u will not find anything better
All pharmaceutical, biologics, and medical device facilities are likely to have high purity water systems. The chemical purification processes are well understood and relatively easily achieved. However, the microbiological purity of the finished water and the impact and control of biofilm on the purification train is NOT widely understood, sometimes even by the site’s microbiologists or QA, let alone by the engineers and other utilities maintenance personnel tasked with maintaining microbial control.
revision of the USP informational chapter on water <1231> "Water for Pharmaceutical Purposes", first published in Supplement 2 to USP28 and current through USP 34
In order to understand the microbiology of a water system, one has to understand biofilms since that is the mode of microbial growth in a water system. There is much hype and fear about water systems biofilms by users and regulators alike who do not understand how they grow, how to effectively control that growth, or even how to monitor their presence. This course will help you understand how microorganisms respond to our efforts (or lack of effort) to control their numbers and even to how we try to count them.
This course is designed to provide a microbiology-focused education in language understandable by all personnel, microbiologist and non-microbiologist alike, who have any involvement with water systems. The instructor can provide the necessary background needed to understand this very important subject matter. This understanding is essential to the proper design, validation, operation, monitoring, maintenance, and investigations of a high purity water system. Without this understanding, water system control consists of a set of rules that often don’t work and can cause very costly system downtime or even product recalls.
A biofilm is a complex aggregation of microorganisms growing on a solid substrate. Biofilms are characterized by structural heterogeneity, genetic diversity, complex community interactions, and an extracellular matrix of polymeric substances.
Formation of a biofilm begins with the attachment of free-floating microorganisms to a surface. These first colonists adhere to the surface initially through weak, reversible van der Waals forces. If the colonists are not immediately separated from the surface, they can anchor themselves more permanently using cell adhesion molecules such as pili.
The first colonists facilitate the arrival of other cells by providing more diverse adhesion sites and beginning to build the matrix that holds the biofilm together. Only some species are able to attach to a surface on their own. Others are often able to anchor themselves to the matrix or directly to earlier colonists. Once colonization has begun, the biofilm grows through a combination of cell division and recruitment.
Biofilms are usually found on solid substrates submerged in or exposed to some aqueous solution. Biofilms consist of many species of bacteria and archaea living within a matrix of excreted polymeric compounds. This matrix protects the cells within it and facilitates communication among them through chemical and physical signals. Some biofilms have been found to contain water channels that help distribute nutrients and signalling molecules. This matrix is strong enough that in some cases, biofilms can become fossilized.
Bacteria living in a biofilm can have significantly different properties from free-floating bacteria, as the dense and protected environment of the film allows them to cooperate and interact in various ways. One benefit of this environment is increased resistance to detergents and antibiotics, as the dense extracellular matrix and the outer layer of cells protect the interior of the community.
Biofilms are common in nature, as bacteria commonly have mechanisms by which they can adhere to surfaces and to each other. Dental plaque is a biofilm. In industrial environments, biofilms can develop on the interiors of pipes and lead to clogs and corrosion. In medicine, biofilms spreading along implanted tubes or wires can lead to pernicious infections in patients. Biofilms on floors and counters can make sanitation difficult in food preparation areas.
Biofilms can also be harnessed for constructive purposes. For example, many sewage treatment plants include a treatment stage in which waste water passes over biofilms grown on filters, which extract and digest harmful organic compounds.
Dental plaque is a yellowish biofilm that build up on the teeth. If not removed regularly, it can lead to dental caries.
Understand biofilm basics and how it develops
www.crcnetbase.com/doi/abs/10.1201/NOE1420053487.ch10the.understanding.and.control.of.biofilms.is.a.relatively.new.area.of.study.in. microbiology ... impact.of.biofilms.in.equipment.contamination.and.pharmaceutical.produc- tion. ..... cells.can.have.detrimental.effects.on.a.process.unit.operation ..... identified.aseptic.connections.as.one.of.the.most.common.reasons.for.introduction.
Understand the impact of biofilm on the commonly used purification unit operations
Benchmarking Waste Water Treatment Systemshttp://kolmetz.com/pdf/articles/WWT%20Paper%20-%20Expanded%20rev%20intro.pdf
á1231ñWATER FOR PHARMACEUTICAL PURPOSES
Water is the most widely used substance,raw material,or ingredient in the production,processing,and formulation of compendial articles.Control of the microbiological quality of these waters is important because proliferation of microorganisms ubiquitous to water may occur during the purification,storage,and distribution of this substance.If water is used in the final product,these microorganisms or their metabolic products may eventually cause adverse consequences.
Water that is used in the early stages of the production of drug substances and that is the 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)(40CFR141)issued by the Environmental Protection Agency (EPA).Comparable regulations for drinking water of the European Union or Japan are acceptable.These requirements ensure the absence of coliforms,which,if determined to be of fecal origin,may portend or indicate the presence of other microorganisms of fecal origin,including viruses that may be pathogenic for humans.On the other hand,meeting these National Primary Drinking Water Regulations would not rule out the presence of other microorganisms,which,while not considered a major public health concern,could,if present,constitute a hazard or be considered undesirable in a drug substance or formulated product.For this reason,there are many different grades of pharmaceutical waters.
TYPES OF WATER
Drinking Water— Drinking Water is not covered by a compendial monograph but must comply with the quality attributes of the EPA NPDWRor comparable regulations of the European Union or Japan.It may be derived from a variety of sources,including a public water utility,a private water supply (e.g.,a well),or a combination of more than one of these sources.Drinking Water may be used in the early stages of chemical synthesis and in the early stages of the cleaning of pharmaceutical manufacturing equipment.It is the prescribed source feed water for the production of pharmaceutical waters.As seasonal variations in the quality attributes of the drinking water supply can occur,processing steps in the production of pharmaceutical waters must be designed for this characteristic.
Purified Water— Purified Water (see USPmonograph)is used as an excipient in the production of official preparations;in pharmaceutical applications,such as cleaning of certain equipment;and in the preparation of some bulk pharmaceutical chemicals.Purified Water must meet the requirements for ionic and organic chemical purity and must be protected from microbial proliferation.It is prepared using Drinking Water as a feed water and is purified using unit operations that include deionization,distillation,ion exchange,reverse osmosis,filtration,or other suitable procedures.Purified Water systems must be validated.
Purified Water systems that produce,store,and circulate water under ambient conditions are susceptible to the establishment of tenacious biofilms of microorganisms,which can be the source of undesirable levels of viable microorganisms or endotoxins in the effluent water.These systems require frequent sanitization and microbiological monitoring to ensure water of appropriate microbiological quality at the points of use.
Sterile Purified Water— Sterile Purified Water is Purified Water that is packaged and rendered sterile.It is used in the preparation of nonparenteral compendial dosage forms where a sterile form of Purified Water is required.
Water for Injection— Water for Injection (see USPmonograph)is an excipient in the production of injections and for use in pharmaceutical applications,such as cleaning of certain equipment and preparation of some bulk pharmaceutical chemicals.The source or feed water for this article is Drinking Water,which may have been preliminarily purified but which is finally subjected to distillation or reverse osmosis.It must meet all the chemical requirements for Purified Water and in addition the requirements under Bacterial Endotoxins Test á85ñ.It also must be protected from microbial contamination.The system used to produce,store,and distribute Water for Injection must be designed to prevent microbial contamination and the formation of microbial endotoxins,and it must be validated.
Sterile Water for Injection— Sterile Water for Injection (see USPmonograph)is Water for Injection that is packaged and rendered sterile.Sterile Water for Injection is intended for extemporaneous prescription compounding and is distributed in sterile units.It is used as a diluent for parenteral products.It is packaged in single-dose containers not larger than 1Lin size.
Bacteriostatic Water for Injection— Bacteriostatic Water for Injection (see USPmonograph)is sterile Water for Injection to which has been added one or more suitable antimicrobial preservatives.It is intended to be used as a diluent in the preparation of parenteral products.It may be packaged in single-dose or multiple-dose containers not larger than 30mL.
Sterile Water for Irrigation— Sterile Water for Irrigation (see USPmonograph)is Water for Injection,packaged in single-dose containers of larger than 1L,that is intended to be delivered rapidly and is rendered sterile.It need not meet the requirement for small-volume injections under Particulate Matter á788ñ.
Sterile Water for Inhalation— Sterile Water for Inhalation (see USPmonograph)is Water for Injection that is packaged and rendered sterile and is intended for use in inhalators and in the preparation of inhalation solutions.
VALIDATION AND QUALIFICATION OF WATER PURIFICATION,STORAGE,AND DISTRIBUTION SYSTEMS
Establishing the dependability of pharmaceutical water purification,storage,and distribution systems requires an appropriate period of monitoring and observation.Ordinarily,few problems are encountered in maintaining the chemical purity of Purified Water and Water for Injection.However,it is more difficult to meet established microbiological quality criteria consistently.Atypical program involves intensive daily sampling and testing of major process points for at least one month after operational criteria have been established for each sampling point.
Validation is the procedure for acquiring and documenting substantiation to a high level of assurance that a specific process will consistently produce a product conforming to an established set of quality attributes.The validation defines the critical process parameters and their operating ranges.Avalidation program qualifies the design,installation,operation,and performance of equipment.It begins when the system is defined and moves through several stages:qualification of the installation (IQ),operational qualification (OQ),and performance qualification (PQ).Agraphical representation of a typical water system validation life cycle is shown in Fig.1.
Avalidation plan for a water system typically includes the following steps:
PHARMACEUTICAL WATER SYSTEMS
The quality attributes of water for a particular application are dictated by the requirements of its usage.Sequential processing steps followed for treating water for different pharmaceutical purposes are shown in Fig.2.
Atypical evaluation process to select an appropriate water quality for a particular pharmaceutical purpose is shown in the decision tree in Fig.3.
These diagrams may be used to assist in defining requirements for specific water uses and in the selection of unit operations.
PURIFIED WATER AND WATER FOR INJECTION SYSTEMS
The design,installation,and operation of systems to produce Purified Waterand Water for Injectioninclude 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 Injectionand 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.The final unit operations used to produce Water for Injectionhave been limited to distillation and reverse osmosis.Distillation has a long history of reliable performance and can be validated as a unit operation for the production of Water for Injection.Other technologies such as ultrafiltration may be suitable in the production of Water for Injection,but at this time,experience with this process is not widespread.
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 most likely mode of failure.It is also necessary to demonstrate the effectiveness of the monitoring scheme and to establish the requirements for 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 be performed only as part of the validation of the installed operational system.
The selection of specific unit operations and design characteristics for a water system should take into consideration 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 reverse osmosis)must have effective capability for bacterial endotoxin reduction and must be validated.
The following is a brief description of selected unit operations and the operation and validation concerns associated with them.This review is not comprehensive in that 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.
Filtration technology plays an important role in water systems,and filtration units are available in a wide range of designs and for various applications.Removal efficiencies differ significantly from coarse filters,such as granular anthracite,quartz,or sand for larger water systems and depth cartridges for smaller water systems,to membrane filters for very small particle control.Unit and system configurations vary widely in type of filtering media and location in the process.(Use of membrane filters is discussed in a later paragraph.)
Granular or cartridge filters are used for prefiltration.They remove solid contaminants from the water supply and protect downstream system components from contamination that can inhibit equipment performance and shorten its effective life.Design and operational issues that may affect performance of depth filters include channeling of the filtering media,blockage from silt,microbial growth,and filtering-media loss.Control measures include pressure and flow monitoring,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.
Activated carbon beds adsorb low-molecular-weight organic material and oxidizing additives,such as chlorine compounds,and remove 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 inability to be regenerated in situ,and the shedding of bacteria,endotoxins,organic chemicals,and fine carbon particles.Control measures include appropriate high water flow rates,sanitization with hot water or steam,backwashing,testing for adsorption capacity,and frequent replacement of the carbon bed.Alternative technologies such as chemical additives and regenerable organic scavenging devices can be used in place of activated carbon beds.
Chemical additives are used in water systems to control microorganisms by use of chlorine compounds and ozone,to enhance the removal of suspended solids by use of flocculating agents,to remove chlorine compounds,to adjust pH,and to remove carbonate compounds.Subsequent processing steps are required in order to remove the added chemicals.Control of additives and subsequent monitoring to ensure removal of additives and of any of their reaction products should be designed into the system and included in the monitoring program.
Organic scavenging devices use macroreticular anion-exchange resins capable of removing organic material and endotoxins from the water.They can be regenerated with appropriate biocidal caustic solutions.Operating concerns are associated with scavenging capacity and shedding of resin fragments.Control measures include testing of effluent,monitoring performance,and using downstream filters to remove resin fines.
Water softeners remove cations such as calcium and magnesium that interfere with the performance of downstream processing equipment such as reverse osmosis membranes,deionization columns,and distillation units.Water softener resin beds are regenerated with sodium chloride solution (brine).Concerns include microorganism proliferation,channeling due to inappropriate water flow rates,organic fouling of resin,fracture of the resin beads,and contamination from the brine solution used for regeneration.Control measures include recirculation of water during periods of low water use,periodic sanitization of the resin and brine system,use of microbial control devices (e.g.,UVand chlorine),appropriate regeneration frequency,effluent monitoring (hardness),and downstream filtration to remove resin fines.
Deionization (DI),electrodeionization (EDI)and Electrodialysis (EDR) are effective methods of improving the chemical quality attributes of water by removing cations and anions.
DIsystems 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.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 separated or so that they form a mixed bed.Rechargeable resin canisters can also be used for this purpose.
The EDIsystem uses a combination of mixed resin,selectively permeable membranes,and an electric charge to provide 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 separation permits continuous regeneration of the resin without the need for regenerant additives.
Electrodialysis (EDR)is a similar process that uses only electricity and selectively permeable membranes to separate,concentrate,and flush the removed ions from the water stream.The process,however,is less efficient than EDIbecause it contains no resin to enhance ion removal and current flow.Also,EDRunits require periodic polarity reversal and flushing to maintain operating performance.
Concerns for all forms of deionization units include microbial and endotoxin control;chemical additive effect on resins and membranes;and loss,degradation,and fouling of resin.Issues of concern specific to DIunits include regeneration frequency,channeling,complete resin separation for mixed bed regeneration,and mixing air contamination (mixed beds).Control measures vary but typically include recirculation loops,microbial control by UVlight,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 use of elevated temperatures.Regeneration piping for mixed bed units should be configured to ensure that regeneration chemicals contact all internal 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 (RO)units employ a semipermeable membrane and a substantial pressure differential to drive water through the membrane to achieve chemical,microbial,and endotoxin quality improvement.The process streams consist of supply water,product water (permeate),and waste water (reject).Pretreatment and system configuration variations may be necessary,depending on source water to achieve desired performance and reliability.Concerns associated with the design and operation of ROunits include membrane material sensitivity to bacteria and sanitizing agents,membrane fouling,membrane integrity,seal integrity,and the volume of waste water.Failure of membrane or seal integrity will result in product water contamination.Methods of control consist of suitable pretreatment of the water stream,appropriate membrane material selection,integrity challenges,membrane design such as spiral wound to promote flushing action,periodic sanitization,monitoring of differential pressures,conductivity,microbial levels,and total organic carbon.The configuration of the ROunit offers control opportunities by expanding the single-pass scheme to parallel-staged,reject-staged,two-pass,and combination designs.An example would be the use of a two-pass design to improve reliability,quality,and efficiency.ROunits can be used alone or in combination with DIand EDIunits for operational and quality enhancements.
Ultrafiltration is another technology that uses a permeable membrane,but unlike ROit works by mechanical separation rather than osmosis.Because of the filtration ability of the membrane,macromolecular and microbial impurities,such as endotoxins,are reduced.This technology may be appropriate as an intermediate or final purification step.As with RO,successful performance is dependent upon other system unit operations and system configuration.
Issues of concern include compatibility of membrane material with sanitizing agents,membrane integrity,fouling by particles and microorganisms,cartridge contaminant retention,and seal integrity.Control measures include sanitization,designs capable of flushing the membrane surface,integrity challenges,regular cartridge changes,elevated feed water temperature,and monitoring total organic carbon and differential pressure.Additional flexibility in operation is possible through arrangement of the units,such as parallel or series configuration.Care should be taken to avoid stagnant water conditions that could promote microorganism growth in backup or standby units.
Microbial retentive filters (membrane filters)prevent the passage of microorganisms and very small particles.They are used in tank air and inert gas vents and for filtration of compressed air gases used in the regeneration of mixed-bed deionization units.Areas of concern are blockage of tank vents by condensed water vapor,which can cause mechanical damage to the tank,and concentration of microorganisms on the surface of the membrane filter,creating the potential for contamination of the tank or deionizer contents.Control measures include the use of hydrophobic filters and heat tracing vent filter housings to prevent vapor condensation.Sterilization of the unit prior to initial use and periodically thereafter or regular filter changes are also recommended control methods.Microbial retentive filters are sometimes incorporated into purification systems or into water distribution piping.This application should be carefully controlled because,as noted above,these units can become a source for microbial contamination.The potential exists for the release of microorganisms should the membrane filter rupture or as a result of microbial grow-through.Other means of controlling microorganisms and fine particles can be employed in place of membrane filters in the purification and distribution section of water systems.Filters that are intended to be microretentive should be sanitized and integrity tested prior to initial use and at appropriate intervals thereafter.
Positively charged filter media reduce endotoxin levels by electrostatic attraction and adsorption.Application may be related to the unit operation or distribution system,depending upon the microbial control requirements.Filter media that are microbial retentive require the same concerns and controls as indicated in the previous paragraph.Concerns include flow rate,membrane and seal integrity,and retention capacity,which can be affected by the development of a finite charge potential on the filter.Control measures include monitoring differential pressure and endotoxin levels,proper sizing,testing membrane integrity,and configuring units in series to control breakthrough.
Distillation units provide chemical and microbial purification via thermal vaporization,mist elimination,and condensing.Avariety of designs are 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 may require less rigorous control of feed water quality than do membrane systems.Areas of concern include carryover of impurities,evaporator flooding,stagnant water,pump and compressor seal design,and conductivity (quality)variations during startup and operation.Methods of control consist of reliable mist elimination,visual or automated high-water-level indication,use of sanitary pumps and compressors,proper drainage,blow down control,and use of on-line conductivity sensing with automated diversion of unacceptable quality water to the waste stream.
Storage tanks are included in water distribution systems to optimize processing equipment capacity.Storage also allows for routine maintenance while maintaining continuous supply to meet manufacturing needs.Design and operation considerations are needed to prevent 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 and the ability to spray the tank head space.This minimizes corrosion and biofilm development and aids in sanitizing thermally or chemically.
Storage tanks require venting to compensate for the dynamics of changing water levels.This can be accomplished with a hydrophobic microbial retentive membrane filter fitted onto an atmospheric vent.Alternatively,an automatic membrane-filtered compressed gas pressurization and venting system may be used.Rupture disks equipped with a rupture alarm device serve as a further safeguard for the mechanical integrity of the tank.
Distribution configuration should allow for the continuous flow of water in the piping by means of recirculation or should provide for the periodic flushing of the system.Experience has shown that continuously recirculated systems are easier to maintain.
Pumps should be designed to deliver fully turbulent flow conditions to retard the development of biofilms.Components and distribution lines should be sloped and fitted with drain points so that the system can be completely drained.In 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 6or less.In ambient temperature distribution systems,particular care should be exercised to avoid pocket areas and provide for complete drainage.Water exiting from a loop should not be returned to the system.Distribution design should include the placement of sampling valves in the storage tank and at other locations such as the return line of the recirculating water system.The primary sampling site for water should be the valves that deliver water to the point of use.Direct connections to processes or auxiliary equipment should be designed to prevent reverse flow into the controlled water system.The distribution system should permit sanitization for microorganism control.The system may be continuously operated at sanitizing conditions or sanitized periodically.
INSTALLATION AND 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 conditions.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 reestablish the passive corrosion-resistant surface.Plastic materials can be fused (welded)in some cases and also require smooth,uniform internal surfaces.Adhesives should be avoided because of the potential for voids and chemical reactions.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,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 used.
Materials should be capable of handling turbulent flow and elevated velocities without wear on the corrosive barrier impact,such as the passivation-related chromium oxide surface of stainless steel.The finish on metallic materials such as stainless steel,whether 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.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,which 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 for contamination intrusion.Heat exchangers should be double tube sheet or concentric tube design.They should include differential pressure monitoring or use heat transfer medium of equal or better quality to avoid problems should leaks develop.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 a flow area should be avoided.
Microbial control in water systems is achieved primarily through sanitization practices.Systems can be sanitized using either thermal or chemical means.In-line UVlight at a wavelength of 254nm can also be used to “sanitize”water in the system continuously.
Thermal approaches to system sanitization include periodic or continuously circulating hot water and the use of steam.These techniques are limited to systems that are compatible with the higher temperatures needed to achieve sanitization,such as stainless steel and some polymer formulations.Although thermal methods control biofilm development,they are not effective in removing established biofilms.
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,or peracetic acid.Halogenated compounds are effective sanitizers but are difficult to flush from the system and tend to 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 these compounds,particularly ozone,may 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 UVlight.
UVlight impacts on the development of biofilms by reducing the rate of new microbial colonization in the system;however,it is only partially effective against planktonic microorganisms.Alone,UVlight is not an effective tool because it does not eliminate existing biofilm.However,when coupled with conventional thermal or chemical sanitization technologies,it is most effective and can prolong the interval between system sanitizations.The use of UVlight also facilitates the degradation of hydrogen peroxide and ozone.
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.Validation of chemical methods requires a demonstration of adequate chemical concentrations throughout the system.In addition,when the sanitization process is completed,effective removal of chemical residues must be demonstrated.
The frequency of sanitization is generally dictated by the results of system monitoring.Conclusions derived from the trend analysis of the microbiological data should be used as the alert mechanism for maintenance.The frequency of sanitization established should be such that the system operates in a state of microbiological control and does not exceed Alert Levels.
Apreventive 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)a schedule for periodic sanitization,(4)preventive maintenance of components,and (5)control of changes to the mechanical system and to operating conditions.
Operating Procedures— 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.
Monitoring Program— Critical quality attributes and operating parameters should be documented and monitored.The program may include a combination of in-line sensors or recorders (e.g.,a conductivity meter and recorder),manual documentation of operational parameters (such as carbon filter pressure drop),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.
Sanitization— 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 Maintenance— Apreventive 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 Control— The mechanical configuration and operating conditions must be controlled.Proposed changes should be evaluated for their effects 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.
Water systems should be monitored frequently enough 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.Unit-operation sites might be sampled less frequently than point-of-use 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.
When sampling water systems,special care should be taken to ensure that the sample is representative.Sampling ports should be sanitized and thoroughly flushed before a sample is taken.Samples containing chemical sanitizing agents require neutralization prior to microbiological analysis.Samples for microbiological analysis should be tested immediately or suitably protected to preserve the sample until analysis can begin.
Samples of flowing water are only indicative of the concentration of planktonic (free-floating)microorganisms present in the system.Benthic (attached)microorganisms present as biofilms are generally present in greater numbers and are the source of the planktonic population.Microorganisms in biofilms represent a continuous source of contamination and are difficult to sample and quantify.Consequently,the planktonic population is used as an indicator of system contamination levels and is the basis for system Alert 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 consequent planktonic population.
The major exogenous source of microbial contamination is source or feed water.Feed water quality must,at a minimum,meet the quality attributes of drinking water for which the level of coliforms are regulated.Awide variety of other microorganisms,chiefly Gram-negative bacteria,may be present.These microorganisms may compromise subsequent purification steps.
Examples of other potential exogenous sources of microbial contamination include unprotected vents,faulty air filters,backflow from contaminated outlets,drain air-breaks,and replacement-activated carbon and deionizer resins.Sufficient care should be given to system design and maintenance to minimize microbial contamination from these sources.
Unit operations can be a major source of endogenous microbial contamination.Microorganisms present in feed water may adsorb to carbon beds,deionizer resins,filter membranes,and other unit operation surfaces and initiate the formation of a biofilm.Biofilm is an adaptive response by certain microorganisms to survive in a low-nutrient environment.Microorganisms in a biofilm are protected from the action of many biocides.Downstream colonization can occur when microorganisms are sloughed off and carried in other areas of the water system.Microorganisms may also attach to suspended particles such as carbon-bed fines and serve as a source of contamination to subsequent purification equipment and distribution systems.
Another source of endogenous microbial contamination is the distribution system.Microorganisms can colonize pipe surfaces,valves,and other areas.There they proliferate,forming a biofilm,which then provides a continuous source of microbial contamination.
Endotoxins are lipopolysaccharides from the cell envelope that is external to the cell wall of Gram-negative bacteria.Gram-negative bacteria readily form biofilms that can become a source of endotoxins.Endotoxins may be associated with either living microorganisms or fragments of dead microorganisms,or they may be free molecules.The free form of endotoxins may be released from cell surfaces or biofilms that colonize the water system,or they may enter the water system via the feed water.Endotoxin levels may be minimized by controlling the introduction of microorganisms and microbial proliferation in the system.This may be accomplished through the normal exclusion or removal action afforded by various unit operations within the treatment 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.The presence of endotoxins may be monitored as described in the chapterBacterial Endotoxins Test á85ñ.
The objective of a water system microbiological monitoring program is to provide sufficient information to control the microbiological quality of the water produced.Product quality requirements should dictate water quality needs.An appropriate level of control may be maintained by using data trending techniques and limiting specific contraindicated microorganisms.Consequently,it may not be necessary to detect all the microorganisms present.The monitoring program and methodology should indicate adverse trends and detect microorganisms that are potentially harmful to the finished product 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 capable of detecting all the potential microbial contaminants of a water system.Methods selected should be capable of isolating the numbers and types of organisms that have been deemed significant relative to 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 recovered,sample throughput,incubation period,cost,and technical complexity.An additional consideration is the use of the classical culture approaches vs.a sophisticated instrument approach.
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 microorganisms that could have a detrimental effect on the product or process.
Two basic forms of media are available for traditional microbiological analysis:“high”nutrient and “low”nutrient.High-nutrient media are intended as general media for the isolation and enumeration of heterotrophic bacteria.Low-nutrient media are beneficial for isolating slow-growing bacteria and bacteria that have been injured by previous exposure to disinfectants and sanitizers such as chlorine.Low-nutrient media may be compared to high-nutrient media,especially during the validation of a water system,to determine whether any additional numbers or types of bacteria are present so that their effect on the end use may be assessed.Additionally,the efficacy of system controls and sanitization on these slower-growing or impaired bacteria can also be assessed.
Duration and temperature of incubation are also critical aspects of a microbiological test method.Classical methodologies using high-nutrient media have required incubation at 30Cto 35Cfor 48to 72hours.In certain water systems,incubation at lower temperatures (e.g.,20Cto 25C)and longer periods (e.g.,5to 7days)can produce higher counts when compared to classical methods.Whether a particular system needs to be monitored using lower incubation temperatures or longer incubation times should be determined during system validation.
The decision to use longer incubation periods should be made after considering the need for timely information and the type of corrective actions required when an Alert or Action Level is exceeded.The advantages gained by incubating for longer times—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.
Examples of instrument approaches include microscopic direct counting techniques (e.g.,epifluorescence and immunofluorescence)and radiometric,impedometric,and biochemically based methodologies.These methods all possess a variety of advantages and disadvantages.
One advantage is their precision and accuracy.In general,instrument approaches often have a shorter lead time for obtaining results,which facilitates timely system control.This advantage,however,is often counterbalanced by limited sample processing throughput due to labor-intensive sample processing or other instrument limitations.In addition,instrumental approaches are destructive in that further isolate manipulation for characterization purposes is precluded.Generally,some form of microbial isolate characterization 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 posttest capabilities.
The following general methods obtained from Standard Methods for the Examination of Water and Wastewater,18th Edition,American Public Health Association,Washington,DC20005,are considered appropriate for establishing trends in the number of colony-forming units observed in the routine microbiological monitoring of ingredient water.It is recognized,however,that other combinations of media,time,and temperature of incubation may occasionally or even consistently result in higher numbers of colony-forming units being observed.The extended incubation periods that are usually required by some of the alternative methods available offer disadvantages that may outweigh the higher counts obtained.The somewhat higher baseline counts would not necessarily have greater utility in detecting an excursion or a trend.
Methodologies that can be recommended as generally satisfactory for monitoring pharmaceutical water systems are as follows.
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 are continuously recovered from a water system.After repeated characterization,an experienced microbiologist may become proficient at their identification from only a few traits such as colonial morphology and staining characteristics.This level of characterization is adequate for most situations.
Alert and Action Levels
The individual monographs Purified Waterand Water for Injectiondo not include specific microbial limits.These were intentionally omitted,since most current microbiological techniques available require at least 48hours to obtain definitive results.By that time,the water from which the sample was taken has already been employed in the production process.Failure to meet a compendial specification would require rejecting the product lot involved,and this is not the intent of an Alert or Action guideline.The establishment of quantitative microbiological guidelines for water for pharmaceutical purposes is in order because such guidelines will establish procedures to be implemented if that significant excursions beyond these limits occur.
Water systems should be microbiologically monitored to confirm that they continue to operate within their design specifications and produce water of acceptable quality.Monitoring data may be compared to established process parameters or product specifications.Arefinement in the use of process parameters and product specifications is the establishment of Alert and Action Levels,which signal a shift in process performance.Alert and Action Levels are distinct from process parameters and product specifications in that they are used for monitoring and control rather than accept or reject decisions.
Alert Levelsare levels or ranges that,when exceeded,indicate that a process may have drifted from its normal operating condition.Alert Levels constitute a warning and do not necessarily require a corrective action.
Action Levelsare levels or ranges that,when exceeded,indicate that a process has drifted from its normal operating range.Exceeding an Action Level indicates that corrective action should be taken to bring the process back into its normal operating range.
Alert and Action Levels are established within process and product specification tolerances and are based on a combination of technical and product-related considerations.Consequently,exceeding an Alert or Action Level does not imply that product quality has been compromised.
Technical considerations used to establish Alert and Action Levels should include a review of equipment design specifications to ensure that the purification equipment is capable of achieving the required level of purity.In addition,samples should be collected and analyzed over a period of time to develop data reflecting normal water quality trends.Historical or statistically based levels can be established using these data.Levels established in this way measure process performance and are independent of product concerns.
Product-related Alert and Action Levels should represent both product-quality concerns and the ability to effectively manage the purification process.These levels are typically based on a review of process data and an assessment of product sensitivity to chemical and microbiological contamination.The assessment of product susceptibility might include preservative efficacy,water activity,pH,etc.The levels set should be such that,when it is exceeded,product quality is not compromised.
Monitoring data should be analyzed on an ongoing basis to ensure that the process continues to perform within acceptable limits.An analysis of data trends is often used to evaluate process performance.This information can be used to predict departures from established operating parameters,thereby signaling the need for appropriate preventive maintenance.
It should be recognized that the microbial Alert and Action Levels established for any pharmaceutical water system are necessarily linked to the monitoring method chosen.Using the recommended methodologies,generally considered appropriate Action Levels are 500cfu per mLfor Drinking Water,100cfu per mLfor Purified Waterand 10cfu per 100mLfor Water for Injection.
It should be emphasized that the above action guidelines are not intended to be totally inclusive for every situation in which ingredient waters are employed.For example,Gram-negative microorganisms are not excluded from ingredient waters,nor is the presence of Gram-negative microorganisms prohibited in Drinking Waterin the Federal Regulations.The reason for this is that these microorganisms are ubiquitous to the aqueous environment and their exclusion would likely require a sterilization process that would not be appropriate or feasible in many manufacturing scenarios.However,there are situations in which they might not be tolerated:in topical products and in some oral dosage forms.It is,therefore,incumbent upon the manufacturer to supplement the general action guidelines to fit each particular manufacturing situation.
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 is shown in the decision tree in Figure 2. 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 ultrafiltration 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 and reliable as distillation. The advent of new materials for older technologies, such as reverse osmosis and ultrafiltration, 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 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.
The purpose of prefiltration—also referred to as initial, coarse, or depth filtration—is to remove solid contaminants down to a size of 7 to 10 μm 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 prefilters 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.
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 “stick” 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.
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 compounds by reverse osmosis. These additives do not constitute “added substances” 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 scavenging devices use macroreticular 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.
Water softeners may be located either upstream or downstream of disinfectant removal units. They utilize sodium-based cation-exchange resins to remove water-hardness 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 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 (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 “twin” 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 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 (RO) units employ semipermeable membranes. The “pores” 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.
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 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, backwashable, 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 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 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 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 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 μm. 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 “filter sterilized” using a 0.45-μm rated filter. Further study revealed that a percentage of cells of this microorganism could reproducibly penetrate the 0.45-μm sterilizing filters. Through historic correlation of B. diminuta retaining tighter filters, thought to be twice as good as 0.45-μm filter, assigned ratings of 0.2 or 0.22 μm 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-μm 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-μm rated filters after a relatively short period of use 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-μm 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 μm. There is general agreement that for a given manufacturer, their 0.1-μm rated filters are tighter than their 0.2- to 0.22-μm 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-μm filter rating. It should be noted that use of 0.1-μm rated membranes generally results in a sacrifice in flow rate compared to 0.2- to 0.22-μm 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 μm 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 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 “polish” 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, in-line 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.
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.
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 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 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 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 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, 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.
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 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 “sanitize” 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.
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 Procedures— 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 Program— Critical quality attributes and operating parameters should be documented and monitored. The program may include a combination of in-line 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 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.
Sanitization— 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 Maintenance— 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 Control— 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.
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 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 on-line 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 complexity and reflection of continuous quality, so the user must decide which approach is most suitable or justifiable.
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 on-line 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 multistaged 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 negative—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 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 (see Water Conductivity 645 ) 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 (see Table 1 The Stage 2 conductivity specification is the lowest value on this table, 2.1 μS/cm. The Stage 1 specifications, designed primarily for on-line measurements, were derived essentially by summing the lowest values in the contributing ion columns for each of a series of tables similar to Table 1, created for each 5 increment between 0 and 100 . For example purposes, the italicized values in Table 1, the conductivity data table for 25 , were summed to yield a conservative value of 1.3 μS/cm, the Stage 1 specification for a nontemperature compensated, nonatmosphere equilibrated water sample that actual had a measured temperature of 25 to 29 . Each 5 increment table was similarly treated to yield the individual values listed in the table of Stage 1 specifications (see Water Conductivity 645 ).
As stated above, this rather radical change to utilizing a conductivity attribute as well as the
inclusion of a TOC attribute allowed for on-line measurements. This was a major philosophical
change and allowed major savings to be realized by industry. The TOC and conductivity tests can
also be performed “off-line” in the laboratories using collected samples, though sample collection
tends to introduce opportunities for adventitious contamination that can cause false high readings.
The collection of on-line data is not, however, without challenges. The continuous readings tend to
create voluminous amounts of data where before only a single data point was available. As stated
under Sampling Considerations, continuous in-process data is excellent for understanding how a
water system performs during all of its various usage and maintenance events in real time, but is
too much data for QC purposes. Therefore, a justifiable fraction or averaging of the data can be
used that is still representative of the overall water quality being used.
Packaged waters present a particular dilemma relative to the attributes of conductivity and TOC.
The package itself is the source of chemicals (inorganics and organics) that leach over time into
the water and can easily be detected. The irony of organic leaching from plastic packaging is that
when the Oxidizable substances test was the only “organic contaminant” test for both bulk and
packaged waters, that test's insensitivity to those organic leachables rendered their presence in
packaged water at high concentrations (many times the TOC specification for bulk water) virtually
undetectable. Similarly, glass containers can also leach inorganics, such as sodium, which are
THANKS AND REGARD'S
DR ANTHONY MELVIN CRASTO Ph.D
GLENMARK SCIENTIST , NAVIMUMBAI, INDIA
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