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Generation of pharmaceutical water

GENERATION OF PHARMACEUTICAL PHARMACEUTICAL WATER Joymalya bhattacharya m.pharm, mba, aic

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Generation of pharmaceutical water

Dedicated To My Parents

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Generation of pharmaceutical water

Contents

Chapter

Page number

INTRODUCTION

4

WATER FOR PHARMACEUTICAL USE- AS

25

PER WHO (WORLD HEALTH ORGANIZATION) WATER FOR PHARMACEUTICAL USE- AS

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PER USP (UNITED STATE PHARMACOPEIA) GUIDE TO INSPECTIONS OF HIGH PURITY

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WATER SYSTEMS WATER SYSTEMS FOR MANUFACTURERS OF

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NON-STERILE PRODUCTS SANITIZATION OF AUTOMATED WATERING

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SYSTEMS USER REQUIREMENTS FOR Water for Injection

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System QC related approach to

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Pharmaceutical Water System Testing REFERENCE

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Generation of pharmaceutical water

CHAPTER 1 INTRODUCTION 1.1 Basic of pharmaceutical water The United States Pharmacopeia (USP) defines several types of water including: Purified Water, Water for Injection, Sterile Purified Water, Sterile Water for Injection, Sterile Bacteriostatic Water for Injection, Sterile Water for Inhalation, and Sterile Water for Irrigation. The USP states qualifications for sterility and packaging methods that delineate between the various specific types of water. However, there are two basic types of water preparation, Water for Injection and Purified Water. The analytical standards for these two types of water are very similar, differing in the fact that Water for Injection has stricter bacterial count standards and must also pass the bacterial endotoxin test. Preparation methods are very similar to a point, however, Water for Injection preparation must incorporate distillation or double pass reverse osmosis. Discussion of the various methodologies used in preparation of USP water applies equally to Purified Water (PW) and Water for Injection (WFI).

The source water supplied to the purification system for preparation of USP water must comply with drinking water standards as defined by the United States Environmental Protection Agency in the National Primary Drinking Water Regulations or equivalent international regulations.

Although the water source must be safe to drink, there is quite a range of problematic contaminants that may be present in the water. Chlorine is most certainly present in the water and will have to be removed at some point in the purification process.

The analytical standards for USP water have been significantly streamlined. In the current USP 24, analyses for conductivity, total organic carbon, and bacteria (plus bacterial endotoxin in the case of WFI) are all that is required. Virtually no water source will meet the conductivity requirement and therefore reduction of ion content of the water is the primary required treatment in USP water preparation systems. TOC reduction is often accomplished by the same processes employed to reduce ion content. However, if no membrane technology is utilized in the ion reduction treatment, specific treatment for TOC reduction is likely to be required. Also, it is fairly common for TOC reduction techniques to be utilized in final storage and distribution systems. Maintaining low bacteria counts throughout the treatment processes, storage, and 4

Generation of pharmaceutical water distribution system is difficult and therefore bacterial control technology is extremely important in USP water preparation systems.

Considering the required treatment objectives of USP water preparation systems, several categories of treatment warrant examination: dechlorination, ion reduction, bacterial control, and removal of specific impurities.

Dechlorination

There are several methods of dechlorinating water. The most common method is filtration through activated carbon media. There are also other dechlorination Medias including dissimilar metals. Injection of a reducing agent, most commonly sodium metabisulfite, is also a common dechlorination method. Recently it has been demonstrated that high dosage exposure to UV light will dechlorinate.

Carbon Filtration

Carbon dechlorinates by chemical reaction with the free chlorine in water, forming hydrochloric acid and carbon monoxide or dioxide. Carbon is effective on chloramines as well as free chlorine although significant increased contact time is required. The carbon bed should be sized for an EBCT value of 2 - 5 for free chlorine removal with the volume dependent on chlorine concentration and background water characteristics.

For chloramine removal, EBCT value

should be 7.5 - 12. Carbon filters are also effective for TOC reduction. The biggest problem with carbon filters is their propensity to become colonized by bacteria.

To combat this

colonization, the carbon bed should be hot water or steam sanitizable. Furthermore, disinfection UV lights should be installed on the inlet and outlet of the carbon filter to prolong the interval between sanitizations. The quality of the carbon used in carbon filters is also important. When carbon is used for removal of specific organic compounds the exact characteristics of the carbon are extremely important. In pharmaceutical dechlorination applications the primary concern is cleanliness of the carbon. Minimal fines, low ash content, and adequate hardness are desired.

All carbon should be acid washed at the production facility. Upon installation, the carbon bed must be rinsed to drain until all fines are washed away.

The bed should be periodically

backwashed throughout its service life. Other granular medias have been demonstrated effective at chlorine removal. Most notable is a dissimilar metal media that is highly effective for free chlorine removal. This media does not readily promote bacterial growth which is a significant 5

Generation of pharmaceutical water advantage.

However, dissimilar metal medias are expensive and very heavy, prompting

significant backwash requirements and for chloramine removal significantly more media is required.

Injection of Reducing Agents

Injection of a reducing agent in the water stream requires very little equipment. Therefore the capital cost of this dechlorination method is extremely low. There is an ongoing expense of chemical procurement. Also, the mixing of reducing agents in water produces hazardous gasses.

Another disadvantage of utilization of reducing agents for dechlorination is the promotion of growth of certain organisms that thrive in a reduced environment. When utilizing a reducing agent the dose must be kept as low as possible to minimize proliferation of these organisms. It can be somewhat difficult to maintain an adequate but low dosage of reducing agent in the presence of widely fluctuating chlorine levels.

UV Light

UV light is widely used in water purification systems for disinfection and TOC reduction. Use of UV for dechlorination is a relatively new process. UV light has long been known as a good energy source for breaking chemical bonds. Use of UV light for destruction of many compounds is proliferating as the proper light dosages are determined and empirically verified. It has been demonstrated that UV light at a 254 nm wavelength at many times disinfection dosage will destroy free chlorine. UV light is also capable of destroying chloramine compounds, but the required dosage is significantly increased. Due to the high dosage required for chloramine destruction, it is sometimes beneficial to use an oxidant in combination with UV for chloramine removal. The capital cost of UV light for dechlorination of free chlorine is very close to that of a properly designed carbon filtration system.

There is an ongoing electrical cost with UV

dechlorination. However, there is an extreme benefit in elimination of bacterial colonization ground.

Furthermore, the water is given a very strong disinfection dosage that benefits

downstream treatment systems.

Ion Removal

There are three basic types of ion reduction processes: membrane processes, ion exchange processes, and distillation processes. There are many types and combinations of these processes, 6

Generation of pharmaceutical water making the possibilities almost endless. It is well beyond the scope of this discussion to examine all these possibilities. However, an overview of the more prevalent and appropriate ion removal systems is relevant.

Membrane Processes

Membranes accomplish a great deal in water purification systems, including: ion removal, particulate removal, removal of organic compounds, and organism removal. Membranes range dramatically in pore size, molecular weight cut off, and ion rejection. Ion removal membranes are at the “tight� end of the spectrum and include reverse osmosis (RO) membranes, and nanofiltration membranes. Actually, membrane chemistry has become so refined that rejection percentage can almost be specified anywhere between 99.9% and 50%, blurring the distinction between nanofiltration, low pressure, standard rejection, and high rejection RO membranes. A major distinction remains between cellulose based and non-cellulosic membranes. Cellulosic membranes tolerate exposure to bactericidal oxidizing agents and in fact must operate with a disinfectant present because organisms will eat the membrane material. Although it may be seen as an advantage to allow a chlorine residual to remain in the water through the reverse osmosis process, the advantages of non-cellulosic membranes far outweigh this advantage.

Non-

cellulosic membranes operate at much lower pressures and can tolerate a broad range of pH. Also, all the advanced formulations are in non-cellulosic membranes. One of the most important characteristics of ion removal membranes is that they will reject a certain percentage of ions no matter how high in ion concentration the feed stream is (up to maximum osmotic pressure). This is a significant advantage over ion exchange that must exchange every ion it removes. It is this characteristic that virtually mandates inclusion of membrane separation in every ion removal system. It is rarely economically feasible to utilize ion exchange alone for ion removal. The primary decision in applying membrane separation is whether to use a single pass system or a double pass system.

The conductivity requirements of USP water systems approximate the capability of double pass RO systems. On many feed waters, double pass RO will consistently produce the required conductivity. Gas content of the second pass permeate is typically the primary contributor to the on line measured conductivity. In most waters, carbon dioxide is the primary reactive gas that increases the measured conductivity. Carbon dioxide content of the second pass permeate can be reduced by increasing the pH of the feed water to the RO system. This will convert free carbon 7

Generation of pharmaceutical water dioxide gas to bicarbonate ion that can be rejected by membranes. However, in applications where chloramines are present in the feed water, raising the pH will convert ammonium ions to free ammonia gas that will pass through the membranes and will contribute to the measured conductivity of the water. Adjusting the pH to be high for one pass and low for another can address the dual gas problem. Also the use of membrane degasification will eliminate the gas problem. It should also be noted that the conductivity requirements for USP water do have provisions for qualifying water that is high in on line conductivity readings due to gas content.

Stage two testing is performed at equilibrium with atmospheric gasses. However, most facilities prefer to qualify conductivity by continuous reading on line instruments.

Proper application of membrane technology requires adherence to proper design criteria and incorporation of proper pretreatment, monitoring, control, and flushing capability. The primary design criteria in membrane systems is flux. This is expressed in gallons of water throughput per square foot of membrane area per day (GFD). The operating flux should generally fall between 10 and 15 GFD for the first pass. Feed water with higher fouling characteristics toward the low end of the range and better water at the high end of the range. Feed water to the membrane system must be pretreated to address constituents in the water that may cause fouling or scaling of the membranes. contaminant removal.

The specific methods of pretreatment will be discussed as specific It is very important to monitor pressure and flow throughout the

membrane system, as these determine required maintenance procedures and protective actions.

Feed and product water characteristics must also be monitored. Quality control consists of acting upon all sensed conditions of the membrane system in the appropriate manner.

Temperature is an important factor in the permeation of water through the membrane. Often feed water to the RO system is heated to a consistent 77E F, although this is not necessarily an economically sound practice. Flushing the membranes with permeate water upon shutdown allows the membranes to reside in non fouling/scaling water when the system is not processing, as opposed to feed water. This is especially important in systems that utilize antiscalants.

Incorporation of automated integral membrane cleaning and sanitization capability in the system enhances system performance and reduces maintenance.

Ion Exchange

Although double pass reverse osmosis may provide adequate ion removal for many pharmaceutical applications, often systems are designed with ion exchange following single or 8

Generation of pharmaceutical water double pass RO. Ion exchange processes will remove carbon dioxide that can cause two pass RO water to fail on line conductivity requirements. Furthermore, it is sometimes deemed appropriate in very low flow PW systems to utilize rented portable ion exchange tanks as the sole ion reduction method. A strong case can be made for ion exchange following reverse osmosis in pharmaceutical systems. The ion exchange system will provide an additional ion reduction process, generally rendering the water much lower in conductivity than required and providing a back up to the membrane process.

However, there are several problems associated with

incorporation of ion exchange in pharmaceutical systems.

Bacterial colonization of ion

exchange beds is common, particularly mixed beds which have a neutral pH.

On site

regeneration of ion exchange beds involves hazardous chemicals and somewhat elaborate equipment. Utilizing exchange tanks continually places a “wild card� into the treatment process.

Some of these problems can be mitigated by certain applications of ion exchange technology.

Use of separate beds for cation and anion resins provides extreme pH in the beds that helps retard bacterial growth. Although a single cation bed followed by a single anion bed does not provide very low conductivity water (primarily due to sodium leakage), adding a second cation bed (cation - anion - cation) greatly reduces conductivity. On site regeneration, although still requiring hazardous chemicals, is much simpler and less expensive for individual resin beds. If non regenerating mixed beds are desired, consideration should be given to replacing resin with virgin resin upon each exhaustion. This is more expensive than utilizing a portable exchange tank from an offsite regeneration supplier, but assures no upset in quality. Furthermore, with double pass reverse osmosis in front of the mixed bed, resin replacement will be infrequent.

Electrodeionization (EDI) technology provides continuous deionization and continuous regeneration without acid and caustic. Feedwater to the EDI system must be treated by reverse osmosis.

Depending on raw water quality, a single pass RO may be adequate for EDI

pretreatment. A 0.2 micron or smaller cartridge filtration unit should be installed at the outlet of the final deionization system.

This will prevent resin or other particulate matter from

contaminating the deionized water.

Distillation

Distillation is natures water purification process, consisting of the vaporization and condensation of water. Distillation equipment is expensive to operate due to the energy cost of vaporizing water. Typically distillation is used after a primary ion reduction process to reduce the potential 9

Generation of pharmaceutical water for scaling and fouling of the still. Any contaminant that vaporizes at a lower temperature than water will not be removed in the distillation process, everything else will be removed in a very high percentage (typically >99%).

Use of distillation in pharmaceutical water purification

systems is primarily for the preparation of Water for Injection, where it (or double pass reverse osmosis) is required.

Bacterial Control

Bacterial control requires more constant attention than any other aspect of the pharmaceutical water purification system.

Bacterial control includes both equipment and procedures.

Equipment utilized is typically ultraviolet (UV) lights, ozone generation systems, heating systems, and chemical injection/recirculation systems.

Procedures are generally periodic

sanitizations and general operational techniques to avoid bacterial intrusion. Bacterial control is applied to both the water purification system and the storage and distribution system.

UV Light

Ultraviolet light at a wavelength of 254 nm and a dosage of 30,000 microwatt seconds per square centimeter will provide an approximate 6 log kill rate of most bacteria. It accomplishes this without imparting any chemical residual to the water.

This makes UV light an excellent

disinfection device for pharmaceutical water systems. Placement of UV lights at numerous points in the water purification system is appropriate. Often UV placement on both the inlet and discharge of a treatment device will significantly prolong the time between periodic sanitizations. If a UV light is used in a location where significant amounts of hardness ions are present in the water, a sleeve wiper should be incorporated in the UV device or Teflon should be used for the water path.

Ozone

Ozone is a powerful oxidizing agent, generally created from atmospheric oxygen by an electrical device. Ozone kills organisms very rapidly by lysing cell walls. Ozone quickly reverts back to oxygen and is also readily destroyed by UV light.

Ozone is a good sanitizing agent for

pharmaceutical systems because it is so powerful and so easily removed from the water.

Because ozone is a powerful oxidizing agent it will harm polyamide membranes, ion exchange resins, and many elastomers.

Ozone is most often used for disinfection in storage and 10

Generation of pharmaceutical water distribution of pharmaceutical water, but can be used in the purification system at any point where materials of construction allow.

Thermal Sanitization

Heat is a reliable method of killing organisms. It can be used to sanitize cartridge filters, carbon filters, ion exchange beds, membrane systems, piping, tanks, etc. All systems that are to be heat sanitized require special materials of construction. This is especially true of membrane systems and ion exchange systems. The capability of heat sanitization adds significant cost to water treatment devices.

The minimum temperature capable of assured sanitization is 160 F.

Membrane systems and ion exchange systems have difficulty accommodating this extreme temperature and are often sanitized at lower temperatures to prevent damage to system components. These systems can not tolerate the higher temperatures that are often used in distribution piping and storage tank sanitization. Typically, system product water that has passed through a steam heat exchanger is used for sanitization.

Chemical Sanitization

A variety of chemical compounds can be used to sanitize various devices in the water purification system. Because heat sanitizable membrane systems are very expensive, often sanitizing chemicals are periodically circulated through the membrane system. This is easily accomplished when the membrane system incorporates an integral clean/flush system. The most important concern with chemical sanitizing agents is the ability to remove them from the system.

Procedures Every system must have written procedures to be followed when performing periodic sanitization. Furthermore, there must be general written procedures for routine maintenance that promote system hygiene, such as requiring disposable gloves and mask be worn during cartridge changes.

Removal of Specific Impurities

Every water source is different and therefore the possibilities of specific problem contaminants are endless. However, since all water sources supplying USP water purification systems must comply with drinking water standards, the specific problem contaminants are never impurities 11

Generation of pharmaceutical water covered by the primary standards. The discussion of specific impurities can be further limited to those items that appear most frequently. Iron, manganese, hydrogen sulfide, hardness ions, particulate matter, high conductivity, and high TOC are all contaminants that occur regularly.

Iron, Manganese, and Hydrogen Sulfide

These contaminants are common in ground water and often occur together. They will precipitate out of solution when oxidized and the standard method of treating these contaminants is by oxidation and filtration. Membranes will reject iron and manganese in solution and therefore it is sometimes beneficial to maintain the water in a reduced state and utilize membrane separation for their removal. Ozone is the preferred oxidant for oxidation/filtration systems, especially if hydrogen sulfide is present. Chlorine can also be used but requires significant increased contact time and a process to remove residual chlorine.

Hardness

Hardness ions can be easily removed from water by ion exchange or membrane separation. Ion exchange systems (softeners) consist of cation resin in the sodium form, regenerated by sodium chloride. Resin volume required in the softening system is determined by both flow rate and total exchange capacity. Flow rate must not exceed 5 GPM per cubic foot of resin and is best at approximately 3 GPM per cubic foot. Flows much less than 2 GPM per cubic foot may promote channeling. The total exchange capacity of the resin is based on regeneration salt dosage. This must be compared with the water hardness and flow rate to determine a resin volume that produces an acceptable frequency of regeneration. Often multiple tanks are used in a softening system to allow the system to remain in service while a tank is regenerating. Membranes will remove hardness ions, but these ions also tend to precipitate on the surface of the membrane, forming scale. Injection of acid or antiscalant chemicals into the membrane feed stream can prevent scale formation. A strong case can be made for both ion exchange softening and membrane removal of hardness ions in pharmaceutical systems. Typically, the usage of other processes in a system will determine which technique is more appropriate in the overall system design.

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Generation of pharmaceutical water

Particulate Matter

All water sources contain particulate matter in a wide variation of sizes. Well water will typically have much lower particle counts than surface water sources. Municipal water sources will generally be very low in particulate matter at the point of distribution, however, it is not unusual for particulate matter to enter the water stream in distribution piping.

All

pharmaceutical systems require particulate removal. On systems with heavy influent particulate loads a filtration method capable of handling heavy loads must be employed. A standard approach to this type of filtration is the backwashing multimedia filter (MMF). MMF’s are capable of removing particles down to a size of approximately 10 microns. If the particulate load is primarily smaller than this size, the MMF is useless. Granular carbon filters and ion exchange resins also provide filtration similar to a multimedia filter.

There is a patented

filtration process utilizing resin beads coated with a cationic polymer that is capable of removing very small charged particles. Cartridge filters may be used to remove essentially any particle size. Often filter cartridge pore size is staged to spread the loading over several banks of cartridges and prolong cartridge life. The biggest problem with cartridge filters is that they are disposable and filtering to a very small size can be very expensive in ongoing cartridge replacement costs.

Reverse osmosis membranes provide very fine filtration.

incoming particulate load is a major factor in membrane fouling.

However,

Water entering an RO

membrane must be prefiltered to at least 5 microns. This retards clogging of the feed channel.

Finer prefiltration can prolong intervals between membrane cleanings. The use of backwashing micro or ultra filters has become increasingly popular in water purification systems. These membrane filters can handle very heavy particulate loads with only a course screen as a prefilter.

The membrane filters provide excellent prefiltration for RO membranes, greatly extending cleaning intervals and RO membrane life. The great benefit of membrane filters is that they remove bacteria. This is of obvious benefit in pharmaceutical systems, greatly minimizing bacterial colonization of downstream treatment equipment.

High Conductivity

There is not a primary standard for conductivity in drinking water. Therefore it is possible to have very high levels. High inlet conductivity will affect the choice of ion reduction processes in the system. The high inlet conductivity may negate the possibility of complying with USP conductivity limits in a two pass RO or may require a two pass RO in front of EDI, etc.

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Generation of pharmaceutical water

High TOC

It may be necessary to specifically address high TOC levels in the influent water. A carbon bed may adequately reduce TOC level. Another alternative is an anion exchange bed specifically targeted to organic removal. This would most likely be regenerated with sodium chloride.

1.2 Generation of pharmaceutical water 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 Systems) 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, later use and insitu 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 50–100% in favor of the investment costs.

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Generation of pharmaceutical water

Purified water (PW)

In order to produce the chemical and microbiological quality 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.

Air break 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 possibleto install a supply separation container or use a supply or non-return valve.

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 exchanger 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.

As the resins have to be regenerated periodically, such facilities are operated discontinuously.

Once exhausted, the ion exchanger is rinsed with a saline solution. In order to assure a continuous softened water supply for the subsequent processes, two ion exchangers 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 exchangers can be regenerated every 24 to 36 hours.

Removal of chlorine 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 water can be used to generate pharmaceutical water.

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Generation of 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 bisulfate (Na2HSO3).

Schematic diagram of Softeningthroughionexchange

Operation of the ion exchanger

Regeneration of the ion exchanger 16

Generation of pharmaceutical water 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 of the activated charcoal (500–1600 m2/g) and the large supply of nutrients for microorganisms, the risk of increased microbiological fouling and the formation of a biofilm are 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 (CO2) 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.

Reverse osmosis

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.

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Generation of pharmaceutical water 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.

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 basically 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 is hollow fiber membranes (operating pressure approx. 28 bar), spiral wound membranes (operating pressure approx. 40 bar) and low pressure membranes (operating pressure approx. 15–18 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.

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Generation of pharmaceutical water

Schematic diagram of the procedure of reverse osmosis

With a multi-staged reverse osmosis unit with upstream ion exchanger, 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.

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Generation of pharmaceutical water • 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 exchangers 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.

Electrodeionization (EDI, CDI)

Electrodeionization (CDI = Continuous Deionization; EDI = Electrodeionization) is a desalination process based on electro dialysis 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.

Through the alternate overlapping of anion or cation permeable ion exchanger 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 exchanger 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 exchanger resin.

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Generation of pharmaceutical water

Schematic diagram of Electrodeionization

The operations inside the EDI module can be imagined as follows: First, the mixed bed ion exchanger 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 exchanger resin is regenerated through the increased level of dissociation of the water. The regeneration zone for the ion exchanger resin moves further towards the end of the product stream the greater the loading of the feed water with ions.

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Generation of pharmaceutical water That is, the lower the conductivity of the feed water, the lower the conductivity of the generated purified water.

Water qualities with 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 0.055 S/cm are possible (theoretical minimum conductivity).

Ultra filtration

Ultra filtration (UF) is a separation technology for separating particles with a size of 0.001 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 can also be displaced from the reverse osmosis membranes to the UF membranes. This is advantageous, as UF membranes are significantly easier to clean.

Ion exchanger

In the ion exchanger (separate bed and mixed bed system) ions are removed from the water.

Ion exchangers are filled with special resins which are usually produced from synthetic polymers as balls (particle size 0.3–1.5 mm). The particular ion exchanger resin must be selected according to the desired exchange or absorption process.

Ion exchanger 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 exchanger 22

Generation of pharmaceutical water • 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 exchangers always have a high potential risk of biological fouling.

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, CO2-degassing and EDI must be combined to achieve the same result. Figure 5.B-7 shows possible combinations depending on the feed water quality.

Deionization ionization 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 <1.1S/cm at 20 °C even with poor raw water qualities.

23

Generation of pharmaceutical water

Examples for purified water generation facilities

24

Generation of pharmaceutical water

CHAPTER 2 WATER FOR PHARMACEUTICAL USEUSE- AS PER WHO (WORLD HEALTH ORGANIZATION) Pharmaceutical water production, storage and distribution systems should be designed, installed, commissioned, validated and maintained to ensure the reliable production of water of an appropriate quality. They should not be operated beyond their designed capacity.

Water should be produced, stored and distributed in a manner that prevents unacceptable microbial, chemical or physical contamination (e.g. with dust and dirt).

The use of the systems following installation, commissioning, validation and any unplanned maintenance or modification work should be approved by the quality assurance (QA) department. If approval is obtained for planned preventive maintenance tasks, they need not be approved after implementation.

Water sources and treated water should be monitored regularly for quality and for chemical, microbiological and, as appropriate, endotoxin contamination. The performance of water purification, storage and distribution systems should also be monitored. Records of the monitoring results and any actions taken should be maintained for an appropriate length of time.

Where chemical sanitization of the water systems is part of the biocontamination control programme, a validated procedure should be followed to ensure that the sanitizing agent has been effectively removed.

Water quality specifications

General

The following requirements concern water processed stored and distributed in bulk form. They do not cover the specification of waters formulated for patient administration. Pharmacopoeias include specifications for both bulk and dosage-form waters.

Pharmacopoeial requirements for WPU are described in national and international pharmacopoeias and limits for various contaminants are given. Companies wishing to supply multiple markets should set specifications that meet the strictest requirements from each of the relevant pharmacopoeias.

Drinking-water

Drinking-water should be supplied under continuous positive pressure in a plumbing system free of any defects that could lead to contamination of any product.

25

Generation of pharmaceutical water Drinking-water is unmodified except for limited treatment of the water derived from a natural or stored source. Examples of natural sources include springs, wells, rivers, lakes and the sea. The condition of the source water will dictate the treatment required to render it safe for human consumption (drinking). Typical treatment includes softening, removal of specific ions, particle reduction and antimicrobial treatment. It is common for drinking-water to be derived from a public water supply that may be a combination of more than one of the natural sources listed above. It is also common for public water supply organizations to conduct tests and guarantee that the drinking water delivered is of potable quality.

Drinking-water quality is covered by the WHO drinking-water guidelines, standards from the International Organization for Standardization (ISO) and other regional and national agencies.

Drinking-water should comply with the relevant regulations laid down by the competent authority.

If drinking-water is used directly in certain stages of pharmaceutical manufacture or is the feedwater for the production of higher qualities of WPU, then testing should be carried out periodically by the water userâ&#x20AC;&#x2122;s site to confirm that the quality meets the standards required for potable water.

Purified water

Purified water (PW) should be prepared from a potable water source as a minimum-quality feedwater, should meet the pharmacopoeial specifications for chemical and microbiological purity, and should be protected from recontamination and microbial proliferation.

Highly purified water

Highly purified water (HPW) should be prepared from potable water as a minimum-quality feedwater. HPW is a unique specification for water found only in the European Pharmacopoeia. This grade of water must meet the same quality standard as water for injections (WFI) including the limit for endotoxin, but the water-treatment methods are not considered to be as reliable as distillation. HPW may be prepared by combinations of methods such as reverse osmosis, ultrafiltration and deionization.

Water for injections

Water for injections (WFI) should be prepared from potable water as a minimum-quality feedwater. WFI is not sterile water and is not a final dosage form. It is an intermediate bulk product.

WFI is the highest quality of pharmacopoeial WPU.

26

Generation of pharmaceutical water Certain pharmacopoeias place constraints upon the permitted purification techniques as part of the specification of the WFI. The International Pharmacopoeia and The European Pharmacopoeia, for example, allow only distillation as the final purification step.

Other grades of water

When a specific process requires a special non-pharmacopoeial grade of water, this should be specified and should at least satisfy the pharmacopoeial requirements of the grade of WPU required for the type of dosage form or process step.

Application of specific waters to processes and dosage forms Product licensing authorities define the requirement to use the specific grades of WPU for different dosage forms or for different stages in washing, preparation, synthesis, manufacturing or formulation.

The grade of water used should take into account the nature and intended use of the intermediate or finished product and the stage in the manufacturing process at which the water is used.

HPW can be used in the preparation of products when water of high quality (i.e. very low in microorganisms and endotoxin) is needed, but the process stage or product requirement does not include the constraint on the production method defined in some of the pharmacopoeial monographs for WFI. WFI should be used in injectable product preparations, for dissolving or diluting substances or preparations for parenteral administration before use, and for sterile water for preparation of injections. WFI should also be used for the final rinse after cleaning of equipment and components that come into contact with injectable products as well as for the final rinse in a washing process in which no subsequent thermal or chemical de pyrogenization process is applied.

When steam comes into contact with an injectable product in its final container, or equipment for preparing injectable products, it should conform with the specification for WFI when condensed.

27

Generation of pharmaceutical water Water purification methods

General considerations

The specifications for WPU found in compendia (e.g. pharmacopoeias) are generally not prescriptive as to permissible water purification methods other than those for WFI The chosen water purification method, or sequence of purification steps, must be appropriate to the application in question. The following should be considered when selecting the water treatment method: — The water quality specification; — The yield or efficiency of the purification system; — Feed-water quality and the variation over time (seasonal changes); — The reliability and robustness of the water-treatment equipment in operation; — The availability of water-treatment equipment on the market; — The ability to adequately support and maintain the water purification equipment; and — The operation costs.

The specifications for water purification equipment, storage and distribution systems should take into account the following: — The risk of contamination from leachates from contact materials; — The adverse impact of adsorptive contact materials; — Hygienic or sanitary design, where required; — Corrosion resistance; — Freedom from leakage; — Configuration to avoid proliferation of microbiological organisms; — Tolerance to cleaning and sanitizing agents (thermal andchemical); — The system capacity and output requirements; and — The provision of all necessary instruments, test and sampling points to allow all the relevant critical quality parameters of the complete system to be monitored.

The design, configuration and layout of the water purification equipment, storage and distribution systems should also take into account the following physical considerations: — The space available for the installation; — Structural loadings on buildings; — The provision of adequate access for maintenance; and — The ability to safely handle regeneration and sanitization chemicals.

28

Generation of pharmaceutical water

Production of drinking-water

Drinking-water is derived from a raw water source such as a well, river or reservoir. There are no prescribed methods for the treatment of raw water to produce potable drinking-water from a specific raw water source.

Typical processes employed at a user plant or by a water supply authority include: — Filtration; — Softening; — Disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection); — Iron (ferrous) removal; — Precipitation; and — Reduction of specific inorganic/organic materials.

The drinking-water quality should be monitored routinely.

Additional testing should be considered if there is any change in the raw-water source, treatment techniques or system configuration.

If the drinking-water quality changes significantly, the direct use of this water as a WPU, or as the feed-water to downstream treatment stages, should be reviewed and the result of the review documented.

Where drinking-water is derived from an “in-house” system for the treatment of raw water, the water-treatment steps used and the system configuration should be documented. Changes to the system or its operation should not be made until a review has been completed and the change approved by the QA department.

Where drinking-water is stored and distributed by the user, the storage systems must not allow degradation of the water quality before use. After any such storage, testing should be carried out routinely in accordance with a defined method. Where water is stored, its use should ensure a turnover of the stored water sufficient to prevent stagnation.

The drinking-water system is usually considered to be an “indirect impact system” and does not need to be qualified.

Drinking-water purchased in bulk and transported to the user by tanker presents special problems and risks not associated with potable water delivered by pipeline. Vendor assessment and authorized certification activities, including confirmation of the acceptability of the delivery vehicle, should be undertaken in a similar way to that used for any other starting material.

29

Generation of pharmaceutical water Equipment and systems used to produce drinking-water should be able to be drained and sanitized. Storage tanks should be closed with appropriately protected vents, allow for visual inspection and for being drained and sanitized. Distribution pipework should be able to be drained, or flushed, and sanitized.

Special care should be taken to control microbiological contamination of sand filters, carbon beds and water softeners. Once microorganisms have infected a system, the contamination can rapidly form biofilms and spread throughout the system. Techniques for controlling contamination such as back-flushing, chemical or thermal sanitization and frequent regeneration should be considered. Additionally, all water-treatment components should be maintained with continuous water flow to inhibit microbial growth.

Production of purified water

There are no prescribed methods for the production of PW in the pharmacopoeias. Any appropriate qualified purification technique or sequence of techniques may be used to prepare PW. Typically ion exchange, ultra filtration and/or reverse osmosis processes are used.

Distillation can also be used.

The following should be considered when configuring a water purification system: — The feed-water quality and its variation over seasons; — The required water-quality specification; — The sequence of purification stages required; — The energy consumption; — The extent of pretreatment required to protect the final purification steps; — Performance optimization, including yield and efficiency of unit treatment-process steps; — Appropriately located sampling points designed in such a way as to avoid potential contamination; and — Unit process steps should be provided with appropriate instrumentation to measure parameters such as flow, pressure, temperature, conductivity, pH and total organic carbon.

Ambient-temperature PW systems are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for water. It is essential to consider the mechanisms for microbiological control and sanitization.

The following techniques should be considered: — Maintenance of flow through water-purification equipment at all times; 30

Generation of pharmaceutical water — Control of temperature in the system by pipeline heat exchange or plant-room cooling to reduce the risk of microbial growth (guidance value <25 °C); — Provision of ultraviolet disinfection; — Selection of water-treatment components that can be thermally sanitized; and/or — Application of chemical sanitization (including agents such as ozone).

Production of highly purified water

There are no prescribed methods for the production of HPW in any major pharmacopoeia, including the European Pharmacopoeia.

Any appropriate qualified purification technique or sequence of techniques may be used to prepare HPW. Typically ion exchange, ultra filtration and/or reverse osmosis processes are used.

The guidance provided in section 5.3 for PW is equally applicable to HPW.

Production of water for injections

The pharmacopoeias prescribe or limit the permitted final water purification stage in the production of WFI. Distillation is the preferred technique; it is considered a more robust technique based on phase change, and in some cases, high temperature operation of the process equipment.

The following should be considered when designing a water purification system: — The feed-water quality; — The required water quality specification; — The optimum generator size to avoid over-frequent start/stop cycling; — blow-down and dump functions; and — cool-down venting to avoid contamination ingress.

Water purification, storage and distribution

Systems

This section applies to WPU systems for PW, HPW and WFI. The water storage and distribution should work in conjunction with the purification plant to ensure consistent delivery of water to the user points, and to ensure optimum operation of the water purification equipment.

General

The storage and distribution system should be considered as a key part of the whole system, and should be designed to be fully integrated with the water purification components of the system.

31

Generation of pharmaceutical water Once water has been purified using an appropriate method, it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The following text describes the requirements for storage and distribution systems.

The storage and distribution system should be configured to prevent recontamination of the water after treatment and be subjected to a combination of online and offline monitoring to ensure that the appropriate water specification is maintained.

Materials that come into contact with systems for water for

Pharmaceutical use

This section applies to generation equipment for PW, HPW and WFI, and the associated storage and distribution systems.

The materials that come into contact with WPU, including pipe work, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.

• Compatibility. All materials used should be compatible with the temperature and chemicals used by or in the system.

• Prevention of leaching. All materials that come into contact with WPU should be non-leaching at the range of working temperatures.

• Corrosion resistance. PW, HPW and WFI are highly corrosive. To prevent failure of the system and contamination of the water, the materials selected must be appropriate, the method of jointing must be carefully controlled, and all fittings and components must be compatible with the pipe work used. Appropriate sanitary specification plastics and stainless steel materials are acceptable for WPU systems. When stainless steel is used it should be at least grade 316L. The system should be passivated after initial installation or after modification. When accelerated passivation is undertaken, the system should be thoroughly cleaned first, and the passivation process should be undertaken in accordance with a clearly defined documented procedure.

• Smooth internal finish. Once water has been purified it is susceptible to microbiological contamination, and the system is subject to the formation of biofilms when cold storage and distribution is employed. Smooth internal surfaces help to avoid roughness and crevices within the WPU system. Crevices are frequently sites where corrosion can commence. The internal finish should have an arithmetical average surface roughness of not greater than 0.8 micrometre arithmetical mean roughness (Ra). When stainless steel is used, mechanical and electropolishing techniques may be employed. Electropolishing improves the resistance of the stainless steel material to surface corrosion.

32

Generation of pharmaceutical water • Jointing. The selected system materials should be able to be easily jointed by welding in a controlled manner. The control of the process should include as a minimum, qualification of the operator, documentation of the welder set-up, work-session test pieces, logs of all welds and visual inspection of a defined proportions of welds.

• Design of flanges or unions. Where flanges or unions are used, they should be of a hygienic or sanitary design. Appropriate checks should be carried out to ensure that the correct seals are used and that they are fitted and tightened correctly.

• Documentation. All system components should be fully documented and be supported by original or certified copies of material certificates.

• Materials. Suitable materials that may be considered for sanitary elements of the system include 316 L (low carbon) stainless steel, polypropylene, polyvinylidenedifluoride and perfluoroalkoxy. Other materials such as unplasticized polyvinylchloride (uPVC) may be used for treatment equipment designed for less pure water such as ion exchangers and softeners.

System sanitization and bioburden control

Water treatment equipment, storage and distribution systems used for PW, HPW and WFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing or sterilizing the system after intervention for maintenance or modification. The techniques employed should be considered during the design of the system and their performance proven during the commissioning and qualification activities.

Systems that operate and are maintained at elevated temperatures, in the range of 70–80 °C, are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures.

When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, then special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants

Storage vessel requirements

The water storage vessel used in a system serves a number of important purposes. The design and size of the vessel should take into consideration the following.

Capacity

The capacity of the storage vessel should be determined on the basis of the following requirements.

33

Generation of pharmaceutical water • It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.

• The water treatment equipment should be able to operate continuously for significant periods to avoid the inefficiencies and equipment stress that occur when the equipment cycles on and off too frequently.

• The capacity should be sufficient to provide short-term reserve capacity in the event of failure of the water-treatment equipment or inability to produce water due to a sanitization or regeneration cycle. When determining the size of such reserve capacity, consideration should be given to providing sufficient water to complete a process batch, work session or other logical period of demand.

Contamination control considerations

The following should be taken into account for the efficient control of contamination.

• The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The water distribution loop should be configured to ensure that the headspace of the storage vessel is effectively wetted by a flow of water. The use of spray ball or distributor devices to wet the surfaces should be considered.

• Nozzles within the storage vessels should be configured to avoid dead zones where microbiological contamination might be harboured.

• Vent filters are fitted to storage vessels to allow the internal level of liquid to fluctuate. The filters should be bacteria-retentive, hydrophobic and ideally be configured to allow in situ testing of integrity.

Offline testing is also acceptable. The use of heated vent filters should be considered to prevent condensation within the filter matrix that might lead to filter blockage and to microbial growth rough that could contaminate the storage vessels.

• Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from over-pressurization, these devices should be of a sanitary design. Bursting discs should be provided with external rupture indicators to prevent accidental loss of system integrity.

Requirements for water distribution pipework

The distribution of PW, HPW and WFI should be accomplished using a continuously circulating pipework loop. Proliferation of contaminants within the storage tank and distribution loop should be controlled.

34

Generation of pharmaceutical water Filtration should not usually be used in distribution loops or at takeoff user points to control biocontamination. Such filters are likely to conceal system contamination.

Temperature control and heat exchangers

Where heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame configuration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered.

Where heat exchangers are used they should be arranged in continually circulating loops or sub loops of the system to avoid unacceptable static water in systems.

When the temperature is reduced for processing purposes, the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the qualification of the system.

Circulation pumps

Circulation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they should be configured or managed to avoid dead zones trapped within the system.

Biocontamination control techniques

The following control techniques may be used alone or more commonly in combination.

• Maintenance of continuous turbulent flow circulation within water distribution systems reduces the propensity for the formation of bio films. The maintenance of the design velocity for a specific system should be proven during the system qualification and the maintenance of satisfactory performance should be monitored. During the operation of a distribution system, short-term fluctuations in the flow velocity are unlikely to cause contamination problems provided that cessation of flow, flow reversal or pressure loss does not occur.

• The system design should ensure the shortest possible length of pipework.

• For ambient temperature systems, pipework should be isolated from adjacent hot pipes.

• Dead legs in the pipework installation greater than 1.5 times the branch diameter should be avoided.

• Pressure gauges should be separated from the system by membranes.

• Hygienic pattern diaphragm valves should be used.

• Pipework should be laid to falls to allow drainage.

35

Generation of pharmaceutical water • The growth of microorganisms can be inhibited by: — Ultraviolet radiation sources in pipework; — maintaining the system heated (guidance temperature 70– 80 °C); — Sanitizing the system periodically using hot water (guidance temperature >70 °C); — sterilizing or sanitizing the system periodically using superheated hot water or clean steam; — Routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.

Operational considerations Start-up and commissioning of water systems Planned, well-defined, successful and well-documented commissioning is an essential precursor to successful validation of water systems.

The commissioning work should include setting to work, system setup, controls loop tuning and recording of all system performance parameters. If it is intended to use or refer to commissioning data within the validation work then the quality of the commissioning work and associated data and documentation must be commensurate with the validation plan requirements.

Qualification WPU, PW, HPW and WFI systems are all considered to be direct impact, quality critical systems that should be qualified. The qualification should follow the validation convention of design review or design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ).

This guidance does not define the standard requirements for the conventional validation stages DQ, IQ and OQ, but concentrates on the particular PQ approach that should be used for WPU systems to demonstrate their consistent and reliable performance. A three-phase approach should be used to satisfy the objective of proving the reliability and robustness of the system in service over an extended period.

Phase 1. A test period of 2–4 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation. The following should be included in the testing approach.

• Undertake chemical and microbiological testing in accordance with a defined plan.

• Sample the incoming feed-water daily to verify its quality.

• Sample after each step in the purification process daily.

36

Generation of pharmaceutical water • Sample at each point of use and at other defined sample points daily.

• Develop appropriate operating ranges.

• Develop and finalize operating, cleaning, sanitizing and maintenance procedures.

• Demonstrate production and delivery of product water of the required quality and quantity.

• Use and refine the standard operating procedures (SOPs) for operation, maintenance, sanitization and troubleshooting.

• Verify provisional alert and action levels.

• Develop and refine test-failure procedure.

Phase 2. A further test period of 2–4 weeks should be spent carrying out further intensive monitoring while deploying all the refined SOPs after the satisfactory completion of phase 1.

The sampling scheme should be generally the same as in phase 1. Water can be used for manufacturing purposes during this phase. The approach should also: — demonstrate consistent operation within established ranges; and — demonstrate consistent production and delivery of water of the required quantity and quality when the system is operated in accordance with the SOPs. Phase 3. Phase 3 typically runs for 1 year after the satisfactory completion of phase 2. Water can be used for manufacturing purposes during this phase which has the following objectives and features.

• Demonstrate extended reliable performance.

• Ensure that seasonal variations are evaluated.

• The sample locations, sampling frequencies and tests should be reduced to the normal routine pattern based on established procedures proven during phases 1 and 2.

Continuous system monitoring After completion of phase 3 of the qualification programme for the WPU system, a system review should be undertaken. Following this review, a routine monitoring plan should be established based on the results of phase 3.

Monitoring should include a combination of online instrument monitoring of parameters such as flow, pressure, temperature, conductivity and total organic carbon, and offline sample testing for physical, chemical and microbiological attributes. Offline samples should be taken from points of use and specific sample points. Samples from points of use should be taken in a similar way to that adopted when the water is being used in service.

37

Generation of pharmaceutical water Tests should be carried out to ensure that the selected pharmacopoeia specification has been satisfied, and should include, as appropriate, determination of conductivity, pH, heavy metals, nitrates, total organic carbon, total viable count, presence of specific pathogens and endotoxins.

Monitoring data should be subject to trend analysis.

Maintenance of water systems WPU systems should be maintained in accordance with a controlled, documented maintenance programme that takes into account the following: — Defined frequency for system elements; — The calibration programme; — SOPs for specific tasks; — Control of approved spares; — Issue of clear maintenance plan and instructions; — Review and approval of systems for use upon completion of work; and — Record and review of problems and faults during maintenance.

System reviews WPU (PW, HPW and WFI) systems should be reviewed at appropriate regular intervals. The review team should comprise representatives from engineering, QA, operations and maintenance. The review should consider matters such as: — Changes made since the last review; — System performance; — Reliability; — Quality trends; — Failure events; — Investigations; — Out-of-specifications results from monitoring; — Changes to the installation; — updated installation documentation; — Log books; and — The status of the current SOP list.

38

Generation of pharmaceutical water Inspection of water systems WPU (PW, HPW and WFI) systems are likely to be the subject of regulatory inspection from time to time. Users should consider conducting routine audit and self-inspection of established water systems.

This GMP guidance can be used as the basis of inspection. The following list identifies items and a logical sequence for a WPU system inspection or audit: — A sampling and monitoring plan with a drawing of all sample points; — The setting of monitoring alert and action levels; — monitoring results and evaluation of trends; — Inspection of the last annual system review; — Review of any changes made to the system since the last audit and check that the change control has been implemented; — Review of deviations recorded and their investigation; — General inspection of system for status and condition; — Review of maintenance, failure and repair logs; and — Checking calibration and standardization of critical instruments.

For an established system that is demonstrably under control, this scope of review should prove adequate.

For new systems, or systems that display instability or unreliability, the following should also be reviewed: — Performance qualification; — Operational qualification; and — Installation qualification.

39

Generation of pharmaceutical water

CHAPTER 3 WATER FOR PHARMACEUTICAL USEUSE- AS PER USP (UNITED STATE PHARMACOPEIA) PHARMACOPEIA) 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. This general information provides additional information about water, its quality attributes that are not included within a water monograph, processing techniques that can be used to improve water quality, and a description of minimum water quality standards that should be considered when selecting a water source.

This information chapter is not intended to replace existing regulations or guides that already exist to cover USA and International (ICH or WHO) GMP issues, engineering guides, or other regulatory (FDA, EPA, or WHO) guidances for water. The contents will help users to better understand pharmaceutical water issues and some of the microbiological and chemical concerns unique to water. This chapter is not an all-inclusive writing on pharmaceutical waters. It contains points that are basic information to be considered, when appropriate, for the processing, holding, and use of water. It is the user's responsibility to assure that pharmaceutical water and its production meet applicable governmental regulations, guidances, and the compendia specifications for the types of water used in compendial articles.

Control of the chemical purity of these waters is important and is the main purpose of the monographs in this compendium. Unlike other official articles, the bulk water monographs (Purified Water and Water for Injection) also limit how the article can be produced because of the belief that the nature and robustness of the purification process is directly related to the resulting purity. The chemical attributes listed in these monographs should be considered as a set of minimum specifications. More stringent specifications may be needed for some applications to ensure suitability for particular uses. Basic guidance on the appropriate applications of these waters is found in the monographs and is further explained in this chapter.

Control of the microbiological quality of water is important for many of its uses. All packaged forms of water that have monograph standards are required to be sterile because some of their intended uses require this attribute for health and safety reasons. USP has determined that a microbial specification for the bulk monographed waters is inappropriate and has not been 40

Generation of pharmaceutical water included within the monographs for these waters. These waters can be used in a variety of applications, some requiring extreme microbiological control and others requiring none. The needed microbial specification for a given bulk water depends upon its use. A single specification for this difficult-to-control attribute would unnecessarily burden some water users with irrelevant specifications and testing. However, some applications may require even more careful microbial control to avoid the proliferation of microorganisms ubiquitous to water during the purification, storage, and distribution of this substance. A microbial specification would also be inappropriate when related to the â&#x20AC;&#x153;utilityâ&#x20AC;? or continuous supply nature of this raw material.

Microbial specifications are typically assessed by test methods that take at least 48 to 72 hours to generate results. Because pharmaceutical waters are generally produced by continuous processes and used in products and manufacturing processes soon after generation, the water is likely to have been used well before definitive test results are available. Failure to meet a compendial specification would require investigating the impact and making a pass/fail decision on all product lots between the previous sampling's acceptable test result and a subsequent sampling's acceptable test result. The technical and logistical problems created by a delay in the result of such an analysis do not eliminate the user's need for microbial specifications. Therefore, such water systems need to be operated and maintained in a controlled manner that requires that the system be validated to provide assurance of operational stability and that its microbial attributes be quantitatively monitored against established alert and action levels that would provide an early indication of system control. The issues of water system validation and alert/action levels and specifications are included in this chapter.

Source or Feed Water Considerations To ensure adherence to certain minimal chemical and microbiological quality standards, water used in the production of drug substances or as source or feed water for the preparation of the various types of purified waters must meet the requirements of the National Primary Drinking Water Regulations (NPDWR) (40 CFR 141) issued by the U.S. Environmental Protection Agency (EPA) or the drinking water regulations of the European Union or Japan, or the WHO drinking water guidelines.

Limits on the types and quantities of certain organic and inorganic contaminants ensure that the water will contain only small, safe quantities of potentially objectionable chemical species.

Therefore, water pretreatment systems will only be challenged to remove small quantities of these potentially difficult-to-remove chemicals. Also, control of objectionable chemical 41

Generation of pharmaceutical water contaminants at the source-water stage eliminates the need to specifically test for some of them (e.g., trihalomethanes and heavy metals) after the water has been further purified.

Microbiological requirements of drinking water ensure the absence of coliforms, which, if determined to be of fecal origin, may indicate the potential presence of other potentially pathogenic microorganisms and viruses of fecal origin. Meeting these microbiological requirements does not rule out the presence of other microorganisms, which could be considered undesirable if found in a drug substance or formulated product.

To accomplish microbial control, Municipal Water Authorities add disinfectants to drinking water. Chlorine-containing and other oxidizing substances have been used for many decades for this purpose and have generally been considered to be relatively innocuous to humans. However, these oxidants can interact with naturally occurring organic matter to produce disinfection byproducts

(DBPs),

such

as

trihalomethanes

(THMs,

including

chloroform,

bromodichloromethane, and dibromochloromethane) and haloacetic acids (HAAs, including dichloroacetic acid and trichloroacetic acid). The levels of DBPs produced vary with the level and type of disinfectant used and the levels and types of organic materials found in the water, which can vary seasonally.

Because high levels of DBPs are considered a health hazard in drinking water, Drinking Water Regulations mandate their control to generally accepted nonhazardous levels. However, depending on the unit operations used for further water purification, a small fraction of the DBPs in the starting water may carry over to the finished water. Therefore, the importance of having minimal levels of DBPs in the starting water, while achieving effective disinfection, is important.

DBP levels in drinking water can be minimized by using disinfectants such as ozone, chloramines, or chlorine dioxide. Like chlorine, their oxidative properties are sufficient to damage some pretreatment unit operations and must be removed early in the pretreatment process. The complete removal of some of these disinfectants can be problematic. For example, chloramines may degrade during the disinfection process or during pretreatment removal, thereby releasing ammonia, which in turn can carry over to the finished water. Pretreatment unit operations must be designed and operated to adequately remove the disinfectant, drinking water DBPs, and objectionable disinfectant degradants. A serious problem can occur if unit operations designed to remove chlorine were, without warning, challenged with chloramine-containing drinking water from a municipality that had been mandated to cease use of chlorine disinfection to comply with ever tightening EPA Drinking Water THM specifications. The dechlorination 42

Generation of pharmaceutical water process might incompletely remove the chloramine, which could irreparably damage downstream unit operations, but also the release of ammonia during this process might carry through pretreatment and prevent the finished water from passing compendial conductivity specifications. The purification process must be reassessed if the drinking water disinfectant is changed, emphasizing the need for a good working relationship between the pharmaceutical water manufacturer and the drinking water provider.

Types of Water There are many different grades of water used for pharmaceutical purposes. Several are described in USP monographs that specify uses, acceptable methods of preparation, and quality attributes. These waters can be divided into two general types: bulk waters, which are typically produced on site where they are used; and packaged waters, which are produced, packaged, and sterilized to preserve microbial quality throughout their packaged shelf life. There are several specialized types of packaged waters, differing in their designated applications, packaging limitations, and other quality attributes.

There are also other types of water for which there are no monographs. These are all bulk waters, with names given for descriptive purposes only. Many of these waters are used in specific analytical methods. The associated text may not specify or imply certain quality attributes or modes of preparation. These non monographic waters may not necessarily adhere strictly to the stated or implied modes of preparation or attributes. Waters produced by other means or controlled by other test attributes may equally satisfy the intended uses for these waters. It is the user's responsibility to ensure that such waters, even if produced and controlled exactly as stated, be suitable for their intended use. Wherever the term â&#x20AC;&#x153;waterâ&#x20AC;? is used within these compendia without other descriptive adjectives or clauses, the intent is that water of no less purity than Purified Water be used.

What follows is a brief description of the various types of pharmaceutical waters and their significant uses or attributes. Figure 1 may also be helpful in understanding some of the various types of waters.

43

Generation of pharmaceutical water

Water for pharmaceutical purposes

The following waters are typically produced in large volume by a multiple-unit operation water system and distributed by a piping system for use at the same site.

These particular pharmaceutical waters must meet the quality attributes as specified in the related monographs.

Purified Waterâ&#x20AC;&#x201D; Purified Water (see USP monograph) is used as an excipient in the production of non parenteral preparations and in other pharmaceutical applications, such as cleaning of certain equipment and non parenteral product-contact components. Unless otherwise specified, Purified Water is also to be used for all tests and assays for which water is indicated (see General Notices and Requirements). Purified Water is also referenced throughout the USPâ&#x20AC;&#x201C; NF. Regardless of the font and letter case used in its spelling, water complying with the Purified Water monograph is intended. Purified Water must meet the requirements for ionic and organic 44

Generation of pharmaceutical water chemical purity and must be protected from microbial contamination. The minimal quality of source or feed water for the production of Purified Water is Drinking Water. 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. Purified water systems that function under ambient conditions are particularly susceptible to the establishment of tenacious bio films of microorganisms, which can be the source of undesirable levels of viable microorganisms or endotoxin in the effluent water.

These systems require frequent sanitization and microbiological monitoring to ensure water of appropriate microbiological quality at the points of use.

The Purified Water monograph also allows bulk packaging for commercial use elsewhere. When this is done, the required specifications are those of the packaged water Sterile Purified Water, except for Sterility and Labeling. There is a potential for microbial contamination and other quality changes of this bulk packaged non sterile water to occur. Therefore, this form of Purified Water should be prepared and stored in such a fashion that limits microbial growth and/or simply used in a timely fashion before microbial proliferation renders it unsuitable for its intended use.

Also depending on the material used for packaging, there could be extractable compounds leaching into the water from the packaging. Though this article may meet its required chemical attributes, such extractable may render the water an inappropriate choice for some applications.

It is the user's responsibility to assure fitness for use of this packaged article when used in manufacturing, clinical, or analytical applications where the pure bulk form of the water is indicated.

Water for Injectionâ&#x20AC;&#x201D; Water for Injection (see USP monograph) is used as an excipient in the production of parenteral and other preparations where product endotoxin content must be controlled, and in other pharmaceutical applications, such as cleaning of certain equipment and parenteral product-contact components.

The minimum quality of source or feed water for the generation of Water for Injection is Drinking Water as defined by the U.S. EPA, EU, Japan, or the WHO. This source water may be pre-treated to render it suitable for subsequent distillation (or whatever other validated process is used according to the monograph). The finished water must meet all of the chemical requirements for Purified Water as well as an additional bacterial endotoxin specification. Since endotoxin are produced by the kinds of microorganisms that are prone to inhabit water, the 45

Generation of pharmaceutical water equipment and procedures used by the system to purify, store, and distribute Water for Injection must be designed to minimize or prevent microbial contamination as well as remove incoming endotoxin from the starting water. Water for Injection systems must be validated to reliably and consistently produce and distribute this quality of water.

The Water for Injection monograph also allows it to be packed in bulk for commercial use.

Required specifications include the test for Bacterial endotoxin, and those of the packaged water Sterile Purified Water, except for Labeling. Bulk packaged Water for Injection is required to be sterile, thus eliminating microbial contamination quality changes. However, packaging extractable may render this water an inappropriate choice for some applications. It is the user's responsibility to ensure fitness for use of this packaged article when used in manufacturing, clinical, or analytical applications where the purer bulk form of the water is indicated.

Water for Hemodialysis— Water for Hemodialysis (see USP monograph) is used for hemodialysis applications, primarily the dilution of hemodialysis concentrate solutions. It is produced and used on-site and is made from EPA Drinking Water which has been further purified to reduce chemical and microbiological components. It may be packaged and stored in un reactive containers that preclude bacterial entry. The term “un reactive containers” implies that the container, especially its water contact surfaces, are not changed in any way by the water, such as by leaching of container-related compounds into the water or by any chemical reaction or corrosion caused by the water. The water contains no added antimicrobials and is not intended for injection. Its attributes include specifications for Water conductivity, Total organic carbon (or oxidizable substances), Microbial limits, and Bacterial endotoxins. The water conductivity and total organic carbon attributes are identical to those established for Purified Water and Water for Injection; however, instead of total organic carbon, the organic content may alternatively be measured by the test for Oxidizable substances. The Microbial limits attribute for this water is unique among the “bulk” water monographs, but is justified on the basis of this water's specific application that has microbial content requirements related to its safe use. The Bacterial endotoxins attribute is likewise established at a level related to its safe use.

Pure Steam— Pure Steam is intended for use in steam sterilizing porous loads and equipment and in other processes such as cleaning where condensate would directly contact official articles, containers for these articles, process surfaces that would in turn contact these articles, or materials which are used in analyzing such articles. Pure Steam may be used for air humidification in controlled manufacturing areas where official articles or article-contact 46

Generation of pharmaceutical water surfaces are exposed to the resulting conditioned air. The primary intent of using this quality of steam is to ensure that official articles or article-contact surfaces exposed to it are not contaminated by residues within the steam. Pure Steam is prepared from suitably pretreated source water, analogous to the pretreatment used for Purified Water or Water for Injection, vaporized with suitable mist elimination, and distributed under pressure. The sources of undesirable contaminants within Pure Steam could be derived from entrained source water droplets, anti-corrosion steam additives, or particulate matter from the steam production and distribution system itself; therefore, the attributes in the monograph should preclude most of the contaminants that could arise from these sources.

These purity attributes are measured on the condensate of the article, rather than the article itself.

This, of course, imparts great importance to the cleanliness of the Pure Steam condensate generation and collection process because it must not adversely impact the quality of the resulting condensed fluid.

Other steam attributes not detailed in the monograph, in particular, the presence of even small quantities of non condensable gases or the existence of a superheated or dry state, may also be important for applications such as sterilization. The large release of energy (latent heat of condensation) as water changes from the gaseous to the liquid state is the key to steam's sterilization efficacy and its efficiency, in general, as a heat transfer agent. If this phase changes (condensation) is not allowed to happen because the steam is extremely hot and in a persistent super heated, dry state, then its usefulness could be seriously compromised. Non condensable gases in steam tend to stratify or collect in certain areas of a steam sterilization chamber or its load. These surfaces would thereby be at least partially insulated from the steam condensation phenomenon, preventing them from experiencing the full energy of the sterilizing conditions.

Therefore, control of these kinds of steam attributes, in addition to its chemical purity, may also be important for certain Pure Steam applications. However, because these additional attributes are use-specific, they are not mentioned in the Pure Steam monograph.

Note that less pure plant steam may be used for steam sterilization of nonporous loads, general cleaning and sterilization of non product contact equipment and analytical materials, humidification of air in nonmanufacturing areas, where used as a non product contact heat exchange medium, and in all compatible applications involved in bulk pharmaceutical chemical and API manufacture.

47

Generation of pharmaceutical water

Purified Water and Water For Injection Systems The design, installation, and operation of systems to produce Purified Water and Water for Injection include similar components, control techniques, and procedures. The quality attributes of both waters differ only in the presence of a bacterial endotoxin requirement for Water for Injection and in their methods of preparation, at least at the last stage of preparation. The similarities in the quality attributes provide considerable common ground in the design of water systems to meet either requirement. The critical difference is the degree of control of the system and the final purification steps needed to ensure bacterial and bacterial endotoxin removal.

Production of pharmaceutical water employs sequential unit operations (processing steps) that address specific water quality attributes and protect the operation of subsequent treatment steps.

A typical evaluation process to select an appropriate water quality for a particular pharmaceutical purpose . This diagram may be used to assist in defining requirements for specific water uses and in the selection of unit operations. The final unit operation used to produce Water for Injection is limited to distillation or other processes equivalent or superior to distillation in the removal of chemical impurities as well as microorganisms and their components. Distillation has a long history of reliable performance and can be validated as a unit operation for the production of Water for Injection, but other technologies or combinations of technologies can be validated as being equivalently effective. Other technologies, such as ultra filtration following other chemical purification process, may be suitable in the production of Water for Injection if they can be shown through validation to be as effective an dreliable as distillation. The advent of new materials for older technologies, such as reverse osmosis and ultra filtration, that allow intermittent or continuous operation at elevated, microbial temperatures, show promise for a valid use in producing Water for Injection.

The validation plan should be designed to establish the suitability of the system and to provide a thorough understanding of the purification mechanism, range of operating conditions, required pretreatment, and the most likely modes of failure. It is also necessary to demonstrate the effectiveness of the monitoring scheme and to establish the documentation and qualification requirements for the system's validation maintenance. Trials conducted in a pilot installation can be valuable in defining the operating parameters and the expected water quality and in identifying failure modes. However, qualification of the specific unit operation can only be performed as part of the validation of the installed operational system. The selection of specific 48

Generation of pharmaceutical water unit operations and design characteristics for a water system should take into account the quality of the feed water, the technology chosen for subsequent processing steps, the extent and complexity of the water distribution system, and the appropriate compendial requirements. For example, in the design of a system for Water for Injection, the final process (distillation or whatever other validated process is used according to the monograph) must have effective bacterial endotoxin reduction capability and must be validated.

Unit Operations Concerns The following is a brief description of selected unit operations and the operation and validation concerns associated with them. Not all unit operations are discussed, nor are all potential problems addressed. The purpose is to highlight issues that focus on the design, installation, operation, maintenance, and monitoring parameters that facilitate water system validation.

Pre filtration The purpose of pre filtration—also referred to as initial, coarse, or depth filtration—is to remove solid contaminants down to a size of 7 to 10 Gm from the incoming source water supply and protect downstream system components from particulates that can inhibit equipment performance and shorten their effective life. This coarse filtration technology utilizes primarily sieving effects for particle capture and a depth of filtration medium that has a high “dirt load” capacity. Such filtration units are available in a wide range of designs and for various applications. Removal efficiencies and capacities differ significantly, from granular bed filters such as multimedia or sand for larger water systems, to depth cartridges for smaller water systems. Unit and system configurations vary widely in type of filtering media and location in the process. Granular or cartridge pre filters are often situated at or near the head of the water pretreatment system prior to unit operations designed to remove the source water disinfectants. This location, however, does not preclude the need for periodic microbial control because biofilm can still proliferate, although at a slower rate in the presence of source water disinfectants. Design and operational issues that may impact performance of depth filters include channeling of the filtering media, blockage from silt, microbial growth, and filtering-media loss during improper backwashing. Control measures involve pressure and flow monitoring during use and backwashing, sanitizing, and replacing filtering media. An important design concern is sizing of the filter to prevent channeling or media loss resulting from inappropriate water flow rates as well as proper sizing to minimize excessively frequent or infrequent backwashing or cartridge filter replacement.

49

Generation of pharmaceutical water Activated Carbon Granular activated carbon beds adsorb low molecular weight organic material and oxidizing additives, such as chlorine and chloramine compounds, removing them from the water. They are used to achieve certain quality attributes and to protect against reaction with downstream stainless steel surfaces, resins, and membranes. The chief operating concerns regarding activated carbon beds include the propensity to support bacteria growth, the potential for hydraulic channeling, the organic adsorption capacity, appropriate water flow rates and contact time, the inability to be regenerated in situ, and the shedding of bacteria, endotoxins, organic chemicals, and fine carbon particles. Control measures may involve monitoring water flow rates and differential pressures, sanitizing with hot water or steam, backwashing, testing for adsorption capacity, and frequent replacement of the carbon bed. If the activated carbon bed is intended for organic reduction, it may also be appropriate to monitor influent and effluent TOC. It is important to note that the use of steam for carbon bed sanitization is often incompletely effective due to steam channeling rather than even permeation through the bed. This phenomenon can usually be avoided by using hot water sanitization. It is also important to note that microbial biofilm development on the surface of the granular carbon particles (as well as on other particles such as found in deionizer beds and even multimedia beds) can cause adjacent bed granules to â&#x20AC;&#x153;stickâ&#x20AC;? together. When large masses of granules are agglomerated in this fashion, normal backwashing and bed fluidization flow parameters may not be sufficient to disperse them, leading to ineffective removal of trapped debris, loose biofilm, and penetration of microbial controlling conditions (as well as regenerant chemicals as in the case of agglomerated deionizer resins). Alternative technologies to activated carbon beds can be used in order to avoid their microbial problems, such as disinfectant-neutralizing chemical additives and regenerable organic scavenging devices. However, these alternatives do not function by the same mechanisms as activated carbon, may not be as effective at removing disinfectants and some organics, and have a different set of operating concerns and control measures that may be nearly as troublesome as activated carbon beds.

Additives Chemical additives are used in water systems (a) to control microorganisms by use of sanitants such as chlorine compounds and ozone, (b) to enhance the removal of suspended solids by use of flocculating agents, (c) to remove chlorine compounds, (d) to avoid scaling on reverse osmosis membranes, and (e) to adjust pH for more effective removal of carbonate and ammonia 50

Generation of pharmaceutical water compounds by reverse osmosis. These additives do not constitute â&#x20AC;&#x153;added substancesâ&#x20AC;? as long as they are either removed by subsequent processing steps or are otherwise absent from the finished water. Control of additives to ensure a continuously effective concentration and subsequent monitoring to ensure their removal should be designed into the system and included in the monitoring program.

Organic Scavengers Organic scavenging devices use macro reticular weakly basic anion-exchange resins capable of removing organic material and endotoxins from the water. They can be regenerated with appropriate biocidal caustic brine solutions. Operating concerns are associated with organic scavenging capacity, particulate, chemical and microbiological fouling of the reactive resin surface, flow rate, regeneration frequency, and shedding of resin fragments. Control measures include TOC testing of influent and effluent, backwashing, monitoring hydraulic performance, and using downstream filters to remove resin fines.

Softeners Water softeners may be located either upstream or downstream of disinfectant removal units.

They utilize sodium-based cation-exchange resins to remove waterhardness ions, such as calcium and magnesium, that could foul or interfere with the performance of downstream processing equipment such as reverse osmosis membranes, deionization devices, and distillation units.

Water softeners can also be used to remove other lower affinity cations, such as the ammonium ion, that may be released from chloramine disinfectants commonly used in drinking water and which might otherwise carryover through other downstream unit operations. If ammonium removal is one of its purposes, the softener must be located downstream of the disinfectant removal operation, which itself may liberate ammonium from neutralized chloramine disinfectants. Water softener resin beds are regenerated with concentrated sodium chloride solution (brine). Concerns include microorganism proliferation, channeling caused by biofilm agglomeration of resin particles, appropriate water flow rates and contact time, ion-exchange capacity, organic and particulate resin fouling, organic leaching from new resins, fracture of the resin beads, resin degradation by excessively chlorinated water, and contamination from the brine solution used for regeneration. Control measures involve recirculation of water during periods of low water use, periodic sanitization of the resin and brine system, use of microbial control devices (e.g., UV light and chlorine), locating the unit upstream of the disinfectant removal step (if used only for softening), appropriate regeneration frequency, effluent chemical 51

Generation of pharmaceutical water monitoring (e.g., hardness ions and possibly ammonium), and downstream filtration to remove resin fines. If a softener is used for ammonium removal from chloramine-containing source water, then capacity, contact time, resin surface fouling, pH, and regeneration frequency are very important.

Deionization Deionization (DI), and continuous electrodeionization (CEDI) are effective methods of improving the chemical quality attributes of water by removing cations and anions. DI systems have charged resins that require periodic regeneration with an acid and base. Typically, cationic resins are regenerated with either hydrochloric or sulfuric acid, which replace the captured positive ions with hydrogen ions. Anionic resins are regenerated with sodium or potassium hydroxide, which replace captured negative ions with hydroxide ions. Because free endotoxin is negatively charged, there is some removal of endotoxin achieved by the anionic resin. Both regenerant chemicals are biocidal and offer a measure of microbial control. The system can be designed so that the cation and anion resins are in separate or â&#x20AC;&#x153;twinâ&#x20AC;? beds or they can be mixed together to form a mixed bed. Twin beds are easily regenerated but deionize water less efficiently than mixed beds, which have a considerably more complex regeneration process.

Rechargeable resin canisters can also be used for this purpose.

The CEDI system uses a combination of mixed resin, selectively permeable membranes, and an electric charge, providing continuous flow (product and waste concentrate) and continuous regeneration. Water enters both the resin section and the waste (concentrate) section. As it passes through the resin, it is deionized to become product water. The resin acts as a conductor enabling the electrical potential to drive the captured cations and anions through the resin and appropriate membranes for concentration and removal in the waste water stream. The electrical potential also separates the water in the resin (product) section into hydrogen and hydroxide ions. This permits continuous regeneration of the resin without the need for regenerant additives. However, unlike conventional deionization, CEDI units must start with water that is already partially purified because they generally cannot produce Purified Water quality when starting with the heavier ion load of unpurified source water.

Concerns for all forms of deionization units include microbial and endotoxin control, chemical additive impact on resins and membranes, and loss, degradation, and fouling of resin. Issues of concern specific to DI units include regeneration frequency and completeness, channeling, caused by biofilm agglomeration of resin particles, organic leaching from new resins, complete 52

Generation of pharmaceutical water resin separation for mixed bed regeneration, and mixing air contamination (mixed beds). Control measures vary but typically include recirculation loops, effluent microbial control by UV light, conductivity monitoring, resin testing, microporous filtration of mixing air, microbial monitoring, frequent regeneration to minimize and control microorganism growth, sizing the equipment for suitable water flow and contact time, and use of elevated temperatures. Internal distributor and regeneration piping for mixed bed units should be configured to ensure that regeneration chemicals contact all internal bed and piping surfaces and resins. Rechargeable canisters can be the source of contamination and should be carefully monitored. Full knowledge of previous resin use, minimum storage time between regeneration and use, and appropriate sanitizing procedures are critical factors ensuring proper performance.

Reverse Osmosis Reverse osmosis (RO) units employ semipermeable membranes. The â&#x20AC;&#x153;poresâ&#x20AC;? of RO membranes are actually intersegmental spaces among the polymer molecules. They are big enough for permeation of water molecules, but too small to permit passage of hydrated chemical ions.

However, many factors including pH, temperature, and differential pressure across the membrane affect the selectivity of this permeation. With the proper controls, RO membranes can achieve chemical, microbial, and endotoxin quality improvement. The process streams consist of supply water, product water (permeate), and wastewater (reject).

Depending on source water, pretreatment and system configuration variations and chemical additives may be necessary to achieve desired performance and reliability.

A major factor affecting RO performance is the permeate recovery rate, that is, the amount of the water passing through the membrane compared to the amount rejected. This is influenced by the several factors, but most significantly by the pump pressure. Recoveries of 75% are typical, and can accomplish a 1 to 2 log purification of most impurities. For most feed waters, this is usually not enough to meet Purified Water conductivity specifications. A second pass of this permeate water through another RO stage usually achieves the necessary permeate purity if other factors such as pH and temperature have been appropriately adjusted and the ammonia from chloraminated source water has been previously removed. Increasing recoveries with higher pressures in order to reduce the volume of reject water will lead to reduced permeate purity. If increased pressures are needed over time to achieve the same permeate flow, this is an indication of partial membrane blockage that needs to be corrected before it becomes irreversibly fouled, and expensive membrane replacement is the only option.

53

Generation of pharmaceutical water Other concerns associated with the design and operation of RO units include membrane materials that are extremely sensitive to sanitizing agents and to particulate, chemical, and microbial membrane fouling; membrane and seal integrity; the passage of dissolved gases, such as carbon dioxide and ammonia; and the volume of wastewater, particularly where water discharge is tightly regulated by local authorities. Failure of membrane or seal integrity will result in product water contamination. Methods of control involve suitable pretreatment of the influent water stream, appropriate membrane material selection, integrity challenges, membrane design and heat tolerance, periodic sanitization, and monitoring of differential pressures, conductivity, microbial levels, and TOC. The development of RO units that can tolerate sanitizing water temperatures as well as operate efficiently and continuously at elevated temperatures has added greatly to their microbial control and to the avoidance of biofouling. RO units can be used alone or in combination with DI and CEDI units as well as ultrafiltration for operational and quality enhancements.

Ultrafiltration Ultrafiltration is a technology most often employed in pharmaceutical water systems for removing endotoxins from a water stream. It can also use semipermeable membranes, but unlike RO, these typically use polysulfone membranes whose intersegmental “pores” have been purposefully exaggerated during their manufacture by preventing the polymer molecules from reaching their smaller equilibrium proximities to each other. Depending on the level of equilibrium control during their fabrication, membranes with differing molecular weight “cutoffs” can be created such that molecules with molecular weights above these cutoffs ratings are rejected and cannot penetrate the filtration matrix.

Ceramic ultrafilters are another molecular sieving technology. Ceramic ultrafilters are self supporting and extremely durable, back washable, chemically cleanable, and steam sterilizable.

However, they may require higher operating pressures than membrane type ultrafilters.

All ultrafiltration devices work primarily by a molecular sieving principle. Ultrafilters with molecular weight cutoff ratings in the range of 10,000 to 20,000 Da are typically used in water systems for removing endotoxins. This technology may be appropriate as an intermediate or final purification step. Similar to RO, successful performance is dependent upon pretreatment of the water by upstream unit operations.

Issues of concern for ultrafilters include compatibility of membrane material with heat and sanitizing agents, membrane integrity, fouling by particles and microorganisms, and seal 54

Generation of pharmaceutical water integrity. Control measures involve filtration medium selection, sanitization, flow design (dead end vs. tangential), integrity challenges, regular cartridge changes, elevated feed water temperature, and monitoring TOC and differential pressure. Additional flexibility in operation is possible based on the way ultrafiltration units are arranged such as in a parallel or series configurations. Care should be taken to avoid stagnant water conditions that could promote microorganism growth in back-up or standby units.

Charge-Modified Filtration

Charge-modified filters are usually microbially retentive filters that are treated during their manufacture to have a positive charge on their surfaces. Microbial retentive filtration will be described in a subsequent section, but the significant feature of these membranes is their electrostatic surface charge. Such charged filters can reduce endotoxin levels in the fluids passing through them by their adsorption (owing to endotoxin's negative charge) onto the membrane surfaces. Though ultrafilters are more often employed as a unit operation for endotoxin removal in water systems, charge-modified filters may also have a place in endotoxin removal particularly where available upstream pressures are not sufficient for ultrafiltration and for a single, relatively short term use. Charge-modified filters may be difficult to validate for long-term or large-volume endotoxin retention. Even though their purified standard endotoxin retention can be well characterized, their retention capacity for “natural” endotoxins is difficult to gauge. Nevertheless, utility could be demonstrated and validated as short-term, single-use filters at points of use in water systems that are not designed for endotoxin control or where only an endotoxin “polishing” (removal of only slight or occasional endotoxin levels) is needed.

Control and validation concerns include volume and duration of use, flow rate, water conductivity and purity, and constancy and concentration of endotoxin levels being removed. All of these factors may have to be evaluated and challenged prior to using this approach, making this a difficult-to-validate application. Even so, there may still be a possible need for additional backup endotoxin testing both upstream and downstream of the filter.

Microbial-Retentive Filtration

Microbial-retentive membrane filters have experienced an evolution of understanding in the past decade that has caused previously held theoretical retention mechanisms to be reconsidered.

These filters have a larger effective “pore size” than ultrafilters and are intended to prevent the passage of microorganisms and similarly sized particles without unduly restricting flow. This 55

Generation of pharmaceutical water type of filtration is widely employed within water systems for filtering the bacteria out of both water and compressed gases as well as for vent filters on tanks and stills and other unit operations. However, the properties of the water system microorganisms seem to challenge a filter's microbial retention from water with phenomena absent from other aseptic filtration applications, such as filter sterilizing of pharmaceutical formulations prior to packaging. In the latter application, sterilizing grade filters are generally considered to have an assigned rating of 0.2 or 0.22 Gm. This rather arbitrary rating is associated with filters that have the ability to retain a high level challenge of a specially prepared inoculum of Brevundimonas (formerly Pseudomonas) diminuta. This is a small microorganism originally isolated decades ago from a product that had been â&#x20AC;&#x153;filter sterilizedâ&#x20AC;? using a 0.45-Gm rated filter.

Further study revealed that a percentage of cells of this microorganism could reproducibly penetrate the 0.45-Gm sterilizing filters. Through historic correlation of B. diminuta retaining tighter filters, thought to be twice as good as 0.45-Gm filter, assigned ratings of 0.2 or 0.22 Gm with their successful use in product solution filter sterilization, both this filter rating and the associated high level B. diminuta challenge have become the current benchmarks for sterilizing filtration. New evidence now suggests that for microbial-retentive filters used for pharmaceutical water, B. diminuta may not be the best model microorganism.

An archaic understanding of microbial retentive filtration would lead one to equate a filter's rating with the false impression of a simple sieve or screen that absolutely retains particles sized at or above the filter's rating. A current understanding of the mechanisms involved in microbial retention and the variables that can affect those mechanisms has yielded a far more complex interaction of phenomena than previously understood. A combination of simple sieve retention and surface adsorption are now known to contribute to microbial retention.

The following all interact to create some unusual and surprising retention phenomena for water system microorganisms: the variability in the range and average pore sizes created by the various membrane fabrication processes, the variability of the surface chemistry and three-dimensional structure related to the different polymers used in these filter matrices, and the size and surface properties of the microorganism intended to be retained by the filters. B. diminuta may not the best challenge microorganisms for demonstrating bacterial retention for 0.2- to 0.22-Gm rated filters for use in water systems because it appears to be more easily retained by these filters than some water system flora. The well-documented appearance of water system microorganisms on the downstream sides of some 0.2- to 0.22-Gm rated filters after a relatively short period of use 56

Generation of pharmaceutical water seems to support that some penetration phenomena are at work. Unknown for certain is if this downstream appearance is caused by a “blow-through” or some other pass-through phenomenon as a result of tiny cells or less cell “stickiness”, or by a “growth through” phenomenon as a result of cells hypothetically replicating their way through the pores to the downstream side. Whatever is the penetration mechanism, 0.2- to 0.22-Gm rated membranes may not be the best choice for some water system uses.

Microbial retention success in water systems has been reported with the use of some manufacturers' filters arbitrarily rated as 0.1 Gm. There is general agreement that for a given manufacturer, their 0.1-Gm rated filters are tighter than their 0.2- to 0.22-Gm rated filters.

However, comparably rated filters from different manufacturers in water filtration applications may not perform equivalently owing to the different filter fabrication processes and the nonstandardized microbial retention challenge processes currently used for defining the 0.1-Gm filter rating. It should be noted that use of 0.1-Gm rated membranes generally results in a sacrifice in flow rate compared to 0.2- to 0.22-Gm membranes, so whatever membranes are chosen for a water system application, the user must verify that the membranes are suitable for their intended application, use period, and use process, including flow rate.

For microbial retentive gas filtrations, the same sieving and adsorptive retention phenomena are at work as in liquid filtration, but the adsorptive phenomenon is enhanced by additional electrostatic interactions between particles and filter matrix. These electrostatic interactions are so strong that particle retention for a given filter rating is significantly more efficient in gas filtration than in water or product solution filtrations. These additional adsorptive interactions render filters rated at 0.2 to 0.22 Gm unquestionably suitable for microbial retentive gas filtrations. When microbially retentive filters are used in these applications, the membrane surface is typically hydrophobic (non-wettable by water). A significant area of concern for gas filtration is blockage of tank vents by condensed water vapor, which can cause mechanical damage to the tank. Control measures include electrical or steam tracing and a self-draining orientation of vent filter housings to prevent accumulation of vapor condensate. However, a continuously high filter temperature will take an oxidative toll on polypropylene components of the filter, so sterilization of the unit prior to initial use, and periodically thereafter, as well as regular visual inspections, integrity tests, and changes are recommended control methods.

In water applications, microbial retentive filters may be used downstream of unit operations that tend to release microorganisms or upstream of unit operations that are sensitive to 57

Generation of pharmaceutical water microorganisms. Microbial retentive filters may also be used to filter water feeding the distribution system. It should be noted that regulatory authorities allow the use of microbial retentive filters within distribution systems or even at use points if they have been properly validated and are appropriately maintained. A point-of-use filter should only be intended to â&#x20AC;&#x153;polishâ&#x20AC;? the microbial quality of an otherwise well-maintained system and not to serve as the primary microbial control device. The efficacy of system microbial control measures can only be assessed by sampling the water upstream of the filters. As an added measure of protection, inline UV lamps, appropriately sized for the flow rate (see Sanitization), may be used just upstream of microbial retentive filters to inactivate microorganisms prior to their capture by the filter. This tandem approach tends to greatly delay potential microbial penetration phenomena and can substantially extend filter service life.

Ultraviolet Light

The use of low-pressure UV lights that emit a 254-nm wavelength for microbial control is discussed under Sanitization, but the application of UV light in chemical purification is also emerging. This 254-nm wavelength is also useful in the destruction of ozone. With intense emissions at wavelengths around 185 nm (as well as at 254 nm), medium pressure UV lights have demonstrated utility in the destruction of the chlorine containing disinfectants used in source water as well as for interim stages of water pretreatment. High intensities of this wavelength alone or in combination with other oxidizing sanitants, such as hydrogen peroxide, have been used to lower TOC levels in recirculating distribution systems. The organics are typically converted to carbon dioxide, which equilibrates to bicarbonate, and incompletely oxidized carboxylic acids, both of which can easily be removed by polishing ion-exchange resins. Areas of concern include adequate UV intensity and residence time, gradual loss of UV emissivity with bulb age, gradual formation of UV-absorbing film at the water contact surface, incomplete photodegradation during unforeseen source water hyperchlorination, release of ammonia from chloramine photodegradation, unapparent UV bulb failure, and conductivity degradation in distribution systems using 185-nm UV lights. Control measures include regular inspection or emissivity alarms to detect bulb failures or film occlusions, regular UV bulb sleeve cleaning and wiping, downstream chlorine detectors, downstream polishing deionizers, and regular (approximately yearly) bulb replacement.

58

Generation of pharmaceutical water

Distillation

Distillation units provide chemical and microbial purification via thermal vaporization, mist elimination, and water vapor condensation. A variety of designs is available including single effect, multiple effect, and vapor compression. The latter two configurations are normally used in larger systems because of their generating capacity and efficiency. Distilled water systems require different feed water controls than required by membrane systems. For distillation, due consideration must be given to prior removal of hardness and silica impurities that may foul or corrode the heat transfer surfaces as well as prior removal of those impurities that could volatize and condense along with the water vapor. In spite of general perceptions, even the best distillation process cannot afford absolute removal of contaminating ions and endotoxin. Most stills are recognized as being able to accomplish at least a 3 to 4 log reduction in these impurity concentrations.

Areas of concern include carry-over of volatile organic impurities such as trihalomethanes (see Source and Feed Water Considerations) and gaseous impurities such as ammonia and carbon dioxide, faulty mist elimination, evaporator flooding, inadequate blowdown, stagnant water in condensers and evaporators, pump and compressor seal design, pinhole evaporator and condenser leaks, and conductivity (quality) variations during start-up and operation.

Methods of control may involve preliminary decarbonation steps to remove both dissolved carbon dioxide and other volatile or noncondensable impurities; reliable mist elimination to minimize feedwater droplet entrainment; visual or automated high water level indication to detect boiler flooding and boil over; use of sanitary pumps and compressors to minimize microbial and lubricant contamination of feedwater and condensate; proper drainage during inactive periods to minimize microbial growth and accumulation of associated endotoxin in boiler water; blow down control to limit the impurity concentration effect in the boiler to manageable levels; on-line conductivity sensing with automated diversion to waste to prevent unacceptable water upon still startup or still malfunction from getting into the finished water distribute system; and periodic integrity testing for pinhole leaks to routinely assure condensate is not compromised by nonvolatized source water contaminants.

Storage Tanks

Storage tanks are included in water distribution systems to optimize processing equipment capacity. Storage also allows for routine maintenance within the pretreatment train while maintaining continuous supply to meet manufacturing needs. Design and operation 59

Generation of pharmaceutical water considerations are needed to prevent or minimize the development of biofilm, to minimize corrosion, to aid in the use of chemical sanitization of the tanks, and to safeguard mechanical integrity. These considerations may include using closed tanks with smooth interiors, the ability to spray the tank headspace using sprayballs on recirculating loop returns, and the use of heated, jacketed/insulated tanks.

This minimizes corrosion and biofilm development and aids in thermal and chemical sanitization. Storage tanks require venting to compensate for the dynamics of changing water levels. This can be accomplished with a properly oriented and heat-traced filter housing fitted with a hydrophobic microbial retentive membrane filter affixed to an atmospheric vent.

Alternatively, an automatic membrane-filtered compressed gas blanketing system may be used.

In both cases, rupture disks equipped with a rupture alarm device should be used as a further safeguard for the mechanical integrity of the tank. Areas of concern include microbial growth or corrosion due to irregular or incomplete sanitization and microbial contamination from unalarmed rupture disk failures caused by condensate-occluded vent filters.

Distribution Systems

Distribution system configuration should allow for the continuous flow of water in the piping by means of recirculation. Use of nonrecirculating, dead-end, or one-way systems or system segments should be avoided whenever possible. If not possible, these systems should be periodically flushed and more closely monitored.

Experience has shown that continuously recirculated systems are easier to maintain. Pumps should be designed to deliver fully turbulent flow conditions to facilitate thorough heat distribution (for hot water sanitized systems) as well as thorough chemical sanitant distribution.

Turbulent flow also appear to either retard the development of biofilms or reduce the tendency of those biofilms to shed bacteria into the water. If redundant pumps are used, they should be configured and used to avoid microbial contamination of the system.

Components and distribution lines should be sloped and fitted with drain points so that the system can be completely drained. In stainless steel distribution systems where the water is circulated at a high temperature, dead legs and low-flow conditions should be avoided, and valved tie-in points should have length-to-diameter ratios of six or less. If constructed of heat tolerant plastic, this ratio should be even less to avoid cool points where biofilm development could occur. In ambient temperature distribution systems, particular care should be exercised to avoid or minimize dead leg ratios of any size and provide for complete drainage. If the system is 60

Generation of pharmaceutical water intended to be steam sanitized, careful sloping and low-point drainage is crucial to condensate removal and sanitization success. If drainage of components or distribution lines is intended as a microbial control strategy, they should also be configured to be completely dried using dry compressed air (or nitrogen if appropriate employee safety measures are used). Drained but still moist surfaces will still support microbial proliferation. Water exiting from the distribution system should not be returned to the system without first passing through all or a portion of the purification train.

The distribution design should include the placement of sampling valves in the storage tank and at other locations, such as in the return line of the recirculating water system. Where feasible, the primary sampling sites for water should be the valves that deliver water to the points of use.

Direct connections to processes or auxiliary equipment should be designed to prevent reverse flow into the controlled water system. Hoses and heat exchangers that are attached to points of use in order to deliver water for a particular use must not chemically or microbiologically degrade the water quality. The distribution system should permit sanitization for microorganism control. The system may be continuously operated at sanitizing conditions or sanitized periodically.

Installation, Materials of Construction, And Component Selection Installation techniques are important because they can affect the mechanical, corrosive, and sanitary integrity of the system. Valve installation attitude should promote gravity drainage. Pipe supports should provide appropriate slopes for drainage and should be designed to support the piping adequately under worst-case thermal and flow conditions. The methods of connecting system components including units of operation, tanks, and distribution piping require careful attention to preclude potential problems. Stainless steel welds should provide reliable joints that are internally smooth and corrosion-free. Low-carbon stainless steel, compatible wire filler, where necessary, inert gas, automatic welding machines, and regular inspection and documentation help to ensure acceptable weld quality.

Follow-up cleaning and passivation are important for removing contamination and corrosion products and to re-establish the passive corrosion resistant surface.

Plastic materials can be fused (welded) in some cases and also require smooth, uniform internal surfaces. Adhesive glues and solvents should be avoided due to the potential for voids and extractables. Mechanical methods of joining, such as flange fittings, require care to avoid the creation of offsets, gaps, penetrations, and voids. Control measures include good alignment, 61

Generation of pharmaceutical water properly sized gaskets, appropriate spacing, uniform sealing force, and the avoidance of threaded fittings.

Materials of construction should be selected to be compatible with control measures such as sanitizing, cleaning, and passivating. Temperature rating is a critical factor in choosing appropriate materials because surfaces may be required to handle elevated operating and sanitization temperatures. Should chemicals or additives be used to clean, control, or sanitize the system, materials resistant to these chemicals or additives must be utilized. Materials should be capable of handling turbulent flow and elevated velocities without wear of the corrosion-resistant film such as the passive chromium oxide surface of stainless steel. The finish on metallic materials such as stainless steel, whether it is a refined mill finish, polished to a specific grit, or an electropolished treatment, should complement system design and provide satisfactory corrosion and microbial activity resistance as well as chemical sanitizability. Auxiliary equipment and fittings that require seals, gaskets, diaphragms, filter media, and membranes should exclude materials that permit the possibility of extractables, shedding, and microbial activity. Insulating materials exposed to stainless steel surfaces should be free of chlorides to avoid the phenomenon of stress corrosion cracking that can lead to system contamination and the destruction of tanks and critical system components.

Specifications are important to ensure proper selection of materials and to serve as a reference for system qualification and maintenance. Information such as mill reports for stainless steel and reports of composition, ratings, and material handling capabilities for nonmetallic substances should be reviewed for suitability and retained for reference. Component (auxiliary equipment) selection should be made with assurance that it does not create a source of contamination intrusion. Heat exchangers should be constructed to prevent leakage of heat transfer medium to the pharmaceutical water and, for heat exchanger designs where prevention may fail; there should be a means to detect leakage. Pumps should be of sanitary design with seals that prevent contamination of the water. Valves should have smooth internal surfaces with the seat and closing device exposed to the flushing action of water, such as occurs in diaphragm valves.

Valves with pocket areas or closing devices (e.g., ball, plug, gate, globe) that move into and out of the flow area should be avoided.

Sanitization Microbial control in water systems is achieved primarily through sanitization practices. Systems can be sanitized using either thermal or chemical means. Thermal approaches to system 62

Generation of pharmaceutical water sanitization include periodic or continuously circulating hot water and the use of steam.

Temperatures of at least 80 are most commonly used for this purpose, but continuously recirculating water of at least 65 has also been used effectively in insulated stainless steel distribution systems when attention is paid to uniformity and distribution of such self-sanitizing temperatures. These techniques are limited to systems that are compatible with the higher temperatures needed to achieve sanitization. Although thermal methods control biofilm development by either continuously inhibiting their growth or, in intermittent applications, by killing the microorganisms within biofilms, they are not effective in removing established biofilms. Killed but intact biofilms can become a nutrient source for rapid biofilm regrowth after the sanitizing conditions are removed or halted. In such cases, a combination of routine thermal and periodic supplementation with chemical sanitization might be more effective. The more frequent the thermal sanitization, the more likely biofilm development and regrowth can be eliminated.

Chemical methods, where compatible, can be used on a wider variety of construction materials.

These methods typically employ oxidizing agents such as halogenated compounds, hydrogen peroxide, ozone, peracetic acid, or combinations thereof. Halogenated compounds are effective sanitizers but are difficult to flush from the system and may leave biofilms intact. Compounds such as hydrogen peroxide, ozone, and peracetic acid oxidize bacteria and biofilms by forming reactive peroxides and free radicals (notably hydroxyl radicals). The short half-life of ozone in particular, and its limitation on achievable concentrations require that it be added continuously during the sanitization process. Hydrogen peroxide and ozone rapidly degrade to water and oxygen; peracetic acid degrades to acetic acid in the presence of UV light. In fact, ozone's ease of degradation to oxygen using 254-nm UV lights at use points allow it to be most effectively used on a continuous basis to provide continuously sanitizing conditions.

In-line UV light at a wavelength of 254 nm can also be used to continuously â&#x20AC;&#x153;sanitizeâ&#x20AC;? water circulating in the system, but these devices must be properly sized for the water flow. Such devices inactivate a high percentage (but not 100%) of microorganisms that flow through the device but cannot be used to directly control existing biofilm upstream or downstream of the device. However, when coupled with conventional thermal or chemical sanitization technologies or located immediately upstream of a microbially retentive filter, it is most effective and can prolong the interval between system sanitizations.

63

Generation of pharmaceutical water It is important to note that microorganisms in a well-developed biofilm can be extremely difficult to kill, even by aggressive oxidizing biocides. The less developed and therefore thinner the biofilm, the more effective the biocidal action. Therefore, optimal biocide control is achieved by frequent biocide use that does not allow significant biofilm development between treatments.

Sanitization steps require validation to demonstrate the capability of reducing and holding microbial contamination at acceptable levels. Validation of thermal methods should include a heat distribution study to demonstrate that sanitization temperatures are achieved throughout the system, including the body of use point valves. Validation of chemical methods require demonstrating adequate chemical concentrations throughout the system, exposure to all wetted surfaces, including the body of use point valves, and complete removal of the sanitant from the system at the completion of treatment. Methods validation for the detection and quantification of residues of the sanitant or its objectionable degradants is an essential part of the validation program. The frequency of sanitization should be supported by, if not triggered by, the results of system microbial monitoring. Conclusions derived from trend analysis of the microbiological data should be used as the alert mechanism for maintenance.The frequency of sanitization should be established in such a way that the system operates in a state of microbiological control and does not routinely exceed alert levels (see Alert and Action Levels and Specifications).

Operation, Maintenance, and Control A preventive maintenance program should be established to ensure that the water system remains in a state of control. The program should include (1) procedures for operating the system, (2) monitoring programs for critical quality attributes and operating conditions including calibration of critical instruments, (3) schedule for periodic sanitization, (4) preventive maintenance of components, and (5) control of changes to the mechanical system and to operating conditions.

Operating Proceduresâ&#x20AC;&#x201D; Procedures for operating the water system and performing routine maintenance and corrective action should be written, and they should also define the point when action is required. The procedures should be well documented, detail the function of each job, assign who is responsible for performing the work, and describe how the job is to be conducted.

The effectiveness of these procedures should be assessed during water system validation.

Monitoring Programâ&#x20AC;&#x201D; Critical quality attributes and operating parameters should be documented and monitored. The program may include a combination of inline sensors or automated instruments (e.g., for TOC, conductivity, hardness, and chlorine), automated or manual documentation of operational parameters (such as flow rates or pressure drop across a 64

Generation of pharmaceutical water carbon bed, filter, or RO unit), and laboratory tests (e.g., total microbial counts). The frequency of sampling, the requirement for evaluating test results, and the necessity for initiating corrective action should be included.

Sanitizationâ&#x20AC;&#x201D; Depending on system design and the selected units of operation, routine periodic sanitization may be necessary to maintain the system in a state of microbial control.

Technologies for sanitization are described above.

Preventive Maintenanceâ&#x20AC;&#x201D; A preventive maintenance program should be in effect. The program should establish what preventive maintenance is to be performed, the frequency of maintenance work, and how the work should be documented.

Change Controlâ&#x20AC;&#x201D; The mechanical configuration and operating conditions must be controlled.

Proposed changes should be evaluated for their impact on the whole system. The need to requalify the system after changes are made should be determined. Following a decision to modify a water system, the affected drawings, manuals, and procedures should be revised.

SAMPLING CONSIDERATIONS Water systems should be monitored at a frequency that is sufficient to ensure that the system is in control and continues to produce water of acceptable quality.

Samples should be taken from representative locations within the processing and distribution system. Established sampling frequencies should be based on system validation data and should cover critical areas including unit operation sites. The sampling plan should take into consideration the desired attributes of the water being sampled. For example, systems for Water for Injection because of their more critical microbiological requirements, may require a more rigorous sampling frequency.

Analyses of water samples often serve two purposes: in-process control assessments and final quality control assessments. In-process control analyses are usually focused on the attributes of the water within the system. Quality control is primarily concerned with the attributes of the water delivered by the system to its various uses. The latter usually employs some sort of transfer device, often a flexible hose, to bridge the gap between the distribution system use-point valve and the actual location of water use. The issue of sample collection location and sampling procedure is often hotly debated because of the typically mixed use of the data generated from the samples, for both in-process control and quality control. In these single sample and mixed data use situations, the worst-case scenario should be utilized. In other words, samples should be collected from use points using the same delivery devices, such as hoses, and procedures, such as 65

Generation of pharmaceutical water preliminary hose or outlet flushing, as are employed by production from those use points. Where use points per se cannot be sampled, such as hard-piped connections to equipment, special sampling ports may be used. In all cases, the sample must represent as closely as possible the quality of the water used in production. If a point of use filter is employed, sampling of the water prior to and after the filter is needed because the filter will mask the microbial control achieved by the normal operating procedures of the system.

Samples containing chemical sanitizing agents require neutralization prior to microbiological analysis. Samples for microbiological analysis should be tested immediately, or suitably refrigerated to preserve the original microbial attributes until analysis can begin. Samples of flowing water are only indicative of the concentration of planktonic (free floating) microorganisms present in the system. Biofilm microorganisms (those attached to water system surfaces) are usually present in greater numbers and are the source of the planktonic population recovered from grab samples. Microorganisms in biofilms represent a continuous source of contamination and are difficult to directly sample and quantify. Consequently, the planktonic population is usually used as an indicator of system contamination levels and is the basis for system Alert and Action Levels. The consistent appearance of elevated planktonic levels is usually an indication of advanced biofilm development in need of remedial control. System control and sanitization are key in controlling biofilm formation and the consequent planktonic population.

Sampling for chemical analyses is also done for in-process control and for quality control purposes. However, unlike microbial analyses, chemical analyses can be and often are performed using on-line instrumentation. Such on-line testing has unequivocal in-process control purposes because it is not performed on the water delivered from the system. However, unlike microbial attributes, chemical attributes are usually not significantly degraded by hoses. Therefore, through verification testing, it may be possible to show that the chemical attributes detected by the online instrumentation (in-process testing) are equivalent to those detected at the ends of the use point hoses (quality control testing). This again creates a single sample and mixed data use scenario. It is far better to operate the instrumentation in a continuous mode, generating large volumes of in-process data, but only using a defined small sampling of that data for QC purposes. Examples of acceptable approaches include using highest values for a given period, highest time-weighted average for a given period (from fixed or rolling sub-periods), or values at a fixed daily time. Each approach has advantages and disadvantages relative to calculation 66

Generation of pharmaceutical water complexity and reflection of continuous quality, so the user must decide which approach is most suitable or justifiable.

Chemical Considerations The chemical attributes of Purified Water and Water for Injection were specified by a series of chemistry tests for various specific and nonspecific attributes with the intent of detecting chemical species indicative of incomplete or inadequate purification. While these methods could have been considered barely adequate to control the quality of these waters, they nevertheless stood the test of time. This was partly because the operation of water systems was, and still is, based on online conductivity measurements and specifications generally thought to preclude the failure of these archaic chemistry attribute tests.

USP moved away from these chemical attribute tests to contemporary analytical technologies for the bulk waters Purified Water and Water for Injection. The intent was to upgrade the analytical technologies without tightening the quality requirements. The two contemporary analytical technologies employed were TOC and conductivity. The TOC test replaced the test for Oxidizable substances that primarily targeted organic contaminants. A multi staged Conductivity test which detects ionic (mostly inorganic) contaminants replaced, with the exception of the test for Heavy metals, all of the inorganic chemical tests (i.e., Ammonia, Calcium, Carbon dioxide, Chloride, Sulfate).

Replacing the heavy metals attribute was considered unnecessary because (a) the source water specifications (found in the NPDWR) for individual Heavy metals were tighter than the approximate limit of detection of the Heavy metals test for USP XXII Water for Injection and Purified Water (approximately 0.1 ppm), (b) contemporary water system construction materials do not leach heavy metal contaminants, and (c) test results for this attribute have uniformly been negativeâ&#x20AC;&#x201D;there has not been a confirmed occurrence of a singular test failure (failure of only the Heavy metals test with all other attributes passing) since the current heavy metal drinking water standards have been in place. Nevertheless, since the presence of heavy metals in Purified Water or Water for Injection could have dire consequences, its absence should at least be documented during new water system commissioning and validation or through prior test results records.

Total solids and pH are the only tests not covered by conductivity testing. The test for Total solids was considered redundant because the nonselective tests of conductivity and TOC could detect most chemical species other than silica, which could remain undetected in its colloidal form. Colloidal silica in Purified Water and Water for Injection is easily removed by most water 67

Generation of pharmaceutical water pretreatment steps and even if present in the water, constitutes no medical or functional hazard except under extreme and rare situations. In such extreme situations, other attribute extremes are also likely to be detected. It is, however, the user's responsibility to ensure fitness for use. If silica is a significant component in the source water, and the purification unit operations could be operated or fail and selectively allow silica to be released into the finished water (in the absence of co-contaminants detectable by conductivity), then either silica-specific or a total solids type testing should be utilized to monitor and control this rare problem.

The pH attribute was eventually recognized to be redundant to the conductivity test (which included pH as an aspect of the test and specification); therefore, pH was dropped as a separate attribute test.

The rationale used by USP to establish its conductivity specification took into consideration the conductivity contributed by the two least conductive former attributes of Chloride and Ammonia, thereby precluding their failure had those wet chemistry tests been performed. In essence, the Stage 3 conductivity specifications were established from the sum of the conductivities of the limit concentrations of chloride ions (from pH 5.0 to 6.2) and ammonia ions (from pH 6.3 to 7.0), plus the unavoidable contribution of other conductivity-contributing ions from water (H+ and OH–), dissolved atmospheric CO2 (as HCO3–), and an electro-balancing quantity of either Na+ of Cl–, depending on the pH-induced ionic imbalance. The Stage 2 conductivity specification is the lowest Value on this table, 2.1 GS/cm.

Microbial Considerations The major exogenous source of microbial contamination of bulk pharmaceutical water is source or feed water. Feed water quality must, at a minimum, meet the quality attributes of Drinking Water for which the level of coli forms are regulated. A wide variety of other microorganisms, chiefly Gram-negative bacteria, may be present in the incoming water. These microorganisms may compromise subsequent purification steps. Examples of other potential exogenous sources of microbial contamination include unprotected vents, faulty air filters, ruptured rupture disks, backflow from contaminated outlets, unsanitized distribution system “openings” including routine component replacements, inspections, repairs, and expansions, inadequate drain and airbreaks, and replacement activated carbon, deionizer resins, and regenerant chemicals. In these situations, the exogenous contaminants may not be normal aquatic bacteria but rather microorganisms of soil or even human origin. The detection of nonaquatic microorganisms may be an indication of a system component failure, which should trigger investigations that will 68

Generation of pharmaceutical water remediate their source. Sufficient care should be given to system design and maintenance in order to minimize microbial contamination from these exogenous sources.

Unit operations can be a major source of endogenous microbial contamination. Microorganisms present in feed water may adsorb to carbon bed, deionizer resins, filter membranes, and other unit operation surfaces and initiate the formation of a biofilm. In a high-purity water system, biofilm is an adaptive response by certain microorganisms to survive in this low nutrient environment. Downstream colonization can occur when microorganisms are shed from existing biofilm-colonized surfaces and carried to other areas of the water system. Microorganisms may also attach to suspended particles such as carbon bed fines or fractured resin particles. When the microorganisms become planktonic, they serve as a source of contamination to subsequent purification equipment (compromising its functionality) and to distribution systems.

Another source of endogenous microbial contamination is the distribution system itself.

Microorganisms can colonize pipe surfaces, rough welds, badly aligned flanges, valves, and unidentified dead legs, where they proliferate, forming a biofilm. The smoothness and composition of the surface may affect the rate of initial microbial adsorption, but once adsorbed, biofilm development, unless otherwise inhibited by sanitizing conditions, will occur regardless of the surface. Once formed, the biofilm becomes a continuous source of microbial contamination.

Endotoxin Considerations Endotoxins are lipopolysaccharides found in and shed from the cell envelope that is external to the cell wall of Gram-negative bacteria. Gram-negative bacteria that form biofilms can become a source of endotoxins in pharmaceutical waters. Endotoxins may occur as clusters of lipopolysaccharide molecules associated with living microorganisms, fragments of dead microorganisms or the polysaccharide slime surrounding biofilm bacteria, or as free molecules.

The free form of endotoxins may be released from cell surfaces of the bacteria that colonize the water system, or from the feed water that may enter the water system. Because of the multiplicity of endotoxin sources in a water system, endotoxin quantitation in a water system is not a good indicator of the level of biofilm abundance within a water system. Endotoxin levels may be minimized by controlling the introduction of free endotoxins and microorganisms in the feed water and minimizing microbial proliferation in the system. This may be accomplished through the normal exclusion or removal action afforded by various unit operations within the treatment

69

Generation of pharmaceutical water system as well as through system sanitization. Other control methods include the use of ultrafilters or charge-modified filters, either in-line or at the point of use.

Microbial Enumeration Considerations The objective of a water system microbiological monitoring program is to provide sufficient information to control and assess the microbiological quality of the water produced. Product quality requirements should dictate water quality specifications. An appropriate level of control may be maintained by using data trending techniques and, if necessary, limiting specific contraindicated microorganisms. Consequently, it may not be necessary to detect all of the microorganisms species present in a given sample. The monitoring program and methodology should indicate adverse trends and detect microorganisms that are potentially harmful to the finished product, process, or consumer. Final selection of method variables should be based on the individual requirements of the system being monitored.

It should be recognized that there is no single method that is capable of detecting all of the potential microbial contaminants of a water system. The methods used for microbial monitoring should be capable of isolating the numbers and types of organisms that have been deemed significant relative to in-process system control and product impact for each individual system.

Several criteria should be considered when selecting a method to monitor the microbial content of a pharmaceutical water system. These include method sensitivity, range of organisms types or species recovered, sample processing throughput, incubation period, cost, and methodological complexity. An alternative consideration to the use of the classical â&#x20AC;&#x153;cultureâ&#x20AC;? approaches is a sophisticated instrumental or rapid test method that may yield more timely results. However, care must be exercised in selecting such an alternative approach to ensure that it has both sensitivity and correlation to classical culture approaches, which are generally considered the accepted standards for microbial enumeration.

Consideration should also be given to the timeliness of microbial enumeration testing after sample collection. The number of detectable planktonic bacteria in a sample collected in a scrupulously clean sample container will usually drop as time passes. The planktonic bacteria within the sample will tend to either die or to irretrievably adsorb to the container walls reducing the number of viable planktonic bacteria that can be withdrawn from the sample for testing. The opposite effect can also occur if the sample container is not scrupulously clean and contains a low concentration of some microbial nutrient that could promote microbial growth within the sample container. Because the number of recoverable bacteria in a sample can change positively 70

Generation of pharmaceutical water or negatively over time after sample collection, it is best to test the samples as soon as possible after being collected. If it is not possible to test the sample within about 2 hours of collection, the sample should be held at refrigerated temperatures (2°C to 8°C) for a maximum of about 12 hours to maintain the microbial attributes until analysis. In situations where even this is not possible (such as when using off-site contract laboratories), testing of these refrigerated samples should be performed within 48 hours after sample collection. In the delayed testing scenario, the recovered microbial levels may not be the same as would have been recovered had the testing been performed shortly after sample collection.

Therefore, studies should be performed to determine the existence and acceptability of potential microbial enumeration aberrations caused by protracted testing delays.

The Classical Culture Approach

Classical culture approaches for microbial testing of water include but are not limited to pour plates, spread plates, membrane filtration, and most probable number (MPN) tests. These methods are generally easy to perform, are less expensive, and provide excellent sample processing throughput. Method sensitivity can be increased via the use of larger sample sizes.

This strategy is used in the membrane filtration method. Culture approaches are further defined by the type of medium used in combination with the incubation temperature and duration. This combination should be selected according to the monitoring needs presented by a specific water system as well as its ability to recover the microorganisms of interest: those that could have a detrimental effect on the product or process uses as well as those that reflect the microbial control status of the system.

There are two basic forms of media available for traditional microbiological analysis: “high nutrient” and “low nutrient”. High-nutrient media such as plate count agar (TGYA) and m-HPC agar (formerly m-SPC agar), are intended as general media for the isolation and enumeration of heterotrophic or “copiotrophic” bacteria. Lownutrient media such as R2A agar and NWRI agar (HPCA), may be beneficial for isolating slow growing “oligotrophic” bacteria and bacteria that require lower levels of nutrients to grow optimally. Often some facultative oligotrophic bacteria are able to grow on high nutrient media and some facultative copiotrophic bacteria are able to grow on low-nutrient media, but this overlap is not complete. Low-nutrient and high-nutrient cultural approaches may be concurrently used, especially during the validation of a water system, as well as periodically thereafter. This concurrent testing could determine if any additional numbers or types of bacteria can be preferentially recovered by one of the approaches. If so, the 71

Generation of pharmaceutical water impact of these additional isolates on system control and the end uses of the water could be assessed.

Also, the efficacy of system controls and sanitization on these additional isolates could be assessed.

Duration and temperature of incubation are also critical aspects of a microbiological test method.

Classical methodologies using high nutrient media are typically incubated at 30 to 35 for 48 to 72 hours. Because of the flora in certain water systems, incubation at lower temperatures (e.g., 20°C to 25°C ) for longer periods (e.g., 5 to 7 days) can recover higher microbial counts when compared to classical methods. Low-nutrient media are designed for these lower temperature and longer incubation conditions (sometimes as long as 14 days to maximize recovery of very slow growing oligotrophs or sanitant injured microorganisms), but even high-nutrient media can sometimes increase their recovery with these longer and cooler incubation conditions. Whether or not a particular system needs to be monitored using high- or low-nutrient media with higher or lower incubation temperatures or shorter or longer incubation times should be determined during or prior to system validation and periodically reassessed as the microbial flora of a new water system gradually establish a steady state relative to its routine maintenance and sanitization procedures. The establishment of a “steady state” can take months or even years and can be perturbed by a change in use patterns, a change in routine and preventative maintenance or sanitization procedures, and frequencies, or any type of system intrusion, such as for component replacement, removal, or addition. The decision to use longer incubation periods should be made after balancing the need for timely information and the type of corrective actions required when an alert or action level is exceeded with the ability to recover the microorganisms of interest.

The advantages gained by incubating for longer times, namely recovery of injured microorganisms, slow growers, or more fastidious microorganisms, should be balanced against the need to have a timely investigation and to take corrective action, as well as the ability of these microorganisms to detrimentally affect products or processes. In no case, however, should incubation at 30°C to 35°C be less than 48 hours or less than 96 hours at 20°C to 25°C. Normally, the microorganisms that can thrive in extreme environments are best cultivated in the laboratory using conditions simulating the extreme environments from which they were taken.

Therefore, thermophilic bacteria might be able to exist in the extreme environment of hot pharmaceutical water systems, and if so, could only be recovered and cultivated in the laboratory if similar thermal conditions were provided. Thermophilic aquatic microorganisms do exist in 72

Generation of pharmaceutical water nature, but they typically derive their energy for growth from harnessing the energy from sunlight, from oxidation/reduction reactions of elements such as sulfur or iron, or indirectly from other microorganisms that do derive their energy from these processes. Such chemical/nutritional conditions do not exist in high purity water systems, whether ambient or hot. Therefore, it is generally considered pointless to search for thermophiles from hot pharmaceutical water systems owing to their inability to grow there.

The microorganisms that inhabit hot systems tend to be found in much cooler locations within these systems, for example, within use-point heat exchangers or transfer hoses. If this occurs, the kinds of microorganisms recovered are usually of the same types that might be expected from ambient water systems. Therefore, the mesophilic microbial cultivation conditions described later in this chapter are usually adequate for their recovery.

â&#x20AC;&#x153;Instrumentalâ&#x20AC;? Approaches

Examples of instrumental approaches include microscopic visual counting techniques (e.g., epifluorescence and immune fluorescence) and similar automated laser scanning approaches and radiometric, impedometric, and biochemically based methodologies. These methods all possess a variety of advantages and disadvantages. Advantages could be their precision and accuracy or their speed of test result availability as compared to the classical cultural approach. In general, instrument approaches often have a shorter lead time for obtaining results, which could facilitate timely system control. This advantage, however, is often counterbalanced by limited sample processing throughput due to extended sample collection time, costly and/or labor-intensive sample processing, or other instrument and sensitivity limitations.

Furthermore, instrumental approaches are typically destructive, precluding subsequent isolate manipulation for characterization purposes. Generally, some form of microbial isolate characterization, if not full identification, may be a required element of water system monitoring.

Consequently, culturing approaches have traditionally been preferred over instrumental approaches because they offer a balance of desirable test attributes and post-test capabilities.

Suggested Methodologies

The following general methods were originally derived from Standard Methods for the Examination of Water and Wastewater, 17th Edition, American Public Health Association, Washington, DC 20005. Even though this publication has undergone several revisions since its first citation in this chapter, the methods are still considered appropriate for establishing trends in the number of colony-forming units observed in the routine microbiological monitoring of 73

Generation of pharmaceutical water pharmaceutical waters. It is recognized, however, that other combinations of media and incubation time and temperature may occasionally or even consistently result in higher numbers of colony-forming units being observed and/or different species being recovered.

The extended incubation periods that are usually required by some of the alternative methods available offer disadvantages that may outweigh the advantages of the higher counts that may be obtained. The somewhat higher baseline counts that might be observed using alternate cultural conditions would not necessarily have greater utility in detecting an excursion or a trend. In addition, some alternate cultural conditions using low-nutrient media tend to lead to the development of microbial colonies that are much less differentiated in colonial appearance, an attribute that microbiologists rely on when selecting representative microbial types for further characterization. It is also ironical that the nature of some of the slow growers and the extended incubation times needed for their development into visible colonies may also lead to those colonies being largely nonviable, which limits their further characterization and precludes their subculture and identification.

Methodologies that can be suggested as generally satisfactory for monitoring pharmaceutical water systems are as follows. However, it must be noted that these are not referee methods nor are they necessarily optimal for recovering microorganisms from all water systems. The users should determine through experimentation with various approaches which methodologies are best for monitoring their water systems for in-process control and quality control purposes as well as for recovering any contraindicated species they may have specified.

Identification of Microorganisms Identifying the isolates recovered from water monitoring methods may be important in instances where specific waterborne microorganisms may be detrimental to the products or processes in which the water is used. Microorganism information such as this may also be useful when identifying the source of microbial contamination in a product or process. Often a limited group of microorganisms is routinely recovered from a water system. After repeated recovery and characterization, an experienced microbiologist may become proficient at their identification based on only a few recognizable traits such as colonial morphology and staining characteristics.

This may allow for a reduction in the number of identifications to representative colony types, or, with proper analyst qualification, may even allow testing short cuts to be taken for these microbial identifications.

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Generation of pharmaceutical water Alert and Action Levels and Specifications Though the use of alert and action levels is most often associated with microbial data, they can be associated with any attribute. In pharmaceutical water systems, almost every quality attribute, other than microbial quality, can be very rapidly determined with near-real time results. These short-delay data can give immediate system performance feedback, serving as ongoing process control indicators. However, because some attributes may not continuously be monitored or have a long delay in data availability (like microbial monitoring data), properly established Alert and Action Levels can serve as an early warning or indication of a potentially approaching quality shift occurring between or at the next periodic monitoring. In a validated water system, process controls should yield relatively constant and more than adequate values for these monitored attributes such that their Alert and Action Levels are infrequently broached.

As process control indicators, alert and action levels are designed to allow remedial action to occur that will prevent a system from deviating completely out of control and producing water unfit for its intended use. This “intended use” minimum quality is sometimes referred to as a “specification” or “limit”. In the opening paragraphs of this chapter, rationale was presented for no microbial specifications being included within the body of the bulk water (Purified Water and Water for Injection) monographs. This does not mean that the user should not have microbial specifications for these waters. To the contrary, in most situations such specifications should be established by the user. The microbial specification should reflect the maximum microbial level at which the water is still fit for use without compromising the quality needs of the process or product where the water is used. Because water from a given system may have many uses, the most stringent of these uses should be used to establish this specification.

Where appropriate, a microbial specification could be qualitative as well as quantitative. In other words, the number of total microorganisms may be as important as the number of a specific microorganism or even the absence of a specific microorganism. Microorganisms that are known to be problematic could include opportunistic or overt pathogens, nonpathogenic indicators of potentially undetected pathogens, or microorganisms known to compromise a process or product, such as by being resistant to a preservative or able to proliferate in or degrade a product. These microorganisms comprise an often ill-defined group referred to as “objectionable microorganisms”. Because objectionable is a term relative to the water's use, the list of microorganisms in such a group should be tailored to those species with the potential to be present and problematic. Their negative impact is most often demonstrated when they are present 75

Generation of pharmaceutical water in high numbers, but depending on the species, an allowable level may exist, below which they may not be considered objectionable.

As stated above, alert and action levels for a given process control attribute are used to help maintain system control and avoid exceeding the pass/fail specification for that attribute. Alert and action levels may be both quantitative and qualitative. They may involve levels of total microbial counts or recoveries of specific microorganisms. Alert levels are events or levels that, when they occur or are exceeded, indicate that a process may have drifted from its normal operating condition. Alert level excursions constitute a warning and do not necessarily require a corrective action. However, alert level excursions usually lead to the alerting of personnel involved in water system operation as well as QA. Alert level excursions may also lead to additional monitoring with more intense scrutiny of resulting and neighboring data as well as other process indicators. Action levels are events or higher levels that, when they occur or are exceeded, indicate that a process is probably drifting from its normal operating range. Examples of kinds of action level “events” include exceeding alert levels repeatedly; or in multiple simultaneous locations, a single occurrence of exceeding a higher microbial level; or the individual or repeated recovery of specific objectionable microorganisms. Exceeding an action level should lead to immediate notification of both QA and personnel involved in water system operations so that corrective actions can immediately be taken to bring the process back into its normal operating range. Such remedial actions should also include efforts to understand and eliminate or at least reduce the incidence of a future occurrence. A root cause investigation may be necessary to devise an effective preventative action strategy. Depending on the nature of the action level excursion, it may also be necessary to evaluate its impact on the water uses during that time. Impact evaluations may include delineation of affected batches and additional or more extensive product testing. It may also involve experimental product challenges.

Alert and action levels should be derived from an evaluation of historic monitoring data called a trend analysis. Other guidelines on approaches that may be used, ranging from “inspectional”to statistical evaluation of the historical data have been published. The ultimate goal is to understand the normal variability of the data during what is considered a typical operational period. Then, trigger points or levels can be established that will signal when future data may be approaching (alert level) or exceeding (action level) the boundaries of that “normal variability”.

Such alert and action levels are based on the control capability of the system as it was being maintained and controlled during that historic period of typical control.

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Generation of pharmaceutical water In new water systems where there is very limited or no historic data from which to derive data trends, it is common to simply establish initial alert and action levels based on a combination of equipment design capabilities but below the process and product specifications where water is used. It is also common, especially for ambient water systems, to microbiologically “mature” over the first year of use. By the end of this period, a relatively steady state microbial population (microorganism types and levels) will have been allowed or promoted to develop as a result of the collective effects of routine system maintenance and operation, including the frequency of unit operation re beddings, back washings, regenerations, and sanitizations. This microbial population will typically be higher than was seen when the water system was new, so it should be expected that the data trends (and the resulting alert and action levels) will increase over this “maturation” period and eventually level off.

A water system should be designed so that performance-based alert and action levels are well below water specifications. With poorly designed or maintained water systems, the system owner may find that initial new system microbial levels were acceptable for the water uses and specifications, but the mature levels are not. This is a serious situation, which if not correctable with more frequent system maintenance and sanitization, may require expensive water system renovation or even replacement. Therefore, it cannot be overemphasized that water systems should be designed for ease of microbial control, so that when monitored against alert and action levels, and maintained accordingly, the water continuously meets all applicable specifications.

An action level should not be established at a level equivalent to the specification. This leaves no room for remedial system maintenance that could avoid a specification excursion. Exceeding a specification is a far more serious event than an action level excursion. A specification excursion may trigger an extensive finished product impact investigation, substantial remedial actions within the water system that may include a complete shutdown, and possibly even product rejection.

Another scenario to be avoided is the establishment of an arbitrarily high and usually nonperformance based action level. Such unrealistic action levels deprive users of meaningful indicator values that could trigger remedial system maintenance. Unrealistically high action levels allow systems to grow well out of control before action is taken, when their intent should be to catch a system imbalance before it goes wildly out of control.

Because alert and action levels should be based on actual system performance, and the system performance data are generated by a given test method, it follows that those alert and action 77

Generation of pharmaceutical water levels should be valid only for test results generated by the same test method. It is invalid to apply alert and action level criteria to test results generated by a different test method. The two test methods may not equivalently recover microorganisms from the same water samples.

Similarly invalid is the use of trend data to derive alert and action levels for one water system, but applying those alert and action levels to a different water system. Alert and action levels are water system and test method specific.

Nevertheless, there are certain maximum microbial levels above which action levels should never be established. Water systems with these levels should unarguably be considered out of control. Using the microbial enumeration methodologies suggested above, generally considered maximum action levels are 100 cfu per mL for Purified Water and 10 cfu per 100 mL for Water for Injection. However, if a given water system controls microorganisms much more tightly than these levels, appropriate alert and action levels should be established from these tighter control levels so that they can truly indicate when water systems may be starting to trend out of control.

These in-process microbial control parameters should be established well below the user-defined microbial specifications that delineate the water's fitness for use.

Special consideration is needed for establishing maximum microbial action levels for Drinking Water because the water is often delivered to the facility in a condition over which the user has little control. High microbial levels in Drinking Water may be indicative of a municipal water system upset, broken water main, or inadequate disinfection, and therefore, potential contamination with objectionable microorganisms. Using the suggested microbial enumeration methodology, a reasonable maximum action level for Drinking Water is 500 cfu per mL. Considering the potential concern for objectionable microorganisms raised by such high microbial levels in the feed water, informing the municipality of the problem so they may begin corrective actions should be an immediate first step. In-house remedial actions may or may not also be needed, but could include performing additional coli form testing on the incoming water and pre treating the water with either additional chlorination or UV light irradiation or filtration or a combination of approaches.

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CHAPTER 4 GUIDE TO INSPECTIONS OF HIGH PURITY WATER SYSTEMS

System Design One of the basic considerations in the design of a system is the type of product that is to be manufactured. For parenteral products where there is a concern for pyrogens, it is expected that Water for Injection will be used. This applies to the formulation of products, as well as to the final washing of components and equipment used in their manufacture. Distillation and Reverse Osmosis (RO) filtration are the only acceptable methods listed in the USP for producing Water for Injection. However, in the bulk Pharmaceutical and Biotechnology industries and some foreign companies, Ultra Filtration (UF) is employed to minimize endotoxins in those drug substances that are administered parenterally.

For some ophthalmic products, such as the ophthalmic irrigating solution, and some inhalation products, such as Sterile Water for Inhalation, where there are pyrogen specifications, it is expected that Water for Injection be used in their formulation. However, for most inhalation and ophthalmic products, purified water is used in their formulation. This also applies to topicals, cosmetics and oral products.

Another design consideration is the temperature of the system. It is recognized that hot (65 80oC) systems are self sanitizing. While the cost of other systems may be less expensive for a company, the cost of maintenance, testing and potential problems may be greater than the cost of energy saved. Whether a system is circulating or one-way is also an important design consideration. Obviously, water in constant motion is less liable to have high levels of contaminant. A one-way water system is basically a "dead-leg".

Finally, and possibly the most important consideration, is the risk assessment or level of quality that is desired. It should be recognized that different products require different quality waters.

Parenterals require very pure water with no endotoxins. Topical and oral products require less pure water and do not have a requirement for endotoxins. Even with topical and oral products there are factors that dictate different qualities for water. For example, preservatives in antacids are marginally effective, so more stringent microbial limits have to be set. The quality control 79

Generation of pharmaceutical water department should assess each product manufactured with the water from their system and determine the microbial action limits based on the most microbial sensitive product. In lieu of stringent water action limits in the system the manufacturer can add a microbial reduction step in the manufacturing process for the sensitive drug product(s).

System Validation The FDA provides guidance and states that, "Validation often involves the use of an appropriate challenge. In this situation, it would be undesirable to introduce microorganisms into an on-line system; therefore, reliance is placed on periodic testing for microbiological quality and on the installation of monitoring equipment at specific checkpoints to ensure that the total system is operating properly and continuously fulfilling its intended function."

In the review of a validation report, or in the validation of a high purity water system, there are several aspects that should be considered. Documentation should include a description of the system along with a print. The drawing needs to show all equipment in the system from the water feed to points of use. It should also show all sampling points and their designations. If a system has no print, it is usually considered an objectionable condition. The thinking is if there is no print, then how can the system be validated? How can a quality control manager or microbiologist know where to sample? In those facilities observed without updated prints, serious problems were identified in these systems. The print should be compared to the actual system annually to insure its accuracy, to detect unreported changes and confirm reported changes to the system.

After all the equipment and piping has been verified as installed correctly and working as specified, the initial phase of the water system validation can begin. During this phase the operational parameters and the cleaning/ sanitization procedures and frequencies will be developed. Sampling should be daily after each step in the purification process and at each point of use for two to four weeks. The sampling procedure for point of use sampling should reflect how the water is to be drawn e.g. if a hose is usually attached the sample should be taken at the end of the hose. If the SOP calls for the line to be flushed before use of the water from that point, then the sample is taken after the flush. At the end of the two to four week time period the firm should have developed itâ&#x20AC;&#x2122;s SOPs for operation of the water system.

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Generation of pharmaceutical water The second phase of the system validation is to demonstrate that the system will consistently produce the desired water quality when operated in conformance with the SOPs. The sampling is performed as in the initial phase and for the same time period. At the end of this phase the data should demonstrate that the system will consistently produce the desired quality of water.

The third phase of validation is designed to demonstrate that when the water system is operated in accordance with the SOPs over a long period of time it will consistently produce water of the desired quality. Any variations in the quality of the feed water that could affect the operation and ultimately the water quality will be picked up during this phase of the validation. Sampling is performed according to routine procedures and frequencies. For Water for Injection systems the samples should be taken daily from a minimum of one point of use, with all points of use tested weekly. The validation of the water system is completed when the firm has a full years worth of data.

While the above validation scheme is not the only way a system can be validated, it contains the necessary elements for validation of a water system. First, there must be data to support the SOPs. Second, there must be data demonstrating that the SOPs are valid and that the system is capable of consistently producing water that meets the desired specifications. Finally, there must be data to demonstrate that seasonal variations in the feed water do not adversely affect the operation of the system or the water quality.

The last part of the validation is the compilation of the data, with any conclusions into the final report. The final validation report must be signed by the appropriate people responsible for operation and quality assurance of the water system.

A typical problem that occurs is the failure of operating procedures to preclude contamination of the system with non-sterile air remaining in a pipe after drainage. A typical problem occurs when a washer or hose connection is flushed and then drained at the end of the operation. After draining, this valve (the second off of the system) is closed. If on the next day or start-up of the operation the primary valve off of the circulating system is opened, then the non-sterile air remaining in the pipe after drainage would contaminate the system. The solution is to pro-vide for operational procedures that provide for opening the secondary valve before the primary valve to flush the pipe prior to use.

Another major consideration in the validation of high purity water systems is the acceptance criteria. Consistent results throughout the system over a period of time constitute the primary element.

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Generation of pharmaceutical water Microbial Limits

Water for Injection Systems

Regarding microbiological results, for Water For Injection, it is expected that they be essentially sterile. Since sampling frequently is performed in non-sterile areas and is not truly aseptic, occasional low level counts due to sampling errors may occur. Agency policy is that less than 10 CFU/100ml is an acceptable action limit. None of the limits for water are pass/fail limits. All limits are action limits. When action limits are exceeded the firm must investigate the cause of the problem, take action to correct the problem and assess the impact of the microbial contamination on products manufactured with the water and document the results of their investigation.

With regard to sample size, 100 - 300 mL is preferred when sampling Water for Injection systems. Sample volumes less than 100 mL are unacceptable.

The real concern in WFI is endotoxins. Because WFI can pass the LAL endotoxin test and still fail the above microbial action limit, it is important to monitor WFI systems for both endotoxins and microorganisms.

Purified Water Systems

For purified water systems, microbiological specifications are not as clear. USP XXII specifications, that it complies with federal Environmental Protection Agency regulations for drinking water, are recognized as being minimal specifications. There have been attempts by some to establish meaningful microbiological specifications for purified water. The CFTA proposed a specification of not more than 500 organisms per ml. The USP XXII has an action guideline of not greater than 100 organisms per ml. Although microbiological specifications have been discussed, none (other than EPA standards) have been established. Agency policy is that any action limit over 100 CFU/mL for a purified water system is unacceptable.

The purpose of establishing any action limit or level is to assure that the water system is under control. Any action limit established will depend upon the overall purified water system and further processing of the finished product and its use. For example, purified water used to manufacture drug products by cold processing should be free of objectionable organisms. We have defined "objectionable organisms" as any organisms that can cause infections when the drug product is used as directed or any organism capable of growth in the drug product. As pointed out in the Guide to Inspections of Microbiological Pharmaceutical Quality Control Laboratories, the specific contaminant, rather than the number is generally more significant.

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Generation of pharmaceutical water Organisms exist in a water system either as free floating in the water or attached to the walls of the pipes and tanks. When they are attached to the walls they are known as biofilm, which continuously slough off organisms. Thus, contamination is not uniformly distributed in a system and the sample may not be representative of the type and level of contamination. A count of 10 CFU/mL in one sample and 100 or even 1000 CFU/mL in a subsequent sample would not be unrealistic.

Thus, in establishing the level of contamination allowed in a high purity water system used in the manufacture of a non-sterile product requires an understanding of the use of the product, the formulation (preservative system) and manufacturing process. For example, antacids, which do not have an effective preservative system, require an action limit below the 100 CFU/mL maximum.

The USP gives some guidance in their monograph on Microbiological Attributes of Non-Sterile Products. It points out that, "The significance of microorganisms in non-sterile pharmaceutical products should be evaluated in terms of the use of the product, the nature of the product, and the potential harm to the user." Thus, not just the indicator organisms listed in some of the specific monographs present problems. It is up to each manufacturer to evaluate their product, the way it is manufactured, and establish an acceptable action level of contamination, not to exceed the maximum, for the water system, based on the highest risk product manufactured with the water.

Water for Injection Systems Pretreatment of feed water is recommended by most manufacturers of distillation equipment and is definitely required for RO units. The incoming feed water quality may fluctuate during the life of the system depending upon seasonal variations and other external factors beyond the control of the pharmaceutical facility. For example, in the spring (at least in the N.E.), increases in gram negative organisms have been known. Also, new construction or fires can cause a depletion of water stores in old mains which can cause an influx of heavily contaminated water of a different flora.

A water system should be designed to operate within these anticipated extremes. Obviously, the only way to know the extremes is to periodically monitor feed water. If the feed water is from a municipal water system, reports from the municipality testing can be used in lieu of in-house testing.

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Generation of pharmaceutical water More common, however, is the failure to adequately treat feed water to reduce levels of endotoxins. Many of the still fabricators will only guarantee a 2.5 log to 3 log reduction in the endotoxin content. Therefore, it is not surprising that in systems where the feed water occasionally spikes to 250 EU/ml, unacceptable levels of endotoxins may occasionally appear in the distillate (WFI). For example, recently three new stills, including two multi-effect, were found to be periodically yielding WFI with levels greater than .25 EU/ml. Pretreatment systems for the stills included only deionization systems with no UF, RO or distillation. Unless a firm has a satisfactory pretreatment system, it would be extremely difficult for them to demonstrate that the system is validated.

The above problems with distillation units used to produce WFI, point to problems with maintenance of the equipment or improper operation of the system indicating that the system has not been properly validated or that the initial validation is no longer valid. If you see these types of problems you should look very closely at the system design, any changes that have been made to the system, the validation report and the routine test data to determine if the system is operating in a state of control.

Typically, conductivity meters are used on water systems to monitor chemical quality and have no meaning regarding microbiological quality.

Heat Exchangers One principal component of the still is the heat exchanger. Because of the similar ionic quality of distilled and deionized water, conductivity meters cannot be used to monitor microbiological quality. Positive pressure such as in vapor compression or double tubesheet design should be employed to prevent possible feed water to distillate contamination in a leaky heat exchanger.

An FDA Inspectors Technical Guide with the subject of "Heat Exchangers to Avoid Contamination" discusses the design and potential problems associated with heat exchangers.

The guide points out that there are two methods for preventing contamination by leakage. One is to provide gauges to constantly monitor pressure differentials to ensure that the higher pressure is always on the clean fluid side. The other is to utilize the double-tubesheet type of heat exchanger.

In some systems, heat exchangers are utilized to cool water at use points. For the most part, cooling water is not circulated through them when not in use. In a few situations, pinholes formed in the tubing after they were drained (on the cooling water side) and not in use. It was determined that a small amount of moisture remaining in the tubes when combined with air 84

Generation of pharmaceutical water caused a corrosion of the stainless steel tubes on the cooling water side. Thus, it is recommended that when not in use, heat exchangers not be drained of the cooling water.

Holding Tank In hot systems, temperature is usually maintained by applying heat to a jacketed holding tank or by placing a heat exchanger in the line prior to an insulated holding tank.

The one component of the holding tank that generates the most discussion is the vent filter. It is expected that there be some program for integrity testing this filter to assure that it is intact.

Typically, filters are now jacketed to prevent condensate or water from blocking the hydrophobic vent filter. If this occurs (the vent filter becomes blocked), possibly either the filter will rupture or the tank will collapse. There are methods for integrity testing of vent filters in place.

It is expected, therefore, that the vent filter be located in a position on the holding tank where it is readily accessible.

Just because a WFI system is relatively new and distillation is employed, it is not problem-free.

In an inspection of a manufacturer of parenterals, a system fabricated in 1984 was observed..

While the system may appear somewhat complex on the initial review, it was found to be relatively simple. The observations at the conclusion of the inspection of this manufacturer included, "Operational procedures for the Water For Injection system failed to provide for periodic complete flushing or draining. The system was also open to the atmosphere and room environment. Compounding equipment consisted of non-sealed, open tanks with lids. The Water for Injection holding tank was also not sealed and was never sampled for endotoxins." Because of these and other comments, the firm recalled several products and discontinued operations.

Pumps Pumps burn out and parts wear. Also, if pumps are static and not continuously in operation, their reservoir can be a static area where water will lie. For example, in an inspection, it was noted that a firm had to install a drain from the low point in a pump housing. Pseudomonas sp. contamination was periodically found in their water system which was attributed in part to a pump which only periodically is operational.

Piping Piping in WFI systems usually consist of a high polished stainless steel. In a few cases, manufacturers have begun to utilize PVDF (polyvinylidene fluoride) piping. It is purported that this piping can tolerate heat with no extractables being leached. A major problem with PVDF tubing is that it requires considerable support. When this tubing is heated, it tends to sag and may 85

Generation of pharmaceutical water stress the weld (fusion) connection and result in leakage. Additionally, initially at least, fluoride levels are high. This piping is of benefit in product delivery systems where low level metal contamination may accelerate the degradation of drug product, such as in the Biotech industry.

One common problem with piping is that of "dead-legs". The proposed LVP Regulations defined dead-legs as not having an unused portion greater in length than six diameters of the unused pipe measured from the axis of the pipe in use. It should be pointed out that this was developed for hot 75 - 80o circulating systems. With colder systems (65 - 75oC), any drops or unused portion of any length of piping has the potential for the formation of a biofilm and should be eliminated if possible or have special sanitizing procedures. There should be n o threaded fittings in a pharmaceutical water system. All pipe joints must utilize sanitary fittings or be butt welded.

Sanitary fittings will usually be used where the piping meets valves, tanks and other equipment that must be removed for maintenance or replacement. Therefore, the firm's procedures for sanitization, as well as the actual piping, should be reviewed and evaluated during the inspection.

Reverse osmosis Another acceptable method for manufacturing Water for Injection is Reverse Osmosis (RO).

However, because these systems are cold, and because RO filters are not absolute, microbiological contamination is not unusual.

Also in this system were ball valves. These valves are not considered sanitary valves since the center of the valve can have water in it when the valve is closed. This is a stagnant pool of water that can harbor microorganisms and provide a starting point for a biofilm.

As an additional comment on RO systems, with the recognition of microbiological problems, some manufacturers have installed heat exchangers immediately after the RO filters to heat the water to 75 - 80oC to minimize microbiological contamination.

With the development of biotechnology products, many small companies are utilizing RO and UF systems to produce high purity water Most of these systems employ PVC or some type of plastic tubing. Because the systems are typically cold, the many joints in the system are subject to contamination. Another potential problem with PVC tubing is extractables. Looking at the WFI from a system to assure that it meets USP requirements without some assurance that there are no extractables would not be acceptable.

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Generation of pharmaceutical water

The systems also contain 0.2 micron point of use filters which can mask the level of microbiological contamination in the system. While it is recognized that endotoxins are the primary concern in such a system, a filter will reduce microbiological contamination, but not necessarily endotoxin contamination. If filters are used in a water system there should be a stated purpose for the filter, i.e., particulate removal or microbial reduction, and an SOP stating the frequency with which the filter is to be changed which is based on data generated during the validation of the system.

As previously discussed, because of the volume of water actually tested (.1ml for endotoxins vs.

100ml for WFI), the microbiological test offers a good index of the level of contamination in a system. Therefore, unless the water is sampled prior to the final 0.2 micron filter, microbiological testing will have little meaning.

Purified Water Systems Many of the comments regarding equipment for WFI systems are applicable to Purified Water Systems. One type system that has been used to control microbiological contamination utilizes ozone.

Published data for Vicks Greensboro, NC facility showed that their system was recontaminated in two to three days after the ozone generator was turned off. In an inspection of another manufacturer, it was noted that a firm was experiencing a contamination problem with Pseudomonas sp. Because of potential problems with employee safety, ozone was removed from the water prior to placing it in their recirculating system. It has been reported that dissolved ozone at a level of 0.45 mg/liter will remain in a system for a maximum of five to six hours.

Another manufacturer, as part of their daily sanitization, removes all drops off of their ozonated water system and disinfects them in filter sterilized 70% isopropyl alcohol. This manufacturer has reported excellent microbiological results. However, sampling is only performed immediately after sanitization and not at the end of operations. Thus, the results are not that meaningful.

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CHAPTER CHAPTER 5 WATER SYSTEMS FOR MANUFACTURERS OF NONNON-STERILE PRODUCTS This chapter provides guidance on the essential requirements for water purification systems, which are installed for the production of water used in the manufacture of non-sterile products. It must be emphasized that the validation of water systems is outside the scope of this document.

Water used in the manufacture of non-sterile medicinal products should comply with the BP, EP or USP monograph for Purified Water. Purified water could be prepared by distillation, by ion exchange, by reverse osmosis (RO) or by any other suitable method from potable water complying with World Health Organization (WHO) standard.

Requirements for Water System A water system for producing purified water typically consists of carbon filters to remove organic compounds dissolved in feed water, de-ionizers or RO units to remove dissolved solids, filters to remove un dissolved solids and bacterial contaminants. Additional features to control microbial growth in water systems include the use of UV irradiation.

Design of Water System Many of the design considerations presented below relates to achieving water with good microbiological properties:

Circulating Loop

Water system should be re-circulating to keep water moving (ideally at 1.5m/sec or higher). No flow or low flow conditions are conducive to microbial proliferation and the development of biofilm especially in water distribution pipings. A one-way water system is basically a â&#x20AC;&#x153;deadlegâ&#x20AC;?.

Piping

Piping should be sloped for proper drainage. Normally, BOP (bottom of pipe) elevations must be measured and documented in order to verify the slope to drain (this ensures that the piping can be completely drained).

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Generation of pharmaceutical water Dead legs should be minimized and eliminated downstream of storage tank. A dead leg is any length of piping more than six diameters away from circulating water.

The construction material of choice is stainless steel (e.g.316L) because of its chemical inertness, ease of sanitization and use over a wide range of temperature. The use of PVC (polyvinyl chloride) should be avoided especially downstream of de-ionizer or RO membrane, because it is prone to biofilm formation. Pipes should have lagging if heated water is circulated to prevent loss of heat.

Quality of Weld â&#x20AC;&#x201C; typically, in stainless steel piping, orbital welding is used and limit on concavity should be defined (convexities and concavities present at welding are focal points for bacterial growth). In plastic piping, solvent welding is commonly used. Screw fitting or push fit should be avoided.

Valves

Diaphragm valves should preferably be used in water systems, particularly downstream of deionizers or RO units, as they could be sanitized effectively. The same restrictions on choice of piping material apply to valves as well.

Storage Tanks

Storage tanks should be made of stainless steel. The size of the tank will depend on the demand on the system. Insulation is necessary on storage tanks in high-temperature systems; the tanks may also need to be jacketed in order to heat (or cool) the contents.

Storage tanks must be vented to allow for fluctuations in water levels in order to prevent collapse. The vent must be fitted with a sterilizing filter to prevent the air entering the tank from microbiologically contaminating the stored water (the filter should have porosity of less than 1 micron and hydrophobic). Integrity testing of the vent filter shall be performed regularly (e.g. once every 6 or 12 months).

Filters Filters are commonly found downstream of carbon and resin beds and on the incoming water supply line. They are typically in the mean porosity ranges of 5-50 micron upstream to the resin or RO unit and 1 to 5 microns after the resin or RO units.

Water Point and Use of Flexible Transfer Hoses Water points should be available at the production areas where water will be used for production.

The transfer of treated water to the point of use is done using transfer piping which are made of

89

Generation of pharmaceutical water suitable non-toxic material. These transfer piping should be drained after use and sanitized before use if necessary so that they do not contaminate the water during the transfer process.

Other Requirements for Water System

Sanitization

There should be written procedures for sanitization of the water system. The water system may be heated to about 80oC for an appropriate holding time and frequency to sanitize the storage tank, distribution pipings and valves. Chemical sanitization involving sodium hypochlorite, peracetic acid, hydrogen peroxide or ozone, may be used where appropriate. The frequency of sanitization will depend on validation results.

Maintenance program for carbon beds, resin/RO units and filters etc. The following maintenance procedures, where applicable, should be available: .

Resin regeneration or change procedure

.

RO membrane sanitization procedure

.

Filter sanitization and change procedure (including filter specifications)

.

Carbon bed sanitization and change procedure

.

Procedure for sanitization and storage of hoses and other equipment/devices not

permanently attached to the water system Procedure(s) for the shut-down and the start-up of the water system should be available.

Monitoring of water quality Treated water should comply with the chemical and microbiological quality specified in the monograph for Purified Water of official pharmacopoeias such as BP, EP or USP upon installation and before the water is used for routine production.

Routine monitoring of water quality should include samples taken at the point(s) of use. The frequency of monitoring should include daily on-line monitoring of conductivity (≤1.3 µs/cm at ≤35°C), weekly monitoring for compliance with microbiological specification (total viable count < 100cfu/mL), and monthly monitoring for compliance with full specification/monograph testing, unless otherwise justified by validation results. The above-mentioned chemical and microbiological specifications and those stipulated in the pharmacopoeial monographs for Purified Water are minimum requirements. It should be emphasized that the specifications are not intended to be totally inclusive for every situation where Purified Water as an ingredient is employed. It is therefore incumbent upon the manufacturer to supplement these general guidance notes to fit its particular situation. For example a manufacturer of creams and ointments may 90

Generation of pharmaceutical water wish to test for the absence of Pseudomonas aeruginosa on a routine basis if the water used as an ingredient is prepared by ion exchange.

Written procedure(s) for monitoring water quality should be available. Alert and action limits should be set and corrective actions to be taken in the event that the limits are exceeded should be documented.

Daily monitoring of key control parameters

Key control parameters, e.g. conductivity, temperature, flow rate and pH of treated water should be monitored on a daily basis and recorded.

91

Generation of pharmaceutical water

CHAPTER 6 SANITIZATION OF AUTOMATED WATERING SYSTEMS Definition of Sanitization Sanitization is not an absolute phenomenon. It is a partial removal of organisms. Depending on the system, a sanitization operation should reduce the organism population by some 90%. In water, sanitization is frequently defined as a 3-logarithm (log) or 1,000-fold reduction in the number of bacteria.

Continuous Treatment or Periodic Sanitization?

There are two basic approaches for controlling bacterial growth in a potable water system. One is to maintain a constant residual level of biocide chemical within the system (continuous dosing).

This is the technique that municipal water treatment facilities use when they inject enough chlorine to provide a residual throughout a citywide distribution system. Some research facilities continuously chlorinate or acidify their animal drinking water to control bacteria. For more information of continuous treatment, refer to these Edstrom Industries documents: â&#x20AC;˘ Drinking Water Chlorination â&#x20AC;˘ Drinking Water Acidification The second approach is to periodically sanitize. If for some reason the research protocol prohibits the use of continuous chlorination, then periodic sanitization will be required. Most systems using continuous dosing will also need a regular, although less frequent, periodic sanitization regimen. For example: in an acidified water system, chlorine sanitization may be needed periodically to kill acid-resistant microorganisms in an automated watering system.

Chemicals Used For Sanitization

Chemical biocides can be divided into two major groups: oxidizing and non-oxidizing. Oxidizing biocides include chlorine, chlorine dioxide, and ozone. Non-oxidizing biocides include quaternary ammonium compounds, formaldehyde, and anionic and nonionic surface-active agents.

92

Generation of pharmaceutical water

Common biocides and typical dosage levels. This table provides some general information about biocides. The table includes recommended contact times for various concentrations, as well as factors to consider when choosing a biocide to use with automated watering systems. Note that some biocides are not recommended for use with automated watering systems at all.

93

Generation of pharmaceutical water

Chlorine

The most common sanitizing agent is chlorine. Chlorine is the least expensive, most readily available, and is effective and easy to use. While ozone and chlorine dioxide are also effective biocides, there is little experience using these chemicals to sanitize automated watering systems.

This document will mainly address chlorine sanitization. For more information of the other sanitizing agents, refer to the Edstrom Industries paper on Biofilm. Since sanitizing chemicals are corrosive, contact Edstrom Industries for recommended concentrations and procedures for any other chemical agents.

The effectiveness of a sanitizing agent is a product of both concentration and contact time.

Typical sanitization of an automated watering system is accomplished using 20 ppm chlorine for 30â&#x20AC;&#x201C;60 minutes. Higher concentrations or longer soak times will increase effectiveness; however, do not use a sanitizing solution with a chlorine concentration higher than 50 ppm. Repeated sanitization at higher concentrations can cause corrosion of stainless steel wetted components in an automated watering system.

Hot-Water Sanitization

Heated water can be used to sanitize a system if it is held in the range above 70°C (158°F). The practical aspects of handling water at this temperature (the materials of construction and the energy used), plus the need to provide for animal and personnel safety normally preclude this method from serious consideration for the total automated watering system. It is applicable for components such as rack manifolds that can be sanitized with heat using rack-washers.

Sanitization Frequency

Since sanitization does not kill 100% of bacteria in a watering system, the remaining bacteria can re grow in the system. This means that the components of a drinking water system will need to be re sanitized periodically. While monthly sanitization is typical, the frequency for your particular system will depend on its design, the frequency of both flushes and filter changes, the supply water quality, and the bacterial quality you are trying to maintain. To determine the sanitization frequency, establish a regular schedule for drawing samples and monitoring the total bacteria count levels. Increase or decrease the frequency of sanitization based on the measured bacterial quality.

To destroy an established biofilm, (for example: a watering system that has been in operation for some time and has never been sanitized) repetitive sanitizing cycles are usually required. The

94

Generation of pharmaceutical water initial chlorine exposure may only kill the top layer of biofilm. Chlorine will also destroy the glycocalyx or slime which is the “glue” that holds biofilm bacteria together and to the pipe wall.

This weakens the biofilm structure. For that reason, it is a good idea to follow chlorine exposure with a high-flow flush. Fresh chlorine is then reintroduced to the piping to kill the next bacterial layer. This chlorine sanitization/flush cycle may need to be repeated several times on consecutive days until the accumulated biofilm has been removed. For a well-established biofilm, 3-10 cycles may be need.

Sanitization of an Automated Watering System All the components in an automated watering system should be sanitized at regular intervals.

This section describes how to sanitize these components. The components are listed in the order of the water flow – water purification components are listed first, drinking vales are listed last (see the figure below).

The components that make up an automated watering system. All components must be sanitized at regular intervals.

RO machines

Continuous chlorination.

For reverse osmosis (RO) systems using cellulose acetate membranes, continuous chlorine pretreatment is used to prevent bacteria growth in the RO machine. Chlorine injection is adjusted to provide 0.5 – 2.0 ppm of free chlorine in the feed water and a minimum of 0.3 ppm free 95

Generation of pharmaceutical water chlorine in the RO product water. This low chlorine concentration in the product water is also beneficial for controlling bacteria growth within the storage tank and downstream in the room distribution system.

Clean-in-place cycle.

Regular cleaning of the RO machine is necessary because contaminants can build up on membrane surfaces, reducing flow rate and quality of the product water. On most of the RO machines available from Edstrom Industries, cleaning is done automatically on a periodic basis.

Low pH cleaners are used to remove precipitated salts and metals, and alkaline or neutral cleaners are used to remove dirt, silt, and organic foulants.

RO membranes can also become fouled with microorganisms. To minimize biofouling, it is best if the RO machine can operate continuously, or as many hours a day as possible, to minimize stagnant downtime. If a microbiological cleaner is needed, follow the membrane manufacturer's recommendations.

Storage tanks In water purification systems by Edstrom Industries, the water in storage tanks will contain a continuous chlorine residual that helps prevent bacterial re growth. If storage tank sanitization is required (based on water testing or once per year as preventative maintenance), refer to the RO system manual. Frequency is typically bi-annually or annually.

Room distribution piping Automated watering systems should contain injection ports where a sanitizing solution can be introduced. These are typically located at the inlet to each pressure reducing station.

The Edstrom Industries portable sanitizer is designed to inject chemical sanitizing solutions into the room distribution piping. Usually, animal racks are disconnected from the room piping during sanitization. Sanitization frequency is typically once every 1-12 months.

Recoil hoses Recoil hoses can be chlorine-sanitized in the cage wash area using the Edstrom Industries Chlorine Injector Station and Recoil Hose Flush Station. Sanitization frequency is typically every 1â&#x20AC;&#x201C;2 weeks.

Manifolds Manifold piping on mobile animal racks can be chlorine-sanitized following the wash cycle in the cage wash area using the Edstrom Industries Chlori-Flush Station. Sanitization frequency is typically every 1-2 weeks (the same as the rack wash frequency).

96

Generation of pharmaceutical water

CHAPTER 7 USER REQUIREMENTS FOR Water for Injection System Operational Requirements

Functions

Operation

The WFI-PS generator shall produce 800 #/hr of pure steam and 25 gph of Water-for-Injection (WFI) as defined by the current United States Pharmacopoeia (USP).

The WFI system will store and circulate water at 80°C from a 400 gallon SS316L storage tank and through SS316L piping to three distribution points.

•

Distribution Site 1: A vial washing station that will accept water at 80°C.

•

Distribution Site 2: A wash sink requiring WFI at < 40°C after passage through a heat exchanger.

•

Distribution Site 3: A Compounding station that will require variable temperature delivery of water from a heat exchanger. Temperature range will be 23°C to 80°C. The PS system will distribute pure steam through SS316L piping to three distribution points.

Distribution Site 1: Autoclave (200 #/hr) Distribution Site 2: Lyophilizer (500 #/hr) Distribution Site 3: Vial Washer (50 #/hr) The system shall operate automatically. Automatic operation shall be initiated locally through operator input. The system shall have fault/alarm indicator automatic shutdown based on operator programming for the severity and type of fault.

I/O Streams

Input Streams:

Cold RODI water to the WFI-PS Generation Equipment 97

Generation of pharmaceutical water Hot WFI makeup from the WFI-PS Generation Equipment.

Plant steam for WFI-PS generation, heating stored or circulating WFI, and for maintaining the vent filters in a non-condensing condition.

Chilled water for cooling (cold WFI drops and WFI generation).

Output Streams:

Hot WFI (from hot WFI drops and WFI generation) Cold WFI (from cold WFI drops) PS Vents – tank and condensers are equipped with absolute rated 0.2 µm hydrophobic vent filters to maintain vessel pressure at or near atmospheric. Gas & vapor flow is in both directions, as required.

Steam Condensate – discharged through steam traps to the process drain.

Warm chilled water – returned from cold WFI drops and WFI generation.

Pure steam condensate / excess steam – to drain.

Process Description: The elements of the WFI-PS Generation and Storage and Distribution Systems work together to maintain the quality of the WFI and PS from production through to delivery to end users at various locations in the facility. The key concept is the continuous circulation of hot WFI to maintain contacted surfaces in a sanitary and clean condition. The following process flow description follows the flow of WFI and PS from the WFI-PS Generator through the WFI Storage and Distribution Systems.

WFI-PS Generator

RODI water is fed to the Generator on a demand based on operating state of the equipment.

The generator converts the RODI water through distillation into Pure Steam for distribution to the users. The Pure Steam is condensed into WFI at 80 ± 2ºC based on tank level. WFI is diverted to drain until the proper temperature and conductivity levels are achieved.

WFI Storage Tank

WFI from the WFI-PS generation equipment is fed to the Storage Tank on a demand based on level. Storage Tank is maintained at 80 ± 2ºC by plant steam through a tank heating jacket. The tank temperature is used to adjust the set point of the temperature controller.

98

Generation of pharmaceutical water WFI returning from the Hot WFI Circulation Loop is sprayed into Storage Tank through a Spray Ball to ensure that the tank’s internal surfaces are completely and continuously wetted by hot WFI and are thus maintained in a sanitary and clean condition. The tank is maintained at atmospheric pressure by a steam-traced hydrophobic vent filter.

Hot WFI Circulation Loop

WFI is continuously circulated through a single 1.5” OD tubing supply header running through the building.

The header is designed to maintain WFI velocity between 10 feet per second (fps) with no user loads and 3 fps during periods of high demand. This ensures that flow is kept fully turbulent in the header. These velocities correspond to circulation flow rates of between 13.78 and 45.95 gpm. This velocity range is maintained based on the hydraulic design of the system; Pump is not speed-controlled.

Note: Individual user drop flows vary widely depending on user requirements. Drop usage is not coordinated and WFI demand can vary randomly.

WFI returning to Storage Tank is throttled to maintain a minimum backpressure of 20 psig on the header. This maintains sufficient pressure at the user drops to ensure adequate WFI flow and to maintain positive pressure at all points in the loop. Short periods of low end-of-header flow due to high WFI demand do not adversely affect the ability of the system to maintain a sanitary condition.

Header temperature is controlled by the heating jacket, with the controller set-point adjusted based on the temperature in Storage Tank (cascade control).

End-of-header water conductivity is monitored on-line.

Pure Steam Distribution

PS is continuously distributed through a single 1.5” OD tubing supply header running through the building.

99

Generation of pharmaceutical water The header is designed to supply PS at 45 psi with a pressure drop less than 10% of the supply value.

The header is designed with sanitary steam traps to remove condensate on a continuous basis.

Cleaning and Sanitization

The WFI Storage and Distribution Systems are effectively self sanitizing and self cleaning.

On start-up, water from the WFI-PS Generator is directed to waste until it meets specification.

This feature is self contained on the condensing unit.

The WFI Storage and Distribution Systems are periodically passivated to reduce corrosion.

The WFI Storage and Distribution Systems are periodically de-rouged to maintain smooth, clean surfaces and reduce the potential for biological contamination.

Configuration (Arrangement & Materials of Construction)

WFI -PS Generator

The WFI-PS Generator is designed to produce Water-for-Injection (WFI) quality, pyrogen-free steam. The pyrogen-free steam produced, when condensed, meets all criteria for Water-forInjection, as directed by the latest edition of the U.S. Pharmacopoeia. The WFI-PS System is designed to produce sterile, pyrogen-free Water-for-Injection (WFI), as well. The distillate produced meets all criteria directed by the latest edition of the U.S. Pharmacopoeia. The WFI-PS System is configured to produce both pure steam and distillate concurrently.

The WFI-PS Generator is designed and constructed to meet all requirements of current Good Manufacturing Practices (cGMPs), as enforced by the U.S. Food and Drug Administration.

The separation of entrained impurities and pyrogenic material is accomplished using gravity and centrifugal force.

Impurities collected in the separation process are continuously removed through the waste outlet.

All surfaces in contact with feed water and pure steam are constructed of type 316L stainless steel for protection against carbide precipitation during the welding process.

100

Generation of pharmaceutical water Evaporator & Separator The evaporator is a double-tubesheet, straight-tube, shell-and-tube heat exchanger, welded and constructed per ASME, Section VIII, Division 1, for Unfired Pressure Vessels.

All connections are sanitary-clamp type fittings.

Condenser The condenser is a "U-tube" shell-and-tube heat exchanger of double-tubesheet design, to ensure that coolant will not leak into the pure vapor and distillate.

The tube side of the condenser is ASME Code stamped per Section VIII, Division 1, for Unfired Pressure Vessels.

The condenser shell is mounted horizontally and pitched toward its round end, with the distillate outlet at the lowest point to ensure full drainage.

The condenser is vented to atmosphere in order to remove non-condensable gases and to equalize pressure during cooling. The vent is protected by a hydrophobic, pharmaceutical-grade, 0.2 Âľm filter, preventing the passage of unfiltered air into the condenser and protecting the condenser from microbial contamination. Filter shall be heat traced with isolation valves for maintenance purposes.

The condenser is constructed of type 316L stainless steel. The connections for feed water, pure steam, and distillate are sanitary-clamp type connections. Coolant connections are NPT fittings.

Feed water Pump The Feed water Pump is contained entirely on the WFI-PS Generator skid and includes all piping and wiring for automatic operation, contactor and overload, and alarm functions.

All connections are sanitary-clamp type fittings.

Minimum feed water pressure to the pump is 2 psig.

The pump is a sanitary, centrifugal-type, 316L stainless pump manufactured by ________. It operates on 460 VAC (or 208 VAC), 3-phase, 60 Hz, electrical current.

101

Generation of pharmaceutical water Table: WFI-PS Generator & Associated Equipment Design Attribute

WFI-PS

Generator WFI

Condenser

Manufacturer/SN Capacity (Working)

800 # / hr

25 gph

Pressure Rating

____ psig

____ psig

Temperature Rating

132 °C

132 °C

Material

316L

316L

WFI Contact Surfaces

20 µ-inch Ra, passivated

20 µ-inch Ra, passivated

Nozzles

<2:1 aspect ratio, free draining, N.A. sanitary fittings

Overpressure Protection

None Installed ____

WFI Storage Tank:

The storage tank is a vertical, cylindrical tank of sanitary design. All WFI contact surfaces are 316L stainless steel with a 20 µ inch Ra or better surface finish. All internal surfaces on the tanks are kept wetted by spray balls on the circulation loop returns. The tanks are designed to be free draining. Nozzles are designed for <2:1 depth to diameter ratio to ensure good spray penetration. The tanks are ASME pressure vessels, although they are normally operated at atmospheric pressure, maintained through steam heated, hydrophobic aseptic filters.

The

following table summarizes the key characteristics of the one storage tank.

102

Generation of pharmaceutical water Table: WFI Storage Tank & Associated Equipment Design Attribute

WFI

Storage

Tank WFI

Storage

Tank

Jacket

Manufacturer/SN Capacity (Working)

400 gal

N.A.

Diameter

___” ID

___” ID

Straight Side

___” T/T

___”

Heads

ASME F&D

N.A.

Pressure Rating

45 psig & Full Vacuum

100 psig

Temperature Rating

132 °C

132 °C

Material

316L

304 (non-contact)

WFI Contact Surfaces

20 µ-inch Ra, passivated

N.A.

Nozzles

<2:1 aspect ratio, free draining, N.A. sanitary fittings

Overpressure Protection

Sanitary Rupture Disc

None Installed

WFI Tank Vent Filter

The WFI tank vent filter is a sanitary design absolute rated 0.2µm filter. The following table summarizes the key characteristics of the one filter.

103

Generation of pharmaceutical water Table: WFI Tank Vent Filter Design Attribute

WFI

Tank

Vent

Filter WFI Vent Filter Housing

Cartrdige Manufacturer

Millipore

____

Model

____

____

Type

Sanitary

Sanitary

Utility Side Ratings

125 ÂşC Continuous

150 psig / -20 to 350 F

Utility

N/A

Steam

WFI Contact MOC

PVDF

316L

Seals

Viton

Viton

WFI Side Surface Finish

N/A

<25 Âľ inch Ra

Filtration Surface Area

____ ft2

WFI Circulation Pump:

The WFI pump is a sanitary design centrifugal pumps. The following table summarizes the key characteristics of the one pump.

104

Generation of pharmaceutical water Table: WFI Circulation Pump

Design Attribute

WFI

Circulation

Pump

Manufacturer / Model ____ Serial Number

____

Inlet

2”

Outlet

1.5”

Impeller

115 mm

Rated Flow

30 gpm

Rated TDH

85 feet

Material

316L

Internal Surface Finish

25 µ inch Ra

Seal Type

Double, SiC – SiC / C – Ceramic w/ Silicone elastomers

Flush

Yes

Speed

3500 rpm

HP

3

HP

TEFC

3Φ/

60

hz

230 / 460 V

POU Heat Exchangers The heat exchangers are of similar design. All are 316L double tube sheet types to control corrosion and eliminate possible WFI contamination due to steam or coolant leakage. The following table summarizes the key characteristics of the two heat exchangers.

105

Generation of pharmaceutical water

Table: Sanitary Heat Exchangers Design Attribute

WFI

Cold

Drop WFI

Cold

Wash Sink

Compounding

Manufacturer

____

____

Model

____

____

Year Mfg

____

____

Type

Sanitary

Sanitary

WFI Side Ratings

150 psig / -20 to 350 F

150 psig / -20 to 350 F

Utility Side Ratings

150 psig / -20 to 350 F

150 psig / -20 to 350 F

Utility

Chilled Water

Chilled Water

WFI Contact MOC

316L

316L

Seals

Viton

Viton

WFI Side Surface Finish

<25 µ inch Ra

<25 µ inch Ra

Ht-X Area

____ ft2

____ ft2

Duty1

____ BTU/hr

____ BTU/hr

2

WFI Side

176 – 104 ºF ____

Utility Side

Calculated BTU/hr-ft2-F

gpm

Uoa

WFI 2

gpm

Drop

WFI

176 – 73 ºF water ____

42 - 52 ºF

42 - 52 ºF

____

____

water

106

Generation of pharmaceutical water

WFI Piping:

WFI is distributed through 316L seamless tubing meeting the requirements of ASME SA270 / BPE for sanitary tubing and fabrication. Tubing is specified with 20 Âľ inch Ra internal and 30 Âľ inch Ra external surface finishes. All feasible WFI service welds are made by automatic orbital welding equipment using qualified welding procedures and operated by a certified operator.

Manual WFI service welds are minimized. Where necessary, they are made by a certified welder using qualified procedures in accordance with ASME BPE (latest edition). All WFI service welds are 100% optically inspected and permanent, retrievable records retained of the inspections. Welds not meeting the acceptance criteria are replaced. All sanitary welds are individually marked to identify the operator/welder.

WFI service welds are made in a controlled environment to maintain the tubing in a clean condition. WFI service tubing is cleaned and passivated before entering service to reduce corrosion in the heat affected zones. WFI piping is supported in accordance with good engineering practices. WFI piping is designed to be free draining with a minimum slope of 1/8â&#x20AC;? per foot of run. Valves and fittings in WFI service are of sanitary design and utilize either butt weld (orbital) tube ends or sanitary clamp connections. Fittings comply with the requirements of ASME BPE (latest edition).

Other Materials of Construction

Clean Steam piping matches WFI requirements for materials of construction and surface finish.

Non-sanitary vents and drains are copper. Plant steam piping is carbon steel, with iron and bronze components, and is rated for 150 psig service. Coolant piping is brass, with bronze or stainless steel components, and is rated for 125 psig service.

Insulation

As an additional barrier to prevent chloride contamination, the evaporator, separator, and blowdown cooler are painted with Thurmalox No. 70. These painted components are insulated with 1-inch (3.8 cm) Parco Mineral Wool. The insulation is covered with embossed aluminum as a vapor barrier. Type 304 stainless steel sheathing is available as an option.

Distribution Piping will be insulated 1-inch (3.8 cm) Parco Mineral Wool with a PVC cover.

107

Generation of pharmaceutical water

Pure Steam Sampling

A Pure Steam Sampling to draw physical samples of condensed pure steam occasionally is desired. Pure steam is bled off and condensed, and the condensed pure steam passes into a sample well. The sample well is equipped with a sample valve through which a sample may be drawn. When the sample valve is closed, the condensed pure steam is routed to drain.

All components in contact with pure steam and condensed pure steam are constructed of type 316L or type 316 stainless steel Components in contact with coolant are constructed of brass, bronze and type 316 stainless steel.

Includes a jacketed condenser, sample well, sample valve, and condensed pure steam temperature control system.

Pure steam consumption is no more than 35 lbs/hr.

Operating Parameters and Quality Requirements These tables summarize the key operating flow rates and conditions in the WFI Storage and Distribution System.

Table: Approximate Operating Flow Rates and Conditions Stream

WFI Makeup from Still

Flow

Pressure

Temperature

(gpm)

(psig)

(ºC)

.42

Atmospheric

88 C

Hot Loop Circulation 30 gpm

Pump Discharge – 35 80 ±2ºC

Rate @ 10 fps (3 m/s)

psig Tank Return – 20 psig

WFI Drops

Various

Minimum – 20 psig

80ºC (hot) 23ºC (cold)

Tank Conditions

N.A.

Atmospheric

80 ±2ºC

108

Generation of pharmaceutical water WFI drop demand varies with service. Cold drop flows may require control to achieve specific temperatures exiting the heat exchangers.

Table: WFI Drop Flows Drop

Service

Flow (gpm)

1

Wash Sink

2

2

Formulation Suite

2

3

Vial Wash

8

WFI must meet USP requirements in the distribution system and at the various drops.

Requirements include meeting the following specifications: TOC Specification of < 500 ppb (Alert > 250 ppb, Action > 350 ppb).

Conductivity (On-Line) to meet USP WFI requirements adjusted for temperature (nominal conductivity <1.3 µS/cm at 25oC to pass Stage 1 requirements).

Endotoxin levels ≤ 0.25 EU/mL (Alert ≥ 0.06 EU/mL, Action ≥ 0.12 EU/mL).

Total Viable Organisms ≤ 10 CFU / 100 mL (Alert ≥ 5 CFU / 100 mL, Action ≥ 10 CFU / 100 mL).

Utilities Required

Chilled water supply/return.

Power is required for the circulating pumps: 3 HP connected (11.2 KW) @ 460 V, 3-Φ Instrument air requirements are minor, for control valve actuation.

Plant steam is required for process heaters: Jacket not rated for specific duty Minor consumption to maintain filters as non-condensing.

109

Generation of pharmaceutical water Control System The WFI Storage and Distribution System is operated by the WFI-PS Generation Equipment PLC and normally operates automatically.

Set up for periodic passivation and de-rouging requires operator intervention with the equipment off-line. Local instrumentation is provided as documented on the P&IDs to aid in system monitoring and troubleshooting.

A "ladder-logic" program, run through an Allen-Bradley SLC 500/03 programmable-logic controller (PLC), controls the operation of the WFI-PS Generator.

An Allen-Bradley Panel View 550 operator-interface terminal (OIT) is provided for complete system monitoring and configuration. Set points, delay times, and PID loop parameters can be changed via the OIT (access to configuration screens is limited with security measures).

Battery backup for both the SLC 500 and the Panel View 550 provides memory retention for up to two (2) years without power. In addition, copies of the "ladder-logic" program and the OIT configuration are stored in external "flash" memory devices, which should be stored in a safe location. If the program in the SLC 500 or the Panel View should be lost or become corrupted, the original program can be uploaded from the "flash" memory device.

Two (2) data communication ports are provided. With the 500/03 CPU, communication with the OIT is accomplished through the DH485 port, and the other communication port (RS232/DF1 or DH485) is available for use.

A hard copy of the "ladder-logic" program, complete with I/O configuration, port settings, and complete cross-reference is provided with the unit. A complete report of the Panel View configuration, including screen images, alarm configuration, and terminal setup is also provided with the unit.

The control enclosure is mounted on the WFI-PS Generator skid. The enclosure is NEMA 4 and consists of a carbon steel box with a smooth, ANSI-61, gray, polyurethane enamel finish and a type 304 stainless steel door. The enclosure is ___ inches high, ___ inches wide and ___ inches deep.

110

Generation of pharmaceutical water All devices and instruments located on the WFI-PS Generator skid (external of the control enclosure) are connected to the control system via molded cord sets and mating receptacles.

All cords are installed neatly in a plastic wireway mounted to the WFI-PS Generator skid. Each cord set and receptacle is labeled for easy identification.

A separate enclosure contains the feed water pump and WFI distribution pump electronics and houses the disconnect switches, motor starters and overloads, fuses, and control transformers.

The enclosure is NEMA 4 and consists of a carbon steel box with smooth, ANSI-61, gray, polyurethane enamel finish and type 304 stainless steel door. The enclosure is ___ inches high, ___ inches wide and ___ inches deep. Use of a separate enclosure allows complete isolation of the high-voltage, 3-phase power required for the pump.

The control system allows for the following operation modes: Pure Steam (Auto) - The pure steam production process starts and stops automatically in response to an external signal.

Pure Steam (Manual) - Once started manually, the pure steam production process continues until it is shut off manually.

Distillate (Auto) - The distillation process starts and stops automatically in response to an external signal and/or a 7-day timer. (The pure steam production process is in progress while the system is producing distillate.)

Distillate (Manual) - Once started manually, the distillation process continues until it is shut off manually. (The pure steam production process is in progress while the system is producing distillate.)

The control system allows for the following control modes: Local Only - Operation may be controlled from the OIT only.

Local/Remote - Operation may be controlled from the OIT or from the data communication port.

The following control devices are located within the NEMA 4 control enclosure: SLC 500 PLC. Panel View 550 OIT. Operation hour meter.

111

Generation of pharmaceutical water Distillate/Feed water conductivity analyzer.

Loop Supply/Return water conductivity analyzer.

The following components are approved in the standard control system: Allen-Bradley SLC 500 PLC Yokogawa Conductivity Analyzer Terminals are provided for connection of an "auto mode - remote start/stop input" signal (e.g., WFI tank level signal) and for connection to a common alarm relay.

Each WFI-PS Generator requires only one electrical drop for power. A 24-volt DC power supply is included to power the PLC inputs and outputs. A single 460 VAC, 3-phase drop for the feed water pump is required. A single 460 VAC, 3-phase drop for the WFI distribution pump is required. A step-down transformer (to 120 VAC) is included to obtain the control voltage.

With the exception of the integral cables on RTDs and conductivity sensors, wiring is 18 AWG (minimum) and includes MTW/AWM insulation. Individual conductors are rated for 600 volts, 105ºC operation. Non-shielded cables utilize PVC or PUR jackets and are rated for 300 volts.

Shielded cables, manufactured by Belden, utilize complete coverage shields with PVC jackets and are rated for 300 volts.

Power Failure and Recovery

On power failure, the system shall fail into a “safe state.” On power restoration, the system shall not restart without operator or communication-link input.

The Supplier shall design the system to include a “safe state” in which the likelihood of injury to personnel and damage to the WFI-PS Generator is minimized.

All equipment must be designed to retain the PLC program in case of power loss, and be able to recover with minimal operator actions.

“Emergency Stop” Switch An emergency-stop switch shall be supplied, which, when activated, shall shut the system down immediately in accordance with the following requirements:

112

Generation of pharmaceutical water Alarms and Warnings The control system includes extensive alarm handling capabilities. Alarms provide notification of problems and shut down the WFI-PS Generator. Each alarm is accompanied by a specific message on the OIT display, a common alarm light, and an audible horn. A common alarm relay is provided for remote indication. The last fifty (50) alarms are stored in an alarm history file (accessible through the OIT).

The WFI-PS Generator shall be equipped with the following critical alarms and non-critical warnings:

Alarm or Warning

Critical*

NonCritical**

Emergency Stop

X

PLC−OIT Communication

X

(“Programmable

Logic

Controller−Operator-Interface

Terminal”) Coolant Low-Pressure

X

Instrument Air Low-Pressure

X

Distillate Low-Temperature

X

Distillate High-Temperature

X

Distillate Temperature Input Error

X

1st-Effect Low-Temperature

X

st

X

st

X

1 -Effect High-Temperature 1 -Effect Temperature Input Error 1st-Effect Low-Level

X

1st-Effect High-Level

X

Distillate Low-Resistivity/High-Conductivity

X

Feed water Low-Resistivity/High-Conductivity

X

Distillate/Feed water Analyzer Fault

X 113

Generation of pharmaceutical water Alarm or Warning

Critical*

NonCritical**

Distillate-to-Tank Valve Fail-to-Close

X

Distillate-to-Tank Valve Fail-to-Open

X

Distillate-to-Drain Valve Fail-to-Open

X

Distillate-to-Drain Valve Fail-to-Close

X

Loop Supply Low-Resistivity/High-Conductivity

X

Loop Return Low-Resistivity/High-Conductivity

X

Loop Supply/Return water Analyzer Fault

X

Tank Low-Temperature

X

Tank High-Temperature

X

Tank Temperature Input Error

X

Loop Supply Low-Temperature

X

Loop Supply High-Temperature

X

Loop Supply Temperature Input Error

X

Loop Return Low-Temperature

X

Loop Return High-Temperature

X

Loop Return Temperature Input Error

X

* “Critical alarms” shall take action automatically to shut the WFI-PS Generator down and notify the operator. The operator shall be required to acknowledge the alarm before the alarm can be reset and the system restarted. Once the alarm is reset, the system may be restarted by the operator pressing the “start” button or by an input through the data-communication link. No other action shall be required to restart the system. ** “Non-critical warnings” shall notify the operator but shall not shut the system down. Noncritical warnings shall sound the alarm horn, illuminate the alarm indicator but allow the system to continue to operate. The operator shall be required to acknowledge the warning in order to silence the alarm horn, and the alarm indicator shall be extinguished when the warning condition disappears.

114

Generation of pharmaceutical water Data & Security Interfaces The Programmable Logic Controller / Operator-Interface Terminal system (hereafter referred to as the “PLC/OIT system”) shall include interfaces with the Operator, Supervisors, external equipment, and the User’s control system to ensure safe, reliable, continuous, and automatic operation and easy, safe, and reliable configuration.

Interface with Operators The PLC/OIT system shall include interfaces with the Operator that ensures easy, safe, and reliable operation.

An operator-interface panel shall be provided and mounted on the skid. This panel shall provide the necessary switches, indicators, and devices to operate the WFI-PS Generator.

The following shall be displayed: Distillate Temperature Pure Steam Pressure Alarms and Warnings.

System Status (e.g., “ready,” “running,” etc.).

Conductivity (in and out) Distribution Loop Conductivity (supply and return) Distribution Loop Temperature (supply and return) Tank Temperature Tank Water Level Interface with Supervisors The PLC/OIT system shall include interfaces with Supervisors to ensure easy, safe, and reliable configuration of the WFI-PS Generator.

The following shall be accessible only to Supervisors Control set points.

Control loop variables (i.e., “PID terms”).

Alarm set points.

115

Generation of pharmaceutical water Interface with Other Systems Access to all Input/Output values and system status bits by an external computer system(s) shall be provided through a data-communication link to the PLC and/or PLC/OIT. The PLC/OIT system shall include interfaces with the User’s control system to facilitate automatic operation and configuration.

A system with an RS-232 communications port shall be provided.

The port shall be configured to communicate the following data to a supervisory control and data acquisition (SCADA) node (Note: the SCADA system shall be supplied and installed by the User): Distillate Temperature Distillate Resistivity Alarms and Warnings.

System Status (e.g. “off,” “ on,” “standby” states, etc.).

Tank Water Level Data Collection Data required for collection to be recorded at 30 minute intervals – continuous.

Distillate Temperature Distillate Resistivity Feed water Resistivity Feed water Temperature Tank Water Level Tank Temperature Loop Supply Conductivity Loop Supply Temperature Loop Return Conductivity Loop Return Temperature

116

Generation of pharmaceutical water Data Collection and Storage Requirements: Compliance with 21CFR Part 11 (electronic records) is required. This includes especially date and time of collection along with data. Data should be stored onto UPS backed computer files and transferred to CD-R recording media once per month.

Environment

Layout

Allocated floor space for the skid is 144” by 60” with a 24” corridor around the periphery for the skid.

Vertical clearance is 18 feet.

Physical Conditions The skid shall be mounted in an environment with a temperature range of 15°C to 40°C and noncondensing humidity.

Vibration levels are:

Negligible.

Electromagnetic interference levels are:

Negligible.

This area is intended for the following use: General purpose/mechanical.

Constraints

Milestones and Timelines

The Supplier shall provide a written proposal within 2 weeks of receipt of this document at the Supplier’s local office.

The Supplier shall provide a Functional and Design Specification within 3 weeks of receipt of the purchase order.

The User shall review, comment and/or approve, and return the Functional and Design Specification to the Supplier within 1 week of receipt from the Supplier.

117

Generation of pharmaceutical water The Supplier shall provide the Factory Acceptance Test Specification within 1 week of receipt of approved the Functional and Design Specification. The User shall review, comment and/or approve, and return the Factory Acceptance Test Specification to the Supplier within 1 week of receipt from the Supplier.

Date written proposal/quote required:

TBD

Date purchase order will be placed by:

TBD

Functional and Design Specification delivery date:

TBD

Factory Acceptance Test Plan due for review:

TBD

Factory Acceptance Test Plan due for approval:

TBD

Date equipment is required on-site:

TBD

Compatibility

PLC Controllers

The Supplier shall utilize Programmable Logic Controllers that shall include a communications port. The Supplier shall provide documentation that the program (embedded software) was developed and coded utilizing program development and documentation software.

Utilities

The User shall ensure that the following utilities are available and that the utility supply lines and piping are terminated with fittings or connections, which are compatible with those described on the Customer Connection Drawing.

The Supplier shall specify utility data, which is marked with an asterisk (â&#x20AC;&#x153;*â&#x20AC;?).

Utility data, which are not specified or marked with an asterisk, shall be brought to the attention of the User. These data shall be specified (by the User or the Supplier) and shall be approved by both the User and the Supplier before system design begins. The Supplier shall inform the User of any schedule changes which result from this delay.

118

Generation of pharmaceutical water

Available Drains Line size: 3 inches.

Maximum flow rate: ___________ gpm.

Maximum temperature: ___________ ° Fahrenheit.

“Primary” Conditions Electrical:

480 VAC, _______ amps, 3 ph, 60 Hz

nstrument Air: 20 cfm @ 80 psig Feed water:

_______ gph @ _______ ± _____ psig (allocated to this skid).

Type: RO / DI Min. Resistivity: Coolant:

10 MΩcm.

_______ gph @ _______ ± _____ psig (allocated to this skid).

Type: Chilled Water.

Supply Steam: _______ lbs/hr @ _______ ± _____ psig (allocated to this skid).

Materials of Construction

All product contact surfaces should be 316L stainless steel unless specifically pointed out otherwise and approved by the owner. All WFI and PS contact gasket materials must be compatible with highly pure WFI and been tested for extractables by USP<381>. All WFI and PS gasket materials must be suitable for the specified operating temperature.

Availability

The WFI Still shall be operated:

Continuously 119

Generation of pharmaceutical water

Operation of the WFI Still shall be suspended, and the system shall be available for maintenance or service: 2

days per month.

2

weeks per year.

Procedural Constraints

Each pressure vessel, which is covered by ASME Code, shall be ASME stamped with the appropriate rating for its application.

Each pressure vessel shall be constructed in accordance with Section VIII, Division 1, of the ASME Code.

Each heat exchanger shall be constructed in accordance with TEMA Class â&#x20AC;&#x153;Câ&#x20AC;? (Tubular Exchange Manufacturers Association) standards.

All piping welds shall meet ASME and 3A specification requirements.

Installation, operation, and maintenance instruction documentation for the system shall be developed to a level that is comprehensible by a high school graduate.

Life-Cycle

Development

The Supplier shall have a quality system in place. Internal quality procedures shall be available for customer review.

The Supplier shall provide a Project Manager for the project to provide a single communication point.

Testing

In order to verify system performance, the User shall witness the execution of the Factory Acceptance Test procedures. The Supplier shall notify the User 2 weeks in advance of the start of this test.

120

Generation of pharmaceutical water

Before shipment, the System undergoes extensive functional testing to ensure mechanical and operational integrity. All operation functions are tested, including operation during a power failure and upon recovery from a power failure. All alarm functions are tested.

Production capacities and utilities consumption data are recorded in the approved protocol.

A biological purity test is performed on the condensed pure steam by a suitable laboratory using the Kinetic Turbidimetric LAL method. The feed water is spiked to a minimum concentration of 100 endotoxin units per milliliter (EU/ml). The maximum acceptable endotoxin concentration in the condensed pure steam is 0.03 EU/ml (the U.S. Pharmacopoeia requirement for Water-forInjection is 0.25 EU/ml).

Delivery

The system with all options, equipment, and documentation listed herein, shall be delivered to the User’s receiving dock.

Documentation

Installation, operation, and maintenance instruction documentation for the system shall be developed to a level that is comprehensible to a high school graduate.

The Supplier shall provide documentation reflecting “as-built” condition with final delivery.

All final documents shall be shipped with transmittals that identify them as contractually required documents. All final documents and drawings shall reflect “as-built” condition.

All documents must be in English and may be delivered in Electronic Format as detailed below.

Design Specifications

Microsoft Word

Controls Test

Microsoft Word

Hardware Installation Test

Microsoft Word

Operational Test

Microsoft Word

Factory Acceptance Test

Microsoft Word

Operator, Maintenance and Service Manuals

Microsoft Word 121

Generation of pharmaceutical water Process and Instrumentation Diagram (P&ID)

AutoCAD

Instrument Listing

Microsoft Word or Excel

Control Schematics

AutoCAD

Control Panel Assembly Drawings

AutoCAD

Equipment Assembly Drawings

AutoCAD

Bill of Materials

Microsoft Word or Excel

Spare Parts List

Microsoft Word or Excel

Component Cut Sheets

Microsoft Word or Excel

Certificates of compliance for materials, welding, surface finish inspection.

Support

Start-up Support (vendor to indicate available options) Training (vendor to indicate available options) Post Start-up Support (vendor to indicate available options) Technical Support Telephone (Voice or Modem) Replacement Parts Availability List (Normal lead times shall be listed) User Site Support Preventative Maintenance (vendor to list maintenance contracts available) System Improvements (supplier shall notify user of any improvements available on a regular basis)

122

Generation of pharmaceutical water Calculation

WFI Tank Simulation

Based on the estimated water consumption, a worst-case model was developed to challenge the size of the generator and storage tank. The following results show that the tank is properly sized.

Inputs:

25 gph input continuous-ish, not to exceed 400 gallon tank capacity 120 gph usage between the hours of 10:00 and 12:00 UTC (every day) 60 gph usage from 14:00 to 16:00 UTC (every day) 9 gph usage continous over the work day (8:00 to 20:00) (every day)

123

Generation of pharmaceutical water

WFI Flow Rate Calculations Select 1-1/2” Tubing @ 30 gpm normal flow rate; If we reduce maximum draw due to tank washing, 1” tubing might be a viable option. There is no real cost savings between 1” and 1-1/2” tubing. Tank spray ball will need a minimum flow rate (typically @10-15 gpm; can be designed special for low flow conditions). Note: For turbulent flow conditions (v = V / A), where V is flow rate.

ID A A Velocity (ft/s)

Minimum

Ideal

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Stainless Steel Tubing - Pharmaceutical Grade 1" OD Tubing 0.87 in.

0.594468 sq.in.

0.004128 sq.ft.

1-1/2" OD Tubing 1.37 in.

1.474114 sq.in.

0.010237 sq.ft.

flow rate flow rate flow rate (ft3 / s) (ft3 / m) (gpm) 0.004128 0.2476949 1.85 0.008256 0.4953899 3.71 0.012385 0.7430848 5.56 0.016513 0.9907798 7.41 0.020641 1.2384747 9.26 0.024769 1.4861697 11.12 0.028898 1.7338646 12.97 0.033026 1.9815596 14.82 0.037154 2.2292545 16.68 0.041282 2.4769495 18.53 0.045411 2.7246444 20.38 0.049539 2.9723393 22.23 0.053667 3.2200343 24.09 0.057795 3.4677292 25.94 0.061924 3.7154242 27.79

flow rate (ft3 / s) 0.010237 0.020474 0.030711 0.040948 0.051185 0.061421 0.071658 0.081895 0.092132 0.102369 0.112606 0.122843 0.13308 0.143317 0.153554

Tank washing

flow rate flow rate (ft3 / m) (gpm) 0.614214 4.59 1.228428 9.19 1.842642 13.78 2.456856 18.38 3.07107 22.97 3.685285 27.57 4.299499 32.16 4.913713 36.76 5.527927 41.35 6.142141 45.95 6.756355 50.54 7.370569 55.14 7.984783 59.73 8.598997 64.32 9.213211 68.92

Tank washing

Maximum peak draw is 15 gpm for tank washing. Assumes no other users.

WFI Distribution Pressure Drop Calculations Calculate Pressure Drop – Flow rate 30 gpm 6 – Full flow through tees 3 – Zero dead leg valves 11 – 90 degree elbows 120’ – Tubing run, includes risers and runs 124

Generation of pharmaceutical water

Friction loss (ft) per foot of tubing or (ft) per fitting

6 x .59 = 3.54 ft 11 x .07 = 0.77 ft 120 x .11 = 13.2 ft 3 x 2.31 = 6.93 ft (true ZDL valve have much less head loss; standard diaphragm valve CV values were used here)

2.31 ft = 1 psi Total loop drop â&#x20AC;&#x201C; 24.44 ft = 10.58 psi Spray ball requires at least 20 psi on return Pump discharge â&#x20AC;&#x201C; 20 + 10.55 = 30.58 psi

Table: Pressure Drop in Sanitary Tubing

125

Generation of pharmaceutical water

Steam Distribution Calculations

Babcok formula For pressure drop when steam with a specific volume (v) flows in a pipe of diameter (d) is Pressure Drop =

(0.470) x (d + 3.6) (d^6) d m L v

x m^2

xLxv ID A A

(inches) (lbm / s) (ft) (ft^3 / lbm)

Stainless Steel Tubing - Pharmaceutical Grade 1" OD Tubing 1-1/2" OD Tubing 0.87 in.

1.37 in.

0.594468 sq.in.

1.474114 sq.in.

0.004128 sq.ft.

0.010237 sq.ft.

Rules (1) If the pressure drop, based on the entrance pressure, is less than 10%, the fluid can be assumed to be incompressible and the gas properties can be evaluated at any point known along the pipe.

(2) 10%-40% pressure drop - Use mid-point properties (3) 40% or greater pressure drop - Calculate using shorter sections

C 121 131 134.6889

Minimum Maximum Generator Pressure

1 Btu

cu.ft. /lb Btu / lb Btu / (F/lb) Specific Volume Enthalpy Entropy F P (psi) Sat. Vapor (ft^3/lbm) Sat. Vapor Sat. Vapor 249.8 29.825 13.821 1164 1.6998 267.8 40.502 10.376 1170 1.6753 274.44 45 9.401 1172 1.6669

778.26 ft. lb

Our generator will operate at a discharge pressure of 45 psi. To optimize cycles we will assume a 131 C (40.5 psi) at the lyo and autoclave inlet. Therefore maximum drop allowed in distribution is 4.5 psi (45-40.5).

All math is performed at generator conditions because of rule (1). Our allowable drop is 10% (4.5 / 45).

Maximum Steam Run Tubing Diameter

20 (ft) 0.87 (in)

Find - steam velocity (m^2) 4.5

0.47

4.47 m 0.433626

0.004939905 m^2 0.070284458 m

lbm / s

1-1/2" Tubing

0.070284458 0.260278809

lbm / s lbm / s

1" Tubing 1-1/2" Tubing

20

9.401

Results mass flow rate mass flow rate

Draw Rates 253.024 lbm / hr 937.0037 lbm / hr

Use 1-1/2" Pipe because we need 800 lbm / hr theoretical peak draw.

126

Generation of pharmaceutical water

CHAPTER 8 QC related approach approach to Pharmaceutical Water System Testing Procedure for test water for injection NO.

TESTS

SPECIFICATION

1.

Description

A clear, colourless, odourless and tasteless liquid

2.

pH

4.5 to 7.0

3.

Acidity and alkalinity

To 10 ml (freshly boiled and cooled) add 0.1 ml of methyl red indicator. The solution should not red in colour.

To 10 ml, freshly boiled and cooled sample add 0.1 ml of bromothymol blue indicator. The solution should not blue in colour.

4.

Conductivity

Not more than 1.3 ÂľS cm-1 at 25Âş C

5.

Chloride

To 10 ml add 1 ml of dilute nitric acid and 0.2 ml of silver nitrate solution; the solution should not show any change in appearance for at least 15 min.

6.

Sulphate

To 10 ml add to 0.1 ml of dilute hydrochloric acid and 0.1 ml of barium chloride solution ; the solution should not show any change in appearance for at least 1 hr.

7.

Nitrate

Not more than 0.2 ppm

8.

Ammonium

Not more than 0.2 ppm

9.

Calcium & magnesium

To 100 ml add to 2 ml of ammonium chloride buffer solution pH 10, 50 mg of mordant black triturate and 0.5 ml of 0.01 M sodium edentate; a pure blue colour should produced.

10.

Heavy metals

Not more than 0.1 ppm

127

Generation of pharmaceutical water

NO.

TESTS

SPECIFICATION

11

Oxidisable matter

To 100 ml add 10 ml of dilute sulphuric acid and 0.1 ml of 0.02 M potassium permanganate and is boiled for 5 min; the solution should remain faintly pink.

12

Residue on evaporation

Not more than 0.001 %

13

Total Organic Carbon

Not more than 500 ppb.

14

Bacterial Endotoxin

Not more than 0.25 EU/mL

128

Generation of pharmaceutical water Procedure for test purified water NO.

TESTS

SPECIFICATION

1.

Description

A clear, colourless, odourless and tasteless liquid

2.

pH

4.5 to 7.0

3.

Acidity and alkalinity

To 10 ml (freshly boiled and cooled) add 0.1 ml of methyl red indicator. The solution should not red in colour.

To 10 ml, freshly boiled and cooled sample add 0.1 ml of bromothymol blue indicator. The solution should not blue in colour.

4.

Conductivity

Not more than 1.3 ÂľS cm-1 at 25Âş C

5.

Chloride

To 10 ml add 1 ml of dilute nitric acid and 0.2 ml of silver nitrate solution; the solution should not show any change in appearance for at least 15 min.

6.

Sulphate

To 10 ml add to 0.1 ml of dilute hydrochloric acid and 0.1 ml of barium chloride solution ; the solution should not show any change in appearance for at least 1 hr.

7.

Nitrate

Not more than 0.2 ppm

8.

Ammonium

Not more than 0.2 ppm

9.

Calcium & magnesium

To 100 ml add to 2 ml of ammonium chloride buffer solution pH 10, 50 mg of mordant black triturate and 0.5 ml of 0.01 M sodium edentate; a pure blue colour should produced.

10.

Heavy metals

Not more than 0.1 ppm

129

Generation of pharmaceutical water NO.

TESTS

SPECIFICATION

11

Oxidisable matter

To 100 ml add 10 ml of dilute sulphuric acid and 0.1 ml of 0.02 M potassium permanganate and is boiled for 5 min; the solution should remain faintly pink.

12

Residue on evaporation

Not more than 0.001 %

13

Total Organic Carbon

Not more than 500 ppb.

130

Generation of pharmaceutical water

CHAPTER 9 REFERENCE 1. WHO Guidelines for drinking-water quality, 3rd edition. Geneva, World Health Organization, 2003. Water and steam systems. International Society for Pharmaceutical Engineering, 2. 2001. ISPE BaselineTM Pharmaceutical Engineering Guide, volume 4.

3. American Society of Mechanical Engineers. Bioprocessing Equipment Standard. ASME — BPE 2000 4. Biotechnology. Equipment. Guidance on testing procedures for cleanability. British Standards Pub lishing Ltd. BS EN 12296.

5. Harfst WH. Selecting piping materials for high-purity water systems. Ultra Pure Water, May/June 1994.

6. Noble PT. Transport considerations for microbial control in piping. Journal of Pharmaceutical Science and Technology, 1994, 48;76–85.

7. Baines PH. Passivation; understanding and performing procedures on austenitic stainless steel systems. Pharmaceutical Engineering, 1990, 10(6).

8. Guide to inspections of high purity water systems. Maryland, US Food and Drug Administration, 1993.

9. Tverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of mechanically polished type 316 L sanitary tube. European 10. Journal of Parenteral Sciences 1998, 3:117–124.

11. European Pharmacopoeia: Web site for the publishers of the European Pharmacopoeia and supplements; http://www.pheur.org/ 12. US Pharmacopoeia: Published annually; see http://www.usp.org/ 13. European Medicines Evaluation Agency. Note for guidance on the quality of water for pharmaceutical use. London. CPMP/QWP/158-01.

14. Pharmaceutical Inspection Cooperation Scheme. PIC/S; Inspection of Utilities; P1 009-1.

Geneva, Pharmaceutical Inspection Cooperation Scheme, 2002.

15. The International Pharmacopoeia, World Health Organization, Geneva; 131

Generation of pharmaceutical water 16. http://www.who.int/medicines 17. Satish Desai, "EDI in Manufacture of Pharmaceuticals", Water Technology, March 2004, p 74-76 18. Satish Desai, "Dialysis Induced Fever", Nephrology News & Issues, March (1989), p 11.

19. Jeff Tate, "An Introduction to Spiral-wound EDI", Water Technology, Jan. 2003.

20. "Ion Permeable Membranes", by T.A. Davis, J. D. Genders and D. Pletcher, Alresford Press, 1997

132