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Pharmaceutical Water System Fundamentals. William V. Collentro, Coordinator

Ion Removal by Reverse Osmosis William V. Collentro

“Pharmaceutical Water System Fundamentals” discusses technical justification, design considerations, operation, maintenance, compliance, and validation for pharmaceutical water systems. It is the intention of this column to be a useful resource for daily work applications. The primary objective of this column is to provide a basic summary of the function, selection, design consideration, proper operation, preventative maintenance, and regulatory expectations associated with the individual unit operations employed in pharmaceutical water systems. Reader comments, questions, and suggestions are needed to help us fulfill our objective for this column. Please send your comments and suggestions to column coordinator William V. Collentro at [email protected] or to journal coordinating editor Susan Haigney at [email protected]. Editor’s Note: This paper continues subject matter previously discussed in “Pharmaceutical Water System Fundamentals.” “Impurities in Raw Water” was published in Volume 16, Number 1, of the Journal of Validation Technology (JVT) (Winter 2010), and “Pretreatment Unit Operations” was published in JVT, Volume 16, Number 2 (Spring 2010).

KEY POINTS The following key points are discussed in this article: • The principle of reverse osmosis (RO) involves the flow of water containing ions through a semipermeable membrane using pressure as a driving force to significantly reduce the ion concentration as well as other undesirable materials.

For more Author information, go to gxpandjvt.com/bios

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• The system array, membrane configuration, and membrane composition and operation are described. • Materials removed from the incoming water stream are described. • All RO membranes will exhibit microbial fouling, organic and colloidal fouling, and scaling. • RO membrane cleaning should be performed periodically to remove bacteria, membrane foulants, membrane scalants, and bacterial endotoxins. Chemical sanitization destroys bacteria and removes biofilm. • Design considerations including instrumentation for RO systems are discussed. • Operating and maintenance considerations for an RO system are discussed.

INTRODUCTION Impurities in raw water and pretreatment unit operations have been discussed in previous papers in this series. Ion removal is required for United States Pharmacopeia (USP) purified water systems to remove dissolved and ionized impurities. Physical tests Section of the United States Pharmacopeia-National Formulary presents the conductivity criteria for both USP purified water and water for injection (WFI). In addition, feed water to multiple effect distillation units and pure steam generators require ion removal. It is suggested that the long-term successful operation of a vapor compression distillation unit is enhanced by ion removal. Finally, ion removal may be appropriate for certain pharmaceutical processing applications that do not technically require compendial water. As an example, the initial rinse in multiple steps for

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ABOUT THE AUTHOR William V. Collentro is a senior consultant and founder of Water Consulting Specialists, Inc., Doylestown, PA (www.waterconsultingspecialists.com), and has more than 40 years experience in water purification. He may be reached by e-mail at [email protected].

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William V. Collentro, Coordinator.

Figure 1: Principals of reverse osmosis.

clean-in-place (CIP) applications using deionized water may decrease the volume of compendial water required for final rinse applications. This paper discusses the use of reverse osmosis for ion removal. General information, design considerations, and operation and maintenance considerations are described. Additional ion removal unit operations such as ion exchange employing cation and anion resins and membrane processes using ion exchange resin membranes and electronic field (continuous electrodeionization) that are used for ion removal in pharmaceutical water systems will be discussed in the next issue of this series.

REVERSE OSMOSIS– GENERAL DISCUSSION The principle of reverse osmosis (RO) is associated with the flow of water containing ions through a semipermeable membrane using pressure as a driving force. This is illustrated in Figure 1. The left section of the figure indicates water in two chambers, separated by a semi-permeable membrane. Initially, water in the left chamber does not contain ions, while water in the right chamber contains ions. Note the level of water in each chamber. The middle section of the figure indicates the results of “osmosis.” The “ion free” water flows through the semi-permeable membrane resulting in a change in water level and an attempt to equalize the concentration of ions in both chambers. To “reverse” the “osmosis” process, the right section of the figure indicates the result of pressure applied to the right chamber. Water and a very small level of ions flow back through the semi-permeable membrane, under pressure, resulting in chamber levels and ionic concentration similar to those in the left section of the figure. The process depicted in the right section of the figure represents the principle of reverse osmosis. gxpandjv t.com

RO System Array A reverse osmosis system consists of three primary flow streams. A pretreated feed water stream to the reverse osmosis unit is pressurized by a high-pressure pump, generally of multi-stage centrifugal-type. The pressurized feed water flows to reverse osmosis membranes contained in pressure vessels configured in a custom arranged “array.” As the pretreated water passes through the reverse osmosis membranes array, a portion of water passes radially through the membrane removing nearly all ionic material. The wastewater (i.e., water that did not pass through the “first” RO membrane) becomes feed water for the next membrane in series. Water from the final reverse osmosis membrane is the waste stream from the reverse osmosis system. Product water from each reverse osmosis membrane array is collected in a common permeate water manifold. Figure 2 demonstrates a reverse osmosis system with two individual membranes per vessel and vessels arranged in a 3:2:1 array. The diagonal line in the rectangular symbol used for a reverse osmosis membranes indicates the membrane. Subsequently, water that flows through the diagonal line indicates water passing from the feed water-waste stream to the permeate collection manifold. Water removed from the membrane that has not passed through the membrane, as indicated, becomes the feed water to the next membrane (or membranes in a pressure vessel) in the next array. While the feed water-waste flow through the membranes in the individual pressure vessels occurs in series, as noted in Figure 2, pressure vessels with membranes are arranged in parallel within an “array” determined by a computerized projection to maximize system operation. Within the indicated 3:2:1 array, pressurized feed water from the discharge of the RO feed water pump flows to three vessels arranged in parallel. As water passes through the first membrane in each array, a Journal

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Figure 2: 3:2:1 reverse osmosis array. Waste

Pretreated feed water

Product portion of water (determined by the capacity of the RO membrane) is removed as product with > 95% of the ions removed. A larger portion of the water, with increased ionic concentration, is the waste from each of the first (lead) membranes in the first array pressure vessels. This waste flows as feed water to each of the three other membranes in the pressure vessel. The combined waste from the first three individual pressure vessels is fed to tubing that directs the feed-waste flow to the second array, containing two pressure vessels. It is important to note that the membrane array is 3:2:1. As feed water passes through each membrane, product water is removed. Subsequently, as indicated, the ionic concentration of the feed-waste water increases and the flow rate decreases. An RO membrane array provides a method of maintaining the velocity of water through the membranes by reducing the number of pressure vessels arranged in parallel as water passes from the “lead” membranes to the final or “tail” membrane(s) minimizing the potential for precipitation of concentrated “salts” of certain ions. For the indicated example, there are three pressure vessels and six membranes in the first array, two pressure vessels and four membranes in the second array, and a single pressure vessel and two membranes in the final array. Feed-waste water from the second array is directed to the final array. Waste from the second membrane in the final array is directed, through instrumentation and valves, to drain. Two calculations may be used to characterize system operation. These include system recovery and system performance. 68

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RO System Recovery. The flow rate of feed water recovered as product water is expressed as “percent recovery,” calculated by the following equation: % Recovery = (Product Water Flow Rate/Feed Water Flow Rate) x 100 Generally, RO units with membranes configured in an array will exhibit about 75% recovery of feed water. RO System Performance. RO unit performance is determined by inline measurement of feed water and product water conductivity. Feed water and product water conductivity values are generally displayed on either a direct reading meter or screen. The “percent rejection” is used to determine ionic removal and is calculated by the following equation where C indicates the conductivity value of indicated feed water and product water: % Ion Rejection = [(Cfeed - Cproduct) / Cfeed] x 100 In theory, reverse osmosis membranes will remove 97–99+ % of the ionic material in water. However, membranes do not remove gases, reactive or non reactive. Carbon dioxide, as an example, will pass through a reverse osmosis membrane. The carbon dioxide will react with the product water from the RO unit, increasing conductivity per the following equation: CO2 + 2 H2O↔ H3O+ + HCO3iv thome.com

William V. Collentro, Coordinator.

As discussed previously, the hydronium ion exhibits a very high equivalent conductance when compared with other ions. While RO membrane manufacturer’s data may indicate a stated reject in excess of 99%, the actual rejection is lower due to the presence of reactive gasses in product, such as carbon dioxide or ammonia. The actual percent ion rejection for a specific application will be a function of the analytical profile of the feed water supply to the system, feed water pressure, and feed water temperature.

Figure 3: Spiral wound reverse osmosis membrane.

RO Membrane Configuration The vast majority of RO membranes employed for pharmaceutical water systems have a spiral wound configuration. A spiral wound membrane is shown in Figure 3. Figure 3 illustrates the feed water and product water flow as well as the waste flow. Water passes “down” the membrane, parallel to the membrane surfaces. As indicated, a portion of the water flows in a perpendicular direction to the feed water flow through the membrane. The permeate collector is a tube down the center of the membrane containing holes for collection of permeate throughout the length of the membrane. The membrane surface is shown. While difficult to demonstrate, Figure 4 depicts a single membrane “envelope.” The membrane is actual flat sheets. The sheets are precision cut to produce the same dimensions. The sheets are placed together with the membrane surfaces facing outward and a permeate carrier positioned between each membrane. The indicated “envelope” is created by sealing three sides of the membrane-permeate-carrier-membrane arrangement. The open side of the envelope is attached to the “permeate collector” shown in Figure 3. The attached membrane is wrapped around the permeate carrier in a configuration similar to a “jelly roll” producing the spiral wound configuration. The spiral wound membrane contains an outer retaining “wrapping” material. Three types of wrapping are described as follows. Tape-wrapped Membranes. Tape-wrapped membranes, as indicated, use a tape material wrapped around the spiral wound membrane. The use of tape wrapped membranes is generally limited to domestic, commercial, and light industrial application. They should not be used for pharmaceutical applications. Brackish-water Membranes. Brackish-water membranes use a hard fiberglass reinforced outer shell to secure the spiral wound membrane. The rigid nature of the exterior of a brackish-water membrane provides gxpandjv t.com

Figure 4: Membrane to permeate collector. Permeate collector tube

End of membrane envelope Water flow

RO membrane surface

an annular space between the exterior of the encased membrane and the inside diameter of the pressure vessel. A mechanism must be provided to avoid “bypass” of feed water around the membrane, through this annual space. A “brine seal” is added to the lead end of the membrane consisting of a flexible annual section of non-organic leaching elastomers. Unfortunately, the brine seal produces a stagnant area down the length of the membrane in the annular space between the pressure vessel and the outer shell. This stagnant area provides a location for bacteria to accumulate and replicate. There are numerous pharmaceutical RO systems employing brackish-water membranes. It is strongly suggested that brackish-water membranes are not appropriate for applications where microbial control is a concern, including all pharmaceutical applications. Full-fit (loose-wrapped) Membranes. These membranes use a mesh-type material to secure the spiral wound configuration. The membranes exhibit a “snug” fit when installed in pressure vessels. When pressurized during normal operation, the exterior of the mesh expands slightly to form a tight seal to the interior walls of the pressure vessels. Bypass of feed water and the undesirable dead leg associated with a brine seal are both eliminated. Any RO membranes used for pharmaceutical applications should be of full-fit (loose-wrapped) type. Journal

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RO Membrane Composition And Operation Virtually all RO membranes used for pharmaceutical applications are thin film-composite polyamide-type. Polyamide exhibits outstanding rejection of ions. Unfortunately, the material is relatively fragile. By supporting polyamide in a “sandwich” with polysulfone, a more rugged polymer, it is possible to provide membrane material with good physical strength and excellent ion rejection. It should be noted that polyamide, unlike polysulfone, is not chlorine tolerant. Subsequently, residual disinfecting agent must be removed from feed water to the RO system with polyamide thin film-composite membranes. An RO system can be designed, fabricated, and operated with hot water sanitization provisions. Fullfit membranes capable of withstanding hot water sanitization temperatures (80°C) are available. RO system design should include 316L Stainless Steel tubing, membrane pressure vessels with elastomers (end adapters), and appropriate support accessories for the hot water sanitization operation. Hot water sanitization may be performed every two to four weeks based on product water total viable bacteria levels. However, it is necessary to conduct chemical sanitization, discussed later in this article, about once every six months to remove biofilm. Removal of Impurities. Unlike deionization systems using cation and anion resin, which only remove anions (with the exception of macroporous or acrylic anion organic scavengers), reverse osmosis will remove other pretreated feed water contaminants such as the following: • Colloids. Colloids should be completely removed. • Colloids in a complex with naturally occurring organic material (NOM). Colloids of silica, aluminum, and iron may exist in a complex with NOM. The complex should be removed by RO. • NOM and all organic material with a molecular weight > 150–250 daltons • Anticipated RO product water total organic carbon (TOC) levels should be more than 0.100 mg/l below the USP “Physical Test” Section implied limit of 0.500 mg/l. • It is important to indicate that the ability of reverse osmosis to remove residual disinfecting agent compounds such as trihalomethanes (THMs), particularly chloroform, is poor. The Table contains a summary of measured THM levels through a classical USP purified water system using RO and continuous electrodeionization (CEDI) (Collentro, unpublished data). 70

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• RO units operating in a continuous mode, discussed later in this article, exhibit product water TOC levels < 0.025 mg/l. • Bacterial endotoxins. RO product water bacterial endotoxin levels are generally < 0.001 IU/ml. Again, continuously operating RO units will provide greater reduction when compared with “cycled” RO units. • Particulate matter. Particulate matter is removed by the RO membranes to non-detectable levels. • Bacteria • From a conservative perspective, RO membranes are capable of removing any material < 0.001 microns in size. Gram-negative bacteria in a water system (non nutrient-starved environment) are rod shaped, approximately 0.6 micron long and approximately 0.2 microns in diameter. While complete bacteria removal should be achieved, many RO systems exhibit the presence of product water total viable bacteria. • Numerous factors impact RO product water total viable bacteria levels. These factors are summarized later in this article. • It is suggested that a properly designed, operated, and maintained RO system should exhibit product water total viable bacteria levels < 10100 cfu/100 ml, membrane filtration of a 100 ml sample, R2A or PCA culture media, 30-35°C incubation temperature, and 72- to 120-hour incubation time period. • Continuous RO system operation (versus cyclic operation) significantly reduces RO product water total viable bacteria levels.

RO SYSTEM PROBLEMS–FOULING AND SCALING As RO membranes concentrate impurities in the feed water stream during normal operation, scaling and fouling of the membranes will occur. Scalants may include sulfate, carbonate, and bicarbonate precipitates formed with trace concentration of cationic impurities such as calcium, magnesium, iron, aluminum, barium, etc. Scale formation can be minimized by proper operation of the pretreatment section water softening unit discussed in the second part of this series of articles. Important water softener parameters include adequate salt dosing during regeneration, “short-cycling” of the operating cycle to avoid multivalent ion “breakthrough,” and operation of two units in series. The concentrating nature of RO system operation makes iv thome.com

William V. Collentro, Coordinator.

Table: Measured trihalomethane compounds in a USP purified water “generation” system. Location

Trihalomethane Compounds

Concentration (μg/l)

Municipal feed water

Chloroform

40

Dibromochloromethane

9.0

Bromodichloromethane

20

Bromoform

0.66

Chloroform

32

Dibromochloromethane

6.6

Bromodichloromethane

17

Bromoform

0.60

Chloroform

11.9

Dibromochloromethane

1.7

Bromodichloromethane

4.6

Bromoform