By Michael Foster
To those not familiar with the detail – the supply of USP (United States Pharmacopoeia) purified water (PW) can appear to be very complicated. In reality it is only simple chemistry and logical process engineering steps- but with many detail steps from start to finish. The definitive international standard – the USP guidelines – are both vague and clear. United States Pharmacopoeia, National Formulary 24 edition number XXIX (USP) provides guidelines for production of Pharmaceutical grade water. The vague portion says “USP water can be produced by any suitable process”. That is a very open statement (hence vague) since it is left up to individual interpretation. At the detail level it becomes clearer. Purified Water (PW) must meet the requirements for ionic and organic chemical purity and must be protected from microbial contamination. The minimum quality for the source of feed water for the production of Purified Water is Potable Drinking Water as defined by the Food and Drug Administration (FDA). This source water may be purified using unit operations that include deionization, distillation, ion exchange, reverse osmosis, filtration, or other suitable purification procedures. Purified water systems must be validated to reliably and consistently produce and distribute water of acceptable chemical and microbiological quality. This is where the vague statement becomes very clear – deliver purified water, deliver it consistently and prove you have that process under control at all times.
In some cases the purified water produced may never come in contact with the product. A large amount of PW is used for cleaning. When PW is used in the product, microbial limits are not always defined by USP/FDA, they are very product specific. Water quality requirements vary, and are product, process, and destination (delivery) dependant.
When first approached to handle a turn-key USP water system, basic good project management principles of “Define It, Design It, and Deliver It” are applied. Within each of these three principles there are many detailed steps that must be followed rigorously to properly achieve a reliable validated water system for the Client. The reader must remember that this is a very brief overview and the subject overall – though straight forward – is a far more complicated process than is explained below. This article will however give you a basic idea of what it takes to provide a turn-key water installation from concept design to a validated finished product.
Written project objectives need to be established. This will give the contractor and the end user a picture of the end product. A project schedule can then be developed that outline the key milestones of the project and give a clear end date that must be achieved. That end date is essentially the delivery of a fully operational validated water system that can be used for production purposes.
The process requirements can be developed now. These process requirements involve the development of a water consumption matrix, and clearly defined water quality specifications for the end product. Final water quality requirements need to be established first. This is driven by what product(s) and/or cleaning processes will be making use of this water at the Point of Use (POU).
Once final water quality has been determined, the operational criterion needs to be defined. Meet with the end users to get water daily/peak water usage. A matrix is then used to determine what pressure, flow, and temperature that is required at each use point. This is used to determine system generation rate and storage tank size to buffer peak demands.
Generation and storage/distribution system criteria:
- Broad design considerations: system availability; is it needed at all times, is production batched or continuous? Maintenance considerations (redundancy). Future growth and expansion needs to be considered.
- Detailed design considerations: tank sizing, loop length, multiple loops, hot loop or ozone for microbial control, size of generation system, etc. which need to be considered at this stage.
Those design considerations along with the water quality specifications are then used to develop a User Requirement Specification (URS). This URS is the official document that drives and defines what the final water purification system will do and what it will deliver to the final users for production use.
Purified Water Specifications:
- Conductivity: 3 stage measurement procedure.
- Total Organic Carbon: ≤ 500 ppb
- Microbial action limit: ≤ 100 cfu/ml
Water for Injection Specifications:
USP Water for injection guidelines are tighter than the USP PW guidelines.
- The USP WFI chemical requirements are the same.
- Maximum endotoxin specification: 0.25 Eu/ml
- Microbial action limit: <10 cfu/100ml.
Once the water system and its final requirements have been defined, the design stage can be started. A preliminary Process and Instrumentation Diagram (P&ID) is developed to get a big picture of what the system will look like. This P&ID is usually a black box P&ID (see figure 1) since it has not been decided what equipment will be purchased to meet our URS. The water consumption matrix is used to decide how much water the generation system will deliver (remember to account for future use, but don’t oversize so that the system sits idle too long), and to determine the size of our storage tank. The size of the storage tank must not be too large so that the water is not turned over (used by production) on a regular basis, but must be large enough to allow a buffer during down times due to maintenance or breakdowns.
Figure 1: Basic Black Box P&ID of a Typical Water Purification System
A water sample is taken of the raw feed water and analyzed for such things as total hardness, free chlorine, iron, conductivity, pH, etc. That water analysis is given to the equipment vendors so that the proper equipment can be tendered that will treat the raw feed water to the specifications outlined in the URS.
A detailed tender package is prepared to issue to the equipment vendors. That tender package includes the URS, water analysis, and a detailed list of specifications. That detailed list of specifications includes surface finishing of piping, materials of construction of product contact components and instruments, room sizes and footprints of equipment, etc.
Even though the USP water generation equipment selection is usually left up to the individual equipment vendors, a brief overview of the most common types of equipment used to produce USP grade water is outlined below.
When looking at the design of generation equipment the feed water source must be taken into account. There are generally three different types of feed water: surface, ground, and ground water under a surface influence. Surface waters give us the most variation since they vary in temperature, chemical (e.g. conductivity), and tend to have more organic material than ground water. Where as ground water tends to be the opposite; temperature is mostly constant, minimal chemical changes, low organic concentrations, but may be higher in silica, and other inorganic materials as opposed to surface water. The third is obviously a mixture of the first two.
Once the feed water characteristics have been looked at, the pre-treatment equipment required to treat the incoming feed water can selected. Typical pre-treatment functions are to control scaling (precipitation) of mineral salts and silica, control fouling due to organic and inorganic materials, control oxidation due to chlorine, and pH control to remove dissolved gas particularly carbon dioxide.
For scale control there are several methods that are used. The most widely used is softening which removes hardness salts and small amounts of iron. Other methods includes lowering the pH to increases the solubility of the hardness salts, anti-scalant addition and nano-filtration.
Fouling control methods for particulate control almost always incorporate a multi-media filter and cartridge filtration. Organic reduction includes technologies such as ultra-filtration, ultraviolet light, organic scavenging, and regular cleaning and sanitization (covers both inorganic and organic fouling removal).
Oxidation control due to chlorine or chloramines include sodium bisulphite addition, activated carbon, and ultraviolet light.
After the pre-treatment has been defined our main methods for further purification of the pre-treated water can be selected. The Revere Osmosis system is the main method for salt and organic material removal. It is a pressure driven semi-permeable process that is used for the reduction of the following: inorganic contaminants, organic contaminants, colloids, micro-organisms, and endo-toxins. Reverse Osmosis is the most commonly used primary process for water purification because it effectively reduces inorganic/organic contaminants except gasses, has relatively low operating costs, and is very reliable depending on the proper care of the pre-treatment equipment.
The next stage of purification is deionization. This is usually referred to as polishing. There are two main types of polishing units. The first is cation and anion resin that removes minerals very similar to a water softener removes hardness salts. These resin beds can be separate or mixed. They are very reliable at producing USP grade water, but require regeneration once exhausted. Regeneration can be performed onsite or offsite depending on the comfort level of handling acids and bases to regenerate each resin. If using a mixed bed, the resin has to be separated prior to regeneration. On-site regeneration capabilities are obviously higher in capital costs but lower on long term maintenance costs.
The second polishing process is continuous electro deionization. Ion exchange resins inside the stack remove cation and anion impurities from the feed water. An electrical current flows through the Stack to continuously regenerate the ion exchange resin. The continuous regeneration allows the production of high quality water without the periodic shut down and regeneration required by conventional ion exchange equipment. A DC electric current is applied across all the chambers, by placing a cathode at one end of the Stack and an anode at the other. The cathode attracts the cations in the ion exchange resin, while the anode attracts the anions. The ions travel through the resin towards their respective electrodes. The ions are driven by the electric potential through the ion exchange membranes into the Concentrate chambers. The applied current also drives a water splitting reaction, which produces hydronium ions (protons) and hydroxyl ions. These ions continuously regenerate the ion exchange resin so that it will continue to remove impurities from the feed water. The salts displaced from the resin are adsorbed by other ion exchange beads as the ions continue their migration towards the concentrate chamber. Once ions are in the Concentrate chambers, they are unable to return to the Dilute chamber. The Concentrate chamber is made up of a cation membrane and an Anion membrane. Cations enter the concentrate chamber by passing through the cation membrane. Once in the Concentrate chamber, the cations continue their migration towards the Cathode. The cations travel across the Concentrate chamber and eventually encounter the Anion membrane. The Anion membrane repels the cations, effectively trapping the cations in the concentrate chamber. The same process occurs with the Anions. The trapped ions are then flushed out of the Stack.
The only method of producing WFI that is accepted by all pharmacopeia’s, is distillation. Even though USP XXIX allows WFI to be produced by distillation or an equivalent process, the equivalent processes are not accepted by the Japanese Pharmacopoeia (also allows ultra filtration) and the European Pharmacopoeia (only distillation).
Therefore since most pharmaceutical manufacturers distribute globally, distillation is the only way to produce WFI at this time. There are two types of processes to produce WFI, vapor compression, and Multi-Effect. Both are equally acceptable and have their advantages and disadvantages. Both systems require some sort of pre-treatment to prevent scale and chloride damage. Both systems exceed (better than) stage 1 conductivity, TOC, and endo-toxin limits. Two other acceptable methods in the USP are double pass RO, and ultra filtration in various configurations.
Once the design package for the generation equipment has been tendered, the detailed design of the distribution system can be looked at. The URS is used as the base document to design the distribution system. Since it outlines the method of sanitization, drop point locations, etc, we can focus on the details instead of the basic design criteria.
The main function of a PW/WFI storage tank and distribution system is to maintain the water quality generated by the purification system, provide sufficient buffer for production needs, and to deliver the water to the end users at the required volume, pressure, and temperature. Since the sanitization method is defined in the URS, we must select the appropriate materials of construction for both the tank and the distribution loop. The storage tank is almost always 316L SS with a surface finish of 15-20 Roughness Average (Ra) for WFI and 25-30 for PW. When we look at the materials of construction for the distribution loop, we have several options. We must first look at the method of sanitization, capital cost, life expectancy, and corrosion resistance. 316L SS is most commonly used in the pharmaceutical industry because that has been the industry standard for many years. Plastic piping is becoming more and more recognized due to lower capital costs, and the very low bacteria adhesive properties. Newer technologies such as BCF (Bead and Crevice Free) Fusion give welds on Poly VinyliDene Fluoride (PVDF) and Poly Propylene (PP) that have a surface finish almost identical to the initial tubing. Since the Fusion is performed by a machine and is software controlled, we are able to get a consistent reproducible weld every time (very similar to reproducible results of an orbital welder used on 316SS). This type of technology is FDA accepted, and recommended by the ISPE (International Standards of Pharmaceutical Engineering). If heat sanitization is used, the piping must be supported more often which raises the capital cost of installation and therefore 316L SS would be a preferred replacement.
316L SS distribution loops can be a higher capital cost for certain applications due to the orbital weld documentation required and the smooth finished weld criteria. Since we cannot inspect the 316L SS tubing using the light method as in plastic, boroscopiong or X-Ray confirmation of weld integrity and smoothness is required. Depending on a company policy, the usual practice is to boroscope 10% of the welds, and if all 10% pass then weld certificates can be issued. If one weld in that 10% fails, then another 10% are boroscoped. If any one of those 10% fail, then 100% of the welds are checked. Some typical weld acceptance criteria are outlined below:
Typical Weld Acceptance Criteria
- All welds must be fully penetrated around the entire weld perimeter with no crevices or entrapment sites.
- All welds will be smooth, uniform, complete and flat, not concave, on the outside.
- The weld should have a complete and uniform weld bead width on the inside with little or no convexity.
- The inner weld bead shall contain no concavity.
- There will be no visible signs of oxidation/discoloration of the inner weld bead.
- The joints should be square facing and properly aligned.
- The weld width should be nominal 1/8” wide.
- The specific recommended acceptance criteria for Orbital tube welds are as follows:
- Weld Bead Widths.
- OD Concavity shall not exceed 10% of the wall thickness
- ID Concavity shall not exceed 10% of the wall thickness
- The weld bead shall not meander leaving less than 25% bead overlap on the joint
- The weld bead shall not narrow to less than 50% of the widest part of the weld
- Misalignment shall not exceed 10% of the wall thickness
Once the materials of construction have been determined and methods of weld confirmations, the next stage is to determine what storage tank and distribution loop accessories are required to meet the specifications set up in the URS. One could go on forever discussing the fine details of a distribution loop design, but it will be keep it to a basic overview.
At this stage detailed tank arrangement drawings can be prepared and issued for tender. Tank connections need to be determined for the top and the bottom of the tank. Important things to consider are the loop return, rupture disk, vent filter, ozone destruct (if applicable), level sensing device, and extra connections that will be blanked for future use. The tank design must be fully drainable, and have a surface finish consistent with the type of water being stored and distributed. You must remember that if a vent filter is used, what is the method of keeping the filter element dry. If steam is available, then steam can be used, otherwise there is a nice electrical “heat blanket” on the market that can also be used. If the tank is vacuum rated, then only a burst rupture disk is required. Otherwise a rupture disk that prevents over pressurization and a vacuum is required. A sprayball is usually incorporated (but not always required for constantly ozonated systems) into the center of the top of the tank and usually but not always has the distribution loop return passing through it. The spray ball is designed to keep all surfaces of the interior of the tank wet at all times.
Distribution loop size can be determined using the water consumption matrix and the URS. It must be taken into account the amount of water required by production at any one time, the number of drops used at any one time, and the minimum 3 ft/s (feet per second) return flow. Since the sanitization method is defined in the URS it is easy to determine what accessories are required for the distribution loop. The most obvious components are a sanitary distribution pump, supply and return conductivity sensors, return Total Organic Carbon (TOC) monitoring, pump discharge and return pressure indicators, and other tank empty safety devices. In constantly ozonated systems, an ozone destruct UV is required to remove ozone prior to entering the distribution loop (SS light traps are required if a PVDF loop is selected), and a cooling exchanger to maintain ambient temperature. In heat sanitization systems, you require both a cooling and a heating exchanger. In WFI storage and distribution systems the temperature should be maintained above 65◦ C, or can be stored at ambient but must be dumped after 24 hours.
Once all the design criteria details have been defined and tendered to vendors to start manufacturing of the various components and equipment skids we can focus on the developing appropriate commissioning protocols, Installation Qualification (IQ) protocols, Operation Qualification (OQ) protocols, and Performance Qualification (PQ) protocols. OBK Technology provides all of the above protocols, and executes all but the PQ. The PQ is always customer driven, since they are the ones that defined the end product quality specifications, and must constantly monitor and test the system after the various PQ phases are complete.
Once the installation is complete, commissioning of the entire system can start. It is becoming more and more common that companies are accepting formally developed and executed commissioning protocols in place of many of the standard tests performed in the installation and operation qualification protocols. Once formal commissioning is complete, validating the USP water system can begin.
The IQ is designed to document various parameters of components such as make, model number, serial number, material of construction, etc. It is also designed to verify that each component that is product contact meets all criteria for product contact. It verifies the material of construction of the product contact component against a pre-determined company quality specification. Such things as material certificates are recorded, surface finish (if Stainless Steel), and chemical compatibility if the material is not SS (Stainless Steel).
The OQ is designed to test all operation attributes with respect to the functional specification and operation manuals of each equipment skid and components installed on each equipment skid as an integrated system. Such things as interlocks and alarms, sequence of operation, emergency shut down, water quality after each equipment skid, etc. In no way is the long term performance of the system tested at this point.
The PQ is designed to prove that the system can meet all USP and users specifications over a defined period of time. Phase 1 is usually 4 weeks of intensive testing of the generation system and the distribution system. Phase 2 requires less testing, but not minimal, testing for up to a period of 1 year. After the system has been proven to meet all the pre-defined specifications, testing can be reduced to a minimum. This minimum testing must be sufficient to show that the company is in control of their water system, and that all USP and user specifications are met on a continuous basis. This minimum testing usually involves alternating points of use testing over a 1 week period where every POU is tested at least once, and the generation system is tested once a week to determine when maintenance should be performed (outside of normal routine maintenance). Since alert and action limits are set up prior to the PQ phase, this ongoing monitoring gives the company time to react once the alert limits are reached and still enables them to use the water since the action limit has not been reached.
From initial concept design to final delivery and completion of the operational qualification this entire process usually takes about 8 months. At this point the PQ phase can begin and depending on a company’s policy for “releasing water for production use”, the eventual release of the purification system for production use.
About the Author
Michael Foster is OBK’s leading water purification specialist with over 10 years of experience in the high purity water purification industry. His experience covers the range of pharmaceutical water, utility water, and person care water purification throughout the North American Continent. He can be reached at 905-299-4331, or at [email protected]
About the Company
OBK Technology Ltd. is a full service consulting engineering firm providing service to the pharmaceutical, food, and personal care industries. OBK is also a full service and validated water turn-key water provider for high end USP water purification systems and industrial utility water systems. For a complete list of services check out our website at www.obkltd.com, or we can be reached at phone 905-761-1120, fax 905-761-1122, or at [email protected]