Water Systems For Pharmaceutical Facilities Mark Keyashian 1.0 INTRODUCTION Common, everyday water is a major consideration in a pharmaceu- tical plant. The final product or any of its intermediate materials can only be as contaminant-free as the water available at that stage. Water may be an ingredient or used principally to wash and rinse product contact components and equipment. Water is also used to humidiethe air, to generate clean steam for sterilization, to cool or heat, as a solvent, for drinking and sanitary uses, etc. To better control this critical media, the pharmaceutical industry has defined two additional types of water: purijied water and water for injection, both of which are highly regulated. Special attention to a good understanding of the water systems in a pharmaceutical facility are essential. 2.0 SCOPE This chapter is an overview of the various water systems used in a pharmaceutical facility. It will help bring about a better understanding ofhow they are generated, stored and distributed and what equipment is involved. Starting with raw water as it is sourced, this chapter will: 590 Water Systems for Pharmaceutical Facilities 591 1. Take the reader step-by-step through various treatments 2. Outline applicable cGMP’s (current Good Manufactur- 3. Point out some potential pitfalls to watch for during In addition, for a better all around understanding, an overview ofhow these systems are designed and some ofthe more important design parameters will be discussed. to generate different types of water. ing Practices) installation and start-up. 3.0 SOURCE OF WATER Water supply to the plant is either ground water (wells), surface water (lakes, rivers), or city water. Raw water is typically contaminated with salts, oils, various organic substances, calcium, clay, silica, magnesium, manganese, aluminum, sulfate, fertilizers, ammonia, insecticides, carbon dioxide and, of course, bacteria and pyrogens. A city water treatment plant removes most of these impurities, but adds chlorine or chloramines and fluoride. Table 1 summarizes the level of contaminants by type of raw water. Table 1. Contaminants by Type of Source Water Tap Water Surface Water Ground Water Particulates 3-5 3-7 4-9 Dissolved Solids 2-5 1-5 5-10 Dissolved Gases 3-5 7-10 5-8 Organics 1-4 3-8 0-5 Colloids 0-5 3-8 0-4 Bacteria 1-2 6-9 2-5 P yrogens 7-9 6-9 2-5 0 =None 10 = Very High 592 Fermentation and Biochemical Engineering Handbook Regardless of the source, the first step in knowing the water supply or designing a system is to obtain a complete analysis of the supply water. Table 2 is an example water analysis. Please note that a water analysis on a sample obtained at the city treatment plant may be significantly different from one obtained at the site. Table 2. Typical Water Supply Analysis Item Plant Feed Turbidity Color Alkalinity Hardness (as CaCO,) Calcium Magnesium Sodium Potassium Iron Manganese Sulfate Chloride Nitrogen (ammonia) Nitrogen (nitrite) Nitrogen (nitrate) Copper SDI (fouling index) PH 0 0 8.8 16 mgk 38 mgk 10 mgk 3.2 mg/L 23 mg/L 3.1 mg/L 0.04 mg/L 0.03 mg/L 27 mgk 49 mg/L 0.05 mg/L 0.30 mg/L 0.002 mg/L 0.002 mg/L 25 Usually, immediately upon entering the plant, supply water is split into potable water and process water. This is done by using an air break or back flow preventers. This is a precaution against process contaminants backing up into potable or city water and vice versa. Often a break tank is used as the air break since it also provides storage capacity for demand surges at the use points. Water Systems for Pharmaceutical Facilities 593 4.0 POTABLE WATER Potable water, also called drinking or tap water, is used for sanitary purposes such as drinking fountains, showers, toilets, hand-wash basins, cooking, etc. If the water supply to the facility is from a public system such as city water, the maximum contaminant levels, are set by the Environmental Protection Agency (EPA) Standards, Title 40 CFR, Part 141. Table 3 is a highlight of a typical water supply standard. Primary drinking water regulations, Appendix I outlines the existing and proposed U. S. EPA drinking water maximum contaminant levels. Table 3: Minimum Potable Water Standard Item Specification Appearance 1 Turbidity Unit Chloride 250 ppm Fluoride 1.4 to 2.4 mg/L Sulfate 250 ppm Lead 0.05 mg/ L Fecal Coliforms Pyrogens Not Specified Other Microbes Not Specified Total Dissolved Solids 500 mg/L Arsenic 0.05 mg/L Barium 1.0 mg/L Cadmium 0.010 mg/L Chromium Hexavalent 0.05 mg/L Chloroform 0.7 mg/L Cyanide 0.2 mgL Mercury 0.002 mg/L Nitrate 10 mg5 Selenium 0.01 mg/L Silver 0.05 mg/L Pesticides 1/100 ml (Proposed: Oh00 ml) Chlorodane 0.003 mg/L Endrin 0.0002 mg/L Heptachlor 0.0001 mg/L Heptachlor Epoxide 0,0001 mg/L Lindane 0.004 mg/L Methoxychlor 0.1 mg/L Toxaphene 0.005 mg/L 2,4-D 0.1 rngL 2,4,5-TP (Silvex) 0.01 mg/L Specific Resistance 10,000 ohmdcm (typically) PH 6.5-8.5 Water Systems for Pharmaceutical Facilities 595 Figure 2. Water pretreatment 6.0 MULTIMEDIA FILTRATION Multimedia filtration (also called prefiltration, sand filtration or multilayered filtration) is mainly aimed at removing sediments and suspended matter. Suspended contaminants are trapped in small crevices and, as a result, water turbidity is improved. A number of media are distinctly layered with the coarsest on top so the suspended matter is collected throughout the depth of the filter according to size. The filter beds need to be backwashed periodically as the back pressure increases; however, backwashing removes the filter from use. To avoid downtime, often a dual filter bed system is installed. During construction, the filtration unit should be installed before all the walls are erected so it can be kept upright, in which case the filters can be charged by the vendor before shipping. This would reduce chances ofdamage to the internals during loading. The unit, of course, should be inspected thoroughly upon receiving. Before shipping, the vendor will often disconnect controls to minimize potential damage. Sufficient time should be allowed to reconnect all of these. Finally, to avoid bacteria building up, start-up should be delayed until a constant water flow is assured. 596 Fermentation and Biochemical Engineering Handbook 7.0 WATER SOFTENING Water is softened to remove the scale-forming hardness elements. Soft water is required for boilers, water heaters, cooling towers, reverse osmosis systems, etc. Softening is an ion-exchange process which replaces almost all ofthe metallic or cations by sodium ions and sometimes, the anions with chlorine ions. Therefore, a constant supply of salt is required. A softener may be used in conjunction with a deionizer on certain water supplies to provide softened water for use in regeneration. This will prevent the formation of insoluble precipitates within the deionizer resin bed. It is important to note that softening does not remove silica, which forms a very hard scale that is not easily removed. In addition, softening does not remove chloride which can cause stress corrosion cracking in stainless steel. A freshly regenerated resin bed is in the sodium @a+) form. When in service, sodium cations are exchanged for undesirable quantities of calcium (Ca++), magnesium (Mg++), and iron (Few) ions. Sodium ions already present in the raw water pass through the process unchanged. Upon exhaustion ofthe resin, as indicated by unacceptable hardness leakage, most systems are designed to go automatically into regeneration. It should be noted that although the water is softened, the total dissolved solids content remains unchanged. Further, the effluent contains the same anions as the supp 1 y water. Softeners can be a microbial concern. A dark and moist column interior can provide a growth environment. The regeneration cycle which uses concentrated brine solution and a backwash cycle aids in reducing the bioburden. Softeners should be regenerated based on a time clock set for twice weekly regenerations and on a volumetric flow of water, whichever is shorter. Since the regeneration cycle removes the softener bed from opera- tion, a dual bed system is often specified. 8.0 ACTIVATED CARBON Activated carbon has long been used as an effective means of removing organics, chlorine, chlorates, other chlorine compounds and objec- tionable tastes and odors. The organics removed include pesticides, herbi- cides and industrial solvents for which activated carbon has diverse capacity. Typically, carbon filters are operated at a flow rate of 1-2 gpm/ft3 of activated carbon. Water Systems for Pharmaceutical Facilities 59 7 Since chlorine is removed from water by the carbon, extra care is required from here on to protect against bioburden growth. Carbon beds themselves are good breeding grounds for bacteria. To keep the system in check, a recirculation system as depicted in Fig. 3 is recommended. The constant recirculation avoids water stagnation and reduces viable bioburden growth. Filtered Water 5 Mlcron Fllter 0 I Drain Figure 3. Activated Carbon. Activated carbon is manufactured by heating selected grades of coal or other higher carbonaceous material in the absence of oxygen. This “activation” process burns out impurities and produces a honeycomb-like structure containing millions of tiny pores. The structure provides a large total surface area that enables the carbon to adsorb (attract and hold to the surface) large quantities of contaminants. Chlorine, or its related elements, are first adsorbed on the surface of the pores where they react with the carbon to liberate chloride. Because ofthis reaction and deterioration of chlorine, the capacity of activated carbon for chlorine removal is exceedingly high. In addition to chlorine removal and adsorption of organics, the granular carbon is an effective filter. Although removal of turbidity will shorten the carbon life by blocking pores, the carbon will function as an excellent filter. Particle removal down to 40 microns can be achieved with freshly backwashed beds of carbon. 598 Fermentation and Biochemical Engineering Handbook Carbon beds are backwashed to remove carbon fines and suspended matter which have been filtered by the bed. Backwashing does not regenerate the carbon. Sanitizing and some degree of regeneration can be effected by passing low pressure steam or hot water through the carbon bed. The degree of regeneration is limited and the carbon must be replaced periodically (once every 1-2 years). Steam is of course more effective than hot water for sanitization, but it does cause some carbon degradation. 9.0 ULTRAVIOLET PURIFICATION In high purity water systems, UV light is often used in-line to control microorganism contamination. Use of UV as a disinfectant is somewhat controversial. In the author’s opinion, UV as an added measure is worth- while; however, it should not be totally relied on to keep the water clear of bacterial contaminants. UV systems cannot correct for a poorly designed water system. Also, note that UV kills microorganisms and hence generates pyrogens.[21 In most cases, microorganisms can be filtered out, while pyrogens cannot be. To be effective, UV radiation at a wavelength of 2537 A must be applied. A minimum dosage of 16,000 microwatt-seconds per cm2 must be reached at all points throughout the water chamber. Appendix I1 is a summary statement by the Department of Health, Education and Welfare on the use of UV as a disinfectant. During construction and installation, extra care should be taken in handling the UV unit. The UV lamp sleeves are made of quartz, since glass filters UV radiation, and are very fragile. The same is true in the start-up; the lamps can break when the unit is first pressurized. It is recommended that spare lamps be kept on hand. Lamps also get broken during start-up if they are turned on when there is no flow. They get hot before the flow is established and then cold water causes them to break. Finally, avoid looking directly at the lamps while they are on. UV radiation can cause eye damage. A port equipped with a thick glass cover is provided to visually check the lamps. 10.0 DEIONIZATION Deionization is the process of removing the dissolved ionized solids from water by ion exchange. Ion exchange can be defined as a reversible exchange of ions between a solid (resin) and a liquid (water). The major Water Systems for Pharmaceutical Facilities 599 portion oftotal dissolved solids is mineral salts, such as calcium bicarbonate, magnesium sulfate, and sodium chloride. Since deionization requires the removal of all ions, both the negatively charged anions and the positively charged cations, materials capable of altering both are required. These materials are known as cation exchange resins and anion exchange resins. The ion exchange resins are contained in pressure tanks, and the water to be deionized is forced through the resins. Typically, deionizers are either dual bed or mixed bed systems. Dual-bed models have two separate resin vessels, the first being a cation unit followed by an anion unit. Cation resin collects the positively charged cations such as calcium, magnesium or sodium and exchanges them for hydrogen. The discharge from the cation tank is very acidic. There are two types of anion units. Strong base anion resin units remove all anions including silica and carbon dioxide. Removal of silica and CO, are specially important prior to distillation in a unit such as a WFI still. They typically produce a deionized water with a pH greater than 7. Weak base anion units are used when removal of silica and carbon dioxide are not required. Mixed bed units contain both the anion and the cation resins in one vessel. Mixed bed discharge pH is typically around 7.0, neutral. After a time, the resins are exhausted and must be regenerated. This is done with a strong acid and a strong base. Cation resin is typically regenerated with hydrochloric or sulfuric acid. Anion resin is normally regenerated with sodium hydroxide. A neutralization tank is generally necessary to adjust the pH before waste effluent from regeneration can be discharged into the sewer. The neutralization tank and system should be placed close to the DI (deionization) system, this is due to the fact that strong acid and base solutions will have to be piped between the two systems. Before hookup, all lines should be flushed. For obvious reasons, mixed bed deionizers are more difficult to regenerate. The quality or degree of deionization is generally expressed in terms of specific resistance (ohms) or specific conductance (mhos). Ionized material in water will conduct electricity. The more ions, the more conduc- tivity and the less resistance. When ions are removed, resistance goes up, and therefore the water quality is improved. Completely deionized water has a specific resistance of 18.3 megohms centimeter. During construction, the DI system should preferably be positioned before all the walls are erected so the skid can be kept upright, in which case the vessels can be charged with the resins by the vendor before they are shipped. This would reduce chances of damage to the internals during loading. Again, sufficient time should be allowed to reconnect all the control 600 Fermentation and Biochemical Engineering Handbook air (or water) lines which are disconnected before shipping. To avoid bacteria buildup, start-up should be delayed until the system is ready to be placed in use with constant water flow. If the vessels are going to be charged with the resins at the site, it is better to pump a slurry solution of the resin into the vessels instead of physically dumping it through the manway. Make sure to backwash for fines after loading. Upon completion, test for resin and other leaks. As usual, good planning is important. Make sure sufficient amounts of all the necessary chemicals are on hand and are of the right grade. Along with the skid, materials will include a number of loose boxes containing plastic pipes and fittings, remote items, and perhaps the resin, all of which should be identified and kept safe for the installation. Do not put chlorinated city water directly into the resin beds even for washing. Also, do not recirculate DI water directly to the carbon unit as it will leach out organics. Here, also, a recirculation system is recommended to keep a constant flow through the unit at all times. To minimize down time, alternating deionization systems are speci- fied so that one DI unit is on line while the second unit regenerates or recirculates in a standby mode. A regeneration cycle is usually 3 to 4 hours long. The frequency of regeneration is governed by both operating cost and potential bacterial buildup. The regeneration with acid and caustic serves to sanitize the resin bed. Deionizers, in the pharmaceutical industry are generally regenerated every one to three days. Off-site regenerated DI canisters are available as a service to the industry. Due to the difficulty associated with handling, storage and sewer discharge ofthe caustic and acid chemicals needed for the regeneration, many users choose this alternative. Service exchange DI (SDI) is economically justified when the quantities of DI needed are relatively small (0.5 to 25 gpm). SDI systems are also used downstream to polish water that has been treated before. When the resins are exhausted, a service technician exchanges them for fully regenerated units. Another alternative for water deionization, is continuous deioniza- tion (CDI). This technologically innovative deionization process was developed by Millipore Corporation and is currently marketed by Ionpure. It uses electricity across ion exchange membranes and resins to remove ions from a continuous water stream. No chemical regeneration is required. A waste stream, carrying the rejected ions, of less than 10% of the feed water is required. Water Systems for Pharmaceutical Facilities 601 11.0 PURIFIED WATER Purified water is typically prepared by ion exchange, reverse osmo- sis or acombination ofthe two treatment processes. Purified water is intended for use as an ingredient in the preparation of compedial dosage forms. It contains no added substances, and is not intended for use in parenteral products. It contains no chloride, calcium, or sulfate, and is essentially free of ammonia, carbon dioxide, heavy metals, and oxidizable substances. Total solids content will be no more than 10 ppm, pH will be 5-7, and the water will contain no coliforms, The United States PharmacopoeiaNational Formulary (USP) requires that purified water comply with EPA regulations for bacte- riological purity of drinking water (40 CFR 141.14, 141.21). Table 4 is a quantitative interpretation of United States Pharmacopoeia XXI standards for purified water.[*] Table 4. USP Purified Water['] Constituent Purified Water PH Chloride Sulfate Ammonia Calcium Carbon Dioxide Heavy Metals Oxidizable Substances Total Solids Total Bacterial Count P yrogens 5.0-7.0 <0.5 mg/L <1 .O mg/L <0.1 mgL <1.0 mg5 4.0 mg/L <0.1 mg/L as Cu Passes USP Permanganate Test <10 mg/L <50 cfu/ml None Specified USP XXII (published 1990) purified water standards remain the same as USP XXI. Purified water is essentially equal to deionized water, at least chemically (not necessarily biologically). Figures 1 and 2 outline the most common methods of purified water generation. After the deionization process, water is collected in a storage tank. A distribution loop takes water from the storage tank to all use points and then back to the storage tanks. 602 Fermentation and Biochemical Engineering Handbook The purified water temperature is typically maintained at 60 to 80°C (hot), ambient, or 4°C (cold). A number of heat exchangers are located around the loop and after the DI system to achieve and maintain the desired temperature. Ifthe system is hot, point-of-use heat exchangers should be used to obtain ambient water. A design engineer would need to evaluate a given system, and strategically locate and size heat exchangers to both maintain the temperature in the loop and to provide water to the use points at the desired temperatures. Regardless of the system temperature selected, the storage tank and the loop must be sanitized periodically. For the stainless steel system outlined above, sanitization implies raising the water temperature to 80°C (at a minimum) at the cold point and maintaining it for the validated time interval. This is often done automatically off shift. Another commonly used approach to purified water generation, storage and distribution is RODI. Figure 4 is a schematic of an ROD1 approach. The components in this type of system are usually all plastic, therefore, sanitization is done chemically. Use of a sterilizing 0.2 micron filter in addition to, or instead of, the resin filter should be resisted. This practice may appear beneficial, but it is specifically prohibited by the proposed LVP GMP’s (proposed CFR 212.49) and it is not recommended. HoI Raw Cold a I m Oll/Ofl PVC Or Polyprop Linu FRP Stwage lank Figure 4. USP purified water (ROD1 water) Water Systems for Pharmaceutical Facilities 603 12.0 REVERSE OSMOSIS The only component of ROD1 purified water not yet discussed is the reverse osmosis system (RO). Reverse osmosis operates at a pressure in the range of 200 to 400 psig or higher, forcing water through membranes. The reverse osmosis process should reject about 95 to 97% of the ionizable salts and 99%oforganics withmolecular weight over 300. It is extremely effective in rejecting bacteria and pyrogens. Due to the significant reduction in ionizable salt concentrations, RO systems are often used as a pretreatment method before a DI system. An RO before a DI reduces the size of the deionizer, reduces the consumption of regenerate chemicals and may reduce the length of the deionizer required service cycle. Osmosis is the procedure by which two solutions separated by semipermeable membrane interchange a solvent. The solvent moves from the solution that is low in solute to the solution that is high in solute through the semipermeable membrane in order to equalize the concentration on both sides of the membrane. By applying water, under pressure, to this semipermeable membrane, the process of osmosis is reversed, forcing pure water through the membrane and leaving a concentrated solution behind. The concentrated side is continuously removed to prevent fouling. A typical RO used in water systems is designed to reject 25 to 50% of the feed water continuously. Even at these rejection rates, the dirty side of the membranes rapidly build up undesirable bacterial concentrations. To alleviate this potential problem, the membranes are normally automatically flushed on a continued cycle basis, say 3 to 8 minutes every four hours. Full sanitization with a sanitization chemical like phosphoric acid is required periodically based on continual monitoring of pressure drop, conductivity and bacterial count. To hrther reduce bacterial count, RO systems should be sized for 24 hours per day operation to minimize water stagnation. The two most common RO membrane configurations used in water treatment today are spiral-wound and hollow fiber. The spiral-wound elements can operate at a higher pressure and at a higher silt density index (SDI) than the hollow fiber type, and thus may require less pretreatment (and are more tolerant of pretreatment upsets). They also are easier to clean than the hollow fiber type. The main advantage of the hollow fiber configuration is that it has the highest amount of membrane area per unit volume, thus requiring less space. Since there is only one hollow fiber element per pressure vessel, it is easier to troubleshoot, and it is easier to replace membrane modules. 604 Fermentation and Biochemical Engineering Handbook Each membrane configuration is available in different materials, the most common being cellulose acetate and polyamide. Cellulose acetate type membranes have a tight feed water pH specification (5.0-6.5) usually requiring acidification of the feed water and are subject to bacterial degra- dation, requiring some (up to 1.0 ppm) free chlorine in the feed water. Polyamide membranes can operate continuously over a broader pH range (4.0-1 1 .O) and thus may utilize softening instead of acidification in order to prevent formation of insoluble precipitates at the membrane interface. They are subject to oxidation by even trace amounts offree chlorine, thus requiring activated carbon prefiltration and/or sodium bisulfite addition. The operat- ing temperature range is typically 32-104°F (O-4O0C), but the membrane productivity usually is rated at 77°F (25"C), thus equipment is often used to regulate the feed water temperature to the 77°F design point. Should the RO system outlet conductivity be unsatisfactory, the outlet water should be diverted automatically to drain until the problem is resolved. 13.0 WATER FOR INJECTION USP requires water for injection (WFI) to be produced by distillation or by reverse osmosis. In the pharmaceutical industry however, distillation is currently the preferred method for WFI generation. A double-pass reverse osmosis unit is sometimes used. A single pass RO is not recommended for WFI generation. Water for injection is intended for use as a solvent for the preparation of parenteral solutions and the final rinse of all parenteral product contact surfaces. Water for injection must meet the USP purified water requirement discussed and contain no added substances. Table 5 is a quantitative interpretation of United States Pharmacopoeia XXI, Standards For Water For Injection.['] Note that WFI is essentially the same as purified water with the exception of endotoxins and bacteriological purity. USP requires WFI to contain less than 0.25 USP Endotoxin Unit per ml. The USP has no bacteriological purity requirements for WFI at all. However, the proposed large volume parental GMP's (CFR 212.49) requires counts less than 10 CFU/100 ml. Water Systems for Pharmaceutical Facilities 605 Table 5. USP Water for Injection['] Constituent Water For Injection PH Chloride Sulfate Ammonia Calcium Carbon Dioxide Heavy Metals Oxidizable Substances Total Solids Total Bacteria Count Pyrogens 5.0-7.0 <OS mg/L <1.0 mg/L <0.1 mg/L <1 .O mg/L -3.0 mg/L <0.1 mg/L as Cu Passes USP Permanganate Test <10 mg/L <lo cfu/lOO ml 0.25 EU/ml Figure 5 summarizes a typical WFI storage and distribution system. Pretreated water is fed to the WFI still preheater by level control and on to an evaporator heated with the plant process steam. The evaporated water should go through filtersheparators to remove entrained droplets. The steam is condensed with cooling water, and then partially reboiled to remove dissolved gases. The distillate is fed to a WFI storage tank. A conductivity monitor diverts under specification distillate to drain. WFI production is controlled by an ordoff level control in the WFI storage tank. Boiler controls are incorporated in the WFI still. The still is vented automatically when on standby waiting for level control to request water. The WFI recirculating loop velocity is designed to ensure turbulent flow and is generally 5-10 Wsec. The WFI recirculation loop is designed to run continuously. At peak use rate, the water velocity in the pipes should be 2 Wsec or more. Standard control methods are used for the WFI tank. A water high level switch (LSH) turns the WFI still off or on depending on whether the water level is at or below the LSH point. A water low level switch (LSL) is interlocked to the recirculation pump to shut it off should the level reach the LSL point. 606 Fermentation and Biochemical Engineering Handbook n Conductlvlty Meter shunt to Draln I c Holding Tank Figure 5. Water For Injection. The WFI storage tank water is usually maintained at about 80°C. This water may be temperature controlled (heated) at the return end of the WFI loop via a WFI heat exchanger (shell and tube double tube sheet) or a hotjacket may be used. A heat exchanger is the preferredmethod. Where cool WFI is required, point of use coolers (double tube sheet) or a cool WFI loop is provided. Considerable control effort is needed for the point of use cooler design to meet the continuous flow non-stagnancy standards. All pipelines used in a WFI generation, storage or distribution must be sloped to provide for complete drainage. No pipe segment not in regular use can be greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. A WFI system must be sampled and tested at least once a day. All sampling ports or points of use in the distribution system shall be sampled at least weekly. It must be kept in mind that WFI is an extremely aggressive solvent, especially at 80°C. Therefore, the still, storage tank(s), and the distribution system are generally 300 series stainless steel with welded joints wherever possible. All surfaces that come in contact with the water are, at a minimum, Water Systems for Pharmaceutical Facilities 60 7 smooth and manually polished to a #4 finish (150 grit) and passivated to prevent corrosion. Welds are made with automatic arc welders under inert atmosphere to prevent chromium migration, carbide and oxide formation, inclusions, or incomplete penetration ofthe joint. All connections that are not welded should be sanitary in design to eliminate crevices where corrosion can occur and bacteria can grow. GMP’s do allow storage at ambient temperatures, but if this option is chosen, the water must be tested on a batch basis, and can only be held for 24 hours before it must be discarded. Therefore, a hot loop may turn out to be less expensive than a system without the heated loop in the long term. All maintenance on the WFI system must be performed by trained personnel and carefully documented. Maintenance personnel must be fully aware of any impact that their activities may have on the system and on the facility. All maintenance will require careful planning and coordination with manufacturing and quality control personnel. 14.0 WATER SYSTEM DOCUMENTATION It is necessary to maintain accurate blueprints of all water systems for FDA review and to comply with cGMP’s. It is also critical to the integrity ofthe system that the validation be kept current. In order to accomplish these objectives, a change control procedure must be implemented that ensures that all changes to the system are fully documented, and all anticipated changes are evaluated by appropriate personnel for potential adverse effects on the system prior to implementation. Based on this evaluation, decisions are made about the need for revalidation to guarantee that the system remains under control. With this procedure in place, it is much less likely that the status of the system will be altered haphazardly, and that changes will not occur without the review and consent of appropriate personnel. 608 Fermentation and Biochemical Engineering Handbook APPENDIX I: EXISTING AND PROPOSED U. S. EPA DRINKING WATER STANDARDS PRIMARY REGULATIONS Contaminants Existing Proposed Best Available MCL mgAl MCL mgA2 Technologies (BAT)3 INORGANICS Arsenic Asbestos Barium Cadmium Chromium Fluoride Lead Mercury Nitrate Nitrite Selenium MICROBIALS Coliforms Giardia Lamblia Legionella Viruses Standard Plate Count Turbidity 0.05 ---- I .o 0.01 0.05 4.0 0.05 0.002 ---- 1-5 mtu 0.05 7 MFL4 5.0 0.005 0.1 4.0 0.005 0.002 10 1 .o 0.05 C/F, LS, RO UF, SF, C/E LS, CS, RO C/F, LS, CS, RO CE, LS, cs, AX, RO AX, RO C/F, LS, CS, SF, RO C/F, GAC, CS, RO AX, RO LS, RO LS, RO, C/F C/F, CL, SF C/F, CL, SF C/F, CL, SF C/F, CL, SF C/F, CL, SF C/F, CS, SF Water Systems for Pharmaceutical Facilities 609 APPENDIX I: (Cont'd) Contaminants Existing Proposed Best Available MCL mgA' MCL mgA2 Technologies (BAT)3 ORGANICS Acrylamide Alachlor Aldicarb Aldicarb Sulfoxide Aldicarb Sulfone Atrazine Carbofuran Chlordane cis- 1,2,-Dichloro- ethylene Dibromochloro- propane (DBCP) 1,2-Dichloro- propane 0-Dichlorobenzene Endrin Ethylenedibromide Epichlorohydrin 2,4-D (EDB) 0.0005 GAC, OX 0.002 GAC 0.01 GAC, OX 0.01 GAC 0.04 GAC 0.003 GAC 0.04 GAC, RO, OX 0.002 GAC, PTA, RO 0.07 GAC, PTA 0.0002 GAC, PTA 0.005 GAC, PTA 0.6 GAC, PTA 0.07 GAC, RO 0.0002 GAC, PTA, RO O.O0005PTA, GAC 0.005 not known 61 0 Fermentation and Biochemical Engineering Handbook APPENDIX I: (Cont’d) Contaminants Existing Proposed Best Available MCL mg/ll MCL mg/12 Technologies (BAT)3 ORGANICS Ethylbenzene ---- Heptachlor ---- Heptachlor epoxide ---- Lindane 0.004 Methoxychlor 0.1 benzene ---- chlorinated Monochloro- PCB’S Poly- Biphenyls ---- Pentachlorophenol ---- Styrene ---- Tetrachloroethylene ---- Toluene ---- 2,4,4 -TP 0.02 Toxaphene 0.005 trans-l,2-Dichloro- Xylenes (Total) ---- Trihalomethanes 0.1 ethylene ---- 0.7 0.0004 0.0002 0.0002 0.4 0.1 0.0005 0.2 0.005 0.005 2 0.05 0.005 0.1 10 0.2 PTA GAC, OX GAC GAC, RO, OX GAC, RO, C/F GAC GAC, OX, RO GAC GAC, PTA, OX GAC, PTA GAC, PTA GAC GAC, PTA GAC, PTA GAC, PTA GAC Water Systems for Pharmaceutical Facilities 61 1 APPENDIX I: (Cont’d) Contaminants Existing Proposed Best Available MCL mg/P MCL mgA2 Technologies (BAT)3 RADIOISOTOPES Beta particles 4 mrem 4 mrem RO Gross alpha Radium 226 & 228 5 pCi/l particles 15 pCiA 15 pCi/l CS, LS, RO CS, LS, RO 5 pci/l RADIOISOTOPES Radon 222 ---- 2 00-2 0 0 0 PTA pci/l Uranium ---- 20-40 pCi/l CS, LS, RO VOLATILE ORGANIC CHEMICALS Benzene 0.005 Carbon Tetra- chloride 0.005 1,l -Dichloro- ethylene 0.007 1,2-Dichloroethane 0.005 para-Dichloro- benzene 0.075 1, 1,l -Trichloro- ethane 0.2 Trichloroethylene 0.005 Vinyl Chloride 0.002 0.005 0.005 0.007 0.005 0.075 0.2 0.005 0.002 GAC, PTA GAC, PTA GAC, PTA GAC, PTA GAC, PTA GAC, PTA GAC, PTA PTA 612 Fermentation and Biochemical Engineering Handbook APPENDIX I: (Conr 'd) In addition to the eight regulated volatile organics, there are 51 unregulated VOC's which may require an initial monitoring once during a four year period. Contaminants Existing Proposed Best Available MCL mg/P MCL mgA2 Technologies (BAT)3 Aluminum Chloride Copper Fluoride Iron Manganese Silver Sulfate TDS zinc ---- 250 1 2 0.3 0.05 250 5 00 5 ---a 0.05 250 1 2 0.3 0.05 0.09 250 5 00 5 CS, RO, LS RO LS, CS, RO AX, RO C/F, LS, CS, SF C/F, LS, CS, RO C/F, LS, CS, RO C/F, AX, RO C/F, RO C/F, LS, CS, RO KEY TO BEST AVAILABLE TECHNOLOGIES (BAT) Ax- c/F - CL - cs - GAC - LS - ox - PTA - RO - SF - us - Anion exchange Coagulatiodflocculation (Le,, addition of alum or ferric sulfate Disinfection by chlorine Cation softening with salt Granular activated carbon Lime softening Oxidation by ozone Packed tower aeration Reverse osmosis Sand filtration or similar media Ultra filtration followed by settling and filtration) * Existing maximum contaminant levels, National Drinking Water Standards. * Proposed or likely maximum contaminant levels under current development per revisions of the Safe Drinking Water Act. The stated best available technologies are a guideline only for general approaches to treatment of the listed contaminants. See key on last page. Million fibers per liter (fibers over 10 micron). Water Systems for Pharmaceutical Facilities 613 APPENDIX 11: DEPARTMENT OF HEALTH, EDUCATION AND WELFARE PUBLIC HEALTH SERVICE Division of Environmental Engineering and Food Protection Policy Statement on Use of the Ultraviolet Process for Disinfection of Water The use ofthe ultraviolet process as a means of disinfecting water to meet the bacteriological requirements of the Public Health Service Drinking Water Standards is acceptable provided the equipment used meets the criteria described herein. In the design of a water treatment system, care must be exercised to insure that all other requirements of the Drinking Water Standards relating to the Source and Protection, Chemical and Physical Characteristics, and Radioactivity are met. (In the case of an individual water supply, the system should meet the criteria contained in theManual oflndividual Water Supply Systems, Public Health Service Publication No. 24.) The ultraviolet process of disinfecting water will not change the chemical and physical characteris- tics of the water. Additional treatment, if otherwise dictated, will still be required, including possible need for residual disinfectant in the distribution system. Color, turbidity, and organic impurities interfere with the transmis- sion of ultraviolet energy and it may be necessary to pretreat some supplies to remove excess turbidity and color. In general, units of color and turbidity are not adequate measures ofthe decrease that may occur in ultraviolet energy transmission. The organic nature of materials present in waters can give rise to significant transmission difficulties. As a result, an ultraviolet intensity meter is required to measure the energy levels to which the water is subjected. Ultraviolet treatment does not provide residual bactericidal action, therefore, the need for periodic flushing and disinfection of the water distribution system must be recognized. Some supplies may require routine chemical disinfection, including the maintenance of a residual bactericidal agent throughout the distribution system. 61 4 Fermentation and Biochemical Engineering Handbook Criteria for the Acceptability of an Ultraviolet Disinfecting Unit 1. Ultraviolet radiation at a level of 2,537 Angstrom units must be applied at a minimum dosage of 16,000 micro- watt-seconds per square centimeter at all points through- out the water disinfection chamber. 2. Maximum water depth in the chamber, measured from the tube surface to the chamber wall, shall not exceed three inches. 3. The ultraviolet tubes shall be: (a) Jacketed so that a proper operating tube tempera- (b) The jacket shall be of quartz or high silica glass with 4. A flow or time delay mechanism shall be provided to permit a two minute tube warm-up period before water flows from the unit. 5. The unit shall be designed to permit frequent mechanical cleaning ofthe water contact surface ofthe jacket without disassembly of the unit. 6. An automatic flow control valve, accurate within the expected pressure range, shall be installed to restrict flow to the maximum design flow of the treatment unit. 7. An accurately calibrated ultraviolet intensity meter, prop- erly filtered to restrict its sensitivity to the disinfection spectrum, shall be installed in the wall of the disinfection chamber at the point of greatest water depth from the tube or tubes. 8. A flow diversion valve or automatic shut-off valve shall be installed which will permit flow into the potable water system only when at least the minimum ultraviolet dosage is applied. When power is not being supplied to the unit, the valve should be in a closed (fail-safe) position which prevents the flow of water into the potable water system. 9. An automatic, audible alarm, shall be installed to warn of malfunction or impending shutdown if considered neces- sary by the Control or Regulatory Agency. ture of about 150°F is maintained. similar optical characteristics. Water Systems for Pharmaceutical Facilities 61 5 10. The materials of construction shall not impart toxic materials into the water either as a result of the presence of toxic constituents in materials of construction or as a result of physical or chemical changes resulting from exposure to ultraviolet emergency. 1 1. The unit shall be designed to protect the operator against electrical shock or excessive radiation. As with any potable water treatment process, due consideration must be given to the reliability, economics, and competent operation of the disinfection process and related equipment, including: 1. Installation ofthe unit in a protected enclosure not subject to extremes of temperature which cause malfunctions. 2. Provision of a spare ultraviolet tube and other necessary equipment to effect prompt repair or qualified personnel properly instructed in the operation and maintenance of the equipment. 3. Frequent inspection of the unit and keeping a record of all operations, including maintenance problems. Special Note This criteria was established after numerous tests were conducted on an Ultra dynamics Ultraviolet Water Purifier System by the U. S. P. H. S. Ultra dynamics Purifiers meet and surpass the above criteria. REFERENCES 1. Brown, J, Jayawardena, N., and Zelmanovich, Y., Water sys- tems for Pharmaceutical Facilities, Pharmaceutical Engineer- ing, 11(4):15-2 (1991) Parise, P. L., Panekh, B. S., and Waddington, G., Ultrapure Water (November, 1990) 2.