Annex2 Who Gmp Water for Pharmaceutical

7/30/2019 Annex2 Who Gmp Water for Pharmaceutical

1/23

67

Annex 2

WHO good manufacturing practices: water forpharmaceutical use1

1. Introduction 68

1.1 Scope o the document 681.2 Background to water requirements and uses 68

1.3 Applicable guides 69

2. General principles or pharmaceutical water systems 69

3. Water quality specifcations 703.1 General 703.2 Drinking-water 70

3.3 Bulk purifed water 713.4 Bulk highly purifed water 713.5 Bulk water or injections 72

3.6 Other grades o water 72

4. Application o specifc types o water to processes and dosage orms 72

5. Water purifcation systems 735.1 General considerations 735.2 Production o drinking-water 74

5.3 Production o purifed water 765.4 Production o highly purifed water 775.5 Production o water or injection(s) 77

6. Water storage and distribution systems 78

6.1 General 786.2 Materials that come into contact with systems or water or pharmaceutical use 786.3 System sanitization and bioburden control 80

6.4 Storage vessel requirements 806.5 Requirements or water distribution pipework 81

7. Operational considerations 837.1 Start-up and commissioning o water systems 83

7.2 Qualifcation 837.3 Continuous system monitoring 85

7.4 Maintenance o water systems 867.5 System reviews 86

8. Inspection o water systems 87

Further reading 88

1 The current document is a revision of WHO good manufacturing practices: water for pharmaceutical use,previously published in WHO Technical Report Series, No. 929, Annex 3, 2005.


2/23

68

WHOTechnicalReportSeriesNo.9

70,2

012

WHO Expert Committee on Specifcations or Pharmaceutical Preparations Forty-sixth report

1. Introduction

1.1 Scope of the document1.1.1 Te guidance contained in this document is intended to provide inormationabout the available specications or water or pharmaceutical use (WPU),guidance about which quality o water to use or specic applications, such asthe manuacture o active pharmaceutical ingredients (APIs) and dosage orms,

and to provide guidance on good manuacturing practices (GMP) regarding thedesign, installation and operation o pharmaceutical water systems. Although theocus o this document is on water or pharmaceutical applications, the guidelines

may also be relevant to other industrial or specic uses where the specicationsand practices can be applied.

Note: Tis document does not cover water or administration to patientsin the ormulated state or the use o small quantities o water in pharmacies tocompound individually prescribed medicines.

1.1.2 Te GMP guidance or WPU contained in this document is intended tobe supplementary to the general GMP guidelines or pharmaceutical productspublished by WHO (WHO Expert Committee on Specifcations or Pharmaceutical

Preparations. Tirty-seventh report. Geneva, World Health Organization, 2003(WHO echnical Report Series, No. 908), Annex 4).

1.1.3 Tis document reers to available specications, such as the pharmaco-poeias and industry guidance or the use, production, storage and distribution owater in bulk orm. In order to avoid conusion it does not attempt to duplicatesuch material.

1.1.4 Te guidance provided in this document can be used in whole or in partas appropriate to the application under consideration.

1.1.5 Where subtle points o diference exist between pharmacopoeial speci-cations, the manuacturer will be expected to decide which option to choose inaccordance with the related marketing authorization submitted to the nationalmedicines regulatory authority.

1.2 Background to water requirements and uses1.2.1 Water is the most widely used substance, raw material or starting materialin the production, processing and ormulation o pharmaceutical products.

It has unique chemical properties due to its polarity and hydrogen bonds.his means it is able to dissolve, absorb, adsorb or suspend many dierentcompounds. hese include contaminants that may represent hazards inthemselves or that may be able to react with intended product substances,resulting in hazards to health.


3/23

Annex 2

69

1.2.2 Control o the quality o water throughout the production, storage and dis-tribution processes, including microbiological and chemical quality, is a major con-

cern. Unlike other product and process ingredients, water is usually drawn rom asystem on demand, and is not subject to testing and batch or lot release beore use.Assurance o quality to meet the on-demand expectation is, thereore, essential.Additionally, certain microbiological tests may require periods o incubation and,thereore, the results are likely to lag behind the water use.

1.2.3 Control o the microbiological quality o WPU is a high priority. Sometypes o microorganism may prolierate in water treatment components and inthe storage and distribution systems. It is crucial to minimize microbial contami-

nation by proper design o the system, periodic sanitization and by taking appro-priate measures to prevent microbial prolieration.

1.2.4 Dierent grades o water quality are required depending on the routeo administration o the pharmaceutical products. Other sources o guidanceabout dierent grades o water can be ound in pharmacopoeias and relateddocuments.

1.3 Applicable guides

1.3.1 In addition to the specic guidance provided in this document, the Furtherreading section includes some relevant publications that can serve as additionalbackground material when planning, installing and using systems intended toprovide WPU.

2. General principles for pharmaceutical water systems

2.1 Pharmaceutical water production, storage and distribution systems should bedesigned, installed, commissioned, qualied and maintained to ensure the reliable

production o water o an appropriate quality. It is necessary to validate the waterproduction process to ensure the water generated, stored and distributed is notbeyond the designed capacity and meets its specications.

2.2 The capacity o the system should be designed to meet the average and thepeak ow demand o the current operation. I necessary, depending on planneduture demands, the system should be designed to permit increases in the capac-ity or designed to permit modication. All systems, regardless o their size andcapacity, should have appropriate recirculation and turnover to assure the system

is well controlled chemically and microbiologically.2.3 The use o the systems ollowing initial validation (installation qualication(IQ), operational qualication (OQ) and perormance qualication (PQ)) and aferany planned and unplanned maintenance or modication work should be approvedby the quality assurance (QA) department using change control documentation.


4/23

70


70,2

012


2.4 Water sources and treated water should be monitored regularly orchemical, microbiological and, as appropriate, endotoxin contamination. Te

perormance o water purication, storage and distribution systems should alsobe monitored. Records o the monitoring results, trend analysis and any actionstaken should be maintained.

2.5 Where chemical sanitization o the water systems is part o the biocon-tamination control programme a validated procedure should be ollowed to en-sure that the sanitizing process has been eective and that the sanitizing agent hasbeen eectively removed.

3. Water quality specifcations

3.1 General3.1.1 Te ollowing requirements concern water processed, stored and distributedin bulk orm. Tey do not cover the specication o water ormulated or patientadministration. Pharmacopoeias include specications or both bulk and dosage-orm types o water.

3.1.2 Pharmacopoeial requirements or guidance or WPU are described

in national, regional and international pharmacopoeias and limits or variousimpurities or classes o impurities are either specied or recommended.Companies wishing to supply multiple markets should set specications thatmeet the strictest requirements rom each o the relevant pharmacopoeias.

Similarly, requirements or guidance are given in pharmacopoeias on themicrobiological quality o water.

3.2 Drinking-water3.2.1

Drinking-water should be supplied under continuous positive pressure in aplumbing system ree o any deects that could lead to contamination o any product.

3.2.2 Drinking-water is unmodied except or limited treatment o the waterderived rom a natural or stored source. Examples o natural sources includesprings, wells, rivers, lakes and the sea. Te condition o the source water willdictate the treatment required to render it sae or human consumption (drink-ing). ypical treatment includes desalinization, sofening, removal o specicions, particle reduction and antimicrobial treatment.

3.2.3

It is common or drinking-water to be derived rom a public water supplythat may be a combination o more than one o the natural sources listed above.It may also be supplied either rom an osite source, e.g. a municipality, or ap-propriate quality may be achieved onsite through appropriate processing.


5/23

Annex 2

71

3.2.4 It is also common or public water supply organizations to conduct testsand guarantee that the drinking-water delivered is o drinking quality. Tis test-

ing is typically perormed on water rom the water source.

3.2.5 It is the responsibility o the pharmaceutical manuacturer to assure thatthe source water supplying the puried water (PW) treatment system meets theappropriate drinking-water requirements. Tere may be situations where thewater treatment system is used rst to achieve drinking-water quality and sub-sequently puried water. In these situations the point at which drinking-waterquality is achieved should be identied and tested.

3.2.6 Drinking-water quality is covered by the WHO drinking-water guide-

lines, standards rom the International Organization or Standardization (ISO)and other regional and national agencies. Drinking-water should comply withthe relevant regulations laid down by the competent authority.

3.2.7 I drinking-water is used directly in certain stages o pharmaceuticalmanuacture or is the eed-water or the production o higher qualities o WPU,then testing should be carried out periodically by the water users site to con-rm that the quality meets the standards required or drinking-water.

3.3 Bulk purifed water3.3.1 Bulk puried water (BPW) should be prepared rom a drinking-water sourceas a minimum-quality eed-water. It should meet the relevant pharmacopoeialspecications or chemical and microbiological purity with appropriate actionand alert limits. It should also be protected rom recontamination and microbialprolieration. BPW may be prepared by a combination o reverse osmosis (RO)RO/electro-deionization (EDI) and vapour compression (VC). Alert levels orthe water system should be determined rom knowledge o the system and arenot specied in the pharmacopoeias.

3.4 Bulk highly purifed water3.4.1 Bulk highly puried water (BHPW) should be prepared rom drinking-

water as a minimum-quality eed-water. BHPW is a unique specication or

water ound only in the European Pharmacopoeia. Tis grade o water must

meet the same quality standard as water or injections (WFI), including the limit

or endotoxins, but the water-treatment process used may be diferent. Current

production methods include, or example, double-pass RO coupled with other

suitable techniques such as ultraltration and deionization.BHPW may be prepared by a combination o diferent methods such as

RO, ultraltration and deionization.


6/23

72


70,2

012


3.4.2 BHPW should also be protected rom recontamination and microbialprolieration.

3.4.3 BHPW and WFI have identical microbiological requirements.

3.5 Bulk water for injections3.5.1 Bulk water or injections (BWFI) should be prepared rom drinking-water(usually with urther treatment) or puried water as a minimum-quality eed-water. BWFI is not sterile water and is not a nal dosage orm. It is an intermediatebulk product and suitable to be used as an ingredient during ormulation. BWFIis the highest quality o pharmacopoeial WPU.

3.5.2 Certain pharmacopoeias place constraints upon the permitted puri-cation techniques as part o the specication o the BWFI. Te InternationalPharmacopoeia and the European Pharmacopoeia, or example, allow only distil-lation as the nal purication step.

3.5.3 BWFI should meet the relevant pharmacopoeial specications or chemi-cal and microbiological purity (including endotoxin) with appropriate action andalert limits.

3.5.4 BWFI should also be protected rom recontamination and microbialprolieration.

3.6 Other grades of water3.6.1 When a specic process requires a special non-pharmacopoeial grade owater, its specication must be documented within the company quality system.As a minimum it must meet the pharmacopoeial requirements relating to thegrade o WPU required or the type o dosage orm or process step.

4. Application o specifc types o waterto processes and dosage orms

4.1 Product licensing authorities speciy the minimum grade o WPU that mustbe used during the manuacture o the diferent dosage orms or or diferentstages in washing, preparation, synthesis, manuacturing or ormulation.

4.2 The grade o water used should take into account the nature and intendeduse o the intermediate or nished product and the stage in the manuacturing

process at which the water is used.

4.3 BHPW can be used in the preparation o products when water o highquality (i.e. very low in microorganisms and endotoxins) is needed, but the


7/23

Annex 2

73

process stage or product requirement does not include the constraint on theproduction method deined in some o the pharmacopoeial monographs or

BWFI.

4.4 BWFI should be used in the manuacture o injectable products ordissolving or diluting substances or preparations during the manuacturing oparenterals, and or manuacture o sterile water or preparation o injections.BWFI should also be used or the nal rinse aer cleaning o equipment andcomponents that come into contact with injectable products as well as or thenal rinse in a washing process in which no subsequent thermal or chemicaldepyrogenization process is applied.

4.5 When steam comes into contact with an injectable product in its nalcontainer or with equipment or preparing injectable products, it should conormto the specication or BWFI when condensed.

5. Water purifcation systems

5.1 General considerations

5.1.1 Te specications or WPU ound in compendia (e.g. pharmacopoeias) do

not dene the permissible water purication methods apart rom or BWFI (reerto section 3.5).

5.1.2 Te chosen water purication method or sequence o purication stepsmust be appropriate to the application in question. Te ollowing should be con-sidered when selecting the water treatment method:

the nal water quality specication;

the quantity o water required by the user;

the available eed-water quality and the variation over time(seasonal changes);

the availability o suitable support acilities or system connection(raw water, electricity, heating steam, chilled water, compressedair, sewage system, exhaust air);

the sanitization strategy;

the availability o water-treatment equipment on the market;

the reliability and robustness o the water-treatment equipmentin operation;

the yield or efciency o the purication system;

the ability to adequately support and maintain the waterpurication equipment;


8/23

74


70,2

012


the continuity o operational usage considering hours/days, days/years and planned downtime;

the total lie-cycle costs (capital and operational includingmaintenance).

5.1.3 Te specifcations or water purifcation equipment, storage anddistribution systems should take into account the ollowing:

the location o the plant room;

extremes in temperature that the system will encounter;

the risk o contamination rom leachates rom contact materials; the adverse impact o adsorptive contact materials;

hygienic or sanitary design, where required;

corrosion resistance;

reedom rom leakage;

a system confguration to avoid prolieration o microbiologicalorganisms;

tolerance to cleaning and sanitizing agents (thermal and/or

chemical); the sanitization strategy;

the system capacity and output requirements;

the provision o all necessary instruments, test and samplingpoints to allow all the relevant critical quality parameters o thecomplete system to be monitored.

5.1.4 Te design, confguration and layout o the water purifcation equipment,

storage and distribution systems should also take into account the ollowingphysical considerations:

ability to collect samples;

the space available or the installation;

structural loadings on buildings;

the provision o adequate access or maintenance;

the ability to saely handle regeneration and sanitization chemicals.

5.2 Production of drinking-water5.2.1 Drinking-water is derived rom a raw water source such as a well, river orreservoir. Tere are no prescribed methods or the treatment o raw water toproduce drinking-water rom a specifc raw water source.


9/23

Annex 2

75

5.2.2 ypical processes employed at a user plant or by a water supply authorityinclude:

desalinization;

ltration;

soening;

disinection or sanitization (e.g. by sodium hypochlorite(chlorine) injection);

iron (errous) removal;

precipitation;

reduction o concentration o specic inorganic and/or organicmaterials.

5.2.3 Te drinking-water quality should be monitored routinely to account orenvironmental, seasonal or supply changes which have an impact on the sourcewater quality.

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

5.2.5 rend review may be used to identiy changes. I the drinking-waterquality changes signicantly, but is still within specication, the direct use o thiswater as a WPU, or as the eed-water to downstream treatment stages, should bereviewed and the result o the review documented.

5.2.6 Where drinking-water is derived rom an in-house system orthe treatment o raw water, the water-treatment steps used and the systemconguration should be documented. Changes to the system or to its operationshould not be made until a review has been completed and the change approved

by the QA department in accordance with change control procedures.5.2.7 Where drinking-water is stored and distributed by the user, the storagesystems must not allow degradation o the water quality beore use. Aer anysuch storage, testing should be carried out routinely in accordance with a denedmethod. Where water is stored, the system design and operation should ensure aturnover or recirculation o the stored water sufcient to prevent stagnation.

5.2.8 Te drinking-water system is usually considered to be an indirect impactsystem and does not need to be qualied.

5.2.9 Drinking-water purchased in bulk and transported to the user by tankerhas additional problems and risks not associated with drinking-water deliveredby pipeline. Vendor assessment and authorized certication activities, includingconrmation o the acceptability o the delivery vehicle, should be undertaken ina similar way to that used or any other starting material.


10/23

76


70,2

012


5.2.10 Equipment and systems used to produce drinking-water should be able to bedrained and sanitized. Storage tanks should be closed with appropriately protected

vents, and should allow or visual inspection and or being drained and sanitized.Distribution pipework should be able to be drained or ushed and sanitized.

5.2.11 Special care should be taken to control microbiological contaminationo sand lters, carbon beds and water soeners. Once microorganisms haveinected a system, the contamination can rapidly orm biolms and spreadthroughout the system. echniques or controlling contamination such as back-ushing, chemical and/or thermal sanitization and requent regeneration shouldbe considered as appropriate.

5.3 Production o purifed water5.3.1 Any appropriate qualied purication technique or sequence o techniquesmay be used to prepare puried water (PW). PW is commonly produced by ionexchange, RO, ultraltration and/or electro-deionization processes and distillation.

5.3.2 Te ollowing should be considered when conguring a waterpurication system or dening user requirement specications (URS):

the eed-water quality and its variation over seasons;

the quantity o water required by the user;

the required water-quality specication;

the sequence o purication stages required;

the energy consumption;

the extent o pretreatment required to protect the nal puricationsteps;

perormance optimization, including yield and efciency o unit

treatment-process steps; appropriately located sampling points designed in such a way as

to avoid potential contamination;

unit process steps should be provided with appropriateinstrumentation to measure parameters such as ow, pressure,temperature, conductivity, pH and total organic carbon.

5.3.3 Ambient-temperature systems such as ion exchange, RO and ultraltrationare especially susceptible to microbiological contamination, particularly when equip-ment is static during periods o no or low demand or water. It is essential to considerthe mechanisms or microbiological control and sanitization.

Te method or sanitizing each stage o purication needs to be denedand must include verication o the removal o any agents used. Tere should bedocumented evidence o its efcacy.


11/23

Annex 2

77

5.3.4 Te ollowing should be considered:

maintenance o minimum fow through the water generationsystem is recommended at all times;

control o temperature in the system by heat exchanger or plant-room cooling to reduce the risk o microbial growth (guidance

value < 25 C);

provision o ultraviolet disinection;

selection o water-treatment components that can periodically bethermally sanitized;

application o chemical sanitization (including agents such asozone, hydrogen peroxide and/or peracetic acid);

thermal sanitization at > 65 C.

5.4 Production o highly purifed water5.4.1 Highly puried water (HPW) can be produced by double-pass reverseosmosis coupled with ultraltration or by any other appropriate qualiedpurication technique or sequence o techniques.

5.4.2 Te guidance provided in section 5.3 or PW is equally applicable toHPW.

5.5 Production o water or injection(s)5.5.1 Some pharmacopoeias prescribe or limit the permitted nal waterpurication stage in the production o BWFI. Distillation is the preerredtechnique; it is considered a more robust technique based on phase change, andin some cases, high-temperature operation o the process equipment.

5.5.2 Te ollowing should be considered when designing a water puricationsystem and dening URS:

the eed-water quality;

the required water quality specication;

the quantity o water;

the optimum generator size or generators with variable control toavoid over-requent start/stop cycling;

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

5.5.3 Te system conguration guidance provided in section 5.3 or PW isequally applicable to water or injection.


12/23

78


70,2

012


6. Water storage and distribution systems

6.1 Tis section applies to WPU systems or PW, BHPW and BWFI. Te waterstorage and distribution should work in conjunction with the purication plantto ensure delivery o water o consistent quality to the user points, and to ensureoptimum operation o the water purication equipment.

6.1 General6.1.1 Te storage and distribution system should be considered as a key part othe whole system and should be designed to be ully integrated with the water

purication components o the system.6.1.2 Once water has been puriied using an appropriate method it caneither be used directly or, more requently, it will be ed into a storage vesselor subsequent distribution to points o use. he ollowing text describes therequirements or storage and distribution systems and point o use (POU).

6.1.3 Te storage and distribution system should be congured to preventmicrobial prolieration and recontamination o the water (PW, BHPW, BWFI)aer treatment. It should be subjected to a combination o online and ofine

monitoring to ensure that the appropriate water specication is maintained.

6.2 Materials that come into contact with systemsfor water for pharmaceutical use

6.2.1 Tis section applies to generation equipment or PW, BHPW and BWFI andthe associated storage and distribution systems.

6.2.2 Te materials that come into contact with WPU, including pipework,valves and ttings, seals, diaphragms and instruments, should be selected to

satisy the ollowing objectives. Compatibility. Te compatibility and suitability o the materials

should encompass the ull range o its working temperature andpotential chemicals that will come into contact with the system atrest, in operation and during sanitization.

Prevention of leaching. All materials that come into contact with WPUshould be non-leaching at the range o working and sanitizationtemperatures o the system.

Corrosion resistance. PW, BHPW and BWFI are highly corrosive.

o prevent ailure o the system and contamination o the water, thematerials selected must be appropriate, the method o jointing must be careullycontrolled and all ttings and components must be compatible with the pipework


13/23

Annex 2

79

used. Appropriate sanitary specication plastics and stainless-steel materials areacceptable or WPU systems.

When stainless steel is used it should be at least grade 316. In general316L or a higher grade o stainless steel is used.

Te system should be passivated afer initial installation or afer signicantmodication. When accelerated passivation is undertaken the system should bethoroughly cleaned rst and the passivation process should be undertaken inaccordance with a clearly dened documented procedure.

Smooth internal nish. Once water has been puried it is susceptible tomicrobiological contamination and the system is subject to the ormation

o biolms when cold storage and distribution are employed. Smoothinternal suraces help to avoid roughness and crevices within the WPUsystem. Crevices can be the source o contamination because o possibleaccumulation o microorganisms and ormation o biolms. Crevices arealso requently sites where corrosion can commence. Te internal materialnish should have an arithmetical average surace roughness o notgreater than 0.8 micrometre (Ra). When stainless steel is used, mechanicaland electro-polishing techniques may be employed. Electro-polishing

improves the resistance o the stainless-steel material to surace corrosion. Jointing. Te selected system materials should be easily joined by

welding in a controlled manner. Te control o the process shouldinclude, as a minimum, qualication o the operator, documentationo the welder set-up, work session test pieces (coupons), logs o allwelds and visual inspection o a dened proportion o welds, e.g.100% hand welds, 10% automatic welds.

Design o fanges, unions and valves. Where anges, unions or valvesare used they should be o a hygienic or sanitary design. Appropriatechecks should be carried out to ensure that the correct seals anddiaphragms are used and that they are tted and tightened correctly.Treaded connections should be avoided.

Documentation. All system components should be ully documentedand be supported by original or certied copies o material certicates.

Materials. Suitable materials that may be considered or sanitaryelements o the system include 316L (low carbon) stainless steel,polypropylene, polyvinylidene-diuoride and peruoroalkoxy. Te

choice o material should take into account the intended sanitizationmethod. Other materials such as unplasticized polyvinyl-chloride(uPVC) may be used or treatment equipment designed or less purewater such as ion exchangers and sofeners.


14/23

80


70,2

012


None o the materials that come into contact with WPU should containchemicals that will be extracted by the water. Plastics should be non-toxic and

should be compatible with all chemicals used. Tey should be manuacturedrom materials that should at least meet minimum ood grade standards. Teirchemical and biological characteristics should meet any relevant pharmacopoeiaspecications or recommendations.

Precautions should be taken to dene operational limits or areas wherewater circulation is reduced and turbulent ow cannot be achieved. Minimumow rate and change volumes should be dened.

6.3 System sanitization and bioburden control6.3.1 Water treatment equipment, storage and distribution systems used or BPW,BHPW and BWFI should be provided with eatures to control the prolierationo microbiological organisms during normal use, as well as techniques orsanitizing the system aer intervention or maintenance or modication. Tetechniques employed should be considered during the design o the system andshould take into account the interdependency between the materials and thesanitization techniques.

6.3.2 Systems that operate and are maintained at elevated temperatures

(e.g. > 65) are generally less susceptible to microbiological contaminationthan systems that are maintained at lower temperatures. When lowertemperatures are required due to the water treatment processes employedor the temperature requirements or the water in use, special precautionsshould be taken to prevent the ingress and prolieration o microbiological

contaminants (see section 6.4.3 or guidance).

6.4 Storage vessel requirements6.4.1

General6.4.1.1 he water storage vessel used in a system serves a number o importantunctions. he design and size o the vessel should take into considerationthe ollowing.

6.4.2 Capacity

6.4.2.1 Te capacity o the storage vessel should be determined on the basis o theollowing requirements:

It is necessary to provide a buer capacity between the steady-stategeneration rate o the water-treatment equipment and the potentially

variable simultaneous demand rom user points.

Te water-treatment equipment should be able to operatecontinuously or signicant periods to avoid the inefciencies and


15/23

Annex 2

81

equipment stress that occur when the equipment cycles on and otoo requently.

Te capacity should be sucient to provide short-term reservecapacity in the event o ailure o the water-treatment equipment orinability to produce water due to a sanitization or regeneration cycle.When determining the size o such reserve capacity, considerationshould be given to providing sucient water to complete a processbatch, work session, tank turnover by recirculation to minimizestagnation, or other logical period o demand.

6.4.3 Contamination control considerations6.4.3.1 Te ollowing should be taken into account or the ecient control ocontamination:

Te headspace in the storage vessel is an area o risk where waterdroplets and air can come into contact at temperatures that encouragethe prolieration o microbiological organisms. Te use o spray-ballor distributor devices should be considered in these systems to wetthe suraces during normal operation, chemical and/or thermal

sanitization. Nozzles within the storage vessels should be congured to avoid dead

zones where microbiological contamination might be harboured.

Vent lters are tted to storage vessels to allow the internal levelo liquid to uctuate. Te lters should be bacteria-retentive,hydrophobic and should ideally be congured to allow in situ testingo integrity. Ofine testing is also acceptable. Te use o heated ventlters should be considered or continuous hot storage or systems

using periodic heat sanitization to prevent condensation within thelter matrix that might lead to lter blockage and to microbial growththat could contaminate the storage vessels.

Where pressure-relie valves and bursting discs are provided onstorage vessels to protect them rom under- and over-pressurization,these devices should be o a sanitary design. Bursting discs shouldbe provided with external rupture indicators to ensure that loss osystem integrity is detected.

6.5 Requirements for water distribution pipework6.5.1 General

6.5.1.1 Te distribution o BPW, BHPW and BWFI should be accomplished usinga continuously circulating pipework loop. Prolieration o contaminants within


16/23

82


70,2

012


the storage tank and distribution loop should be controlled. Good justicationor using a non-recirculating one-way system should be provided.

6.5.1.2 Filtration should not usually be used in distribution loops or at takeof-user points to control biocontamination. Such lters are likely to concealsystem contamination.

6.5.2 Temperature control and heat exchangers

6.5.2.1 Where heat exchangers are employed to heat or cool WPU within a system,precautions should be taken to prevent the heating or cooling utility romcontaminating the water. Te more secure types o heat exchangers o the double

tube plate or double plate and rame or tube and shell conguration should beconsidered. Where these types are not used, an alternative approach whereby theutility is maintained and monitored at a lower pressure than the WPU may beconsidered. Te latter approach is not usually adopted in BWFI systems.

6.5.2.2 Where heat exchangers are used they should be arranged incontinually circulating loops or subloops o the system to avoid unacceptablestatic water in systems.

6.5.2.3 When the temperature is reduced or processing purposes the reduction

should occur or the minimum necessary time. Te cooling cycles and their dura-tion should be proven satisactory during the qualication o the system.

6.5.3 Circulation pumps

6.5.3.1 Circulation pumps should be o a sanitary design with appropriateseals that prevent contamination o the system. Where stand-by pumps areprovided, they should be conigured or managed to avoid dead zones trappedwithin the system.

Consideration should be given to preventing contamination in systemswhere parallel pump systems are used, especially i there is stagnant water whenone o the pumps is not being used.

6.5.4 Biocontamination control techniques

6.5.4.1 Water purication systems should be sanitized using chemical or thermalsanitization procedures as appropriate (production and distribution). Te proce-dure and conditions used (such as times and temperatures) should be suitable.

6.5.4.2

Te ollowing control techniques may be used alone or more commonlyin combination:

maintenance o continuous turbulent low circulation withinwater distribution systems reduces the propensity or theormation o bioilms;


17/23

Annex 2

83

the system design should ensure the shortest possible length opipework;

or ambient temperature systems, pipework should be isolated romadjacent hot pipes;

deadlegs in the pipework should be minimized through appropriatedesign, and as a guide should not signicantly exceed three times thebranch diameter as measured rom the ID pipe wall to centre line othe point-o-use valve where signicant stagnation potential exists;

pressure gauges should be separated rom the system by membranes;

hygienic pattern diaphragm valves should be used;

pipework or steam-sanitized systems should be sloped and ullydrainable;

the growth o microorganisms can be inhibited by:

ultraviolet radiation sources in pipework;

maintaining the system heated (greater than 65 C);

sanitizing the system periodically using hot water (guidancetemperature > 70 C);

sanitizing the system periodically using superheated hot water orclean steam;

routine chemical sanitization using ozone or other suitablechemical agents. When chemical sanitization is used, it is essentialto prove that the agent has been removed prior to using the water.Ozone can be efectively removed by using ultraviolet radiation.

7. Operational considerations

7.1 Start-up and commissioning o water systems7.1.1 Planned, well-dened, successul and well-documented commissioning andqualication is an essential precursor to successul validation o water systems.

7.1.2 Te commissioning work should include setting to work, system set-up,controls, loop tuning and recording o all system perormance parameters. I it isintended to use or to reer to commissioning data within the validation work thenthe quality o the commissioning work and associated data and documentation

must be commensurate with the validation plan requirements.

7.2 Qualifcation7.2.1 WPU, BPW, BHPW and BWFI systems are all considered to be directimpact, quality critical systems that should be qualied. Te qualication


18/23

84


70,2

012


should ollow the validation convention o design review or design qualication(DQ), IQ, OQ, and PQ.

7.2.2 Tis guidance does not dene the standard requirements or the conven-

tional qualication stages DQ, IQ and OQ, but concentrates on the particular PQapproach that should be used or WPU systems to demonstrate their consistentand reliable perormance. A three-phase approach should be used to satisy theobjective o proving the reliability and robustness o the system in service over anextended period.

ests on the source water must be included within the validationprogramme and continued as part o the routine monitoring. Te source water

should meet the requirements or drinking-water and any internal specication.Phase 1. Sample daily or continuously monitor the incoming eed-water

to veriy its quality.A test period o two weeks should be spent monitoring the system

intensively. During this period, the system should operate continuouslywithout ailure or perormance deviation. Usually water is not used or nished

pharmaceutical product (FPP) manuacturing during this period. Te ollowingactivities should be included in the testing approach.

Undertake chemical and microbiological testing in accordance witha dened plan.

Sample or continuously monitor the incoming eed-water daily toveriy its quality.

Sample or continuously monitor afer each step in the purication process.

Sample or continuously monitor at each point o use and at otherdened sample points.

Develop appropriate operating ranges.

Develop and nalize operating, cleaning, sanitizing and maintenanceprocedures.

Demonstrate production and delivery o product water o therequired quality and quantity.

Use and rene the standard operating procedures (SOPs) oroperation, maintenance, sanitization and troubleshooting.

Veriy provisional alert levels.

Develop and rene test-ailure procedure.

Phase 2. A urther test period o two weeks should be spent carryingout urther intensive monitoring while deploying all the rened SOPs afer thesatisactory completion o phase 1. Te sampling scheme should be generally the


19/23

Annex 2

85

same as in phase 1. Use o the water or FPP manuacturing purposes during thisphase may be acceptable, provided that both commissioning and phase 1 data

demonstrate appropriate water quality and the practice is approved by QA. Teapproach should also:

demonstrate consistent operation within established ranges;

demonstrate consistent production and delivery o water o therequired quantity and quality when the system is operated inaccordance with the SOPs.

Phase 3. Phase 3 typically runs or one year aer the satisactory completion

o phase 2. Water can be used or FFP manuacturing purposes during this phasewhich has the ollowing objectives:

to demonstrate reliable perormance over an extended period;

to ensure that seasonal variations are evaluated.

Te sample locations, sampling requencies and tests should be reducedto the normal routine pattern based on established procedures proven duringphases 1 and 2.

7.3 Continuous system monitoring7.3.1 Aer completion o phase 3 o the qualication programme or the WPUsystem, a system review should be undertaken. Following this review a routinemonitoring plan should be established based on the results o phase 3.

Monitoring should include a combination o monitoring with onlineinstruments (with appropriately qualied alarm systems) o parameters such asow, pressure, temperature, conductivity and total organic carbon, and ofinesample testing or physical, chemical and microbiological attributes. Ofinesamples should be taken rom points o use or dedicated sample points wherepoints o use cannot be sampled. All water samples should be taken using thesame methodology as detailed in production procedures. Tere should be asuitable ushing and drainage procedure in place.

7.3.2 ests should be carried out to ensure that the approved pharmacopoeialand company specication has been met.

Tis may include the microbiological quality o water as appropriate.Monitoring data should be subject to trend analysis (trending should

typically be within 2 sigma). Suitable alert and action levels should be establishedbased on historical reported data.

7.3.3 Any trend towards requently exceeding alert limits should trigger a thor-ough investigation o the root cause, ollowed by appropriate corrective actions.


20/23

86


70,2

012


7.4 Maintenance of water systems7.4.1

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

defned requency or system elements;

the calibration programme;

SOPs or specifc tasks;

control o approved spares;

issue o a clear maintenance plan and instructions;

review and approval o systems or use upon completion o work; record and review o problems and aults during maintenance.

7.5 System reviews7.5.1 WPU (BPW, BHPW and BWFI) systems should be reviewed at appropriateregular intervals. Te review team should comprise representatives romengineering, QA, microbiology, operations and maintenance. Te review shouldconsider matters such as:

changes made since the last review;

system perormance;

reliability;

quality trends;

ailure events;

investigations;

out-o-specifcations results rom monitoring;

changes to the installation; updated installation documentation;

log books;

the status o the current SOP list.

7.5.2 For new systems, or systems that display instability or unreliability, theollowing should also be reviewed:

need or investigation; corrective actions and preventative actions (CAPA);


21/23

Annex 2

87

qualifcation (DQ, actory acceptance test (FA), IQ, siteacceptance test (SA), OQ, PQ) or equivalent verifcation

documents, and monitoring phases o the system.

8. Inspection of water systems

8.1 WPU (BPW, BHPW and BWFI) systems are likely to be the subject oregulatory inspection rom time to time. Users should consider conductingroutine audit and sel-inspection o established water systems.

8.2 This GMP guidance can be used as the basis o inspection. A tour o the

water generation plant and visible pipework (including user points) should beperormed to ensure that the system is appropriately designed, installed andmaintained (e.g. that there are no leaks and that the system matches the pipingand instrumentation diagram or drawing (P&ID).

Te ollowing list identifes items and a logical sequence or a WPU

system inspection or audit:

a current drawing o the water system showing all equipment inthe system rom the inlet to the points o use along with sampling

points and their designations; approved piping drawings (e.g. orthographic and/or isometric);

a sampling and monitoring plan with a drawing o all samplepoints;

training programme or sample collection and testing;

the setting o monitoring alert and action levels;

monitoring results and evaluation o trends;

inspection o the last annual system review; review o any changes made to the system since the last audit anda check that the change control has been implemented;

review o deviations recorded and their investigation;

general inspection o system or status and condition;

review o maintenance, ailure and repair logs;

checking calibration and standardization o critical instruments.

8.3 For an established system that is demonstrably under control this scope oreview should prove adequate.


22/23

88


70,2

012


Further reading

Te International Pharmacopoeia. Geneva, World Health Organization; http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html.

WHO guidelines on good manufacturing practices: validation. In: WHO ExpertCommittee on Specifcations or Pharmaceutical Preparations. Fortieth report.Geneva, World Health Organization, 2006, Annex 4 (WHO Technical ReportSeries, No. 937); http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf#page=119.

WHO Guidelines or drinking-water quality, 3rd edition. Geneva, World HealthOrganization, 2008; http://www.who.int/water_sanitation_health/dwq/gdwq3rev/en/index.html.

American Society of Mechanical Engineers. Bioprocessing Equipment Standard.ASME BPE 2000.

Banes PH. Passivation; understanding and performing procedures on austeniticstainless steel systems. Pharmaceutical Engineering, 1990: 41.

Guide to inspections of high purity water systems. Maryland, US Food and DrugAdministration, 1993; http://www.fda.gov/ICECI/InspectionGuides.

Biotechnology. Equipment. Guidance on testing procedures or cleanability. BritishStandards Publishing. BS EN 12296, 1998.

European Medicines Agency. Note or guidance on the quality o water orpharmaceutical use. London, 2002 (CPMP/QWP/158-01); http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003394.pdf.

European Pharmacopoeia: see web site for the publishers of the EuropeanPharmacopoeia and supplements; http://www.pheur.org/.

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

ISPE Good practice guide: commissioning and qualifcation o pharmaceuticalwater and steam systems.ISPE Baseline M Pharmaceutical Engineering Guide,Vol. 4. International Society for Pharmaceutical Engineering, 2007.

ISPE Baseline Guide Volume 4: Water and Steam Systems. International Societyfor Pharmaceutical Engineering, 2001.

Noble PT. Transport considerations for microbial control in piping. Journal oPharmaceutical Science and echnology, 1994, 48: 7685.


23/23

Annex 2

Pharmaceutical Inspection Co-operation Scheme. PIC/S; Inspection of utilities;P1 009-1. Geneva, Pharmaceutical Inspection Co-operation Scheme, 2002.

Tverberg JC, Kerber SJ. Efect o nitric acid passivation on the surace compositiono mechanically polished type 316 L sanitary tube. EuropeanJournal of ParenteralSciences, 1998, 3: 117124.

US Food and Drug Administration. Guide to inspections of high purity watersystems, high purity water systems (7/93), 2009; http://www.da.gov/ICECI/Inspections/InspectionGuides/ucm074905.htm.

US Pharmacopeia: Published annually; see http://www.usp.org/.

Date post:	14-Apr-2018
Category:	Documents
Upload:	pamy26250
View:	260 times
Download:	2 times

Annex2 Who Gmp Water for Pharmaceutical

Documents