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QAS20 842 GMP Water For Pharmaceutical Use
QAS20 842 GMP Water For Pharmaceutical Use
842
May 2020
Please send your comments to Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals,
Technical Standards and Specifications (kopps@who.int), with a copy to Ms Claire Vogel (vogelc@who.int)
before 30 June 2020. Please use our attached Comments Table for this purpose.
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9 © World Health Organization 2020
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19 Please send any request for permission to:
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21 Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications, Department
22 of Health Products Policy and Standards, World Health Organization, CH-1211 Geneva 27, Switzerland, email: kopps@who.int.
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24 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
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Working document QAS/20.842
Page 2
Preparation of the document following recommendation of the Fifty- February- April 2020
fourth WHO Expert Committee on Specifications for Pharmaceutical
Preparations (ECSPP).
Discussion of working document and feedback received during the June 2020
informal consultation on Screening Technologies, Laboratory Tools
and Pharmacopoeial Specifications for Medicines, replaced by virtual
meetings.
50 Background
51
52 The control of water quality, including microbiological and chemical quality, throughout production,
53 storage and distribution processes is a major concern. Unlike other product and process ingredients,
54 water is usually drawn from an on-demand system and is not subject to testing and batch or lot release
55 prior to use. The assurance of water quality to meet the on-demand expectation is, therefore,
56 essential.
57
58 In recent years, following extensive consultation with stakeholders, several pharmacopoeias have
59 adopted revised monographs on water for injection (WFI) that allow for production by non-distillation
60 technologies, such as reverse osmosis (RO). In 2017, the World Health Organization (WHO) Expert
61 Committee on Specifications for Pharmaceutical Preparations (ECSPP) recommended that the WHO
62 Secretariat collect feedback on whether or not they should revise the WHO specifications and good
63 manufacturing practices (GMP) on WFI, and how to do so. Following discussions during several
64 consultations, the ECSPP agreed that the monograph in The International Pharmacopoeia (Water for
65 injections) and the guideline WHO Good manufacturing practices: water for pharmaceutical use (1)
66 should both be revised to allow for technologies other than distillation for the production of WFI. In
67 early 2019, the WHO Secretariat commissioned the preparation of a draft guidance text for the
68 production of WFI by means other than distillation. Following several public consultations, the text
69 was presented to the Fifty-fourth ECSPP. The Expert Committee adopted the Production of water for
70 injection by means other than distillation guideline and recommended that it should also be integrated
71 into WHO’s existing guideline on Good manufacturing practices: water for pharmaceutical use.
72
73 This current document is a revision of WHO Good manufacturing practices: water for pharmaceutical
74 use, previously published in the WHO Technical Report Series, No. 970, Annex 2, 2011.
75
76 1. Introduction
77 2. Background to water requirements and uses
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135 has unique chemical properties due to its polarity and hydrogen bonds. It is able to dissolve,
136 absorb, adsorb or suspend different compounds. These would include contaminants that may
137 represent hazards in themselves or that may be able to react with intended product
138 substances, resulting in hazards to health. Water should therefore meet the required quality
139 standards to mitigate these risks.
140
141 2.2 The microbiological and chemical quality of water should be controlled throughout the
142 production, storage and distribution of water. Water is not usually subjected to testing and
143 batch or lot release before use. It is usually drawn from a system on-demand for use. Results
144 from testing are normally available only after water has already been used as microbiological
145 tests may require periods of incubation. The assurance of quality to meet the on-demand
146 expectation of water is therefore essential.
147
148 2.3 To reduce the risks associated with the production, storage and distribution of water and,
149 considering the properties and use of water, it is essential:
150 • to ensure the appropriate design, installation, operation and maintenance of the pre-
151 treatment (production of drinking-water), treatment (production of WPU such as
152 purified water (PW) and WFI), and storage and distribution systems;
153 • to perform periodic sanitization;
154 • to take the appropriate measures in order to prevent chemical and microbial
155 contamination; and
156 • to prevent microbial proliferation.
157
158 2.4 Different grades of water quality exist. The appropriate water quality, meeting its defined
159 specification, should be used for the intended application.
160
167 3.2 The capacity of these systems should be appropriate to meet the average and peak flow
168 demand. The systems should be able to operate continuously for significant periods of time
169 in order to avoid the inefficiencies and equipment stresses that occur when equipment cycles
170 turn on and off too frequently.
171
172 3.3 The use of the systems following an initial qualification such as installation qualification (IQ),
173 operational qualification (OQ), performance qualification (PQ) and validation should be
174 approved by the quality unit, e.g. quality assurance (QA).
175
176 3.4 Water sources and treated water should be monitored regularly for chemical, microbiological
177 and, as appropriate, endotoxin contamination. The performance of water treatment, storage
178 and distribution systems should also be monitored. Records of the results monitored, trend
179 analysis and any actions taken should be maintained.
180
231 achieved should be identified and a water sample taken and tested at defined
232 intervals thereafter.
233
234 4.2.7 If drinking-water is used directly in certain stages of pharmaceutical manufacture,
235 such as in the production of APIs or in the feedwater for the production of higher
236 qualities of WPU, then testing should be carried out periodically by the water user’s
237 site to confirm that the quality meets the standards required for drinking-water.
238
239 4.2.8 Where drinking-water is produced through the treatment of raw water by a system
240 on-site, the system configuration and water-treatment steps used should be
241 described.
242
243 4.2.9 Examples of typical processes employed to produce drinking-water may include:
244 • desalinization;
245 • filtration;
246 • softening;
247 • disinfection or sanitization (e.g. by sodium hypochlorite {chlorine} injection);
248 • iron (ferrous) removal;
249 • precipitation; and
250 • the reduction of concentration of specific inorganic and/or organic materials.
251
252 4.2.10 Controls should be implemented to prevent the microbiological contamination of
253 sand filters, carbon beds and water softeners. The techniques selected should be
254 appropriate and may include backflushing, chemical and/or thermal sanitization and
255 frequent regeneration.
256
257 4.2.11 The quality of drinking-water should be monitored routinely to account for
258 environmental, seasonal or supply changes which may have an impact on the source
259 water quality.
260
261 4.2.12 Where drinking-water is stored and distributed by the user, the storage and
262 distribution systems should not allow the degradation of the water quality prior to
263 use. After any such storage, testing should be carried out routinely and in accordance
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264 with a defined procedure. The storage and distribution of drinking-water should be
265 done in a manner to ensure a turnover or recirculation of the stored water sufficient
266 enough to prevent stagnation.
267
268 4.2.13 The equipment and systems used to produce and store drinking-water should be able
269 to be drained and sanitized.
270
271 4.2.14 Storage tanks should be closed with appropriately protected vents and should allow
272 for visual inspection.
273
274 4.2.15 Distribution pipework should be able to be drained or flushed and sanitized.
275
276 4.2.16 The scope and extent of qualification for the system should be identified and justified.
277
278 4.2.17 The results from testing drinking-water should be subjected to statistical analysis in
279 order to identify trends and changes. If the drinking-water quality changes
280 significantly, but is still within specification, the direct use of this water as a WPU, or
281 as the feedwater to downstream treatment stages, should be reviewed for any risks
282 and the results of the review and action to be taken and documented.
283
284 4.2.18 Changes to a system or to its operation should be made in accordance with change
285 control procedures.
286
287 4.2.19 Additional testing should be considered if there is any change in the raw water source,
288 treatment techniques or system configuration.
289
297 4.3.3 Any appropriate, qualified purification technique, or sequence of techniques, may be
298 used to prepare BPW. BPW may be prepared by, for example, a combination of ion
299 exchange, RO, RO/electro-deionization (EDI), ultrafiltration and vapour compression.
300
301 4.3.4 The following should be considered when configuring a water purification system or
302 defining user requirement specifications (URS):
303 • the quality of feedwater and its variation over seasons;
304 • the quantity of water required by the user;
305 • the required water-quality specification;
306 • the sequence of purification stages required;
307 • energy consumption;
308 • appropriately located sampling points designed in such a way so as to avoid
309 potential contamination; and
310 • unit process steps provided and documented with the appropriate
311 instrumentation to measure parameters such as flow, pressure, temperature,
312 conductivity, pH and total organic carbon.
313
314 4.3.5 Ambient-temperature systems such as ion exchange, RO and ultrafiltration are
315 especially susceptible to microbiological contamination, particularly when equipment
316 is static during periods of no or low demand for water. Sanitization, at defined
317 intervals, as well as other controls, should be defined to prevent and minimize
318 microbiological contamination.
319
320 4.3.6 Appropriate, validated methods for sanitizing each stage of purification needs to be
321 in place. Where agents are used for sanitization, their removal must be proven.
322
323 4.3.7 The following controls should be considered:
324 • the maintenance of water flow at all times, in order to prevent water from
325 stagnating;
326 • control of temperature in the system by heat exchangers or plant room
327 cooling in order to reduce the risk of microbial growth (guidance value < 25
328 °C);
329 • the provision of ultraviolet disinfection at appropriate locations in the system;
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362 4.5.2 BWFI is not sterile water and is not a final dosage form. It is an intermediate bulk
363 product suitable to be used as an ingredient during formulation.
364
365 4.5.3 As a robust technique should be used for the production of BWFI, the following should
366 be considered when designing a water purification system:
367 • the quality of feedwater (e.g. drinking-water, usually with further treatment,
368 or PW);
369 • the required water quality specification;
370 • the quantity of water;
371 • based on the selection of components and type of system, the appropriate
372 URS, qualification and validation;
373 • the optimum generator size or generators with variable control to avoid over-
374 frequent start/stop cycling;
375 • blow-down and dump functions; and
376 • cool-down venting to avoid contamination ingress.
377
378 4.5.4 BWFI may be prepared, for example, by distillation as the final purification step.
379 Alternatively, techniques such as deionisation, electro deionization, nano filtration,
380 ultrafiltration, water softening, descaling, pre-filtration and degasification, ultraviolet
381 treatment, along with other techniques, may be considered in conjunction with a
382 single or double pass RO system.
383
384 4.5.5 BWFI should have the appropriate action and alert limits and should also be protected
385 from recontamination and microbial proliferation.
386
387 Note: For a full description, see Production of water for injection by means other than distillation.
388 [Note from Secretariat: the text published in the WHO Technical Report Series, No. 1025, 2020, Annex
389 3 will be attached as Annex 1 to this text.]
390
395 meet the pharmacopoeial requirements relating to the grade of WPU required for the type of
396 dosage form or process step.
397
459 5.8 The design, configuration and layout of the water purification equipment, storage and
460 distribution systems should also take into account the following physical considerations:
461 • the ability to collect samples;
462 • the space available for the installation and environment around the system;
463 • structural loadings on buildings;
464 • the provision of adequate access for maintenance and monitoring; and
465 • the ability to safely handle regeneration and sanitization chemicals.
466
555 • capacity, including buffer capacity, between the steady state, water generation rate
556 and the potentially variable simultaneous demand from user points, short-term
557 reserve capacity in the event of failure of the water-treatment system or the inability
558 to produce water (e.g. due to a regeneration cycle);
559 • prevention of stagnant water in the vessel (e.g. the headspace where water droplets
560 can accumulate);
561 • the need for the use of a spray-ball or distributor devices to wet the inner surfaces of
562 the vessel;
563 • limitation and design of nozzles within the storage vessels;
564 • the fitting of heated, bacteria-retentive, hydrophobic vent filters which are tested for
565 their integrity at appropriate intervals;
566 • the fitting of pressure-relief valves and bursting discs which are of a sanitary design
567 (bursting discs should be provided with external rupture indicators to ensure that loss
568 of system integrity is detected);
569 • the design and sanitization, as required, of level indicators;
570 • the design and location of valves, sampling points and monitoring devices and
571 sensors; and
572 • the need for heat exchangers or jacketed vessels. Where these are used, controls
573 should be put in place in order to ensure that there is no risk of contamination of
574 water.
575
586 • design and location of devices, sensors and instruments such as flow meters, total
587 organic carbon (TOC) analysers and temperature sensors;
588
589 10.3 Filtration should not usually be used in distribution loops or at take-off user points as these
590 are likely to conceal system contamination.
591
592 10.4 Where heat exchangers are employed to heat or cool WPU within a system, precautions
593 should be taken in order to prevent the heating or cooling utility from contaminating the
594 water.
595
596 10.5 Secure types of heat exchangers, such as double tube plate, double plate and frame, or tube
597 and shell configuration, should be considered. Where these types are not used, an alternative
598 approach whereby the utility is maintained and monitored at a lower pressure than the WPU
599 may be considered. The latter approach is not usually appropriate in BWFI systems.
600
601 10.6 Where heat exchangers are used, they should be arranged in continually circulating loops or
602 sub-loops in order to avoid unacceptable static water in the system.
603
604 10.7 When the temperature is reduced for processing purposes, the reduction should occur for the
605 minimum necessary time. The cooling cycles and their duration should be proven satisfactory
606 during the qualification of the system.
607
608 10.8 Circulation pumps should be of a sanitary design with the appropriate seals to prevent
609 contamination of the system.
610
611 10.9 Where stand-by pumps are provided, they should be configured or managed to avoid dead
612 zones trapped within the system.
613
614 10.10 Consideration should be given to preventing contamination in systems where parallel pumps
615 are used, especially if there is stagnant water when one of the pumps is not being used.
616
617
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649 12.2 There should be documented evidence of consideration and execution of stages of
650 qualification including, as appropriate, URS, factory acceptance testing (FAT), site acceptance
651 testing (SAT), design qualification (DQ), IQ, OQ and PQ.
652
653 12.3 Commissioning work done should be documented. Commissioning is not a replacement for
654 qualification.
655
656 12.4 In order to validate the reliability and robustness of a system and its performance, a three-
657 phase approach should be used over an extended period of time. Tests on the source water
658 (drinking-water) should be included within the validation programme and continued as part
659 of the routine monitoring, and these results should meet specifications.
660
714 13.2 A monitoring plan should be followed where samples are collected in accordance with a
715 written procedure.
716
717 13.3 A combination of online and offline instruments, linked to appropriately qualified alarm
718 systems, should be used. Parameters such as flow, pressure, temperature, conductivity and
719 TOC should be monitored with online devices with periodic offline testing to confirm the
720 results. Other parameters may be monitored through offline testing.
721
722 13.4 Offline testing (including physical, chemical and microbiological attributes) should be done in
723 accordance with a predetermined programme.
724
725 13.5 Offline samples should be taken from points of use or dedicated sample points where points
726 of use cannot be sampled. All water samples should be taken using the same methodology as
727 detailed in production procedures, e.g. with a suitable flushing and drainage procedure in
728 place.
729
730 13.6 Tests should be carried out to ensure that the approved pharmacopoeial specification (and
731 company specification, where applicable) has been met. This may include the microbiological
732 quality of water, as appropriate.
733
734 13.7 Monitoring data should be subjected to trend analysis, e.g. monthly, quarterly and annually.
735 The results should be within defined control limits, such as 2 or 3 sigma.
736
737 13.8 Alert and action levels should be established based on historically reported data.
738
739 13.9 Trends and out-of-limit results should be investigated for the root cause, followed by the
740 appropriate corrective actions.
741
747 14.2 The programme should take into account at least the following:
748 • defined frequency for system elements;
749 • the calibration programme;
750 • SOPs for specific tasks;
751 • control of approved spares;
752 • preventive maintenance and maintenance plan and instructions;
753 • a review and approval of systems for use upon completion of work; and
754 • a record and review of problems and faults during maintenance
755
778 15.4 The application of specific types of water to processes and dosage forms should be
779 considered.
780
781 15.5 Pharmaceutical manufacturers should use the appropriate grade of WPU during, for example,
782 the manufacture of APIs and different dosage forms; for different stages in washing and
783 cleaning; in the preparation of reagents and solutions; and in the synthesis of materials and
784 products.
785
786 15.6 The grade of water used should take into account the nature and intended use of the
787 intermediate or finished product and the stage in the manufacturing process at which the
788 water is used.
789
790 15.7 BHPW can be used in the preparation of products when water of high quality (i.e. very low in
791 microorganisms and endotoxins) is needed, but the process stage or product requirement
792 does not include the constraint on the production method defined in some of the
793 pharmacopoeia monographs for BWFI.
794
795 15.8 BWFI should be used, for example, in the manufacture of injectable products, such as
796 dissolving or diluting substances or preparations during the manufacturing of parenteral
797 products, and for the manufacture of sterile water for preparation of injections. BWFI should
798 also be used for the final rinse after the cleaning of equipment and components that come
799 into contact with injectable products, as well as for the final rinse in a washing process in
800 which no subsequent thermal or chemical depyrogenization process is applied.
801
802 15.9 When steam comes into contact with an injectable product in its final container or with
803 equipment for preparing injectable products, it should conform to the specification for BWFI
804 when condensed.
805
811 16.2 This document can be used as the basis of an audit and inspection. A tour of the water system,
812 treatment system, storage and distribution system, as well as visible pipework and user
813 points, should be performed to ensure that the system is appropriately designed, installed,
814 qualified, validated, maintained and monitored.
815
816 16.3 The following items could be included in an audit or inspection:
817 • a review of current drawings of the water system showing all components in the
818 system from the inlet to the points of use, along with sampling points and their
819 designations;
820 • a physical check to ensure that the system matches the piping and instrumentation
821 diagram or drawing (P&ID);
822 • approved piping drawings (e.g. orthographic and/or isometric);
823 • qualification and validation protocols, reports and results;
824 • a sampling and monitoring plan with a drawing of all sample points with evidence of
825 sample management, sample preparation, testing and results;
826 • a training programme for sample collection and testing;
827 • the setting and monitoring of alert and action levels;
828 • monitoring of results and evaluation of trends;
829 • absence of leaks;
830 • a review of any changes made to the system since the last audit or inspection;
831 • a review of deviations recorded and their investigation;
832 • a general inspection of the system for status and condition;
833 • a review of maintenance, failure and repair logs;
834 • a check of calibration and standardization of critical instruments and devices;
835 • a review of the performance capability of the system; and
836 • procedures and records for sanitization.
837
838
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839 References
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842
843 2. WHO Good manufacturing practices for active pharmaceutical ingredients (WHO Technical
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845
846 3. WHO Good manufacturing practices for pharmaceutical products: main principles (WHO
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848
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852
853 5. WHO Guidelines for drinking-water quality, 4th edition, incorporating the 1st addendum,
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856
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860
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864
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897
898 ***