Good manufacturing practices: water for pharmaceutical use · 47 Good manufacturing practices: 48 water for pharmaceutical use 49 50 Background 51 52 The control of water quality,

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

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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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49

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

57

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

72

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

75

1. Introduction 76

2. Background to water requirements and uses 77


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


1. Introduction and scope 103

104

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

110

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

113

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

117

1.4 The document can be used in whole or in part, as appropriate, to the section and application 118

under consideration. 119

120

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

124

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

128

2. Background to water requirements and uses 129

130

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


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

140

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

147

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

157

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

160

3. General principles for pharmaceutical water 161

systems 162

163

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


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

171

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

175

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

180

4. Water quality specifications 181

182

4.1 Pharmacopoeial specifications 183

184

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

196

197

198


4.2 Drinking-water 199

200

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

205

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

211

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

214

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

221

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

227

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


achieved should be identified and a water sample taken and tested at defined 231

intervals thereafter. 232

233

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

238

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

242

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

251

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

256

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

260

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


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

267

4.2.13 The equipment and systems used to produce and store drinking-water should be able 268

to be drained and sanitized. 269

270

4.2.14 Storage tanks should be closed with appropriately protected vents and should allow 271

for visual inspection. 272

273

4.2.15 Distribution pipework should be able to be drained or flushed and sanitized. 274

275

4.2.16 The scope and extent of qualification for the system should be identified and justified. 276

277

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

283

4.2.18 Changes to a system or to its operation should be made in accordance with change 284

control procedures. 285

286

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

289

4.3 Bulk purified water 290

291

4.3.1 Bulk purified water (BPW) should meet the relevant pharmacopoeial specifications 292

for chemical and microbiological purity. 293

294

4.3.2 BPW should be prepared from drinking-water as a minimum-quality feedwater. 295

296


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

300

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

313

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

319

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

322

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


• 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

335

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

339

4.4 Bulk highly purified water 340

341

4.4.1 Bulk highly purified water (BHPW) must meet the same quality standards as WFI, 342

including the limit for endotoxins. 343

344

4.4.2 BHPW should be prepared from drinking water as a minimum-quality feedwater. 345

346

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

350

4.4.4 BHPW should also be protected from recontamination and microbial proliferation. 351

352

4.4.5 BHPW and WFI have identical microbiological requirements. 353

354

Note: The guidance provided in section 4.3 for BPW is equally applicable to BHPW. 355

356

4.5 Bulk water for injections 357

358

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


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

364

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

377

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

383

4.5.5 BWFI should have the appropriate action and alert limits and should also be protected 384

from recontamination and microbial proliferation. 385

386

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

390

4.6 Other grades of water 391

392

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


meet the pharmacopoeial requirements relating to the grade of WPU required for the type of 395

dosage form or process step. 396

397

5. General considerations for water purification 398

systems 399

400

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

404

5.2 Risks and controls should be identified for each stage of the production, storage, distribution, 405

use and monitoring of WPU. 406

407

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

411

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

415

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

419

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


• 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


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

478

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


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


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


• the design and shape; 552

• the provision for drainage of water from the vessel, when required; 553

• construction materials; 554


• 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


• 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


• 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


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


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


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


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


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


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


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


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

https://www.who.int/medicines/publications/pharmacopoeia/en/

https://apps.who.int/phint/2019/index.html#p/home

https://www.who.int/water_sanitation_health/publications/drinking-water-quality-guidelines-4-including-1st-addendum/en/

https://www.who.int/water_sanitation_health/publications/drinking-water-quality-guidelines-4-including-1st-addendum/en/

https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex2%20TRS-981.pdf?ua=1

https://www.who.int/medicines/areas/quality_safety/quality_assurance/Annex2%20TRS-981.pdf?ua=1

https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1




• 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

http://www.fda.gov/ICECI/InspectionGuides

https://www.ema.europa.eu/en/documents/scientific-guideline/note-guidance-quality-water-pharmaceutical-use_en.pdf

https://www.ema.europa.eu/en/documents/scientific-guideline/note-guidance-quality-water-pharmaceutical-use_en.pdf

http://www.pheur.org/

http://www.fda.gov/ICECI/Inspections/%20InspectionGuides/ucm074905.htm

http://www.fda.gov/ICECI/Inspections/%20InspectionGuides/ucm074905.htm

http://www.usp.org/