Working document QAS/20.

842
May 2020

3 DRAFT WORKING DOCUMENT FOR COMMENTS:

4

5 Good manufacturing practices:

6 water for pharmaceutical use
7

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.
Our working documents are sent out electronically and they will also be placed on the WHO Medicines
website (http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines/en/) for
comments under the “Current projects” link. If you wish to receive all our draft guidelines, please send
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8
9 © World Health Organization 2020
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11 All rights reserved.
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13 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft
14 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated o r adapted, in part or in whole, in
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16 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any
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19 Please send any request for permission to:
20
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.
23
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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26 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate
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39 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
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41 SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/20.842:

42 Good manufacturing practices:

43 water for pharmaceutical use
44

Description of activity Date

Preparation of the document following recommendation of the Fifty- February- April 2020
fourth WHO Expert Committee on Specifications for Pharmaceutical
Preparations (ECSPP).

Mailing of working document inviting comments, including to the May 2020

Expert Advisory Panel on the International Pharmacopoeia and
Pharmaceutical Preparations (EAP), and posting of the working
document on the WHO website for public consultation.

Consolidation of comments received and review of feedback. June 2020

Preparation of working document for discussion.

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.

Preparation of working document for next round of public July 2020

consultation.

Mailing of the revised working document inviting comments, August 2020

including to the EAP, and posting the working document on the WHO
website for a second round of public consultation.

Consolidation of comments received and review of feedback by a September 2020

sub-team composed of the participants of the virtual meetings.
Preparation of working document for discussion.

Presentation to the Fifty-fifth ECSPP meeting. 12-16 October 2020

Any other follow-up action as required.

45
46
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47 Good manufacturing practices:

48 water for pharmaceutical use
49

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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78 3. General principles for pharmaceutical water systems

79 4. Water quality specifications
80 4.1. Pharmacopoeial specifications
81 4.2. Drinking-water
82 4.3. Bulk purified water
83 4.4. Bulk highly purified water
84 4.5. Bulk water for injections
85 4.6. Other grades of water
86 5. General considerations for water purification systems
87 6. Water storage and distribution systems
88 7. Good practices for water systems
89 8. System sanitization and bioburden control
90 9. Storage vessels
91 10. Water distribution
92 11. Biocontamination control techniques
93 12. Operational considerations
94 12.5 Phase 1
95 12.6 Phase 2
96 12.7 Phase 3
97 13. Continuous system monitoring
98 14. Maintenance of water systems
99 15. System reviews
100 16. Inspection of water systems
101 References
102 Further reading
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103 1. Introduction and scope

104
105 1.1 This document concerns water for pharmaceutical use (WPU) produced, stored and
106 distributed in bulk form. It intends to provide information about different specifications for
107 WPU; guidance on GMP regarding the quality management of water systems; water
108 treatment (production) systems; water storage and distribution systems; qualification and
109 validation; and sampling, testing and the routine monitoring of water.
110
111 1.2 Although drinking-water is addressed, the focus of this document is on the treatment, storage
112 and distribution of treated water used in pharmaceutical applications.
113
114 1.3 This document does not cover water for administration to patients in the formulated state or
115 the use of small quantities of water in pharmacies to compound individually prescribed
116 medicines.
117
118 1.4 The document can be used in whole or in part, as appropriate, to the section and application
119 under consideration.
120
121 1.5 In addition to this document, the “Further reading” section at the end of this document
122 includes some relevant publications that can serve as additional background material when
123 planning, installing and using systems intended to provide WPU.
124
125 1.6 This document is supplementary to the World Health Organization (WHO) Good
126 manufacturing practices for active pharmaceutical ingredients (2), and WHO Good
127 manufacturing practices for pharmaceutical products: main principles (3).
128

129 2. Background to water requirements and uses

130
131 2.1 Water is a widely used substance in the pharmaceutical industry. It is extensively used as a
132 raw material or starting material in the production, processing and formulation of active
133 pharmaceutical ingredients (APIs), intermediates and finished pharmaceutical products (FPP),
134 in the preparation of solvents and reagents, and for cleaning (e.g. washing and rinsing). Water
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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

161 3. General principles for pharmaceutical water

162 systems
163
164 3.1 Pharmaceutical water production, storage and distribution systems should be designed,
165 installed, commissioned, qualified, validated, operated and maintained to ensure the
166 consistent and reliable production of water of intended quality.
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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

181 4. Water quality specifications

182

183 4.1 Pharmacopoeial specifications

184
185 4.1.1 Pharmacopoeias include specifications for both bulk and dosage form types of water.
186 Where this document refers to specifications, such as the pharmacopoeias, the
187 relevant, current publications should be used. This document does not attempt to
188 duplicate such material. Where subtle points of difference exist between
189 pharmacopoeial specifications, the manufacturer should choose the appropriate
190 specification in accordance with the related marketing authorization submitted to the
191 relevant medicine’s regulatory authority. Pharmacopoeial requirements or guidance
192 for WPU are described in national, regional and international pharmacopoeias (4) and
193 limits for various impurities or classes of impurities are either specified or
194 recommended. Requirements or guidance are given in pharmacopoeias on the
195 microbiological quality of water.
196
197
198
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199 4.2 Drinking-water

200
201 4.2.1 The quality of drinking-water is covered by the WHO drinking-water quality guidelines
202 (5) and standards from the International Organization for Standardization (ISO) and
203 other regional and national agencies. Drinking-water should comply with the relevant
204 regulations laid down by the competent authority.
205
206 4.2.2 Drinking-water may be derived from a natural or stored source. Examples of natural
207 sources include springs, wells, rivers, lakes and the sea. The condition of the source
208 water should be considered when choosing a treatment to produce drinking- water.
209 A typical treatment would include desalinization, softening, removal of specific ions,
210 particle reduction and antimicrobial treatment.
211
212 4.2.3 Drinking-water should be supplied under continuous positive pressure by a plumbing
213 system free of any defects that could lead to contamination of any product.
214
215 4.2.4 Drinking-water may be derived from a public water supply system. This includes an
216 off-site source, such as a municipality. The appropriate drinking-water quality should
217 be ensured by the supplier. Tests should be conducted to guarantee that the drinking-
218 water delivered is of drinking quality. This testing is typically performed on water
219 from the water source. Where required, the quality may be achieved through
220 appropriate processing on-site.
221
222 4.2.5 Where drinking-water is purchased in bulk and transported to the user by water
223 tanker, controls should be put in place to mitigate any risks associated therewith.
224 Vendor assessment and authorized certification activities, including confirmation of
225 the acceptability of the delivery vehicle, should be undertaken in a way similar to that
226 used for any other starting material.
227
228 4.2.6 It is the responsibility of the pharmaceutical manufacturer to assure that the source
229 water supplying the PW treatment system meets the appropriate drinking-water
230 requirements. In these situations, the point at which drinking-water quality is
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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

290 4.3 Bulk purified water

291
292 4.3.1 Bulk purified water (BPW) should meet the relevant pharmacopoeial specifications
293 for chemical and microbiological purity.
294
295 4.3.2 BPW should be prepared from drinking-water as a minimum-quality feedwater.
296
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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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330 • the use of water-treatment system components that can periodically be

331 thermally sanitized;
332 • in addition to thermal sanitization, the application of chemical sanitization
333 such as ozone, hydrogen peroxide and/or peracetic acid; and
334 • thermal sanitization at > 70 °C.
335
336 4.3.8 BPW should have the appropriate action and alert limits for microbiological purity
337 determined from a knowledge of the system and data trending. BPW should be
338 protected from recontamination and microbial proliferation.
339

340 4.4 Bulk highly purified water

341
342 4.4.1 Bulk highly purified water (BHPW) must meet the same quality standards as WFI,
343 including the limit for endotoxins.
344
345 4.4.2 BHPW should be prepared from drinking water as a minimum-quality feedwater.
346
347 4.4.3 Any appropriate and qualified purification technique, or sequence of techniques, may
348 be used to prepare BHPW. BHPW is often produced by double pass RO coupled with
349 other suitable techniques such as ultrafiltration and deionization.
350
351 4.4.4 BHPW should also be protected from recontamination and microbial proliferation.
352
353 4.4.5 BHPW and WFI have identical microbiological requirements.
354
355 Note: The guidance provided in section 4.3 for BPW is equally applicable to BHPW.
356

357 4.5 Bulk water for injections

358
359 4.5.1 Bulk water for injections (BWFI) should meet the relevant pharmacopoeial
360 specifications for chemical and microbiological purity (including endotoxins). BWFI is
361 the highest quality of pharmacopoeial WPU.
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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

391 4.6 Other grades of water

392
393 When a specific process requires a special non-pharmacopoeial grade of water, its
394 specification must be documented within a company’s quality system. As a minimum, it must
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395 meet the pharmacopoeial requirements relating to the grade of WPU required for the type of
396 dosage form or process step.
397

398 5. General considerations for water purification

399 systems
400
401 5.1 Pharmaceutical manufacturers should apply the current principles of quality risk management
402 (6) in selecting and using the appropriate water purification systems. An appropriate method
403 for the production of WPU should be used.
404
405 5.2 Risks and controls should be identified for each stage of the production, storage, distribution,
406 use and monitoring of WPU.
407
408 5.3 Risks identified should be analyzed and evaluated in order to determine the scope and extent
409 of validation and qualification of the system, including the computerized systems used for the
410 production, control and monitoring of WPU.
411
412 5.4 Risk management should be an ongoing part of the quality management process for WPU. A
413 mechanism to review or monitor events associated with the production, storage, distribution
414 and use of WPU should be implemented.
415
416 5.5 Procedures for managing changes and deviations should be followed. Where applicable, the
417 appropriate risk and impact assessments should be done where changes and deviations are
418 managed.
419
420 5.6 The chosen water purification system, method or sequence of purification steps must be
421 appropriate in order to ensure the production of water of an intended grade. Based on the
422 outcome of the risk assessment, the following should at least be considered when selecting
423 the water treatment system and method:
424 • the quality of the available feedwater and the variation over time (seasonal changes);
425 • the availability of suitable support facilities for the system (e.g. electricity, heating,
426 steam, chilled water and compressed air);
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427 • the extent of pre-treatment required;

428 • the sequence of purification steps required;
429 • the design and location of sampling points;
430 • the sanitization strategy;
431 • the availability of water-treatment equipment on the market;
432 • the reliability and robustness of the water-treatment equipment in operation;
433 • the yield or efficiency of the purification system;
434 • the ability to adequately support and maintain the water purification equipment;
435 • the continuity of operational usage considering hours/days/years and planned
436 downtime;
437 • the total life-cycle of the system (including capital, operation and maintenance);
438 • the final water quality specification; and
439 • the quantity of water required by the user.
440
441 5.7 The specifications for water purification equipment, storage and distribution systems should
442 take into account the following:
443 • the location of the plant room;
444 • the extremes in temperature that the system will encounter;
445 • the risk of contamination, for example, from materials of construction (contact
446 materials) and the environment;
447 • the adverse impact of adsorptive contact materials;
448 • hygienic or sanitary design, where required;
449 • corrosion resistance;
450 • freedom from leakage;
451 • system configuration to avoid proliferation of microbiological organisms;
452 • tolerance to cleaning and sanitizing agents (thermal and/or chemical);
453 • the sanitization strategy;
454 • system capacity and output requirements; and
455 • the provision of all necessary instruments, test and sampling points in order to allow
456 for all the relevant critical quality parameters of the complete system to be
457 monitored.
458
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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

467 6. Water storage and distribution systems

468
469 6.1 Where drinking water is stored and distributed, the appropriate controls should be
470 determined and implemented in order to mitigate risks. This applies to all stages in the supply,
471 storage and distribution of drinking-water.
472
473 6.2 The water storage and distribution systems for PW, BHPW and BWFI should be appropriately
474 designed, installed, qualified, operated and maintained in order to ensure the storage and
475 distribution of water is of consistent quality to the user points.
476

477 7. Good practices for water systems

478
479 7.1 The components of water systems, including but not limited to pipework, valves and fittings,
480 seals, diaphragms and instruments, should be appropriate and should satisfy the following
481 objectives for the full range of the working temperature and potential chemicals that will
482 come into contact with the system at rest, in operation and during sanitization. The
483 construction materials should be of an appropriate quality.
484
485 7.2 As a minimum, the following should be considered:
486 • Compatibility and suitability.
487 • No leaching, adsorbing and absorbing.
488 • Corrosion resistance.
489 • Materials of construction: the materials used should be appropriate, for example,
490 sanitary specification plastics such as polypropylene, polyvinylidene-difluoride and
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491 perfluoro alkoxy. Other materials, such as unplasticized polyvinyl-chloride (uPVC),

492 may be used for treatment equipment designed for less pure water such as ion
493 exchangers and softeners. Plastics used should be manufactured from materials that
494 should at least meet the minimum food grade standards, be non-toxic and be
495 compatible with all chemicals used. Their chemical and biological characteristics
496 should meet any relevant pharmacopoeial specifications or recommendations.
497 Stainless-steel grade 316L or higher is generally recommended. The choice of
498 material should take into account the intended sanitization method.
499 • Passivation: passivation should be considered after initial installation and after
500 significant modification in accordance with a documented procedure defining the
501 solution to be used, its concentration, the temperature and contact time.
502 • Smooth internal finish: internal finish should be smooth in order to prevent the
503 formation of biofilms and corrosion (e.g. an arithmetical average surface roughness
504 of not greater than 0.8 micrometre (Ra); mechanical and electro-polishing of stainless
505 steel).
506 • Jointing: the manner in which pieces are jointed should be appropriate and controlled.
507 Where welding is used, the process should include, as a minimum, the qualification of
508 the operator, documentation of the welder set-up, work session test pieces (coupons
509 or weld samples), logs of all welds and records (e.g. photographs or videos) of visual
510 inspection of a defined proportion of welds (e.g. 100% hand welds or 10% automatic
511 welds). Threaded connections should be avoided.
512 • Flanges, unions and valves: where flanges, unions or valves are used, they should be
513 of a hygienic or sanitary design. The appropriate checks should be carried out in order
514 to ensure that the correct seals and diaphragms are used and that they are fitted and
515 tightened correctly.
516 • Documentation: all system components should be fully documented and be
517 supported by original or certified copies of material quality certificates. Where these
518 are not available or traceable, on-site tests should be performed and test reports
519 should be available. All documentation related to the qualification and validation of
520 the system should be available. Documents should include, as a minimum, system
521 drawing, isometric drawings, specifications for components, qualification and
522 validation protocols and reports, calibration certificates.
523
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524 8. System sanitization and bioburden control

525
526 8.1 Water-treatment, storage and distribution systems should be subjected to controls that will
527 reduce the risk of contamination and the proliferation of microbiological organisms.
528
529 8.2 Validated, detailed procedures for sanitizing all relevant parts of the system should be
530 followed. The techniques employed should be considered during the design stage of the
531 system as the procedure and technique may impact on the components and materials of
532 construction.
533
534 8.3 Systems that operate and are maintained at elevated temperatures (e.g. > 65) are generally
535 less susceptible to microbiological contamination than systems that are maintained at lower
536 temperatures. When lower temperatures are required due to the water treatment processes
537 employed, or the temperature requirements for the water in use, special precautions should
538 be taken to prevent the ingress of contaminants including microorganisms (see section 9.2 for
539 guidance).
540
541 8.4 Where the chemical sanitization of the water systems is part of the biocontamination control
542 programme, a validated procedure should be followed in order to ensure that the sanitizing
543 process selected is effective and that the sanitizing agent has been effectively removed.
544
545 8.5 Records of sanitization should be maintained.
546

547 9. Storage vessels

548
549 9.1 Storage vessels installed and used later should be appropriate for their intended use.
550
551 9.2 As a minimum, the following should be considered:
552 • the design and shape;
553 • the provision for drainage of water from the vessel, when required;
554 • construction materials;
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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

576 10. Water distribution

577
578 10.1 The water distribution system should be designed as a loop, with continuous circulation of
579 BPW, BHPW and BWFI. Where this is not the case, a good justification for using a non-
580 recirculating one-way system should be provided.
581
582 10.2 As a minimum, the following should be considered:
583 • controls to prevent proliferation of contaminants;
584 • the length of the distribution system;
585 • material of construction, joints and impact as a result of sanitization; and
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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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618 11. Biocontamination control techniques

619
620 11.1 Water purification systems should be sanitized using chemical and or thermal sanitization
621 procedures as appropriate (e.g. production, storage and distribution). The procedure and
622 conditions used, such as times and temperatures, should be suitable.
623
624 11.2 Other control techniques to be considered include:
625 • The maintenance of a continuous circulation of water: a turbulent flow of 1.2m/s, for
626 example.
627 • Ensuring the shortest possible length of pipework.
628 • Isolating pipework for ambient temperature systems from adjacent hot pipes.
629 • Minimizing dead legs, including in the pipework, through the appropriate design.
630 Dead legs are measured and calculated and, as a guide, should not exceed three times
631 the branch diameter (3D).
632 • Separate pressure gauges from the system by membranes.
633 • Using hygienic pattern diaphragm valves.
634 • Installing pipework to allow for full drainage. A guidance figure for the slope is 1:100.
635 • Considering ultraviolet radiation sources in pipework and maintaining the system at
636 an elevated temperature (e.g. >65 °C).
637 • Periodic sanitization by suitable means, e.g. hot water (guidance temperature > 70
638 °C), super-heated hot water or clean steam, and/or routine chemical sanitization
639 using ozone or other suitable chemical agents.
640
641 11.3 When chemical sanitization is used, it is essential to prove that the agent has been removed
642 prior to using the water.
643

644 12. Operational considerations

645
646 12.1 Water systems should be appropriately qualified and validated (7). The scope and extent of
647 qualification should be determined based upon risk assessment.
648
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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

661 12.5 Phase 1

662
663 Phase I should cover a period of at least two weeks. The system should be monitored
664 intensively for its performance. The system should operate continuously without failure or
665 performance deviation. Normally, water should not be used for FPP manufacturing during
666 this phase.
667
668 The procedures and protocols for Phase I should cover at least the following activities and
669 testing approaches:
670 • chemical and microbiological testing in accordance with a defined plan;
671 • sample, test and monitoring of the incoming feedwater daily to verify its quality;
672 • sample, test and monitoring after each step in the purification process;
673 • sample, test and monitoring at each point of use and at other defined sample points;
674 • develop the appropriate operating ranges;
675 • develop and finalize the operating, cleaning, sanitizing and maintenance procedures;
676 • demonstrate the production and delivery of product water of the required quality and
677 quantity;
678 • use and refine the standard operating procedures (SOPs) for operation, maintenance,
679 sanitization and troubleshooting;
680 • verify provisional alert levels; and
681 • develop and refine test-failure procedure.
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682 12.6 Phase 2

683
684 Phase 2 should cover at least a further test period of two weeks. The system should be
685 monitored while deploying all the refined SOPs after the satisfactory completion of Phase 1.
686 The sampling program should be generally the same as in Phase 1. The use of the water for
687 FPP manufacturing purposes during this phase may be acceptable, provided that both
688 commissioning and Phase 1 data demonstrate the appropriate water quality and the practice
689 is approved by QA.
690
691 The approach should also:
692 • demonstrate consistent operation within established ranges; and
693 • demonstrate consistent production and delivery of water of the required quantity and
694 quality when the system is operated in accordance with the SOPs.
695

696 12.7 Phase 3

697
698 Phase 3 should cover at least a further 12 months after the satisfactory completion of Phase
699 2. The sample locations, sampling frequencies and tests may be reduced to the normal
700 routine pattern based on the established procedures proven during Phase 1 and Phase 2.
701 After completion of the qualification and validation programme of Phase 3, a system review
702 should be undertaken. This may include the trending of results and the evaluation of system
703 performance capability. The appropriate action should be taken where identified.
704
705 Water can be used during this phase (e.g. for manufacturing and cleaning) which has the
706 following objectives:
707 • to demonstrate a reliable performance over an extended period of time; and
708 • to ensure that seasonal variations are evaluated.
709

710 13. Continuous system monitoring

711
712 13.1 The system should be subject to continuous monitoring.
713
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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

742 14. Maintenance of water systems

743
744 14.1 WPU systems should be maintained and recorded in accordance with an approved and
745 documented maintenance programme.
746
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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

756 15. System reviews

757
758 15.1 WPU systems should be reviewed at described intervals.
759
760 15.3 The review team should be comprised of representatives from engineering, utilities,
761 validation, QA, quality control, microbiology, production and maintenance, and so on.
762
763 15.3 The review team should consider matters such as:
764 • changes made since the last review;
765 • system performance and capability;
766 • reliability;
767 • quality trends;
768 • failure events and alarms;
769 • investigations;
770 • out-of-specification and out-of-limit results;
771 • compliance with current GMP requirements for WPU systems;
772 • documentation being a current reflection of the WPU system;
773 • records including log books and electronic data;
774 • the current SOPs relating to WPU; and
775 • the computerized system linked to the water system, e.g. SCADA (Supervisory Control
776 and Data Acquisition).
777
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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

806 16. Inspection of water systems

807
808 16.1 WPU (BPW, BHPW and BWFI) systems are likely to be the subject of regulatory inspection
809 from time to time. Users should consider conducting routine audits and self-inspection of
810 established water systems.
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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
840 1. WHO Good manufacturing practices: water for pharmaceutical use (WHO Technical Report
841 Series, No. 970, Annex 2, 2011).
842
843 2. WHO Good manufacturing practices for active pharmaceutical ingredients (WHO Technical
844 Report Series No. 957, 2010, Annex 2).
845
846 3. WHO Good manufacturing practices for pharmaceutical products: main principles (WHO
847 Technical Report Series, No. 986, 2014, Annex 2).
848
849 4. The International Pharmacopoeia. Geneva, World Health Organization; updated regularly
850 (https://www.who.int/medicines/publications/pharmacopoeia/en/ and
851 https://apps.who.int/phint/2019/index.html#p/home, accessed 1 May 2020).
852
853 5. WHO Guidelines for drinking-water quality, 4th edition, incorporating the 1st addendum,
854 2017 (https://www.who.int/water_sanitation_health/publications/drinking-water-quality-
855 guidelines-4-including-1st-addendum/en/, accessed 1 May 2020).
856
857 6. WHO Guidelines on quality risk management (WHO Technical Report Series, No. 981, 2013,
858 Annex 2; https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex2
859 TRS-981.pdf?ua=1, accessed 1 May 2020).
860
861 7. WHO Guidelines on validation (WHO Technical Report Series, No. 1019, 2019, Annex 3;
862 https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_A
863 nnex3.pdf?ua=1, accessed 1 May 2020).
864

865 Further reading

866 Will be updated further
867 • American Society of Mechanical Engineers. Bioprocessing Equipment Standard.
868 ASME — BPE 2019.
869 • Banes PH. Passivation: understanding and performing procedures on austenitic stainless-steel
870 systems. Pharmaceutical Engineering, 1990: 41.
 Working document QAS/20.842
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871 • Guide to inspections of high purity water systems. Maryland, US Food and Drug
872 Administration, 1993 (http://www.fda.gov/ICECI/InspectionGuides).
873 • Biotechnology. Equipment. Guidance on testing procedures for cleanability. British
874 Standards Publishing. BS EN 12296, 1998.
875 • European Medicines Agency. Note for guidance on the quality of water for pharmaceutical
876 use. London, 2002 (CPMP/QWP/158-01) (https://www.ema.europa.eu/en/documents/
877 scientific-guideline/note-guidance-quality-water-pharmaceutical-use_en.pdf).
878 • European Pharmacopoeia: see website for the publishers of the European Pharmacopoeia and
879 supplements (http://www.pheur.org/).
880 • Harfst WH. Selecting piping materials for high-purity water systems. Ultra-pure water,
881 May/June 1994.
882 • ISPE Good practice guide: commissioning and qualification of pharmaceutical water and steam
883 systems. ISPE Baseline TM Pharmaceutical Engineering Guide, Vol. 4. International Society
884 for Pharmaceutical Engineering, 2007.
885 • ISPE Baseline Guide Volume 4: Water and Steam Systems. International Society for
886 Pharmaceutical Engineering, 2001. Noble PT. Transport considerations for microbial control
887 in piping. Journal of Pharmaceutical Science and Technology, 1994, 48: 76–85.
888 • Pharmaceutical Inspection Co-operation Scheme. PIC/S; Inspection of utilities; P1 009-1.
889 Geneva, Pharmaceutical Inspection Co-operation Scheme, 2002.
890 • Tverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of
891 mechanically polished type 316 L sanitary tube. European Journal of Parenteral Sciences,
892 1998, 3: 117–124.
893 • US Food and Drug Administration. Guide to inspections of high purity water systems, high
894 purity water systems (7/93), 2009 (http://www.fda.gov/ICECI/Inspections/
895 InspectionGuides/ucm074905.htm).
896 • US Pharmacopeia: published annually (see http://www.usp.org/).
897
898 ***