5.B Generation of pharmaceutical water Author: Michael Gronwald Co-Author: Dr. Ralph Gomez / Up06

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1 Generation of pharmaceutical water Generation of pharmaceutical water Author: Michael Gronwald Co-Author: Dr. Ralph Gomez / Up06 Here you will find answers to the following questions: What are the different procedures for purifying potable water? How can you generate purified water? How can you generate WFI (Water for Injection)? What are the advantages and disadvantages of the different systems? According to what principles do the different systems work? In the pharmaceutical industry, water systems represent one of the core pieces of production. In particular when planning facilities, the importance of the design of the water systems soon becomes clear. It is not unusual for large parts of a product to consist of pure water. For parenteral products, this share is close to 100%. The task of planning and installing new systems must take into account the regulations (FDA: Guide to Inspections of High Purity Water s) to assure a reproducible quality of pharmaceutical water. In addition to these requirements, systems must also be readily available. In light of this, the principles that are fundamental for engineering, qualification (see chapter 5.D Qualification of water supplies ), later use and in-situ inspection must be addressed here. Depending on the application of the pharmaceutical water and the necessary availability in the company, a pharmaceutical user should consider whether or not the facilities should be designed redundantly, i.e. in multiple implementations. This may increase the investment costs, but they can be recovered again quickly through business management. All facilities presented below are subject to a certain level of maintenance that can be planned. That is, they must be shut down and maintained at specific intervals. Even if the scope of maintenance can take several days, it can be carried out during times in which no production is to take place, depending on the order of magnitude of the system. Unfortunately, these systems have limited reliability and failures in the system will rule out an availability of 100%. Therefore, when calculating availability, the losses that might occur during one day of operating downtime must be taken into account. Last but not least, system downtimes always pose a quality risk. The quality must not be neglected under the pressure of production constraints. If high availability of the facilities is required, a redundant design is absolutely recommended. This can vary the percentage rate for which one facility can cover the total demand in the event of failure of the other facility from % in favor of the investment costs. (1)

2 5 Pharmaceutical Water.1 Purified water (PW) In order to produce the chemical and microbiological quality described in chapter 5.A Water types and at the same time comply with the regulations, facility components are required which, in a certain composition, can be considered as a facility for generating purified water. The raw water must be pretreated before actual purification. Thus, a facility for generating purified water consists of several components which are described below..1.1 Airbreak In order to protect the public water supply from contamination, it is necessary to install an airbreak between the first processing step in the generation of purified water and the feed of potable water. This is in order to prevent reverse contamination in the public water supply. The only requirement for this is the physical separation of the two systems. The systems can be separated in various ways. It is possible to install a supply separation container or use a supply or non-return valve..1.2 Softener The potable water is first coarsely filtered, then the scale (calcium, magnesium, sulfate, carbonate) is removed in a first stage. Softened water is the prerequisite for the next stage in the manufacturing of purified water, as otherwise there could be scaling of magnesium and calcium sulfates on the downstream equipment, such as membranes of the reverse osmosis units, deionization devices, and distillation units. A choice procedure would be softening using ion exchange technology. A sodium can be used for this purpose. The magnesium and calcium ions present in the water are deposited in the resin in exchange for sodium ions. Figure -1 illustrates this operation.. As the resins have to be regenerated periodically, such facilities are operated discontinuously. Once exhausted, the ion is rinsed with a saline solution. In order to assure a continuous softened water supply for the subsequent processes, two ion s are often operated in reciprocating mode. The softened water generated is monitored by means of a hardness measurement. In order to counteract a biological fouling of the resins, the facility should be dimensioned so that the ion s can be regenerated every 24 to 36 hours. Figure -2 and figure -3 show the operating and regeneration phases of a facility. The medium flow and the valve settings should also be illustrated..1.3 Removal of chlorine (2) When designing a facility for generating purified water, the individual circumstances of the generation location must also always be taken into account. In addition to dimensioning the facility in line with the water volumes to be provided, it is important to pay attention to the quality of the raw water used. Only potable

3 Generation of pharmaceutical water Exchanger material Exchanger material Figure -1 Schematic diagram of softening through ion exchange Public water supply Public water supply Ion Waste water Ion Ion Waste water Ion NaCl NaCl Softened water Softened water Figure -2 Operation of the ion Figure -3 Regeneration of the ion water can be used to generate pharmaceutical water. However, the composition can vary greatly and it is possible that the potable water may have been chlorinated. As the raw water must be free from oxidation media, dechlorination must be carried out through the use of activated charcoal filters or sodium bisulfite (Na 2 HSO 3 ). Activated charcoal filter The use of an activated charcoal filter for dechlorination of the potable water is a simple and very effective method that should only be used for purification of potable water. Activated charcoal absorbs low molecular weight organics, such as chlorine and chloramine compounds. However, when manufacturing ultra pure water the use of activated charcoal could be problematic. Due to the large inner surface (3)

4 5 Pharmaceutical Water of the activated charcoal ( m 2 /g) and the large supply of nutrients for microorganisms, the risk of increased microbiological fouling and the formation of a biofilm (see chapter 5.C.4 Formation of biofilms) is very high. Impregnation of the activated charcoal with elementary silver reduces the microbial load of the activated charcoal. Due to the oligodynamic effect of silver, it kills microorganisms in the water. Dosage of sodium bisulfite Sodium bisulfite is added to the raw water. Sodium bisulfite combines with the chlorine, which is then separated through reverse osmosis. The added quantity must be adjusted. Removal of carbon dioxide (CO 2 ) Carbon dioxide represents a problem when generating purified water via reverse osmosis, as it is not retained by the reverse osmosis membrane and thus leads to increased conductivity. In practice, two methods are used to remove carbon dioxide. Dosage of sodium hydroxide solution: By adding small quantities of sodium hydroxide solution (ph value increase), carbon dioxide is converted into carbonate, which is retained by reverse osmosis. Membrane degassing: The gases dissolved in the water are diffused through a membrane through the creation of a particle pressure difference and are rinsed from the membrane using air..1.4 Reverse osmosis (4) Deionization and removal of microorganisms can be carried out in the reverse osmosis unit. Reverse osmosis is a physical operation which takes place on membranes. It reverses the process of osmosis known from the animal and plant world. A semipermeable membrane retains cations, anions, colloidal systems and bacteria. The membrane lets through water that is almost pure. With reverse osmosis, more than 98% of salts and 90% of organic compounds are retained, as well as bacteria and organisms, but 100% retention is not achieved. In order to reverse the process of osmosis, pressure higher than the osmotic pressure must be applied to the concentrate stream in order to push water with a low amount of solids through the membrane. This process is shown schematically in figure -4. The reverse osmosis units therefore work with a high operating pressure of more than 15 bar (positive pressure). Reverse osmosis units are today designed so that feed water flows over the membranes tangentially. The flow of water splits into two parts, the concentrate and the permeate. The concentrate with the high amount of solids is rejected and fed into the wastewater system down to a residual share of around 10% which is fed again before reverse osmosis. As the purified, low salinity permeate does not yet meet the required level of quality, it flows to the inlet side of the second stage of reverse osmosis. This basi-

5 Generation of pharmaceutical water Pressure Salzlösung Salt solution Water with low Salzarmes Wasser amount of solids Semipermeable membrane Figure -4 Schematic diagram of the procedure of reverse osmosis cally works in the same way as the first stage. However, the quality of the concentrate is better than that of the pretreated raw water. Therefore, it is all fed to the first stage. The permeate of the second stage has the quality of purified water and is fed into the loop for purified water. Reverse osmosis units essentially consist of: high pressure pump membranes (filter/permeator) pressure valve safety valves measurement and control devices The core of the reverse osmosis unit is the membranes. There are hollow fiber membranes (operating pressure approx. 28 bar), spiral wound membranes (operating pressure approx. 40 bar) and low pressure membranes (operating pressure approx bar). Low pressure membranes are used for the desalination of water with a lower total salt content of a maximum of 2000 ppm. They are designed as spiral wound membranes. The performance of a reverse osmosis unit depends on how many membranes are operated in parallel. For protection against heavy mechanical loading, a fine filter is fitted 5 m upstream of these membranes. The salt rejection of reverse osmosis is essentially influenced by the yield. The yield is the ratio between the permeate volume flow and the supply water volume flow. The salt passage increases as the yield rises. Therefore, an optimum between permeate quality and permeate yield must be determined for each application case. (5)

6 5 Pharmaceutical Water With a multi-staged reverse osmosis unit with upstream ion, a permeate with a TOC content of less than 100 ppm and a conductivity of around 0.5 to 0.6 S/cm can be achieved. For consistently good water quality with a reverse osmosis unit, the following points must be noted: Measurement of the colloidal index of the feed water and removal of the total alkalinity as well as sulfates and carbonates The feed water should be pre-filtered and adjusted to a ph value that does not damage the membrane. The feed water and the product water are to be monitored in terms of microbiological quality. The system should then be disinfected if the microbiological limits are exceeded. All systems should be mechanically cleaned before disinfection. Corresponding test results must then confirm that the disinfection chemicals have been completely removed from the system. The use of filters or ion s after the reverse osmosis modules should be avoided due to the associated risk of fouling. The reverse osmosis system should be designed so that there are no closures, dead legs and pipes in which standing water can form..1.5 Electrodeionization (EDI, CDI) Electrodeionization (CDI = Continuous Deionization; EDI = Electrodeionization) is a desalination process based on electrodialysis and mixed bed technology. EDI works by coupling the behavior of ions in the electrical field with membrane technology. The anions wander towards the anode and pass an ion-selective membrane which transports the anions but not the cations or electrically charged particles. The cations are transported towards the cathode in the same manner. Electrodeionization is illustrated schematically in figure -5. Through the alternate overlapping of anion or cation permeable ion membranes, parallel water flows are formed which feed water with alternating high ion concentration (concentrate) and low ion concentration (diluate) through the creation of an electric field. By bundling these channels, a diluate and a concentrate reject stream are led away. The concentrate is fed into the reverse osmosis as feed water. The diluate stream meets the requirements of purified water and is fed into the water loop. Water with a low ion concentration has a very high electrical resistance, which leads to diminished ion transport. For economical generation of pure water, a mixed bed ion resin has therefore been included in the product stream. This counteracts the electrical resistance and keeps the ion migration process in order. The creation of an increased electrical current means that not only the ions are transported in the electrical field, it also means that water is split into hydrogen and hydroxide ions. These permanently regenerate the ion resin. (6)

7 Generation of pharmaceutical water Feed water Na + Na + Anode (+) Na + OH - OH - OH - Cathode (-) Na + Na + OH - OH - Concentrate (waste water) Pure water (permeate) Highly acidic cation Highly alkaline anion Anion-permeable membrane Cation-permeable membrane Figure -5 Schematic diagram of electrodeionization The operations inside the EDI module can be imagined as follows: First, the mixed bed ion resin is charged with ions. These then migrate towards the cathode or anode, as described above. Desalination at the start of the electrodeionization module causes the conductivity in the product stream to fall. In the lower part of the electrodeionization, the water is dissociated due to the reduced conductivity. The ph value changes locally, which means that weaker electrolytes, such as carbon dioxide, are also separated. In the lower part, the ion resin is regenerated through the increased level of dissociation of the water. The regeneration zone for the ion resin moves further towards the end of the product stream the greater the loading of the feed water with ions. That is, the lower the conductivity of the feed water, the lower the conductivity of the generated purified water. Water qualities with a conductivity of less than 0.1 S/cm cannot be achieved with an EDI/CDI module alone. In order to achieve these conductivities, the feed water must be pretreated. If, for example, an upstream reverse osmosis produces a permeate with a conductivity of <50 S/cm, which feeds the EDI/CDI module, conductivities of S/cm are possible (theoretical minimum conductivity). (7)

8 5 Pharmaceutical Water Advantages of EDI High desalination level (>98%) with small membrane area Continuous operation through self-regeneration No use of chemicals for regeneration or neutralization Retention of high ph values through water division and thus regeneration Optimum carbon dioxide, silicate and TOC removal Prevention of multiplication of microorganisms Low energy consumption ( KW/m 3 ) with very low voltage Minimum space requirement due to compact design of the module Figure -6 Advantages of EDI For a water feed with a TOC content (Total Organic Carbon) of less than 0.1 ppm, a TOC content of less than 5 ppb can be achieved during continuous processing. This very good TOC removal with EDI/CDI technology is due to two mechanisms: After hydrolysis, the ions are transported through the membrane and removed. Other molecules are polarized, superficially electrically charged and then pass the membrane. A positive side effect of the EDI/CDI process is that electrochemical membrane processes, and thus also the EDI/CDI, are antibacterial due to the electric field. The advantages are summarized in figure Ultra filtration Ultra filtration (UF) is a separation technology for separating particles with a size of to 0.1 m. For ultra pure water production UF hollow fiber membranes are usually used. As a UF membrane cannot retain salts, the conductivity of the permeate remains nearly the same as that of the feed water. The operational costs of a UF facility are lower than those of a reverse osmosis unit due to the lower operating pressure (lower energy consumption). Another advantage over reverse osmosis is the temperature tolerance of the membranes. The working temperature can reach 80 C and steam sterilization is possible in modern UF membranes up to 128 C. Ultra filtration is often seen as an alternative to microfiltration plants. Often, older microfiltration plants which are used as pretreatment sections for reverse osmosis are replaced by ultra filtration modules. This means a higher flux and a longer life can be achieved with the reverse osmosis modules. The problem of biofilm formation (see chapter 5.C.4 Formation of biofilms ) can also be displaced from the reverse osmosis membranes to the UF membranes. This is advantageous, as UF membranes are significantly easier to clean. (8)

9 Generation of pharmaceutical water.1.7 Ion In the ion (separate bed and mixed bed system) ions are removed from the water. Ion s are filled with special resins which are usually produced from synthetic polymers as balls (particle size mm) (see chapter.1.2 Softener ). The particular ion resin must be selected according to the desired exchange or absorption process. Ion operations used today should fulfill the following points: wide utilization of the exchange capacity ultra high quality of produced water consistent quality of produced pure water minimum regeneration material excesses low pressure losses in the ion maximum mechanical and chemical stability of the resin high availability compact, cost-effective construction simple design simple operation simple process automation possibility of external regeneration (backwash) of the resin without interrupting production This procedure has become less important than EDI, as ion s always have a high potential risk of biological fouling..1.8 Purification plants The particular combination of procedures usually depends on the feed water quality. Usually, the analysis results from the potable water supplier can be used for initial planning regarding which combinations will give the desired result. There are feed water qualities for which the combination of reverse osmosis with an EDI is sufficient for the generation of purified water. For other feed water qualities, softening, reverse osmosis, CO 2 -degassing and EDI must be combined to achieve the same result. Figure -7 shows possible combinations depending on the feed water quality. Deionizationeionization using ion exchange technology with mixed bed technology or ultra filtration is possible. However, operational practice has shown that purification through two series connected reverse osmosis units or by a combination of reverse osmosis and electrodeionization is preferred for the production of purified water. These procedures also result in a permeate conductivity of <1.1 S/cm at 20 C even with poor raw water qualities. The main composition of these two systems is shown in figure -8. (9)

10 5 Pharmaceutical Water Procedure combinations for generating purified water Activated charcoal filter X Softener X X X X Mixed bed technology X X Ultra filtration X X Reverse osmosis X X X X X Degassing X X EDI/CDI X X X Figure -7 Procedure combinations for generating purified water Membrane degassing Softening Reverse osmosis Reverse osmosis Waste water Waste water Purified water Softening Reverse osmosis Electrodeionisation Waste water Figure -8 Examples for purified water generation facilities Waste water (10)