WORLD HEALTH ORGANIZATION
ORGANISATION MONDIALE DE LA SANTE
WHO GOOD MANUFACTURING PRACTICES (GMP):
WATER FOR PHARMACEUTICAL USE (WPU)
© World Health Organization 2004
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TENTATIVE SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/04.047/Rev.1: WHO GOOD MANUFACTURING PRACTICES (GMP):
WATER FOR PHARMACEUTICAL USE (WPU)
First draft prepared and mailed for comments
Deadline for receipt of comments
30 May 2003
Collation of comments
Discussion at a consultation held on
23-26 June 2003
end June 2003
Second draft prepared
Mailing of draft for second round of
Deadline for receipt of comments
31 March 2004
Collation of comments
Preparation of third draft
Mailing of draft for third round of comments
Presentation to Thirty-ninth WHO Expert Committee on Specifications for
(planned November 2004)
WHO GOOD MANUFACTURING PRACTICES (GMP):
WATER FOR PHARMACEUTICAL USE (WPU)
1.1 Scope of the document
The guidance contained in this document is intended to provide information about the available specifications for Water for Pharmaceutical Use (WPU), guidance about which quality of water to use for specific applications, and to provide Good Manufacturing Practice (GMP) guidance about the design, installation and operation of pharmaceutical water systems.
This guideline is intended to provide the reader with guidance about current good water system practice and reference to available specifications and engineering guidelines.
The GMP Guidelines for WPU contained in this document are intended to be supplementary to the general GMP guidelines for pharmaceutical products published by WHO (WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-seventh Report. Geneva, World Health Organization, 2003 (WHO Technical Report Series, No. 908, Annex 4).
This document makes reference to available specifications, such as the pharmacopoeias and industry guidelines for the use, production, storage and distribution of water in bulk form. It does not cover waters for patient administration in their formulated state. In order to avoid confusion it does not attempt to duplicate such material.
Where subtle points of difference exist between pharmacopoeial specifications the pharmaceutical company in question will be expected to resolve which option to choose in accordance with the related marketing authorization submitted to the national drug regulatory authority.
1.2 Background to water requirements and uses
Water is the most widely used substance, raw material or starting material in the production, processing and formulation of pharmaceutical products. It has unique chemical properties due to its polarity and hydrogen bonds. This means it is able to dissolve, absorb, adsorb or suspend many different compounds, including contaminants that may represent hazards themselves or that are able to react with intended product substances, resulting in hazards to health.
Different grades of water quality are required depending on the route of administration of different pharmaceutical products.
Control of the quality of water throughout the treatment, storage and distribution processes, including microbiological and chemical quality, is a major concern. Unlike other product and process ingredients, water is usually drawn from a system on demand, and is not subject to testing and batch or lot release before use. Assurance of quality to meet the on-demand expectation is, therefore, essential. Additionally, certain microbiological tests may require incubation periods and, therefore, the results are likely to lag the water use. Control of the microbiological quality of WPU is a high priority. Avoiding biological contamination in water treatment system components is no less important than avoidance of their proliferation in storage and distribution.
1.3 Applicable guides
In addition to the specific guidance provided in this document Section 9 (Bibliography) identifies some relevant guidance that can serve as additional background material when planning, installing and using systems intended to provide WPU.
2. Water system general requirements
Water treatment plants shall be designed, installed, commissioned, validated and maintained to ensure the reliable production of water of an appropriate quality. They shall not be operated beyond their designed capacity. Water shall be produced, stored and distributed in a manner that prevents unacceptable microbial growth.
Water treatment systems shall be subject to planned maintenance and validation. Their use following maintenance work shall be approved by Quality Assurance (QA).
Water sources, water treatment equipment and treated water shall be monitored regularly for chemical and microbiological contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the monitoring and of any action taken.
After any chemical sanitization of the water systems a validated flushing procedure shall be followed to ensure that the sanitizing agent has been effectively removed.
3. Water quality specifications
The following requirements concern water processed, stored and distributed in bulk form. It does not cover the specification of waters formulated for patient administration. Pharmacopoeias include specifications for both bulk and dosage form waters.
Pharmacopoeial requirements for WPU are described in national and international pharmacopoeias and give limits for contaminants. Where pharmaceutical companies wish to supply multiple markets they should resolve any of the variations between pharmacopoeias.
3.2 Potable water
3.3 Purified water (PW)
Purified water (PW) shall be prepared from a potable water source as a minimum quality feed water to purification equipment. PW shall meet the pharmacopoeial specifications for chemical and microbiological purity, and should be protected from recontamination and microbial proliferation.
3.4 Water highly purified (WHP)
Water highly purified (WHP) should be prepared from potable water as a minimum quality feed water to purification equipment. WHP is a unique specification for water only found in few pharmacopoeias. This grade of water must meet the same quality standard as water for injections (WFI) including the limit for endotoxins, but the water treatment methods are not constrained. WHP may be prepared by combinations of methods such as double-pass reverse osmosis (RO), ultrafiltration (UF) and deionization (DI).
3.5 Water for injections (WFI)
3.6 Other grades of water
When a specific process requires a special non-compendial grade of water these shall be specified and shall at least satisfy the compendial requirements of the grade of WPU required for the type of dosage form or process step.
4. Application of specific waters to processes and dosage
Product licensing authorities define the requirement to use the specific grades of WPU for different dosage forms or for different stages in washing and preparation, synthesis, manufacturing or formulation.
WHP is used in the preparation of products when water of high biological and endotoxin quality is needed but does not justify the constraint to production method defined in the monograph for WFI.
5. Water purification methods
5.1 General considerations
The specifications for WPU found in compendia (e.g. pharmacopoeias) are generally not prescriptive as to permissible water purification methods other than for WFI (refer to Section 2.5).
The chosen water purification method or sequence of treatment steps must be appropriate to the application in question. The following should be considered when selecting the water treatment methods:
· the water quality specified;
· the yield or efficiency required;
· the nature and quantity of the contaminants in the feed water and the anticipated
variance (Note: matters such as change in water source and seasonal changes can
· reliability and robustness of the water treatment equipment in operation;
· the availability of water treatment equipment on the market;
· the ability to adequately support and maintain the equipment; and
· operation costs.
Selection of water purification equipment should take into account the following:
· leaching from contact materials;
· adsorptive contact materials;
· hygienic or sanitary design where required;
· corrosion resistance;
· freedom from leakage;
· configuration to avoid proliferation of microbiological organisms;
· tolerance cleaning and sanitizing agents (thermal and chemical); and
· capacity and output.
5.2 Production of potable water
There are no prescribed methods for the treatment of raw water to produce potable water from a specific raw water source.
Typical processes employed at a user plant or by a water supply authority include:
· disinfection or sanitization (e.g. by sodium hypochlorite (chlorine) injection);
· iron removal;
· precipitation; and
· specific inorganic/organic reduction.
The water quality shall be monitored routinely. Additional testing should be considered if there is a change in the potable water raw water source, treatment techniques or system configuration. If the potable water quality changes significantly, the direct use of the water as a WPU or the downstream treatment stages should be reviewed and the result of the review documented.
Where potable water is derived from an “in-house” raw water treatment system, the water treatment steps used and the system configuration should be documented. Changes to the system or its operation should not be made until a review has been completed and the change approved by the QA department.
Where potable water is stored and distributed by the user the storage systems must not allow degradation of the water quality before use. Testing should be carried out routinely in accordance with a defined method after any such storage. Where water is stored its use should ensure a turnover of the stored water.
The potable water system is usually considered to be an “indirect impact” and does not need to be qualified.
Potable water purchased in bulk and transported to the user by tanker presents special problems and risks compared with potable water delivered by pipeline. Vendor assessment and authorized certification activities, including confirmation of the acceptability of the delivery vehicle, should be undertaken in a similar way as for any other starting material.
Equipment and systems used for potable water should be capable of being drained and sanitized. Storage tanks should be closed and be capable of visual inspection.
Special care should be taken to control microbiological contamination of sand filters, carbon beds and water softeners. Once microorganisms infect systems the contamination can rapidly form biofilms and spread through the system. Techniques such as back-flushing, chemical or thermal sanitization and frequent regeneration should be considered. Additionally, all water treatment components should be maintained with continuous water flow to inhibit microbial growth.
5.3 Production of PW
There are no prescribed methods for the production of PW in the pharmacopoeias. An appropriate qualified purification technique or sequence of techniques may be used to prepare PW. Typically ion exchange, ultrafiltration and reverse osmosis processes are used. Distillation can also be used, but this is rare.
The following shall be considered when configuring a water purification network:
· the feed water quality and variation over time;
· the required water quality specification;
· the sequence of treatment stages required;
· performance optimization of unit treatment process steps; and
· unit process steps should be provided with appropriate instrumentation to
measure parameters such as flow, pressure, temperature, conductivity, pH, etc.
Ambient temperature PW systems are especially susceptible to microbiological contamination, particularly when equipment is static during periods of no or low demand for water. It is essential to consider the mechanisms for microbiological control and sanitization. The following techniques should be considered:
· maintenance of flow through water treatment equipment at all times;
· control of temperature in the system to avoid incubation conditions
(guidance value <22 °C);
· provision of UV disinfection in recycle loops;
· selection of water treatment components that can be thermally sanitized; and
· application of chemical sanitization.
5.4 Production of WFI
The pharmacopoeias prescribe or limit the available final water treatment stages to produce WFI. Distillation is the preferred technique due to the phase change and high temperature operation of the process.
Distillation is considered to be a robust process. However, the following shall be considered when designing a water treatment system:
· the feed water quality;
· the required water quality specification;
· optimum generator sizing to avoid over frequent start/stop cycling;
· blow-down and dump functions; and
· cool-down venting to avoid contamination ingress.
6. Water storage and distribution systems
This section applies to WPU systems for PW and WFI. The water storage and distribution should work in conjunction with the generation plant to ensure consistent delivery of water to the user points, and to ensure optimum operation of the water treatment or generation plant.
The storage and distribution system should be considered as a key part of the whole system, and should be designed fully integrated with the water system treatment components.
Once water has been treated using an approved 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 of storage and distribution systems.
After water treatment the storage and distribution system shall be configured so as to prevent recontamination of the water. The storage and distribution system should be subjected to a combination of online and offline monitoring in order to ensure that the appropriate water specification is maintained.
6.2 WPU system contact materials
This section applies to PW, WHP and WFI systems generation equipment, storage and distribution systems.
The materials that come into contact with WPU, including pipework, valves and fittings, seals, diaphragms and instruments, should be selected to satisfy the following objectives.
· Be tolerant of the temperature and chemicals used by or in the system.
· Leaching. All materials that come into contact with WPU shall be non-leaching at the
range of working temperatures. Some materials on approved lists for food processing
applications may be suitable.
· Corrosion resistance. PW and WFI are highly corrosive materials and in order to prevent
failure of the system and contamination of the water the materials selected must be
appropriate, the method of jointing must be carefully controlled and all fittings and
components must be compatible with the pipework used. Appropriate 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 fabrication or
installation. When accelerated passivation is undertaken the system should be thoroughly
cleaned first, and the passivation process should be undertaken in accordance with a
clearly defined documented procedure.
· Smooth internal finish. Once water has been purified it is susceptible to microbiological
contamination, and the system is subject to the formation of biofilms when cold storage
and distribution is employed. Smooth internal surfaces help to reduce the occurrence of
roughness and crevices within the WPU system. Crevices are also frequently sites where
corrosion can commence. The internal finish should have an arithmetical average surface
roughness of not greater than 0.8 micrometer arithmetical mean roughness (Ra). When
stainless steel is used mechanical and electropolishing techniques may be employed.
Electropolishing also improves the surface corrosion resistance of the stainless steel
· The selected system materials should be easily jointed by welding in a controlled manner.
The control of the process should include as a minimum qualification of the operator,
documentation of the welder set up, work session test pieces, logs of all welds and visual
inspection of welds.
· Where sanitary unions are unavoidable they should be of a hygienic or sanitary design.
Appropriate controls should be applied to control of the seals used and tightening of the
· Documentary evidence. All system components should be fully documented and be
supported by original or certified copies of material certificates.
· Suitable materials that may be considered for sanitary elements of the system include
316 L (low carbon) stainless steel, polypropylene (PP), polyvinylidenedifluoride (PVDF)
and perfluoroalkoxy (PFA). Other materials such as unplasticized polyvinylchloride
(uPVC) may be used for non-hygienic designed water treatment equipment such as ion
exchangers and softeners.
6.3 System sanitization and bioburden control
Water treatment equipment, storage and distribution systems used for PW, WHP and WFI shall be provided with features to control the proliferation of microbiological organisms in normal use, as well as techniques for sanitizing or sterilizing the system after intervention for maintenance or modification. The techniques deployed shall be considered during the design of the system and their performance proven during the commissioning and qualification activities.
Systems which operate and are maintained at elevated temperatures typically greater than 65 °C are generally less susceptible to microbiological contamination than systems which 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 contamination.
6.4 Storage vessel requirements
The water storage vessel used in a system serves a number of important purposes. The design and sizing of the vessel shall take into consideration the following.
· 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.
· To ensure that the water treatment equipment is able to operate for significant periods in
order to avoid the inefficiencies and equipment stress that occurs when equipment cycles
on and off too frequently.
· To provide short-term reserve capacity in the event of water treatment equipment failure
or inability to produce water due to a sanitized nation or regeneration cycle. When
determining the size of such reserve capacity consideration should be given to providing
sufficient water to complete a process batch, work sessions, or other logical periods of
6.4.2 Contamination control considerations
· The headspace in the storage vessel is an area of risk where water droplets and air can be
in contact at temperatures that encourage the proliferation of microbiological organisms.
The water distribution loop should be configured to ensure that the headspace of the
storage vessel is effectively wetted by a flow of water. Spray ball or distributor devices
should be considered in order to wet the surfaces.
· Nozzles within the storage vessels should be configured to avoid dead zones where
microbiological contamination might be harboured.
· Vent filters are fitted to storage vessels in order to allow the internal liquid level to
fluctuate. The filters should be bacteria retentive, sterilizing grade, hydrophobic and
configured to allow in situ integrity testing. The use of heated vent filters should be
considered to prevent condensation within the filter matrix that might give rise to
microbial growth that could contaminate the storage vessels.
· Where pressure relief valves and bursting disks are provided to storage vessels in order to
protect them from over pressure, these devices shall be of a sanitary design. Bursting
disks should be provided with external rupture indications to avoid accidental loss of
6.5 Water distribution requirements
The distribution of PW, WHP and WFI should be accomplished using a continuously circulating pipework loop. Contamination proliferation within the storage tank and distribution loop shall be controlled.
Filtration shall not be used in distribution loops or at take-off user points to control bio-contamination. Such filters are likely to conceal system contamination.
6.5.1 Temperature control and heat exchangers
Where heat exchangers are employed to heat or cool WPU within a system, precautions shall be taken to prevent the heating or cooling utility from contaminating the water. Heat exchangers of the double tube plate or double plate and frame configuration should be considered. Where these types of more secure heat exchangers are not used, then 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 so as 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 duration should be proven to be satisfactory during qualification work.
6.5.2 Circulation pumps
Circulation pumps should be of a sanitary design with appropriate seals that prevent contamination of the system. Where stand-by pumps are provided, they shall be configured or managed so as to avoid trapped dead zones within the system.
6.5.3 Bio-contamination control techniques
· The maintenance of continuous turbulent flow circulation within water distribution
systems reduces the propensity for the formation of biofilms. Typical flow velocities in
the range of 1-2 m/s are found to be satisfactory. The maintenance of such velocities
should be proven during the system qualification and the maintenance of satisfactory
performance should be monitored. During the operation of a distribution system short-
term fluctuations in the flow velocity are unlikely to cause contamination problems.
However, the system should be designed in the performance conifer to demonstrate that
at no time does flow cease, reverse or a loss of pressure occur
· Maintaining the system heated (guidance temperature > 65 °C).
· Sanitizing the system periodically using hot water (guidance temperature 80 °C).
· Sterilizing the system periodically using high temperature hot water or steam.
· Routine chemical sanitization using ozone or other suitable chemical agents. When
chemical sanitization is used, it is essential to prove removal of the agent prior to using
7. Operational considerations
7.1 Start up and commissioning of water systems
Planned, well-defined, successful and well-documented commissioning is an essential precursor to successful validation of water systems. The commissioning work should include setting to work, system set-up, loop tuning and recording of all system performance parameters. If it is intended to use or refer to commissioning data within the validation work then the quality of the commissioning work and associated data must be commensurate with the validation plan requirements.
When the water system is a direct impact quality critical system it shall be qualified. The qualification should follow the validation convention of design review or design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ).
For WPU systems the following particular requirements should be considered for the PQ stage in order to demonstrate consistent and reliable performance of the system. A 3-phase approach should be considered to satisfy the objective of proving the reliability and robustness of the system in service over an extended period.
Phase 1. A test period of 2-4 weeks should be spent monitoring the system intensively. During this period the system should operate continuously without failure or performance deviation.
· Sample daily.
· Sample incoming feed water to verify its quality.
· Develop appropriate operating ranges.
· Develop and finalize operating, cleaning, sanitizing and maintenance procedures.
· Demonstrate production and delivery of product water of the required quality and
· Sample after each step in the treatment process.
· Sample at each point of use.
· Undertake chemical testing specific to unit process steps.
· Undertake microbiological testing for each unit process step.
· Use and refine the SOPs for operation, maintenance, sanitization and trouble
· Verify alarm response/action levels.
· Develop and refine test failure procedure.
Phase 2. A further test period of 2-4 weeks should be spent carrying out further intensive monitoring whilst deploying all the refined SOPs. The sampling scheme should be generally the same as in Phase 1.
· Demonstrate consistent operation within established ranges.
· Demonstrate consistent production and delivery of water of the required quality
when the system is operated in accordance with the SOPs.
Phase 3. The final phase, extending up to one year from the start of Phase 1.
· Demonstrate extended reliable performance.
· Ensure that seasonal variations are evaluated.
· Sample locations, sampling frequencies and tests reduced to the normal routine
pattern based on established procedures proven during Phases 1 and 2.
7.3 Ongoing system monitoring
Following Phase 3 of the qualification monitoring of the system should continue at a frequency similar to Phase 3.
Monitoring should include a combination of on-line or off-line grab sample monitoring from the system and from points of use. Samples taken from point of use shall be taken in a similar way to how the water is used in service.
Tests shall be carried out so as to satisfy the selected pharmacopoeia specification, and should include as appropriate, determination of conductivity, total organic carbons, total viable count, heavy metals and nitrates.
Monitoring data should be subject to trending analysis.
7.4 Maintenance of water systems
WPU systems should be maintained in accordance with a controlled, documented maintenance programme that takes into account the following:
· defined frequency for system elements;
· SOPs for specific tasks;
· control of approved spares;
· issue of clear maintenance instructions;
· review and approval of systems for use upon completion of work; and
· record and review problems and faults during maintenance.
7.5 System reviews
WPU systems should be reviewed annually. The review team should comprise representatives from engineering, quality assurance, operations and maintenance. The review should consider matters such as performance, reliability, quality trends, failure events, investigations and out of specifications (OOS) results from monitoring.
8. Inspection of water systems
Water systems are likely to be the subject of regulatory inspection from time to time. Users should consider routine audit and self-inspection of established water systems. This GMP guidance can be used as the basis of inspection. The following list identifies items and a logical sequence for a WPU system inspection or audit:
· sampling and monitoring plan;
· the setting of monitoring alert and action levels;
· monitoring results and evaluation of trends;
· inspection of the last annual system review;
· review any changes made to the system since the last audit and check the change
· the setting of monitoring alert and action levels;
· deviations recorded and their investigation;
· general system inspection for status and condition;
· review maintenance, failure and repair logs; and
· check critical instrument calibration and standardization.
For an established system that is demonstrably under control this range of review should prove adequate.
For new systems, or systems that display instability or unreliability, the following should also be reviewed:
· OQ; and
1. WHO Guidelines for Drinking-Water Quality, 3rd edition. Geneva, World Health
2. Water and steam systems. International Society for Pharmaceutical Engineering.
ISPE Baseline TM Pharmaceutical Engineering Guide.
3. Bioprocessing Equipment Standard. ASME - BPE 2000
4. Surface finishes applied to stainless steels. BS 1449, Part 2, 1975.
5. Biotechnology- Equipment- Guidance on testing procedures for cleanability.
BS EN 12296.
6. US IDF Bulletin 189, 1993.
7. Harfst WH. Selecting piping materials for high-purity water systems. Ultra Pure Water,
8. Noble PT. Transport considerations for microbial control in piping. Journal of
Pharmaceutical Science and Technology, March-April 1994, Vol. 48, No. 2.
9. Baines PH. Passivation; understanding and performing procedures on austenitic stainless
steel systems. Pharmaceutical Engineering, November-December 1990, Vol. 10, No. 6.
10. Guide to inspections of high purity water systems. Food and Drug Administration.
11. Tverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of
mechanically polished type 316 L sanitary tube. European Journal of Parenteral
Sciences 1998, 3(4):1 17-124.