” with air from the top of the tank during tank fill. If the membrane filter element is not maintained at an elevated temperature (by heating of the exterior of the housing), water vapor will condense on the membrane material. This can result in filter “blinding” with decrease in available membrane filter area, creation of a vacuum in the tank during drawdown, and potential microbial introduction. While housing heating is desired, temperature control is critical since most hydrophobic vent filter cartridges are constructed of Teflon contained in a temperature limited polypropylene “cage”. Heating above a temperature of about 230-240°F will result in thermal decomposition and degradation of the polypropylene material.
Another issue of concern relates to sizing of hydrophobic vent filtration systems. Observations indicate that a 10-20” long single element filter housing is employed on tanks with a capacity from 50 gallons to 5,000 gallons and tank drawdown rates ranging from <1 to several hundred gallons per minute. The air flow rating for a specified hydrophobic membrane filter must be calculated for each application considering design parameters.
Finally, the type of seal mechanism is critical. The use of a flat gasket seal is discouraged. The use of a double O-ring seal with locking tabs insures that air “leaks” by the sealing mechanism will not occur.
6. Tank Accessories – Spray Ball Assembly
Spray balls are positioned in the distribution loop return line at its terminal point inside the storage tank. The intent of the system is to eliminate stagnant water that could accumulate on tank surfaces. Spray ball assemblies (single or multiple spherical fixtures) are critical in storage systems that are operated hot (continuously or periodically) or periodically chemically sanitized.
Ozonated systems employ periodic sanitization of the distribution system, generally once per day, by inhibiting power to the post storage tank ozone destruct inline UV and allowing ozonated water to recirculate through the distribution loop. It is undesirable to employ a spray ball assembly in ozone systems since the spray action will “strip” dissolved ozone from the return water. Further, in an ozonated tank, gaseous ozone will be present above the stored water, controlling bacteria growth in any water that accumulates on the interior of tank walls. It is suggested that a “dip tube” assembly directing loop return flow below the tank water level, is appropriate for this application.
Finally, the “coverage area” desired for a spray ball assembly should be carefully evaluated considering tank design and tank fitting location. Full 360° area coverage may not be practical for all applications. As an example water can be sprayed directly into a hydrophobic vent filter, producing undesirable results as discussed in Item 5. A 180-270° coverage area may be more appropriate for specific applications.
7. Tank Accessories – Access Manway
If a stainless steel tank is employed, a sanitary manway should be included to provide access to the interior of the tank. The dimensions of the tank, access to the top of the installed tank, and the location and number of fittings on the domed top of the tank, are factors that determine the size and physical location of the manway. A 24” circular manway is preferred. The preferred location of the manway is either the domed top or the upper straight side vertical sidewall of the tank.
8. Tank Accessories – Level Sensing and Control
The sensors employed for tank level should not provide a dead leg or introduce impurities. For plastic tanks, proximity switches, mounted external to the tank, can be employed as an optical-type sensor for detecting level. For stainless steel tanks, pressure sensing may be employed. For applications where a slight pressure may exists above the stored water such as tanks operated hot, thermally cycled, or ozonated, differential pressure should be considered.
The level control system should be multi-point with adjustable set points. A four point system for most application is appropriate. This arrangement employs a “high-high”, “low-low”, low and high (normal operating band) set points. The “high-high” and “low-low” set points should generate alarm and initiate system action. As an example, a “low-low” level alarm should inhibit operation of the downstream distribution system pump.
9. Ozone Systems – Corona Discharge versus Electrolytic
For PWS employing ozone for microbial control, the selection of the ozone generation technique is important. Corona discharge systems generate gaseous ozone which is introduced to the tank water through various methods. The dissolved ozone concentration required for microbial control is generally 0.10 to 0.50 mg/l. Gaseous ozone systems may require loop polishing to remove nitrogen based ionic compounds associated with the inability of oxygen generators feeding gaseous ozone generators to eliminate all of the nitrogen from air. These compounds may increase conductivity and reduce pH. Electrolytic ozone generators provide dissolved ozone for feed to the storage tank. The dissolved ozone concentration required for microbial control is generally about 0.03 to 0.05 mg/l. The cathode/anode/membrane and related electronics employed for ozone generally operate well during normal operation. Relatively small changes in operating parameters, power supply, feed water temperature, flow rate, and pressure can effect system operation.
10. Ozone Systems – Microbial Destruction, Rouging, Oxidation of Organic Material, Ozone Concentration, and Competing Reactions
Microbial control in properly designed ozonated PWS is excellent. However, preventative maintenance is required for long term successful operation. Ozone, a very powerful oxidant, will not only destroy bacteria but also oxidize any organic material in water and the SS surfaces of the storage tank and distribution system. It is suggested that the feed water to the storage tank contain <100 mg/l TOC. It is further suggested that the SS storage tank be derouged about once every 12-18 months.
11. Ozone Systems – Dissolved Ozone Destruct Inline UV System Sizing
Inline UV units using low pressure mercury vapor lamps operating at a wave length of 254 nanometers are employed downstream of the distribution system pump for ozone removal during normal operation. The suggested UV radiation intensity for complete dissolved ozone destruction is 80,000 to 100,000 microwatt-seconds per square centimeter. Units are often undersized. To complicate this situation, conventional dissolved ozone measuring techniques are not consistently capable of verifying the absence of ozone.
12. Ozone Systems – Gaseous Ozone Destruction System Selection, Operation, Design, and Maintenance
While numerous methods are employed for tank venting and air intake, a sound technical approach should be considered. For venting, the release of gaseous ozone must be addressed. While chemical removal of gaseous ozone is possible, it is suggested that thermal ozone destruction is a very reliable and low maintenance alternative. Chemical removal requires periodic replacement of media and operating concerns. It is strongly suggested that the final discharge location, after the thermal ozone destruct system, be directed to an exterior area of the facility.
The displacement air supply to the tank should flow through a 0.2 micron hydrophobic vent filtration system. This eliminates bacteria introduction from displacement air. Many systems do not filter displacement air, relying upon the highly oxidative ozone environment in the tank to destroy any bacteria introduced. This is technically undesirable.
13. TOC Destruct Inline UV Units – Purpose, Results, and Consequences
A newer technique used in smaller capacity PWS employs low pressure mercury vapor lamp inline UV units operating at a wave length of 185 nanometers and an intensity > 50,000 microwatt-seconds per square centimeter. These units produce the hydroxyl radical, an unstable highly oxidative substance. While excellent storage and distribution bacteria control is achieved by the presence of the hydroxyl radical, its presence as an anti-microbial agent in compendial water conflicts with the requirements set forth in the General Notices Section of USP.
14. Distribution Pumps – Selection, Sizing, Materials of Construction, Seal Mechanism, Motor Size, and Use of VFD
It is suggested that distribution pumps for PWS and WFI Systems be of sanitary centrifugal type. Metallic surfaces in contact with water should be 316L SS. For PWS, an inert mechanical seal should be employed. For WFI Systems similar seals may be employed. However, the use of a double mechanical seal with WFI flush provides a definitive barrier.
Pump size, feed water connection size, discharge connection size, pump impeller size, and motor size should be specified based on consideration of projected operating parameters. As an example, pump impeller diameter size selection should allow increase or decrease in diameter for flexibility. Specification of minimum and maximum impeller diameter for a pump should not be considered. This provides flexibility for potential distribution loop expansion without pump change.
For applications were point-of-use demand may change significantly, the use of Variable Frequency Drive (VFD) should be considered to maintain turbulent flow in return tubing at maximum demand.
15. Distribution Loop – Sizing, Return Flow Rate, Slope, and Welding/Fusion Methods
Distribution loop internal diameter should be specified considering the maximum instantaneous demand for points-of-use and the ability to maintain turbulent flow in return tubing at this demand. For applications where the recirculating flow rate exceeds the maximum draw-off flow rate by a factor greater than 2-3X, “tapering” of distribution loop tubing diameter, use of distribution pump VFD, and point-of-use valve “lockout” may be appropriate. It is suggested that the maximum water pressure should be <120 psig. If “positive acting” (air-to-open, spring-to-close) valves are used at points-of-use, the actuator must be capable of closing at the maximum pressure.
It is generally suggested that tubing have an installed slope of about 1/8” per linear foot. Proper slope may require multiple low point drains. If plastic material is employed for PWS the TVB Alert and Action Limits as well as sanitization frequency dictates the heat welding/fusion method. Plastic PWS with lower TVB Alert and Action Limits (<1 cfu/ml) should consider “seamless” tube connection technology. SS distribution loops should employ orbitally welded sanitary tubing with sanitary ferrule connects, where appropriate.
16. Distribution Loops – Weld Inspection, Documentation, and Third Party Inspection
Inspection of plastic piping/tubing fusion welds and stainless steel orbital welds in distribution systems should be performed. “Bioprocessing Equipment” published by ASME provides an excellent reference for appropriate criteria. Further, it is suggested that inspection of connections be performed by an independent third party, not the company/organization installing the tubing/piping. Failure to verify the connections can not only result in mechanical failure but contribute to accumulation and replication of bacteria.
17. Valves – Manual, Automatic, Sample, and End Connections
Valves employed in both PWS and WFI Systems that provide a point for withdrawal of water should be zero dead leg (ZDL) diaphragm type. Manual sample and point-of-use ZDL valves should be selected to provide reduction in the “delivery” diameter as appropriate. Automatic valves should be positive acting, diaphragm type. Valve diaphragm material should be selected for the application. For ozonated PWS and WFI applications diaphragm material should be Teflon with an EPDM backing. It is suggested that annual replacement of valve diaphragms be performed to avoid excessive diaphragm-to-weir wear on the seal portion of the diaphragm. In general, valves should be provided with welded end connections to minimize the use of sanitary ferrule gaskets which will require periodic replacement. However, for certain applications where point-of-use physical locations may change, sanitary ferrule end connections may be appropriate.
18. Distribution Loops – Online Instrumentation (TOC, and Conductivity)
Online measurement of conductivity and TOC is desirable. However, these online techniques must be calibrated per the applicable Physical Tests Sections of USP. Conductivity readings must be non temperature compensated. Online measurement does not eliminate the need for point-of-use measurement for all applications. The TOC and conductivity of “delivered” water for points-of-use using delivery hoses, as an example, should be verified periodically.
19. Hot, Cold, and Ambient Sub Loops – Design, Application, Operation, and Maintenance
WFI and PWS Storage and Distribution Systems Storage and Distribution Systems with low TVB Action and Alert Limits may employ hot or cold loop operation with ambient temperature sub loops. Cold (2-8°C) loops as well as ambient loops should be operated at elevated temperature (?80°C) for a portion of a 24 hour day, suggested as two hours minimum. Lower loop temperature is associated with the potential for bacteria introduction and subsequent development of a biofilm. While the indicated elevated temperature will destroy bacteria, it will not remove biofilm. Subsequently, periodic chemical sanitization may be required for removal of biofilm.
Finally, an effective method of controlling bacteria is to maintain hot storage and ambient (or cold) distribution. The majority of the loop return can be directed to the suction side of the distribution pump with the balance, suggested as 10%, to the hot storage tank. This method of operation insures that the water in the storage tank is bacteria free. Periodic hot water sanitization is required.
20. Mechanical Heat Input – Operation, and Control
Sanitary centrifugal pumps operate at low efficiency. Mechanical heat from the pumps will increase the temperature of the stored and recirculated water. For ambient systems, a loop cooling heat exchanger may be required for avoiding loop temperatures > 30°C. Further, cooling to maintain a temperature of about 20°C can reduce bacteria growth in non ozonated PWS by a factor of 10X.