The supply of USP (United States Pharmacopoeia) purified water (PW) can appear to be very complicated. In reality, it is 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 must meet the requirements for ionic and organic chemical purity and must be protected from microbial contamination. The minimum quality for the source of feedwater for the production of PW is Potable Drinking Water as defined by the US Food and Drug Administration (FDA). This source water may be purified using unit operations that include deionization, distillation, ion exchange, reverse osmosis (RO), filtration, or other suitable purification procedures. PW 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 PW 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 actual 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) dependent.
When first approached to handle a turnkey USP water system, the project management principles of Define It, Design It and Deliver It are applied. Within each of these, 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 here. This article will, however, give you a basic idea of what it takes to provide a turnkey water installation from concept design to a validated finished product.
Written project objectives must 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 outlines the key milestones and gives 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 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 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 daily/peak water usage. A matrix is then used to determine what pressure, flow and temperature is required at each use point. This data 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.
Those considerations along with the water quality specifications are then used to develop a user requirement specification (URS). This URS becomes 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.
- Conductivity: three-stage measurement procedure.
- Total Organic Carbon: ≤ 500 ppb
- Microbial action limit: ≤ 100 cfu/ml
Water for injection specifications:
USP water for injection(WFI) guidelines are tighter than the USP PW guidelines.
- The USP WFI chemical requirements are the same.
- Maximum endotoxin specification: 0.25 Endotoxin units(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 is usually a ‘black box’ P&ID (see figure 1) since it has not been decided what equipment will be purchased to meet this URS. The 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 much that the system sits idle too long) and to determine the size of the storage tank. The size of the storage tank must not be too large so that it prevents the turn over (use by production) of the water in the storage tank on a regular basis, yet must be large enough to allow a buffer during downtimes due to maintenance or breakdowns.
A water sample is taken of the raw feedwater and analyzed for such things as total hardness, free chlorine, iron, conductivity, pH, etc. That analysis is given to the equipment vendors so that proper equipment can be tendered to treat the raw feedwater to the specifications outlined in the URS.
A detailed tender package is prepared to issue to the equipment vendors. It includes the URS, water analysis and a detailed list of specifications (surface finishing of piping, materials of construction of product contact components and instruments, room sizes and footprints of equipment, etc.).
USP water generation equipment selection is usually left up to the individual equipment vendors. The most common types of equipment used to produce USP grade water is briefly outlined here.
When looking at the design of generation equipment the feedwater source must be taken into account. There are generally three different types of feedwater: surface, ground and groundwater under a surface influence. Surface waters give the most variation since they vary in temperature, chemical (e.g. conductivity) and tend to have more organic material than groundwater, which 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 feedwater characteristics have been determined, the pretreatment equipment required can be selected. Typical pretreatment functions are to control scaling (precipitation) of mineral salts and silica; fouling due to organic and inorganic materials; oxidation due to chlorine and pH to remove dissolved gas, particularly carbon dioxide.
For scale control, several methods are used; softening is most common, which removes hardness salts and small amounts of iron. Other methods include lowering the pH to increase the solubility of the hardness salts, anti-scalant additions and nanofiltration.
Fouling control methods almost always incorporate a multi-media filter and cartridge filtration. Organic reduction includes technologies such as ultrafiltration (UF), ultraviolet (UV) 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 UV light. Any one of these methods can be used for de-chlorination of the feed water prior to entering the Reverse Osmosis system. The method chosen will depend on the level of chlorine/chloramines, and the utilities available for sanitization of the equipment that will be selected.
After the pretreatment has been defined, the main methods for further purification of the pretreated water can be selected. RO systems are the main method for salt and organic material removal, used for the reduction of inorganic contaminants, organic contaminants, colloids, micro-organisms and endotoxins. RO 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 with the proper care of the pretreatment 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. 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 on- or offsite. If using a mixed bed, the resin has to be separated prior to regeneration. Onsite regeneration capabilities are obviously higher in capital costs but lower on longterm maintenance costs.
The second polishing process is continuous electrodeionization. Ion exchange resins inside a stack remove cation and anion impurities from the feedwater; an electrical current flows through the stack to continuously regenerate the resin. The continuous regeneration allows the production of high quality water without the periodic shut down and regeneration required by conventional ion exchange equipment. Electric current (DC) is applied across all chambers by placing a cathode at one end of the tack and an anode at the other. The cathode attracts the cations in the resin, while the anode attracts the anions. The ions travel through the resin toward 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 resin so that it will continue to remove impurities from the feedwater. The salts displaced from the resin are adsorbed by other ion exchange beads as the ions continue their migration toward concentrate chambers. Once ions are in these 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 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 UF) or the European Pharmacopoeia (only allows 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 advantages and disadvantages. Both systems require some sort of pretreatment to prevent scale and chloride damage. Both systems exceed (better than) stage 1 conductivity, TOC and endotoxin limits. Two other acceptable methods in the USP are double-pass RO and UF in various configurations.
Once the design package for 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, which outlines the method of sanitization, drop point locations, etc.
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 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 appropriate materials. The storage tank is almost always 316L stainless steel SS with a surface finish of 15-20 roughness average (Ra) for WFI and 25-30 for PW. For materials of construction for the distribution loop, there are several options. First, ascertain the method of sanitization, capital cost, life expectancy and corrosion resistance. 316L SS is most commonly used in pharmaceutical applications and has been the industry standard for many years. Plastic piping is becoming more and more prevalent 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) with a surface finish almost identical to the initial tubing. Since the fusion is performed by a software controlled machine, users are able to get a consistent, reproducible weld every time (very similar to reproducible results of an orbital welder used on 316SS). This technology is FDA accepted and recommended by the International Standards of Pharmaceutical Engineering (ISPE). If heat sanitization is used, the piping must be supported more often, which raises the capital cost of installation; therefore, 316L SS would be a preferred replacement.
316L SS distribution loops can have a higher capital cost for certain applications due to the orbital weld documentation and smooth finished weld criteria. 316L SS tubing cannot be inspected using the light method as in plastic; boroscoping or X ray confirmation of weld integrity and smoothness is required. Depending on company policy, the usual practice is to boroscope 10 percent of the welds and if all 10 percent pass, then weld certificates can be issued. If one weld in that 10 percent fails, then another 10 percent are boroscoped. If any fail, then 100 percent of the welds are checked. Some typical weld acceptance criteria are outlined as follows.
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:
- D concavity shall not exceed 10 percent of the wall thickness
- ID concavity shall not exceed 10 percent of the wall thickness
- The weld bead shall not meander leaving less than 25 percent bead overlap on the joint
- The weld bead shall not narrow to less than 50 percent of the widest part of the weld
- Misalignment shall not exceed 10 percent of the wall thickness
Once the materials of construction have been determined and methods of weld confirmed, the next stage is to determine what storage tank and distribution loop accessories are required to meet the specifications set up in the URS.
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. Remember, if a vent filter is used, to include 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 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 sprayball is designed to keep all surfaces of the tank interior wet at all times.
Distribution loop size can be determined using the water consumption matrix and the URS. Take 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 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. Heat sanitization systems require both a cooling and a heating exchanger. In WFI storage and distribution systems the temperature should be maintained above 65◦ C (149◦ F), or can be stored at ambient but must be dumped after 24 hours.
Once all the design criteria details have been defined and tendered, vendors start manufacturing the various components and equipment skids and focus shifts to developing appropriate commissioning protocols, installation qualification (IQ) protocols, operation qualification (OQ) protocols and performance qualification (PQ) protocols. The PQ is always customer driven, since they 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 common for companies to accept 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 has 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, as well as surface finish (if Stainless Steel) and chemical compatibility if the material is not SS.
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 shutdown, 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 user specifications over a defined period of time. Phase one is usually four weeks of intensive testing of the generation system and the distribution system. Phase two requires less (but not minimal) testing for up to a period of one 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 its water system and that all USP and user specifications are met on a continuous basis. This usually involves alternating points of use testing over a one-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 eight 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, utility and personal 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 turnkey water provider for high-end USP water purification systems and industrial utility water systems. For a complete list of services check our website at www.obkltd.com, or we can be reached at phone 905-761-1120, fax 905-761-1122, or at [email protected]