Presentation on theme: "World Health Organization"— Presentation transcript:
1 World Health Organization 1 April, 2017Supplementary Training Modules on Good Manufacturing PracticeWater for Pharmaceutical UsePart 2: Water purification and engineeringWHO Technical Report Series No 929, Annex 3
2 World Health Organization 1 April, 2017Water for Pharmaceutical UseObjectivesTo examine the basic technology and requirements for:Water treatment systemsStorage and distribution requirementsSampling and testingSanitization6. Water purification, storage and distribution systemsThis section applies to WPU systems for PW, HPW and WFI. The water storage and distribution should work in conjunction with the puri.cation plant to ensure consistent delivery of water to the user points, and to ensure optimum operation of the water puri.cation equipment.6.
3 World Health Organization 1 April, 2017Water for Pharmaceutical UseGeneralPart 1 – reviewed types of water and water purification systemsWater can be used directly, or stored in a storage vessel for subsequent distribution to points of useDesign appropriately to prevent recontamination after treatmentCombination of on-line and off-line monitoring to ensure compliance with water specification6.1 GeneralThe storage and distribution system should be considered as a key part of the whole system, and should be designed to be fully integrated with the water puri.cation components of the system. Once water has been puri.ed using an appropriate method, it can either be used directly or, more frequently, it will be fed into a storage vessel for subsequent distribution to points of use. The following text describes the requirements for storage and distribution systems. The storage and distribution system should be con.gured to prevent recontamination of the water after treatment and be subjected to a combination of online and of.ine monitoring to ensure that theappropriate water speci.cation is maintained.6.1
4 World Health Organization 1 April, 2017Water for Pharmaceutical UseWPU system contact materialsContact materials include:PipesValves and fittingsSealsDiaphragms and instrumentsTanksPumps, etc.Proper selection to ensure these are suitable6.2 Materials that come into contact with systems for water for pharmaceutical useThis section applies to generation equipment for PW, HPW and WFI, and the associated storage and distribution systems. The materials that come into contact with WPU, including pipework,valves and .ttings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.• Compatibility. All materials used should be compatible with the temperature and chemicals used by or in the system.• Prevention of leaching. All materials that come into contact with WPU should be non-leaching at the range of working temperatures.• Corrosion resistance. PW, HPW and WFI are highly corrosive. To prevent failure of the system and contamination of the water, the materials selected must be appropriate, the method of jointing must be carefully controlled, and all .ttings and components must be compatible with the pipework used. Appropriate sanitaryspeci .cation plastics and stainless steel materials are acceptable for WPU systems. When stainless steel is used it should be at least grade 316L. The system should be passivated after initial installation or after modi.cation. When accelerated passivation is undertaken, the system should be thoroughly cleaned .rst, and the passivation process should be undertaken in accordance with a clearly de.ned documented procedure.• Smooth internal finish. Once water has been puri.ed it is susceptible to microbiological contamination, and the system is subject to the formation of bio.lms when cold storage and distribution is employed. Smooth internal surfaces help to avoid roughness and crevices within the WPU system. Crevices are frequently sites where corrosion can commence. The internal .nish should have an arithmetical average surface roughness of not greater than 0.8 micrometre arithmetical mean roughness (Ra). When stainless steel is used, mechanical and electropolishing techniques may be employed. Electropolishing improves the resistance of the stainless steel material to surface corrosion.• 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, quali.cation of the operator, documentation of the welder set-up, work-session test pieces, logs of all welds and visual inspection of a de.ned proportions of welds.• Design of flanges or unions. Where .anges or unions are used, they should be of a hygienic or sanitary design. Appropriate checks should be carried out to ensure that the correct seals are used and that they are .tted and tightened correctly.• Documentation. All system components should be fully documented and be supported by original or certi.ed copies of material certi.cates.• Materials. Suitable materials that may be considered for sanitary elements of the system include 316 L (low carbon) stainless steel, polypropylene, polyvinylidenedi.uoride and per.uoroalkoxy. Other materials such as unplasticized polyvinylchloride (uPVC) may be used for treatment equipment designed for less pure water such as ion exchangers and softeners.6.2
5 World Health Organization 1 April, 2017Water for Pharmaceutical UseWPU system contact materials (2)Factors to consider (including components)Compatibility and leaching effectCorrosion resistanceSmooth internal finishing, ease of jointingHygienic / sanitary designDocumentationMaterials of construction (MOC) - (including original/certified copies of material certificates6.2
6 World Health Organization 1 April, 2017Water for Pharmaceutical UseWPU system contact materials (3)CompatibilityWith temperature and chemicals used in the systemLeaching effectNon-leaching at temperature rangeCorrosion resistancePW, HPW, WFI highly corrosiveStainless steel Grade 316L to be usedSystem passivated after installation and modification according to SOP6.2
7 World Health Organization 1 April, 2017Water for Pharmaceutical UseWPU system contact materials (4)Smooth internal finishBiofilms and microbial contaminationCrevices and roughness result in problem areas associated with contamination and corrosionInternal finish to have arithmetical average surface roughness not greater than 0.8 micrometer arithmetical mean roughness (Ra)Mechanical and electropolishing needed when stainless steel is used6.2
8 World Health Organization 1 April, 2017Water for Pharmaceutical UseWPU system contact materials (5)JointsSystem materials easily jointed, e.g. by weldingProcess controlled including requirements such as:Qualification of operatordocumentation of welder set upwork session test piecesweld logsvisual inspection of defined proportions of welds6.2
9 World Health Organization 1 April, 2017Water for Pharmaceutical UseWPU system contact materials (6)Suitable materials include:Stainless steel Grade 315 L (low carbon)Polypropylene (PP)Polyvinylidenedifluoride (PVDF)Perfluoroalkoxy (PFA)Unplasticized polyvinylchloride (uPVC) used for non- hygienic designed water treatment equipment such as ion exchangers and softeners6.2
10 World Health Organization 1 April, 2017Water for Pharmaceutical UseSystem sanitization and bioburden controlSystems in place to control proliferation of microbesTechniques for sanitizing or sterilizationConsideration already during design stage – then validatedSpecial precautions if water not kept in the range of 70 to 80 degrees Celsius6.3 System sanitization and bioburden controlWater treatment equipment, storage and distribution systems used for PW, HPW and WFI should be provided with features to control the proliferation of microbiological organisms during normal use, as well as techniques for sanitizing or sterilizing the system after intervention for maintenance or modi.cation. The techniques employed should be considered during the design of the system and their performance proven during the commissioning and quali.cation activities. Systems that operate and are maintained at elevated temperatures, in the range of 70–80 °C, are generally less susceptible to microbiological contamination than systems that are maintained at lower temperatures. When lower temperatures are required due to the water treatment processes employed or the temperature requirements for the water in use, then special precautions should be taken to prevent the ingress and proliferation of microbiological contaminants (see section6.5.3 for guidance).6.3
11 World Health Organization 1 April, 2017Water for Pharmaceutical UseStorage and distribution - Storage vesselsDesign and size importantServes as buffer between generation and useAvoid inefficiencies and equipment stress during frequent on-off cyclesShort-term reserve in case of failureContamination control considerationHeadspace (kept wet with spray ball / distributor device)Nozzles (no dead zone design)Vent filters (type, testing, use of heat)Pressure relief valves and burst discs (sanitary design)6.4 Storage vessel requirementsThe water storage vessel used in a system serves a number of important purposes. The design and size of the vessel should take into consideration the following.6.4.1 CapacityThe capacity of the storage vessel should be determined on the basis of the following requirements.• It is necessary to provide a buffer capacity between the steady-state generation rate of the water-treatment equipment and the potentially variable simultaneous demand from user points.• The water treatment equipment should be able to operate continuously for signi.cant periods to avoid the inef.ciencies and equipment stress that occur when the equipment cycles on and off too frequently.• The capacity should be suf.cient to provide short-term reserve capacity in the event of failure of the water-treatment equipment or inability to produce water due to a sanitization or regeneration cycle. When determining the size of such reserve capacity, consideration should be given to providing suf.cient water to complete a process batch, work session or other logical period ofdemand.6.4.2 Contamination control considerationsThe following should be taken into account for the ef.cient control of contamination.• The headspace in the storage vessel is an area of risk where water droplets and air can come into contact at temperatures that encourage the proliferation of microbiological organisms. The water distribution loop should be con.gured to ensure that the headspace of the storage vessel is effectively wetted by a .ow of water. The use of spray ball or distributor devices to wet the surfaces should be considered.• Nozzles within the storage vessels should be con.gured to avoid dead zones where microbiological contamination might be harboured.• Vent .lters are .tted to storage vessels to allow the internal level of liquid to .uctuate. The .lters should be bacteria-retentive, hydrophobic and ideally be con.gured to allow in situ testing of integrity. Of.ine testing is also acceptable. The use of heated vent .lters should be considered to prevent condensation within the .lter matrix that might lead to .lter blockage and to microbial growthrough that could contaminate the storage vessels.• Where pressure-relief valves and bursting discs are provided on storage vessels to protect them from over-pressurization, these devices should be of a sanitary design. Bursting discs should beprovided with external rupture indicators to prevent accidental loss of system integrity.6.4
12 World Health Organization 1 April, 2017Water for Pharmaceutical UseStorage and distribution – Pipes and heat exchangersContinuous circulating loop neededFiltration not recommended in loop and take-off pointHeat exchangers:Double tube plate or double plate and frame typeDesigned to ensure no stasis of waterWhere water is cooled before use, done in minimum time, and validated process6.5 Requirements for water distribution pipeworkThe distribution of PW, HPW and WFI should be accomplished using a continuously circulating pipework loop. Proliferation of contaminants within the storage tank and distribution loop should be controlled. Filtration should not usually be used in distribution loops or at takeoff user points to control biocontamination. Such .lters are likely to conceal system contamination.6.5.1 Temperature control and heat exchangersWhere heat exchangers are employed to heat or cool WPU within a system, precautions should be taken to prevent the heating or cooling utility from contaminating the water. The more secure types of heat exchangers of the double tube plate or double plate and frame con-guration should be considered. Where these types are not used, an alternative approach whereby the utility is maintained and monitored at a lower pressure than the WPU may be considered.Where heat exchangers are used they should be arranged in continually circulating loops or subloops of the system to avoid unacceptable static water in systems. When the temperature is reduced for processing purposes, the reduction should occur for the minimum necessary time. The cooling cycles and their duration should be proven satisfactory during the quali.cationof the system.6.5, 6.5.1
13 World Health Organization 1 April, 2017Water for Pharmaceutical UseStorage and distribution – Circulation pumpsSanitary design with appropriate sealsStandby pumpsCan be usedConfigured or managed in a way to avoid trapped dead zones6.5.2 Circulation pumpsCirculation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they should be con.gured or managed to avoid dead zones trapped within the system.6.5.2
14 World Health Organization 1 April, 2017Water for Pharmaceutical UseTypical water storage and distribution schematicWater must be kept circulatingSpray ballCartridgefilter 1 µmAir breakto drainOutletsHygienic pumpOptionalin-line filter0,2 µmUV lightFeed Water fromDI or ROHeat ExchangerOzone GeneratorHydrophobic air filter& burst discThe storage of highly purified water types is critical because of the risk of re-contamination by micro-organisms and other contaminants. This schematic drawing is included in handout Use it to explain the design features of a good storage system.Good design elements, not mentioned previously, include:Closed system with continuous re-circulation at 1-2 (or more) linear metres per second;Hydrophobic vent filters, which can be sterilized and integrity-tested;Burst disc if tank is heated, to prevent the tank collapsing as it cools; Re- circulation via spray ball, to ensure the tank lid is wet with moving water;In-line disinfection, by periodic heating, ozonization or UV;Air breaks to drains;In-line 0.2 micrometer filter to “polish” the water in purified water systemsWFI storage, which must be 70oC or above, and preferably above 80oC. (No ozone and filtration in WfI storage and distribution systems).
15 World Health Organization 1 April, 2017Water for Pharmaceutical UseBiocontamination control techniquesContinuous turbulent flow circulationSpecified velocity proven (qualification), and monitoredAvoid dead legsHygienic pattern diaphragm valvesShortest possible length of pipe workPipe work of ambient temperature systems, isolated from hot pipes6.5.3 Biocontamination control techniquesThe following control techniques may be used alone or more commonly in combination.• Maintenance of continuous turbulent .ow circulation within water distribution systems reduces the propensity for the formation of bio.lms. The maintenance of the design velocity for a speci.c system should be proven during the system quali.cation and the maintenance of satisfactory performance should be monitored. During the operation of a distribution system, short-term .uctuations in the .ow velocity are unlikely to cause contamination problems provided that cessation of .ow, .ow reversal or pressure loss does not occur.• The system design should ensure the shortest possible length of pipework.• For ambient temperature systems, pipework should be isolated from adjacent hot pipes.• Deadlegs in the pipework installation greater than 1.5 times the branch diameter should be avoided.• Pressure gauges should be separated from the system by membranes.• Hygienic pattern diaphragm valves should be used.• Pipework should be laid to falls to allow drainage.• The growth of microorganisms can be inhibited by:— ultraviolet radiation sources in pipework;— maintaining the system heated (guidance temperature 70– 80 °C);— sanitizing the system periodically using hot water (guidance temperature >70 °C);— sterilizing or sanitizing the system periodically using superheated hot water or clean steam; and— routine chemical sanitization using ozone or other suitable chemical agents. When chemical sanitization is used, it is essential to prove that the agent has been removed prior to using the water. Ozone can be effectively removed by using ultraviolet radiation.6.5.3
16 World Health Organization 1 April, 2017Water for Pharmaceutical UseBiocontamination control techniques (2)There should be no dead legsWater scours dead legIf D=25mm & distance X is greater than 50mm, we havea dead leg that is too longDead leg section>1.5DFlow direction arrows on pipes are importantSanitary ValveDXWater system design:There should be no dead legs!Stagnant areas allow microbial contamination as a result of colonization of surfaces with the formation of biofilm, as discussed in Part 1. Dead legs are stagnant areas where there is no water flow.There do not appear to be any regulations which give a specification for dead legs. Deciding when a dead leg is unacceptable is therefore not easy, as it involves the respective diameters of the pipes and the velocity, but there is a consensus in the industry that a dead leg should not be greater than twice the diameter of the pipe.If there are long runs of pipe to outlets without circulation, the pharmaceutical manufacturer must have a procedure in place which allows the pipework to be completely drained, left dry and sanitized or sterilized before use. This should be done on a daily basis. Special attention needs to be given to samples and test frequency for microbial counts from this type of outlet.Check that the piping has direction arrows on it. If the flow is in the wrong direction through a fitting it will not “scour” the fitting, resulting in the formation of biofilm.
17 World Health Organization 1 April, 2017Water for Pharmaceutical UseBiocontamination control techniques (3)1. Ball valves are unacceptable2. Bacteria can grow when the valve is closed3. The water is contaminated as it passes through the valveStagnant waterinside valveWater system design: (Contd.)Although ball valves can be used in the early stages of water treatment, they (and the related cone valve) should not be used in the water treatment system downstream of RO and DI outlets. This is because the “ball in socket” construction can be easily contaminated. Ball valves are not easy to clean unless dismantled. The space between the ball and the housing can be easily colonised by bacteria. Consequently, the water will become contaminated as it passes through the valve.Valves that can be used include diaphragm valves (as long as the diaphragm is made of a suitable material, ideally teflon coated neoprene), and butterfly valves.Zero dead leg valves are now available for high purity water systems.
18 World Health Organization 1 April, 2017Water for Pharmaceutical UseBiocontamination control techniques (4)Pressure gauges separated from system membranesPipe work laid to fall (slope) – allows drainageMaintain system at high temperature (above 70 degrees Celsius)Use UV radiationFlow rate, life-cycle of the lampSuitable construction material6.5.3
19 World Health Organization 1 April, 2017Water for Pharmaceutical UseBiocontamination control techniques (5)Periodic sanitization with hot waterPeriodic sanitization with super-heated hot water or clean steamReliableMonitoring temperature during cycleRoutine chemical sanitization using, e.g. ozoneRemoval of agent before use of water important6.5.3