How fundamental is water to pharmaceutical manufacturing? The United States Pharmacopeia (USP) describes it this way in USP 37 {1231} “Water for Pharmaceutical Purposes.” According to USP: “Water is widely used as a raw material, ingredient and solvent in the processing, formulation and manufacture of pharmaceutical products, active pharmaceutical ingredients (APIs) and intermediates, compendial articles, and analytical reagents.” In short, water is everything to pharmaceutical manufacturers and its proper and effective treatment and conditioning to serve processing demands is critical.
Sexton and her colleagues agree that the primary mission of a good water system design is to minimize any opportunity for microbial contamination. Most root-cause system analyses confirm microbial contamination often arises when aquatic bacteria colonize on surfaces and in stagnant areas and form what’s known as biofilm. So when it comes to good water system design, faster is better, smoother surfaces are better and eliminating all dead spots and low-flow sections are even better. Here are some quick tips:
• Do specify that all sanitary fittings and connections are free from crevices and other bacterial “traps.”
• Do specify that piping and fittings are fabricated with correct and suitable materials like 316L stainless steel (and a surface finish equal to or better than 0.5 µm Ra) or polymers to prevent bacteria from adhering to pipe surfaces.
• Do slope piping to prevent pooling and promote complete drainage and place valves in vertical legs.
• Don’t design a distribution loop that has less than 0.5 percent slope, isn’t sanitary or fully drainable and unable to maintain a minimum velocity to assure turbulent flow (Reynolds number is greater than 4000).
• Do consider designing in backflow-preventing check valves to prevent contaminated water from mixing with clean water.
• Don’t forget antiscale treatment to reduce the calcium carbonate content entering the RO unit.
• Do integrate process analytical technologies to gain real-time information on conductivity and total organic compound levels; you’ll be glad you did. Constant sampling can be problematic.
• Don’t use ball valves as they can hold stagnant water.
• Do use diaphragm valves of sanitary design (Ethylene Propylene Diene Monomer (EPDM diaphragm) with a Polytetrafluoroethylene seal (PTFE) to maintain the integrity of the distribution system. EPDM is compatible with hot and cold water and has high heat resistance. PTFE is very non-reactive partly because of the strength of the carbon and fluorine bond. PTFE is used as it is non-reactive and water will not adhere to surfaces.
• Don’t use anything less than the most current welding methods or joining technologies; fabrication should address weld quality requirements, welder’s qualification, welding procedures, welding processes, and passivation requirements and documentation.
• Do specify pumps be centrifugal and of sanitary design and connect them using sanitary clamp connections to ease service.
• Don’t install backup pumps; they can create another surface for microbial growth. Sure they can be installed, but if you do, they require regular cycling between pumps and sanitizing. It’s better not to use them.
• Don’t forget to design in key redundancies or other functional aspects that support actual operations, accommodate operating cycles and ease maintenance and component replacement routines.
• Don’t slow it down. Most clearly understand circulating water at high velocities prevents bacteria from adhering and growing on system surfaces. Industry professionals agree general guidelines say velocities should stay above 2 lm/sec.
• Final API: This is the final product-manufacturing step in the process and is the substance in a pharmaceutical drug that is biologically active.
• Intermediate API: Most chemical reactions require more than one step to complete. An intermediate is the reaction product of each of these steps, except for the last one that forms the final API (i.e., final product).
• API cleaning: This is the term used to denote if the water will be used for equipment cleaning after a final or intermediate API.
“With intermediate or final API,” says Sexton, “a judgment call has to be made based on risk assessment and the nature of the products.” If the water is for initial or intermediate API steps, we tend to use the equivalent of municipal water, that is, deionized process water.” The reason for this, she explains, is that typically in the early stages of manufacturing there usually is a distillation, or solvent step. “So if there was anything in the water, it would be removed either by the distillation step or the solvent coming in. For those stages, most drug makers use municipal water as the basis for process water, says Sexton.
To justify a lower water grade quality for API initial and intermediate steps, there is typically further solvent addition and/or distillation prior to commencing the manufacture of the final API, says Sexton. Solvent additions and/or a distillation minimize the growth of microorganisms, and the risk of impact to the final API is minimized by the subsequent solvent addition and/or distillation prior to commencing the manufacture of this step.
TYPICAL MUNICIPAL WATER SYSTEM DESIGN
Typically, a municipal water generation system incorporates a storage tank, chlorine dosing unit and distribution piping. To accomplish preliminary filtration, a set of sand filters can be entrained or, in some cases, ultrafiltration (UF) units are added and installed before the chlorine-dosing unit. Sand filters present many opportunities to capture particulate solids on the surface of an individual grain of sand. “They are usually used to separate small amounts of fine solids from aqueous solutions and are usually used to purify the fluid rather than capture the solids as a valuable material,” says Sexton, “therefore, they are mostly used in water treatment.”
Alternately, UF is accomplished when pressure forces a liquid through a semi-permeable membrane, which captures or retains suspended high molecular weight while water and low molecular solutes pass through. The membrane chosen, says Sexton, must be able to withstand microbiological organisms present in the water system and the incoming water type (i.e., the ability to reduce the water color and total viable count to the municipal water specifications). The total viable count is a measure of the quantity of microorganisms such as bacteria, yeast, and mold in the water system, explains Sexton, and that a synthetic type membrane rather than a cellulose type membrane should be used for a particular water type application. “In the event of any water stagnation, a synthetic type membrane will minimize the formation of microbes,” says Sexton. A cellulose type membrane, she notes, can be metabolized by bacteria thus leading to the degradation of the membrane surface which, in turn, can lead to a loss of retention in the membrane. “The synthetic type membrane,” Sexton says, “is indigestible by bacteria, has a higher tensile strength, and is more rigid therefore less resistant to handling damage.”
Sexton explains the municipal water or deionized water is typically the input to the purified water system. In the event where there is no further subsequent solvent addition or distillation preceding the water addition (i.e., typically API final isolation), a higher water grade is required to minimize the impact to the final API. However, “If API is the final entity of the product and if we’re using water (not followed by a distillation step or a solvent step) in that stage, it’s even more critical that we have water of even a higher quality.” Obviously, notes Sexton, the requirements for purified water manufacturing are a lot more demanding than for processed water manufacturing.
PURIFIED WATER SYSTEM DESIGN
Sexton explains that a typical purified water generation system takes feed water (i.e., municipal water or equivalent), dechlorinates it and softens it to remove water hardness. “For purified water,” says Sexton, “we would typically have to remove the chlorine and scale if there’s any there. The reason for performing descaling and dechlorination operations up front is too much chlorine or too much hardness going into the reverse osmosis system can impede performance.”
The first major unit of operation is a reverse osmosis (RO) kit, says Sexton. Reverse osmosis is applying an external pressure to reverse the natural flow. Reverse osmosis is most commonly known for its use in drinking water purification from seawater (i.e., removing the salt and other substances from the water molecules). “To meet purified water microbiological requirements, reverse osmosis is the preferred technology; however, other technologies may also be used.” According to Sexton, in the normal osmosis process the solvent naturally moves from areas of low solid concentration through a membrane to areas of high solid concentration.To meet conductivity requirements electrodeionization (EDI) is available; however, mixed-bed deionization may also be used, says Sexton. “That usually brings down the water to meet the chemical requirements for our purified water and system.” EDI employs an electrode to ionize water molecules and separate dissolved ions from water. It is done without the use of chemical treatments and, says Sexton, is usually a tertiary treatment to RO. “The resulting water is then passed through an ultraviolet lamp and then stored in the main purified water storage tank. The purified water distribution loop takes water from the storage tank and back to the storage tank in a continuous loop.” Use points, she says, are included on the distribution loop so that water can be delivered to the plant when required.On the systems she’s designed and managed, Sexton says what usually follows is a UV lamp. “In a sense,” says Sexton, a UV lamp is not a full treatment on its own. It’s kind of there as an extra measure. If you want to get your TOCs or any micro requirements down, this will work well.” UV sanitization uses a UV light source typically enclosed in a protective transparent sleeve (usually quartz). Sexton says the lamp is mounted so that water passing through a flow chamber is exposed to the UV-C light rays. When microbes are exposed to the UV rays, they are rendered sterile and can no longer reproduce. The microbes are now considered dead; UV water treatment does not introduce any chemicals to the water, generates no byproducts and won’t alter the taste, pH or other properties. However, Sexton notes that UV lights are not recommended as the primary method to control microbial growth. The UV method is best applied in conjunction with other pretreatments units (0.2 micron filters for example) to provide secondary microbial control. “Typically UV lamps are installed after the EDI unit,” says Sexton, recommending that UV intensity should be monitored and documented.
