Annex 5_ Water for Pharmaceutical Use

8/11/2019 Annex 5_ Water for Pharmaceutical Use

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accordance with the related marketing authorization submitted to the nationaldrug regu latory authority .

1.2 Backgr ound to water r equir ements and uses

Water is the most widely used substance, raw material or startingmaterial in the production, processing and formulation of pharmaceutical

products. It has unique chemical properties due to its polarity andhydrogen bonds. This means it is able to dissolve, absorb, adsorb orsuspend many different compounds. These include contaminants thatmay represent hazards in themselves or that m ay be able to react withintended product substances, resulting in hazards t o health.

Different grades of water quality are required depending on the route of

administration of the pharmaceutical products. One source of guidance aboutdifferent grades of water is the European Medicines Agency (EMEA) Note forguidance on quality of water for pharmaceutical use (CPMP/QWP/158/01).

Control of the quality of water throughout the production, storage anddis tribution processes, including microbiological and chemical quality , is amajor concern. Unlike other product and process ingredients, water is usuallydrawn from a system on demand, and is not subject to testing and batch or lotrelease before use. Assurance of quality to meet the on-demand expectation is,therefore, essential. Additionally , certain microbiological tests may requireperiods of incubation and, therefore, the resu lts are likely to lag behind the

water use. Control of the microbiological quality of WPU is a high priority .

Annex 5: Water for Pharmaceutical Use

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Some types of microorganism may proliferate in water treatment componentsand in the storage and distribution systems. It is very i mportant to minimizemicrobial con tamination by routine sanitization and taking appropriatemeasures to prevent microbial proliferation.

1.3 Applicable guides

In addition to the specic guidance provided in this document, theBibliography lists so me relevant publications that can serve a s additional

background material when planning, installing and using systemsintended to provide WPU.

2. General requirements for pharmaceutical water systems

Pharmaceutical water production, storage and distribution systemsshould be designed, installed, commissioned, validated and maintained toensure the reliable production of water o f an appropriate quality. Theyshould not be operated beyond their designed capacity. Water should beproduced, stored and distributed in a manner that prevents unacceptablemicrobial, chemical or p hysical contamination (e.g. with dust and dirt).

The use of the systems following installation, commissioning, vand any unplanned maintenance or modication work should be approved

by the quality assurance (QA) department. If approval is obtained for

planned preventive maintenance tasks, they need not be approved afterimplementation. Water sources and treated water should be monitoredregularly for qu ality and for ch emical, microbiological and, as a ppropriate,endotoxin contamination. The performance of water pu rication, storageand distribution systems should also be monitored. Records of the


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monitoring results and any actions taken should be maintained for anappropriate length of time.

Where chemical sanitization of the water systems is part of the biocontamination control programme, a validated procedure should be

followed to ensure t hat t he sa nitizing agent has b een effectively rem oved.

3. Water quality specications

3.1 General

The following requirements concern water processed stored anddistributed in bulk form. They do not cover the specication of watersformulated for patient administration. Pharmacopoeias includespecications for bot h bulk and dosage-form waters.

Pharmacopoeial requirements for WPU are described in national andinter- national pharmacopoeias and limits for various contaminants aregiven. Companies wishing to supply multiple markets should setspecications that meet the strictest requirements from each of therelevant pharmacopoeias.

3.2 Drinking water

Drinking-water should be su pplied under continuous p ositive pressure ina plumbing system free of any defects t hat could lead to contamination ofany product.


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Drinking-water is unmodied except for limited treatment of the waterderived from a natural or s tored source. Examples of natural sourcesinclude springs, wells, rivers, lakes and the sea. T he condition of thesource water will dictate the treatment required to render it sa fe for

human consumption (drinking). Typical treatment includes softening,removal of specic ions, particle red uction and antimicrobial treatment. Itis common for drinking-water to be derived from a public water supplythat may be a combination of more than one of the natural sources listedabove. It is al so co mmon for pu blic water- supply organ izations to con ducttests a nd guarantee th at the d rinking-water d elivered is o f potable q uality.

Drinking-water quality is covered by the WHO drinking-water guidelines,standards from the International O rganization for Standardization (ISO)and other r egional and national agencies. Drinking-water sh ould comply

with the relevant regulations laid down by the mpetent

If drinking-water is used directly in certain stages of pharmaceuticalmanufacture or is t he feed-water for t he production of higher qu alities o f

WPU, then testing should be carried out periodically by the watsite to conrm that t he quality meets the standards required for p otable

water.

3.3 Puried water

Puried water (PW) should be prepared from a potable water source as aminimum-quality feed-water, should meet the pharmacopoeial

specications for chemical an d microbiological purity, an d should beprotected from recontamination and microbial proliferation.

3.4 Highly puried water


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Highly puried water (HPW) should be prepared from potable water asminimum-quality feed-water. HPW is a unique specication for waterfound only in the European Pharmacopoeia. This grade of water mustmeet the sa me qu ality st andard as water for injections (WFI) including the

limit for en dotoxins, but the water-treatment methods a re not consideredto be as reliable as d istillation. HPW may be prepared by combinations ofmethods su ch as r everse osm osis, ultra ltration and deionization.

3.5 Water f or i njections

Water for injections (WFI) should be prepared from potable water asa minimum-quality feed-water. WFI is n ot sterile water and is not a naldosage form. It is a n intermediate b ulk product. WFI is t he h ighest qualityof pharmacopoeial WPU.

Certain pharmacopoeias place constraints upon the permittedpurication techniques as part of t he specication of the WFI. TheInternational Pharmacopoeia and the European Pharmacopoeia, forexample, allow only distillation as t he nal purication step.

3.6 Other grades of water

When a specic process requires a special non-pharmacopoeial grade of water, this should be specied and should at least satisfy the

pharmacopoeial requirements of the grade of WPU required for the type of

dosage form or process st ep.

4. Application of specic waters to processes and dosage forms


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Product licensing authorities dene the requirement to use the specicgrades of WPU for different dosage forms or for different stages in

washing, preparation, synthesis, manufacturing or formulation The grade of water used should take into account the nature and

intended use of the intermediate or n ished product and the stage in themanufacturing process at which the water is u sed.

HPW can be used in the preparation of products when water of highquality

(i.e. very low in microorganisms and endotoxins) is needed, but theprocess st age or product requirement does n ot include the constraint onthe production method dened in some of the pharmacopoeialmonographs for WFI.

WFI should be used in injectable product preparations, for ddiluting substances or preparations for parenteral ad ministration beforeuse, and for st erile water f or p reparation of injections. WFI should also beused for the nal rinse after cleaning of equipment and components thatcome into contact with injectable products a s well as for t he nal rinse i na washing process in which no subsequent thermal or chemicaldepyrogenization process i s a pplied.

When steam comes into contact with an injectable product in its nal

container, or equipment for preparing injectable products, it sh ouldconform to the specication for WFI when condensed.

5. Water purication methods


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5.1 General considerations

The specications for WPU found in compendia (e.g. pharmacopoeias) aregenerally not p rescriptive as to permissible water p urication methodsother t han those for W FI (refer t o s ection 3.5).

The chosen water purication method, or sequence of purication steps,must be appropriate to the application in question. The following should

be considered when selecting the water treatment method:

the water qu ality s pecication; the yield or efficiency of the purication system; feed-water qu ality and the va riation over t ime (seasonal changes); the reliability and robustness of the water-treatment equipment in

operation; the ava ilability of water-treatment equipment on the m arket; the ability to adequately support and maintain the water

purication equipment; and

the op eration costs.

The specications for water purication equipment, storage anddistribution systems sh ould take into account the following:

the risk of contamination from leachates from contact materials; the a dverse i mpact of adsorptive con tact m aterials; hygienic or sanitary d esign, where required; corrosion resistance; freedom from leakage; conguration to avoid proliferation of microbiological organisms; tolerance t o cleaning and sanitizing a gents (thermal and chemical); the system capacity and output requirements; and the p rovision of all necessary instruments, test and sampling points


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to allow all the rel evant critical quality parameters o f the completesystem to be monitored.

The design, conguration and layout of the water purication equiment,storage and distribution systems should also take into account thefollowing physical considerations:

the s pace available for t he i nstallation; structural loadings o n buildings; the p rovision of adequate a ccess f or m aintenance; and the ability to sa fely handle regeneration and sanitization chemicals.

5.2 Production of drinking-water

Drinking-water is derived from a raw water source su ch as a well, river orreservoir. There a re n o prescribed methods for t he treatment of raw waterto produce potable drinking-water from a sp ecic raw water source.

Typical processes employed at a user plant or by a water include:

ltration; softening; disinfection or sanitization (e.g. b y sodium hypochlorite (chlorine)

injection); iron (ferrous) removal; precipitation; and reduction of specic inorganic/organic m aterials.

The drinking-water quality should be monitored routinely. Additionaltesting should be considered if there is any change in the raw-watersource, treatment techniques or sys tem conguration. If the drinking

water quality changes signicantly, the direct


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or as t he feed-water to downstream treatment stages, should be reviewedand the result of the review documented.

Where drinking-water is derived from an in-house system for the

treatment of raw water, the water-treatment steps used and the systemconguration should be documented. Changes to the system or itsoperation should not be made until a review has been completed and thechange approved by t he QA department.

Where drinking-water is stored and distributed by the user, systems m ust not allow degradation of the water qu ality before u se. Afterany such storage, testing should be carried out routinely in accordance

with a dened method. Where water is stored, its use should ensure a

turnover of the st ored w ater sufficient to prevent stagnation.

The drinking-water system is usually considered to be an system and does not need to be qualied.

Drinking-water purchased in bulk and transported to the user by tanker

presents special problems and risks not associated with potable waterdelivered by pipeline. Vendor assessment and authorized certicationactivities, i ncluding conrmation of the acceptability of the delivery

vehicle, should be undertaken in a similar way to tastarting material.

Equipment and systems u sed to produce drinking-water should be able to be drained and sanitized. Storage tanks should be closed with

appropriately protected vents, al low for visual inspection and for beingdrained and sanitized. Distribution pipe work should be able to bedrained, or ushed, and sanitized.


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avoid potential contamination; and unit process steps should be provided with appropriate

instrumentation to measure parameters such as ow, pressure,temperature, conductivity, pH and total organic ca rbon.

Ambient-temperature PW systems are especially susceptible tomicrobiological con tamination, particularly when equipment is staticduring periods of no or low demand for water. It is essen tial to considerthe m echanisms for m icrobiological control and sanitization. The followingtechniques sh ould be con sidered:

maintenance of ow through water-purication equipment at al ltimes;

control of temperature in the system by pipeline heat e xchange orplant- room cooling to redu ce t he ri sk of microbial growth (guidance

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The pharmacopoeias prescribe or limit the permitted nal waterpurication stage in the production of WFI. Distillation is the preferred

technique; it is considered a more robust technique based on phasechange, and in some cases, high temperature operation of the processequipment.

The following should be considered when designing a water puricationsystem:

the feed-water qu ality;

the requ ired water qu ality s pecication; the optimum generator size to avoid over-frequent start/stop

cycling; blow-down and dump functions; and cool-down venting to avoid contamination ingress.

6. Water purication, storage and distribution systems

This section applies to WPU systems for PW, HPW and WFI. The waterstorage a nd distribution should work in conjunction with the puricationplant to ensure consistent d elivery of water to the user p oints, and toensure optimum operation of the water purication equipment.

6.1 General


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The storage and distribution system should be considered as the whole system, and should be designed to be fully integrated with the

water purication components of the system.Once water has been puried using an appropriate method, it can either

be used directly or, more frequently, it subsequent distribution to points of use. The following text de scribes th erequirements for st orage a nd distribution systems.

The storage and distribution system should be congured to prevent

recontamination of the water after treatment and be subjected to acombination of online and offline monitoring to ensure that theappropriate water specication is m aintained.

6.2 Materials t hat come into contact with systems for water for ph armaceuticaluse

This section applies to generation equipment for PW, HPW and WFI, andthe a ssociated storage and distribution systems.

The materials that come into contact with WPU, including pipe work, valves and ttings, seals, diaphragms and instruments, should be

selected to satisfy the following objectives.

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

Prevention of leaching. All materials t hat come into contact w ith WPUshould be non-leaching at the range of working temperatures.

Corrosion resistance. PW, HPW and WFI are highly corrosive. To


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prevent failure of the system and contamination of the water, thematerials selected must be appropriate, the method of jointing must

be carefully controlled, and all ttings and components must becompatible with the pipe work used. Appropriate sanitary-specication plastics and stainless steel materials are acceptable for

WPU systems. When stainless steel is used it should be at least grade316 L. The system should be passivated after initial installation orafter m odication. When accelerated passivation is undertaken, thesystem should be thoroughly cleaned rst, and the passivationprocess sho uld be undertaken in accordance with a clearly deneddocumented procedure.

Smooth internal nish. Once water has b een puried it is su sceptibleto microbiological contamination, and the system is subject to theformation of biolms when cold storage and distribution is em ployed.

Smooth internal surfaces help to avoid roughness a nd crevices w ithinthe WPU system. Crevices a re frequently sites where corrosion cancommence. The internal nish should have an arithmetical averagesurface roughness of not greater than 0.8 micrometre arithmeticalmean roughness (Ra). When stainless steel is used, mechanical andelectropolishing techniques may be employed. Electropolishingimproves the resistance of the stainless steel m aterial to surfacecorrosion.

Jointing. The selected system materials should be able to be easily jointed by welding in a controlled manner. The control of the process

should include as a minimum, qualication of the operator,documentation of the welder set -up, work-session test pieces, logs ofall welds a nd visual inspection of a dened proportions of welds.

Design of anges or u nions. Where anges or u nions are used, theyshould be of a h ygienic or san itary d esign. Appropriate ch ecks sh ould

be carried out to ensure that the correct seals are used are tt ed and tight- ened correctly.

Documentation. All system components sh ould be fully documentedand be supported by original or certied copies of material

certicates. Materials. Suitable materials that m ay be considered for sanitary

elements of the system include 316 L (low carbon) stainless steel,polypropylene, polyvinylidenediuoride and peruoroalkoxy. Othermaterials such as unplasticized polyvinylchloride (uPVC) may be


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used for treatment equipment designed for less p ure water such asion exchangers an d softeners.

6.3 System sanitization and bioburden control

Water treatment equipment, storage and distribution systems used forPW, HPW and WFI should be provided with features to control theproliferation of microbiological organisms during normal use, as well astechniques for san- i tizing or st erilizing the system after intervention formaintenance or modication. The techniques employed should beconsidered during the design of the system and their per formance proven

during t he co mmissioning and qualica- t ion activities.

Systems that operate an d are m aintained at elevated temperatures, in therange of 7080C, are generally less susceptible to microbiologicalcontamination than systems that ar e maintained at lower temperatures.

When lower temperatures are required due to the water treatmentprocesses e mployed or the temperature requirements for the water in use,

then special precautions should be taken to prevent the ingress andproliferation of microbiological contaminants (see section 6.5.3 forguidance).

6.4 Storage vessel requirements

The water storage vessel used in a system serves a number ofimportant pu rposes. The design and size of the vessel should take intoconsideration the following.


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liquid to uctuate. The lters should be bacteria-retentive,hydrophobic and ideally be congured to allow in situ testing ofintegrity. Offline testing is also accept- ab le. The use of heated ventlters sh ould be con sidered to prevent condensation within the ltermatrix that might lead to lter blockage and to microbial grow-through that c ould contaminate t he st orage vessels.

Where pressure-relief valves and bursting discs are provided onstorage vessels to protect them from over-pressurization, thesedevices sh ould be of a sanitary design. Bursting discs sh ould beprovided with external rupture indicators t o prevent accidental loss ofsystem integrity.

6.5 Requirements for water distribution pipework

The distribution of PW, HPW and WFI should be accomplished using acontinuously circulating pipework loop. Proliferation of contaminants

within the storage tank and distribution loop

Filtration should not u sually be used in distribution loops or a t t akeoffuser p oints to control biocontamination. Such lters are l ikely to concealsystem contamination.

6.5.1 Temperature control and heat exchangers

Where heat exchangers are employed to heat or cool WPU within a system,pre- cau tions should be taken to prevent t he heating or cooling utilityfrom conta- minating the water. The m ore secu re types of heat exchangersof the double tube plate or d ouble plate and frame conguration should

be considered. Where these types are not used, an alternative whereby the utility is maintained and monitored at a lower pressure

than the WPU may be considered. Where heat exchangers are used they


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should be arranged in continually circulating loops or su bloops of thesystem to avoid unacceptable st atic water in systems.

When the temperature is reduced for processing purposes, the reductionshould occur for the minimum necessary time. The cooling cycles andtheir d uration should be proven satisfactory during the qualication ofthe system.

6.5.2 Circulation pumps

Circulation pumps sh ould be of a sanitary d esign with appropriate seal sthat prevent contamination of the system. Where stand-by pumps are

provided, they should be congured or managed to avoid dead zonestrapped within the sys tem.

6.5.3 Biocontamination control techniques

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

Maintenance of continuous turbulent ow circulation within waterdistribu- tion systems reduces the propensity for the formation of

biolms. The maintenance of the design velocity for a specicsystem should be proven during the system qualication and themaintenance of satisfactory performance should be monitored.During the operation of a distribution system, short- termuctuations in the ow velocity are u nlikely to cause contaminationproblems provided that ces sation of ow, ow reversal or pressureloss d oes n ot occur.

The system design should ensure the shortest possible length ofpipework.

For am bient temperature systems, pipework should be isolated fromadjacent hot pipes.


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Deadlegs in the pipework installation greater than 1.5 times the branch diameter should be avoided.

Pressure gauges shou ld be separated from the system by membranes. Hygienic pattern diaphragm valves sh ould be used.

Pipework should be laid to falls t o allow drainage. The growth of microorganisms can be inhibited by:

1. ultraviolet radiation sources i n pipework;2.maintaining the system heated (guidance temperature 7080C);3.sanitizing the system periodically using hot water (guidance

temperature >70C);4. sterilizing or sa nitizing the system periodically using superheated

hot water or clean steam; and

5.routine chemical sanitization using ozone or other suitablechemical agents. When chemical sanitization is used, it isessential to prove that t he agent has been removed prior to usingthe water. Ozone can be effectively removed by using ultravioletradiation.

7. Operational considerations

7.1 Start-up and commissioning of water systems

Planned, well-dened, successful and well-documented commissioning isan essential precursor to successful validation of water syst ems. Thecommissioning work should include setting to work, system setup,controls loop tuning and recording of all system performance parameters.If it is intended to u se o r r efer t o commissioning data within the va lidation

work then the quality of the commissioning work and associated data documentation must be commensurate with the validation planrequirements.


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7.2 Qualication

WPU, PW, HPW and WFI systems are all considered to be direct impact,

quality critical systems that sh ould be qualied. The qualication shouldfollow the validation convention of design review or design qualication(DQ), installation qualication (IQ), operational qualication (OQ) an dperformance q ualication (PQ).

This guidance does not dene the standard requirements for theconventional validation stages DQ, IQ and OQ, but concentrates on theparticular PQ approach that should be used for WPU systems todemonstrate their consistent a nd reliable performance. A three-phaseapproach should be used to satisfy the objective of proving the reliabilityand robustness of the syst em in service over an extended period.

Phase1: A test period of 24 weeks should be spent monitoring thesystem intensively. During this period the system should operatecontinuously without failure or performance deviation. The followingshould be included in the testing approach.

Undertake chemical and microbiological testing in accordance witha dened plan.Sample t he incoming feed-water d aily to verify its q uality.Sample a fter each step in the p urication process daily.Sample at each point of use and at other dened sample pointsdaily.Develop appropriate operating ranges.Develop and nalize operating, cleaning, sanitizing andmaintenance procedures.Demonstrate production and delivery of product water of t herequired quality and quantity.Use and rene the standard operating procedures (SOPs) for


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operation, maintenance, sanitization and troubleshooting. Verify provisional alert and action levels.

Develop and rene t est-failure p rocedure.

Phase 2: A further test period of 24 weeks sh ould be spen t carrying outfurther i ntensive m onitoring while d eploying all the ren ed SOPs a fter t hesatisfactory completion of phase 1. The sampling scheme should begenerally the same as i n phase 1. Water can be used for manufacturingpurposes du ring this ph ase. The approach should also:

demonstrate con sistent operation within established ranges; and

demonstrate consistent production and delivery of water of t herequired quantity and quality when the system is operated inaccordance with the SOPs.

Phase 3: Phase 3 typically runs for 1 year after the satisfactorycompletion of phase 2. Water can be used for manufacturing purposesduring this p hase w hich has t he following objectives an d features.

Demonstrate extended reliable performance.Ensure that seasonal variations a re evaluated.

The sample locations, sampling frequencies and tests should bereduced to the normal routine pattern based on establishedprocedures proven during phases 1 and 2.

7.3 Continuous system monitoring

After completion of phase 3 of the qualication programme for the WPUsystem, a system review should be undertaken. Following this review, a


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routine monitoring plan should be established based on the results ofphase 3.

Monitoring should include a com bination of online instrument monitoring

of parameters su ch as ow, pressure, temperature, conductivity and totalorganic carbon, and offline sample testing for physical, chemical andmicrobiological attributes. Offline sam ples sh ould be taken from points ofuse and specic sample points. Samples from points of use should betaken in a similar way to that adopted when the water is being used inservice.

Tests should be carried out to ensure that the selected harmacopoeiaspecication has been satised, and should include, as appropriate,

determination of con ductivity, pH, heavy metals, nitrates, total organiccarbon, total viable cou nt, presence of specic pathogens a nd endotoxins.

Monitoring data sh ould be su bject to trend analysis.

7.4 Maintenance of water systems

WPU systems should be maintained in accordance with a controlled,documented maintenance programme that takes into account thefollowing:

dened frequency for system elements;the calibration programme;SOPs for specic tasks;

control of approved spares;issue of clear m aintenance p lan and instructions;review and approval of systems for use upon completion of work;andrecord and review of problems an d faults during maintenance.


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7.5 System reviews

WPU (PW, HPW and WFI) systems should be reviewed at appropriateregular intervals. The review team should comprise rep resentatives fromengineering, QA, operations an d maintenance. The review should considermatters su ch as:

changes m ade since the last review;system performance;reliability;quality t rends;failure eve nts;investigations;out-of-specications resu lts from monitoring;changes to th e installation;updated installation documentation;log books; andthe st atus of the cu rrent SOP list.


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Annex 5_ Water for Pharmaceutical Use

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