Good manufacturing practices: water for pharmaceutical use · 47 Good manufacturing practices: 48...
Transcript of Good manufacturing practices: water for pharmaceutical use · 47 Good manufacturing practices: 48...
Working document QAS/20.842 May 2020
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DRAFT WORKING DOCUMENT FOR COMMENTS: 3
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Good manufacturing practices: 5
water for pharmaceutical use 6
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Please send your comments to Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications ([email protected]), with a copy to Ms Claire Vogel ([email protected]) 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” l ink. If you wish to receive all our draft guidelines, please send your email address to [email protected] and your name will be added to our electronic mailing l ist.
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© World Health Organization 2020 9 10 All rights reserved. 11 12 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 13 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated o r adapted, in part or in whole, in 14 any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 15 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 16 website. 17 18 Please send any request for permission to: 19 20 Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications, Department 21 of Health Products Policy and Standards, World Health Organization, CH-1211 Geneva 27, Switzerland, email: [email protected]. 22 23 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 24 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 25 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 26 border lines for which there may not yet be full agreement. 27 28 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 29 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 30 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 31 32 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 33 34 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 35 responsibility for the interpretation and the use of the material lies with the reader. In no event shall the World Health 36 Organization be liable for damages arising from its use. 37 38 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 39
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Working document QAS/20.842 Page 2
SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/20.842: 41
Good manufacturing practices: 42
water for pharmaceutical use 43
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Description of activity Date
Preparation of the document following recommendation of the Fifty-fourth WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP).
February- April 2020
Mailing of working document inviting comments, including to the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations (EAP), and posting of the working document on the WHO website for public consultation.
May 2020
Consolidation of comments received and review of feedback. Preparation of working document for discussion.
June 2020
Discussion of working document and feedback received during the informal consultation on Screening Technologies, Laboratory Tools and Pharmacopoeial Specifications for Medicines, replaced by virtual meetings.
June 2020
Preparation of working document for next round of public consultation.
July 2020
Mailing of the revised working document inviting comments, including to the EAP, and posting the working document on the WHO website for a second round of public consultation.
August 2020
Consolidation of comments received and review of feedback by a sub-team composed of the participants of the virtual meetings. Preparation of working document for discussion.
September 2020
Presentation to the Fifty-fifth ECSPP meeting. 12-16 October 2020
Any other follow-up action as required.
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Good manufacturing practices: 47
water for pharmaceutical use 48
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Background 50
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The control of water quality, including microbiological and chemical quality, throughout production, 52
storage and distribution processes is a major concern. Unlike other product and process ingredients, 53
water is usually drawn from an on-demand system and is not subject to testing and batch or lot release 54
prior to use. The assurance of water quality to meet the on-demand expectation is, therefore, 55
essential. 56
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In recent years, following extensive consultation with stakeholders, several pharmacopoeias have 58
adopted revised monographs on water for injection (WFI) that allow for production by non-distillation 59
technologies, such as reverse osmosis (RO). In 2017, the World Health Organization (WHO) Expert 60
Committee on Specifications for Pharmaceutical Preparations (ECSPP) recommended that the WHO 61
Secretariat collect feedback on whether or not they should revise the WHO specifications and good 62
manufacturing practices (GMP) on WFI, and how to do so. Following discussions during several 63
consultations, the ECSPP agreed that the monograph in The International Pharmacopoeia (Water for 64
injections) and the guideline WHO Good manufacturing practices: water for pharmaceutical use (1) 65
should both be revised to allow for technologies other than distillation for the production of WFI. In 66
early 2019, the WHO Secretariat commissioned the preparation of a draft guidance text for the 67
production of WFI by means other than distillation. Following several public consultations, the text 68
was presented to the Fifty-fourth ECSPP. The Expert Committee adopted the Production of water for 69
injection by means other than distillation guideline and recommended that it should also be integrated 70
into WHO’s existing guideline on Good manufacturing practices: water for pharmaceutical use. 71
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This current document is a revision of WHO Good manufacturing practices: water for pharmaceutical 73
use, previously published in the WHO Technical Report Series, No. 970, Annex 2, 2011. 74
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1. Introduction 76
2. Background to water requirements and uses 77
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3. General principles for pharmaceutical water systems 78
4. Water quality specifications 79
4.1. Pharmacopoeial specifications 80
4.2. Drinking-water 81
4.3. Bulk purified water 82
4.4. Bulk highly purified water 83
4.5. Bulk water for injections 84
4.6. Other grades of water 85
5. General considerations for water purification systems 86
6. Water storage and distribution systems 87
7. Good practices for water systems 88
8. System sanitization and bioburden control 89
9. Storage vessels 90
10. Water distribution 91
11. Biocontamination control techniques 92
12. Operational considerations 93
12.5 Phase 1 94
12.6 Phase 2 95
12.7 Phase 3 96
13. Continuous system monitoring 97
14. Maintenance of water systems 98
15. System reviews 99
16. Inspection of water systems 100
References 101
Further reading 102
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1. Introduction and scope 103
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1.1 This document concerns water for pharmaceutical use (WPU) produced, stored and 105
distributed in bulk form. It intends to provide information about different specifications for 106
WPU; guidance on GMP regarding the quality management of water systems; water 107
treatment (production) systems; water storage and distribution systems; qualification and 108
validation; and sampling, testing and the routine monitoring of water. 109
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1.2 Although drinking-water is addressed, the focus of this document is on the treatment, storage 111
and distribution of treated water used in pharmaceutical applications. 112
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1.3 This document does not cover water for administration to patients in the formulated state or 114
the use of small quantities of water in pharmacies to compound individually prescribed 115
medicines. 116
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1.4 The document can be used in whole or in part, as appropriate, to the section and application 118
under consideration. 119
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1.5 In addition to this document, the “Further reading” section at the end of this document 121
includes some relevant publications that can serve as additional background material when 122
planning, installing and using systems intended to provide WPU. 123
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1.6 This document is supplementary to the World Health Organization (WHO) Good 125
manufacturing practices for active pharmaceutical ingredients (2), and WHO Good 126
manufacturing practices for pharmaceutical products: main principles (3). 127
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2. Background to water requirements and uses 129
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2.1 Water is a widely used substance in the pharmaceutical industry. It is extensively used as a 131
raw material or starting material in the production, processing and formulation of active 132
pharmaceutical ingredients (APIs), intermediates and finished pharmaceutical products (FPP), 133
in the preparation of solvents and reagents, and for cleaning (e.g. washing and rinsing). Water 134
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has unique chemical properties due to its polarity and hydrogen bonds. It is able to dissolve, 135
absorb, adsorb or suspend different compounds. These would include contaminants that may 136
represent hazards in themselves or that may be able to react with intended product 137
substances, resulting in hazards to health. Water should therefore meet the required quality 138
standards to mitigate these risks. 139
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2.2 The microbiological and chemical quality of water should be controlled throughout the 141
production, storage and distribution of water. Water is not usually subjected to testing and 142
batch or lot release before use. It is usually drawn from a system on-demand for use. Results 143
from testing are normally available only after water has already been used as microbiological 144
tests may require periods of incubation. The assurance of quality to meet the on-demand 145
expectation of water is therefore essential. 146
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2.3 To reduce the risks associated with the production, storage and distribution of water and, 148
considering the properties and use of water, it is essential: 149
• to ensure the appropriate design, installation, operation and maintenance of the pre-150
treatment (production of drinking-water), treatment (production of WPU such as 151
purified water (PW) and WFI), and storage and distribution systems; 152
• to perform periodic sanitization; 153
• to take the appropriate measures in order to prevent chemical and microbial 154
contamination; and 155
• to prevent microbial proliferation. 156
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2.4 Different grades of water quality exist. The appropriate water quality, meeting its defined 158
specification, should be used for the intended application. 159
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3. General principles for pharmaceutical water 161
systems 162
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3.1 Pharmaceutical water production, storage and distribution systems should be designed, 164
installed, commissioned, qualified, validated, operated and maintained to ensure the 165
consistent and reliable production of water of intended quality. 166
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3.2 The capacity of these systems should be appropriate to meet the average and peak flow 167
demand. The systems should be able to operate continuously for significant periods of time 168
in order to avoid the inefficiencies and equipment stresses that occur when equipment cycles 169
turn on and off too frequently. 170
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3.3 The use of the systems following an initial qualification such as installation qualification (IQ), 172
operational qualification (OQ), performance qualification (PQ) and validation should be 173
approved by the quality unit, e.g. quality assurance (QA). 174
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3.4 Water sources and treated water should be monitored regularly for chemical, microbiological 176
and, as appropriate, endotoxin contamination. The performance of water treatment, storage 177
and distribution systems should also be monitored. Records of the results monitored, trend 178
analysis and any actions taken should be maintained. 179
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4. Water quality specifications 181
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4.1 Pharmacopoeial specifications 183
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4.1.1 Pharmacopoeias include specifications for both bulk and dosage form types of water. 185
Where this document refers to specifications, such as the pharmacopoeias, the 186
relevant, current publications should be used. This document does not attempt to 187
duplicate such material. Where subtle points of difference exist between 188
pharmacopoeial specifications, the manufacturer should choose the appropriate 189
specification in accordance with the related marketing authorization submitted to the 190
relevant medicine’s regulatory authority. Pharmacopoeial requirements or guidance 191
for WPU are described in national, regional and international pharmacopoeias (4) and 192
limits for various impurities or classes of impurities are either specified or 193
recommended. Requirements or guidance are given in pharmacopoeias on the 194
microbiological quality of water. 195
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4.2 Drinking-water 199
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4.2.1 The quality of drinking-water is covered by the WHO drinking-water quality guidelines 201
(5) and standards from the International Organization for Standardization (ISO) and 202
other regional and national agencies. Drinking-water should comply with the relevant 203
regulations laid down by the competent authority. 204
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4.2.2 Drinking-water may be derived from a natural or stored source. Examples of natural 206
sources include springs, wells, rivers, lakes and the sea. The condition of the source 207
water should be considered when choosing a treatment to produce drinking- water. 208
A typical treatment would include desalinization, softening, removal of specific ions, 209
particle reduction and antimicrobial treatment. 210
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4.2.3 Drinking-water should be supplied under continuous positive pressure by a plumbing 212
system free of any defects that could lead to contamination of any product. 213
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4.2.4 Drinking-water may be derived from a public water supply system. This includes an 215
off-site source, such as a municipality. The appropriate drinking-water quality should 216
be ensured by the supplier. Tests should be conducted to guarantee that the drinking-217
water delivered is of drinking quality. This testing is typically performed on water 218
from the water source. Where required, the quality may be achieved through 219
appropriate processing on-site. 220
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4.2.5 Where drinking-water is purchased in bulk and transported to the user by water 222
tanker, controls should be put in place to mitigate any risks associated therewith. 223
Vendor assessment and authorized certification activities, including confirmation of 224
the acceptability of the delivery vehicle, should be undertaken in a way similar to that 225
used for any other starting material. 226
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4.2.6 It is the responsibility of the pharmaceutical manufacturer to assure that the source 228
water supplying the PW treatment system meets the appropriate drinking-water 229
requirements. In these situations, the point at which drinking-water quality is 230
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achieved should be identified and a water sample taken and tested at defined 231
intervals thereafter. 232
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4.2.7 If drinking-water is used directly in certain stages of pharmaceutical manufacture, 234
such as in the production of APIs or in the feedwater for the production of higher 235
qualities of WPU, then testing should be carried out periodically by the water user’s 236
site to confirm that the quality meets the standards required for drinking-water. 237
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4.2.8 Where drinking-water is produced through the treatment of raw water by a system 239
on-site, the system configuration and water-treatment steps used should be 240
described. 241
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4.2.9 Examples of typical processes employed to produce drinking-water may include: 243
• desalinization; 244
• filtration; 245
• softening; 246
• disinfection or sanitization (e.g. by sodium hypochlorite {chlorine} injection); 247
• iron (ferrous) removal; 248
• precipitation; and 249
• the reduction of concentration of specific inorganic and/or organic materials. 250
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4.2.10 Controls should be implemented to prevent the microbiological contamination of 252
sand filters, carbon beds and water softeners. The techniques selected should be 253
appropriate and may include backflushing, chemical and/or thermal sanitization and 254
frequent regeneration. 255
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4.2.11 The quality of drinking-water should be monitored routinely to account for 257
environmental, seasonal or supply changes which may have an impact on the source 258
water quality. 259
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4.2.12 Where drinking-water is stored and distributed by the user, the storage and 261
distribution systems should not allow the degradation of the water quality prior to 262
use. After any such storage, testing should be carried out routinely and in accordance 263
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with a defined procedure. The storage and distribution of drinking-water should be 264
done in a manner to ensure a turnover or recirculation of the stored water sufficient 265
enough to prevent stagnation. 266
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4.2.13 The equipment and systems used to produce and store drinking-water should be able 268
to be drained and sanitized. 269
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4.2.14 Storage tanks should be closed with appropriately protected vents and should allow 271
for visual inspection. 272
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4.2.15 Distribution pipework should be able to be drained or flushed and sanitized. 274
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4.2.16 The scope and extent of qualification for the system should be identified and justified. 276
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4.2.17 The results from testing drinking-water should be subjected to statistical analysis in 278
order to identify trends and changes. If the drinking-water quality changes 279
significantly, but is still within specification, the direct use of this water as a WPU, or 280
as the feedwater to downstream treatment stages, should be reviewed for any risks 281
and the results of the review and action to be taken and documented. 282
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4.2.18 Changes to a system or to its operation should be made in accordance with change 284
control procedures. 285
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4.2.19 Additional testing should be considered if there is any change in the raw water source, 287
treatment techniques or system configuration. 288
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4.3 Bulk purified water 290
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4.3.1 Bulk purified water (BPW) should meet the relevant pharmacopoeial specifications 292
for chemical and microbiological purity. 293
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4.3.2 BPW should be prepared from drinking-water as a minimum-quality feedwater. 295
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4.3.3 Any appropriate, qualified purification technique, or sequence of techniques, may be 297
used to prepare BPW. BPW may be prepared by, for example, a combination of ion 298
exchange, RO, RO/electro-deionization (EDI), ultrafiltration and vapour compression. 299
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4.3.4 The following should be considered when configuring a water purification system or 301
defining user requirement specifications (URS): 302
• the quality of feedwater and its variation over seasons; 303
• the quantity of water required by the user; 304
• the required water-quality specification; 305
• the sequence of purification stages required; 306
• energy consumption; 307
• appropriately located sampling points designed in such a way so as to avoid 308
potential contamination; and 309
• unit process steps provided and documented with the appropriate 310
instrumentation to measure parameters such as flow, pressure, temperature, 311
conductivity, pH and total organic carbon. 312
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4.3.5 Ambient-temperature systems such as ion exchange, RO and ultrafiltration are 314
especially susceptible to microbiological contamination, particularly when equipment 315
is static during periods of no or low demand for water. Sanitization, at defined 316
intervals, as well as other controls, should be defined to prevent and minimize 317
microbiological contamination. 318
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4.3.6 Appropriate, validated methods for sanitizing each stage of purification needs to be 320
in place. Where agents are used for sanitization, their removal must be proven. 321
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4.3.7 The following controls should be considered: 323
• the maintenance of water flow at all times, in order to prevent water from 324
stagnating; 325
• control of temperature in the system by heat exchangers or plant room 326
cooling in order to reduce the risk of microbial growth (guidance value < 25 327
°C); 328
• the provision of ultraviolet disinfection at appropriate locations in the system; 329
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• the use of water-treatment system components that can periodically be 330
thermally sanitized; 331
• in addition to thermal sanitization, the application of chemical sanitization 332
such as ozone, hydrogen peroxide and/or peracetic acid; and 333
• thermal sanitization at > 70 °C. 334
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4.3.8 BPW should have the appropriate action and alert limits for microbiological purity 336
determined from a knowledge of the system and data trending. BPW should be 337
protected from recontamination and microbial proliferation. 338
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4.4 Bulk highly purified water 340
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4.4.1 Bulk highly purified water (BHPW) must meet the same quality standards as WFI, 342
including the limit for endotoxins. 343
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4.4.2 BHPW should be prepared from drinking water as a minimum-quality feedwater. 345
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4.4.3 Any appropriate and qualified purification technique, or sequence of techniques, may 347
be used to prepare BHPW. BHPW is often produced by double pass RO coupled with 348
other suitable techniques such as ultrafiltration and deionization. 349
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4.4.4 BHPW should also be protected from recontamination and microbial proliferation. 351
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4.4.5 BHPW and WFI have identical microbiological requirements. 353
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Note: The guidance provided in section 4.3 for BPW is equally applicable to BHPW. 355
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4.5 Bulk water for injections 357
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4.5.1 Bulk water for injections (BWFI) should meet the relevant pharmacopoeial 359
specifications for chemical and microbiological purity (including endotoxins). BWFI is 360
the highest quality of pharmacopoeial WPU. 361
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4.5.2 BWFI is not sterile water and is not a final dosage form. It is an intermediate bulk 362
product suitable to be used as an ingredient during formulation. 363
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4.5.3 As a robust technique should be used for the production of BWFI, the following should 365
be considered when designing a water purification system: 366
• the quality of feedwater (e.g. drinking-water, usually with further treatment, 367
or PW); 368
• the required water quality specification; 369
• the quantity of water; 370
• based on the selection of components and type of system, the appropriate 371
URS, qualification and validation; 372
• the optimum generator size or generators with variable control to avoid over-373
frequent start/stop cycling; 374
• blow-down and dump functions; and 375
• cool-down venting to avoid contamination ingress. 376
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4.5.4 BWFI may be prepared, for example, by distillation as the final purification step. 378
Alternatively, techniques such as deionisation, electro deionization, nano filtration, 379
ultrafiltration, water softening, descaling, pre-filtration and degasification, ultraviolet 380
treatment, along with other techniques, may be considered in conjunction with a 381
single or double pass RO system. 382
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4.5.5 BWFI should have the appropriate action and alert limits and should also be protected 384
from recontamination and microbial proliferation. 385
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Note: For a full description, see Production of water for injection by means other than distillation. 387
[Note from Secretariat: the text published in the WHO Technical Report Series, No. 1025, 2020, Annex 388
3 will be attached as Annex 1 to this text.] 389
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4.6 Other grades of water 391
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When a specific process requires a special non-pharmacopoeial grade of water, its 393
specification must be documented within a company’s quality system. As a minimum, it must 394
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meet the pharmacopoeial requirements relating to the grade of WPU required for the type of 395
dosage form or process step. 396
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5. General considerations for water purification 398
systems 399
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5.1 Pharmaceutical manufacturers should apply the current principles of quality risk management 401
(6) in selecting and using the appropriate water purification systems. An appropriate method 402
for the production of WPU should be used. 403
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5.2 Risks and controls should be identified for each stage of the production, storage, distribution, 405
use and monitoring of WPU. 406
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5.3 Risks identified should be analyzed and evaluated in order to determine the scope and extent 408
of validation and qualification of the system, including the computerized systems used for the 409
production, control and monitoring of WPU. 410
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5.4 Risk management should be an ongoing part of the quality management process for WPU. A 412
mechanism to review or monitor events associated with the production, storage, distribution 413
and use of WPU should be implemented. 414
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5.5 Procedures for managing changes and deviations should be followed. Where applicable, the 416
appropriate risk and impact assessments should be done where changes and deviations are 417
managed. 418
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5.6 The chosen water purification system, method or sequence of purification steps must be 420
appropriate in order to ensure the production of water of an intended grade. Based on the 421
outcome of the risk assessment, the following should at least be considered when selecting 422
the water treatment system and method: 423
• the quality of the available feedwater and the variation over time (seasonal changes); 424
• the availability of suitable support facilities for the system (e.g. electricity, heating, 425
steam, chilled water and compressed air); 426
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• the extent of pre-treatment required; 427
• the sequence of purification steps required; 428
• the design and location of sampling points; 429
• the sanitization strategy; 430
• the availability of water-treatment equipment on the market; 431
• the reliability and robustness of the water-treatment equipment in operation; 432
• the yield or efficiency of the purification system; 433
• the ability to adequately support and maintain the water purification equipment; 434
• the continuity of operational usage considering hours/days/years and planned 435
downtime; 436
• the total life-cycle of the system (including capital, operation and maintenance); 437
• the final water quality specification; and 438
• the quantity of water required by the user. 439
440
5.7 The specifications for water purification equipment, storage and distribution systems should 441
take into account the following: 442
• the location of the plant room; 443
• the extremes in temperature that the system will encounter; 444
• the risk of contamination, for example, from materials of construction (contact 445
materials) and the environment; 446
• the adverse impact of adsorptive contact materials; 447
• hygienic or sanitary design, where required; 448
• corrosion resistance; 449
• freedom from leakage; 450
• system configuration to avoid proliferation of microbiological organisms; 451
• tolerance to cleaning and sanitizing agents (thermal and/or chemical); 452
• the sanitization strategy; 453
• system capacity and output requirements; and 454
• the provision of all necessary instruments, test and sampling points in order to allow 455
for all the relevant critical quality parameters of the complete system to be 456
monitored. 457
458
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5.8 The design, configuration and layout of the water purification equipment, storage and 459
distribution systems should also take into account the following physical considerations: 460
• the ability to collect samples; 461
• the space available for the installation and environment around the system; 462
• structural loadings on buildings; 463
• the provision of adequate access for maintenance and monitoring; and 464
• the ability to safely handle regeneration and sanitization chemicals. 465
466
6. Water storage and distribution systems 467
468
6.1 Where drinking water is stored and distributed, the appropriate controls should be 469
determined and implemented in order to mitigate risks. This applies to all stages in the supply, 470
storage and distribution of drinking-water. 471
472
6.2 The water storage and distribution systems for PW, BHPW and BWFI should be appropriately 473
designed, installed, qualified, operated and maintained in order to ensure the storage and 474
distribution of water is of consistent quality to the user points. 475
476
7. Good practices for water systems 477
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7.1 The components of water systems, including but not limited to pipework, valves and fittings, 479
seals, diaphragms and instruments, should be appropriate and should satisfy the following 480
objectives for the full range of the working temperature and potential chemicals that will 481
come into contact with the system at rest, in operation and during sanitization. The 482
construction materials should be of an appropriate quality. 483
484
7.2 As a minimum, the following should be considered: 485
• Compatibility and suitability. 486
• No leaching, adsorbing and absorbing. 487
• Corrosion resistance. 488
• Materials of construction: the materials used should be appropriate, for example, 489
sanitary specification plastics such as polypropylene, polyvinylidene-difluoride and 490
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perfluoro alkoxy. Other materials, such as unplasticized polyvinyl-chloride (uPVC), 491
may be used for treatment equipment designed for less pure water such as ion 492
exchangers and softeners. Plastics used should be manufactured from materials that 493
should at least meet the minimum food grade standards, be non-toxic and be 494
compatible with all chemicals used. Their chemical and biological characteristics 495
should meet any relevant pharmacopoeial specifications or recommendations. 496
Stainless-steel grade 316L or higher is generally recommended. The choice of 497
material should take into account the intended sanitization method. 498
• Passivation: passivation should be considered after initial installation and after 499
significant modification in accordance with a documented procedure defining the 500
solution to be used, its concentration, the temperature and contact time. 501
• Smooth internal finish: internal finish should be smooth in order to prevent the 502
formation of biofilms and corrosion (e.g. an arithmetical average surface roughness 503
of not greater than 0.8 micrometre (Ra); mechanical and electro-polishing of stainless 504
steel). 505
• Jointing: the manner in which pieces are jointed should be appropriate and controlled. 506
Where welding is used, the process should include, as a minimum, the qualification of 507
the operator, documentation of the welder set-up, work session test pieces (coupons 508
or weld samples), logs of all welds and records (e.g. photographs or videos) of visual 509
inspection of a defined proportion of welds (e.g. 100% hand welds or 10% automatic 510
welds). Threaded connections should be avoided. 511
• Flanges, unions and valves: where flanges, unions or valves are used, they should be 512
of a hygienic or sanitary design. The appropriate checks should be carried out in order 513
to ensure that the correct seals and diaphragms are used and that they are fitted and 514
tightened correctly. 515
• Documentation: all system components should be fully documented and be 516
supported by original or certified copies of material quality certificates. Where these 517
are not available or traceable, on-site tests should be performed and test reports 518
should be available. All documentation related to the qualification and validation of 519
the system should be available. Documents should include, as a minimum, system 520
drawing, isometric drawings, specifications for components, qualification and 521
validation protocols and reports, calibration certificates. 522
523
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8. System sanitization and bioburden control 524
525
8.1 Water-treatment, storage and distribution systems should be subjected to controls that will 526
reduce the risk of contamination and the proliferation of microbiological organisms. 527
528
8.2 Validated, detailed procedures for sanitizing all relevant parts of the system should be 529
followed. The techniques employed should be considered during the design stage of the 530
system as the procedure and technique may impact on the components and materials of 531
construction. 532
533
8.3 Systems that operate and are maintained at elevated temperatures (e.g. > 65) are generally 534
less susceptible to microbiological contamination than systems that are maintained at lower 535
temperatures. When lower temperatures are required due to the water treatment processes 536
employed, or the temperature requirements for the water in use, special precautions should 537
be taken to prevent the ingress of contaminants including microorganisms (see section 9.2 for 538
guidance). 539
540
8.4 Where the chemical sanitization of the water systems is part of the biocontamination control 541
programme, a validated procedure should be followed in order to ensure that the sanitizing 542
process selected is effective and that the sanitizing agent has been effectively removed. 543
544
8.5 Records of sanitization should be maintained. 545
546
9. Storage vessels 547
548
9.1 Storage vessels installed and used later should be appropriate for their intended use. 549
550
9.2 As a minimum, the following should be considered: 551
• the design and shape; 552
• the provision for drainage of water from the vessel, when required; 553
• construction materials; 554
Working document QAS/20.842 Page 19
• capacity, including buffer capacity, between the steady state, water generation rate 555
and the potentially variable simultaneous demand from user points, short-term 556
reserve capacity in the event of failure of the water-treatment system or the inability 557
to produce water (e.g. due to a regeneration cycle); 558
• prevention of stagnant water in the vessel (e.g. the headspace where water droplets 559
can accumulate); 560
• the need for the use of a spray-ball or distributor devices to wet the inner surfaces of 561
the vessel; 562
• limitation and design of nozzles within the storage vessels; 563
• the fitting of heated, bacteria-retentive, hydrophobic vent filters which are tested for 564
their integrity at appropriate intervals; 565
• the fitting of pressure-relief valves and bursting discs which are of a sanitary design 566
(bursting discs should be provided with external rupture indicators to ensure that loss 567
of system integrity is detected); 568
• the design and sanitization, as required, of level indicators; 569
• the design and location of valves, sampling points and monitoring devices and 570
sensors; and 571
• the need for heat exchangers or jacketed vessels. Where these are used, controls 572
should be put in place in order to ensure that there is no risk of contamination of 573
water. 574
575
10. Water distribution 576
577
10.1 The water distribution system should be designed as a loop, with continuous circulation of 578
BPW, BHPW and BWFI. Where this is not the case, a good justification for using a non-579
recirculating one-way system should be provided. 580
581
10.2 As a minimum, the following should be considered: 582
• controls to prevent proliferation of contaminants; 583
• the length of the distribution system; 584
• material of construction, joints and impact as a result of sanitization; and 585
Working document QAS/20.842 Page 20
• design and location of devices, sensors and instruments such as flow meters, total 586
organic carbon (TOC) analysers and temperature sensors; 587
588
10.3 Filtration should not usually be used in distribution loops or at take-off user points as these 589
are likely to conceal system contamination. 590
591
10.4 Where heat exchangers are employed to heat or cool WPU within a system, precautions 592
should be taken in order to prevent the heating or cooling utility from contaminating the 593
water. 594
595
10.5 Secure types of heat exchangers, such as double tube plate, double plate and frame, or tube 596
and shell configuration, should be considered. Where these types are not used, an alternative 597
approach whereby the utility is maintained and monitored at a lower pressure than the WPU 598
may be considered. The latter approach is not usually appropriate in BWFI systems. 599
600
10.6 Where heat exchangers are used, they should be arranged in continually circulating loops or 601
sub-loops in order to avoid unacceptable static water in the system. 602
603
10.7 When the temperature is reduced for processing purposes, the reduction should occur for the 604
minimum necessary time. The cooling cycles and their duration should be proven satisfactory 605
during the qualification of the system. 606
607
10.8 Circulation pumps should be of a sanitary design with the appropriate seals to prevent 608
contamination of the system. 609
610
10.9 Where stand-by pumps are provided, they should be configured or managed to avoid dead 611
zones trapped within the system. 612
613
10.10 Consideration should be given to preventing contamination in systems where parallel pumps 614
are used, especially if there is stagnant water when one of the pumps is not being used. 615
616
617
Working document QAS/20.842 Page 21
11. Biocontamination control techniques 618
619
11.1 Water purification systems should be sanitized using chemical and or thermal sanitization 620
procedures as appropriate (e.g. production, storage and distribution). The procedure and 621
conditions used, such as times and temperatures, should be suitable. 622
623
11.2 Other control techniques to be considered include: 624
• The maintenance of a continuous circulation of water: a turbulent flow of 1.2m/s, for 625
example. 626
• Ensuring the shortest possible length of pipework. 627
• Isolating pipework for ambient temperature systems from adjacent hot pipes. 628
• Minimizing dead legs, including in the pipework, through the appropriate design. 629
Dead legs are measured and calculated and, as a guide, should not exceed three times 630
the branch diameter (3D). 631
• Separate pressure gauges from the system by membranes. 632
• Using hygienic pattern diaphragm valves. 633
• Installing pipework to allow for full drainage. A guidance figure for the slope is 1:100. 634
• Considering ultraviolet radiation sources in pipework and maintaining the system at 635
an elevated temperature (e.g. >65 °C). 636
• Periodic sanitization by suitable means, e.g. hot water (guidance temperature > 70 637
°C), super-heated hot water or clean steam, and/or routine chemical sanitization 638
using ozone or other suitable chemical agents. 639
640
11.3 When chemical sanitization is used, it is essential to prove that the agent has been removed 641
prior to using the water. 642
643
12. Operational considerations 644
645
12.1 Water systems should be appropriately qualified and validated (7). The scope and extent of 646
qualification should be determined based upon risk assessment. 647
648
Working document QAS/20.842 Page 22
12.2 There should be documented evidence of consideration and execution of stages of 649
qualification including, as appropriate, URS, factory acceptance testing (FAT), site acceptance 650
testing (SAT), design qualification (DQ), IQ, OQ and PQ. 651
652
12.3 Commissioning work done should be documented. Commissioning is not a replacement for 653
qualification. 654
655
12.4 In order to validate the reliability and robustness of a system and its performance, a three-656
phase approach should be used over an extended period of time. Tests on the source water 657
(drinking-water) should be included within the validation programme and continued as part 658
of the routine monitoring, and these results should meet specifications. 659
660
12.5 Phase 1 661
662
Phase I should cover a period of at least two weeks. The system should be monitored 663
intensively for its performance. The system should operate continuously without failure or 664
performance deviation. Normally, water should not be used for FPP manufacturing during 665
this phase. 666
667
The procedures and protocols for Phase I should cover at least the following activities and 668
testing approaches: 669
• chemical and microbiological testing in accordance with a defined plan; 670
• sample, test and monitoring of the incoming feedwater daily to verify its quality; 671
• sample, test and monitoring after each step in the purification process; 672
• sample, test and monitoring at each point of use and at other defined sample points; 673
• develop the appropriate operating ranges; 674
• develop and finalize the operating, cleaning, sanitizing and maintenance procedures; 675
• demonstrate the production and delivery of product water of the required quality and 676
quantity; 677
• use and refine the standard operating procedures (SOPs) for operation, maintenance, 678
sanitization and troubleshooting; 679
• verify provisional alert levels; and 680
• develop and refine test-failure procedure. 681
Working document QAS/20.842 Page 23
12.6 Phase 2 682
683
Phase 2 should cover at least a further test period of two weeks. The system should be 684
monitored while deploying all the refined SOPs after the satisfactory completion of Phase 1. 685
The sampling program should be generally the same as in Phase 1. The use of the water for 686
FPP manufacturing purposes during this phase may be acceptable, provided that both 687
commissioning and Phase 1 data demonstrate the appropriate water quality and the practice 688
is approved by QA. 689
690
The approach should also: 691
• demonstrate consistent operation within established ranges; and 692
• demonstrate consistent production and delivery of water of the required quantity and 693
quality when the system is operated in accordance with the SOPs. 694
695
12.7 Phase 3 696
697
Phase 3 should cover at least a further 12 months after the satisfactory completion of Phase 698
2. The sample locations, sampling frequencies and tests may be reduced to the normal 699
routine pattern based on the established procedures proven during Phase 1 and Phase 2. 700
After completion of the qualification and validation programme of Phase 3, a system review 701
should be undertaken. This may include the trending of results and the evaluation of system 702
performance capability. The appropriate action should be taken where identified. 703
704
Water can be used during this phase (e.g. for manufacturing and cleaning) which has the 705
following objectives: 706
• to demonstrate a reliable performance over an extended period of time; and 707
• to ensure that seasonal variations are evaluated. 708
709
13. Continuous system monitoring 710
711
13.1 The system should be subject to continuous monitoring. 712
713
Working document QAS/20.842 Page 24
13.2 A monitoring plan should be followed where samples are collected in accordance with a 714
written procedure. 715
716
13.3 A combination of online and offline instruments, linked to appropriately qualified alarm 717
systems, should be used. Parameters such as flow, pressure, temperature, conductivity and 718
TOC should be monitored with online devices with periodic offline testing to confirm the 719
results. Other parameters may be monitored through offline testing. 720
721
13.4 Offline testing (including physical, chemical and microbiological attributes) should be done in 722
accordance with a predetermined programme. 723
724
13.5 Offline samples should be taken from points of use or dedicated sample points where points 725
of use cannot be sampled. All water samples should be taken using the same methodology as 726
detailed in production procedures, e.g. with a suitable flushing and drainage procedure in 727
place. 728
729
13.6 Tests should be carried out to ensure that the approved pharmacopoeial specification (and 730
company specification, where applicable) has been met. This may include the microbiological 731
quality of water, as appropriate. 732
733
13.7 Monitoring data should be subjected to trend analysis, e.g. monthly, quarterly and annually. 734
The results should be within defined control limits, such as 2 or 3 sigma. 735
736
13.8 Alert and action levels should be established based on historically reported data. 737
738
13.9 Trends and out-of-limit results should be investigated for the root cause, followed by the 739
appropriate corrective actions. 740
741
14. Maintenance of water systems 742
743
14.1 WPU systems should be maintained and recorded in accordance with an approved and 744
documented maintenance programme. 745
746
Working document QAS/20.842 Page 25
14.2 The programme should take into account at least the following: 747
• defined frequency for system elements; 748
• the calibration programme; 749
• SOPs for specific tasks; 750
• control of approved spares; 751
• preventive maintenance and maintenance plan and instructions; 752
• a review and approval of systems for use upon completion of work; and 753
• a record and review of problems and faults during maintenance 754
755
15. System reviews 756
757
15.1 WPU systems should be reviewed at described intervals. 758
759
15.3 The review team should be comprised of representatives from engineering, utilities, 760
validation, QA, quality control, microbiology, production and maintenance, and so on. 761
762
15.3 The review team should consider matters such as: 763
• changes made since the last review; 764
• system performance and capability; 765
• reliability; 766
• quality trends; 767
• failure events and alarms; 768
• investigations; 769
• out-of-specification and out-of-limit results; 770
• compliance with current GMP requirements for WPU systems; 771
• documentation being a current reflection of the WPU system; 772
• records including log books and electronic data; 773
• the current SOPs relating to WPU; and 774
• the computerized system linked to the water system, e.g. SCADA (Supervisory Control 775
and Data Acquisition). 776
777
Working document QAS/20.842 Page 26
15.4 The application of specific types of water to processes and dosage forms should be 778
considered. 779
780
15.5 Pharmaceutical manufacturers should use the appropriate grade of WPU during, for example, 781
the manufacture of APIs and different dosage forms; for different stages in washing and 782
cleaning; in the preparation of reagents and solutions; and in the synthesis of materials and 783
products. 784
785
15.6 The grade of water used should take into account the nature and intended use of the 786
intermediate or finished product and the stage in the manufacturing process at which the 787
water is used. 788
789
15.7 BHPW can be used in the preparation of products when water of high quality (i.e. very low in 790
microorganisms and endotoxins) is needed, but the process stage or product requirement 791
does not include the constraint on the production method defined in some of the 792
pharmacopoeia monographs for BWFI. 793
794
15.8 BWFI should be used, for example, in the manufacture of injectable products, such as 795
dissolving or diluting substances or preparations during the manufacturing of parenteral 796
products, and for the manufacture of sterile water for preparation of injections. BWFI should 797
also be used for the final rinse after the cleaning of equipment and components that come 798
into contact with injectable products, as well as for the final rinse in a washing process in 799
which no subsequent thermal or chemical depyrogenization process is applied. 800
801
15.9 When steam comes into contact with an injectable product in its final container or with 802
equipment for preparing injectable products, it should conform to the specification for BWFI 803
when condensed. 804
805
16. Inspection of water systems 806
807
16.1 WPU (BPW, BHPW and BWFI) systems are likely to be the subject of regulatory inspection 808
from time to time. Users should consider conducting routine audits and self-inspection of 809
established water systems. 810
Working document QAS/20.842 Page 27
16.2 This document can be used as the basis of an audit and inspection. A tour of the water system, 811
treatment system, storage and distribution system, as well as visible pipework and user 812
points, should be performed to ensure that the system is appropriately designed, installed, 813
qualified, validated, maintained and monitored. 814
815
16.3 The following items could be included in an audit or inspection: 816
• a review of current drawings of the water system showing all components in the 817
system from the inlet to the points of use, along with sampling points and their 818
designations; 819
• a physical check to ensure that the system matches the piping and instrumentation 820
diagram or drawing (P&ID); 821
• approved piping drawings (e.g. orthographic and/or isometric); 822
• qualification and validation protocols, reports and results; 823
• a sampling and monitoring plan with a drawing of all sample points with evidence of 824
sample management, sample preparation, testing and results; 825
• a training programme for sample collection and testing; 826
• the setting and monitoring of alert and action levels; 827
• monitoring of results and evaluation of trends; 828
• absence of leaks; 829
• a review of any changes made to the system since the last audit or inspection; 830
• a review of deviations recorded and their investigation; 831
• a general inspection of the system for status and condition; 832
• a review of maintenance, failure and repair logs; 833
• a check of calibration and standardization of critical instruments and devices; 834
• a review of the performance capability of the system; and 835
• procedures and records for sanitization. 836
837
838
Working document QAS/20.842 Page 28
References 839
1. WHO Good manufacturing practices: water for pharmaceutical use (WHO Technical Report 840
Series, No. 970, Annex 2, 2011). 841
842
2. WHO Good manufacturing practices for active pharmaceutical ingredients (WHO Technical 843
Report Series No. 957, 2010, Annex 2). 844
845
3. WHO Good manufacturing practices for pharmaceutical products: main principles (WHO 846
Technical Report Series, No. 986, 2014, Annex 2). 847
848
4. The International Pharmacopoeia. Geneva, World Health Organization; updated regularly 849
(https://www.who.int/medicines/publications/pharmacopoeia/en/ and 850
https://apps.who.int/phint/2019/index.html#p/home, accessed 1 May 2020). 851
852
5. WHO Guidelines for drinking-water quality, 4th edition, incorporating the 1st addendum, 853
2017 (https://www.who.int/water_sanitation_health/publications/drinking-water-quality-854
guidelines-4-including-1st-addendum/en/, accessed 1 May 2020). 855
856
6. WHO Guidelines on quality risk management (WHO Technical Report Series, No. 981, 2013, 857
Annex 2; https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex2 858
TRS-981.pdf?ua=1, accessed 1 May 2020). 859
860
7. WHO Guidelines on validation (WHO Technical Report Series, No. 1019, 2019, Annex 3; 861
https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_A862
nnex3.pdf?ua=1, accessed 1 May 2020). 863
864
Further reading 865
Will be updated further 866
• American Society of Mechanical Engineers. Bioprocessing Equipment Standard. 867
ASME — BPE 2019. 868
• Banes PH. Passivation: understanding and performing procedures on austenitic stainless-steel 869
systems. Pharmaceutical Engineering, 1990: 41. 870
Working document QAS/20.842 Page 29
• Guide to inspections of high purity water systems. Maryland, US Food and Drug 871
Administration, 1993 (http://www.fda.gov/ICECI/InspectionGuides). 872
• Biotechnology. Equipment. Guidance on testing procedures for cleanability. British 873
Standards Publishing. BS EN 12296, 1998. 874
• European Medicines Agency. Note for guidance on the quality of water for pharmaceutical 875
use. London, 2002 (CPMP/QWP/158-01) (https://www.ema.europa.eu/en/documents/ 876
scientific-guideline/note-guidance-quality-water-pharmaceutical-use_en.pdf). 877
• European Pharmacopoeia: see website for the publishers of the European Pharmacopoeia and 878
supplements (http://www.pheur.org/). 879
• Harfst WH. Selecting piping materials for high-purity water systems. Ultra-pure water, 880
May/June 1994. 881
• ISPE Good practice guide: commissioning and qualification of pharmaceutical water and steam 882
systems. ISPE Baseline TM Pharmaceutical Engineering Guide, Vol. 4. International Society 883
for Pharmaceutical Engineering, 2007. 884
• ISPE Baseline Guide Volume 4: Water and Steam Systems. International Society for 885
Pharmaceutical Engineering, 2001. Noble PT. Transport considerations for microbial control 886
in piping. Journal of Pharmaceutical Science and Technology, 1994, 48: 76–85. 887
• Pharmaceutical Inspection Co-operation Scheme. PIC/S; Inspection of utilities; P1 009-1. 888
Geneva, Pharmaceutical Inspection Co-operation Scheme, 2002. 889
• Tverberg JC, Kerber SJ. Effect of nitric acid passivation on the surface composition of 890
mechanically polished type 316 L sanitary tube. European Journal of Parenteral Sciences, 891
1998, 3: 117–124. 892
• US Food and Drug Administration. Guide to inspections of high purity water systems, high 893
purity water systems (7/93), 2009 (http://www.fda.gov/ICECI/Inspections/ 894
InspectionGuides/ucm074905.htm). 895
• US Pharmacopeia: published annually (see http://www.usp.org/). 896
897
*** 898