Working document QAS/20.849 May 2020

1

DRAFT WORKING DOCUMENT FOR COMMENTS: 2

3

Points to consider on the different approaches – 4

including HBEL – to establish carryover limits in 5

cleaning validation for identification of contamination 6

risks when manufacturing in shared facilities 7

8

Please send your comments to Dr Valeria Gigante, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications (gigantev@who.int), with a copy to Ms Claire Vogel (vogelc@who.int) before 30 June 2020. Please use our attached Comments Table for this purpose.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines/en/) for comments under the “Current projects” l ink. If you wish to receive all our draft guidelines, please send your email address to jonessi@who.int and your name will be added to our electronic mailing l ist.

9 © W o rld Health Organization 2020 10 11 All rights reserved. 12 13 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft 14 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in 15 any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member 16 organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. 17 18 Please send any request for permission to: Dr Sabine Kopp, Group Lead, Norms and Standards for Pharmaceuticals, Department 19 of Access to Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland, email: 20 kopps@who.int. 21 22 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 23 whatsoever on the part of the World Health Organization concerning the legal status o f any country, territory, city or area or 24 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 25 border lines for which there may not yet be full agreement. 26 27 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 28 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and 29 omissions excepted, the names of proprietary products are distinguished by initial capital letters. 30 31 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 32 However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibilit y 33 for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liab le for 34 damages arising from its use. 35 36 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 37

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Working document QAS/20.849 Page 2

SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/20.849 39

Points to consider on the different approaches – including HBEL – 40

to establish carryover limits in cleaning validation for identification 41

of contamination risks when manufacturing in shared facilities 42

Description of Activity Date

During the Fifty-third Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP), the WHO Secretariat was recommended to revise the Appendix 3, Cleaning Validation of Annex 3, Good manufacturing practices: guidelines on validation (WHO Technical Report Series, No. 1025, 2019).

October 2018

The update of Appendix 3, Cleaning Validation, was further discussed during the informal consultation on Good Practices for Health Products Manufacture and Inspection.

July 2019

Following a recommendation by the ECSPP, the WHO Secretariat was recommended to develop a Points to consider document on cleaning validation introducing the possibility of using HBEL-based approaches to setting safe cleaning limits and establishing a common understanding on which to develop guidelines that are appropriate for all stakeholders.

October 2019

Preparation of first draft working document. April – May 2020

Mailing of working document to the Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations (EAP) inviting comments and posting of the working document on the WHO website for public consultation

May – June 2020

Discussion of working document during the informal consultation on Good Practices for Health Products Manufacture and Inspection

June 2020

Revision of the working document based on comments received during the informal Consultation on Good Practices for Health Products Manufacture and Inspection.

July 2020

Mailing of revised working document to the EAP inviting comments

and posting the working document on the WHO website for public consultation.

August – September 2020

Consolidation of comments received and review of feedback. Preparation of working document for discussion.

End of September 2020

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

Working document QAS/20.849 Page 3

43

44

Any other follow-up action as required.

Working document QAS/20.849 Page 4

Points to consider on the different 45

approaches – including HBEL – to 46

establish carryover limits in cleaning 47

validation for identification of 48

contamination risks when manufacturing 49

in shared facilities 50

51

1. Introduction and background 52

2. Scope 53

3. Glossary 54

4. Traditional approach 55

5. New approaches 56

References 57

58

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1. Introduction and background 59

60

The World Health Organization (WHO) has published the guideline entitled Good Manufacturing 61

Practices for pharmaceutical products: main principles in the WHO Technical Report Series, No. 986, 62

Annex 2, 2014 (1). 63

64

The WHO Supplementary guidelines on good manufacturing practice: validation were published in 2006 65

and were supported by seven appendices. In 2019, the WHO Good manufacturing practices: guidelines 66

on validation (2) were updated and republished. Some of the seven appendices were also individually 67

updated between 2013 and 2019: 68

• Appendix 1. Validation of heating, ventilation and air conditioning systems (3). 69

• Appendix 2. Validation of water systems for pharmaceutical use (4). 70

• Appendix 3. Cleaning validation (5). 71

• Appendix 4. Analytical procedure validation (6). 72

• Appendix 5. Validation of computerized systems (7). 73

• Appendix 6. Guidelines on qualification (8). 74

• Appendix 7. Non-sterile process validation (9). 75

76

Appendix 3, relating to cleaning validation (5), was not updated at that time. Its revision, however, was 77

discussed during an informal consultation held in Geneva, Switzerland, in July 2019. The outcome of 78

the discussion was presented to the WHO Expert Committee on Specifications for Pharmaceutical 79

Products (ECSPP) meeting in October 2019. The ECSPP acknowledged the importance of 80

harmonization in regulatory expectations with regards to cleaning validation approaches. The Expert 81

Committee recommended a “Points to consider” document be prepared in order to describe the 82

current approaches used in cleaning validation and highlighting the complexities involved in order to 83

establish a common understanding. A revision of the relevant appendix would then be considered by 84

the Expert Committee thereafter. 85

86

Many manufacturers produce products in multi-product facilities where there is a risk of contamination 87

and cross-contamination. Some of the main principles of good manufacturing practices (GMP) include 88

the prevention of mix-ups and the prevention of contamination and cross-contamination. It is 89

therefore important that manufacturers identify all risks for contamination and cross-contamination 90

Working document QAS/20.849 Page 6

and identify and implement the appropriate controls to mitigate these risks. These controls include, 91

for example, technical and organizational measures, dedicated facilities, closed systems, cleaning and 92

cleaning validation. 93

94

2. Scope 95

96

The scope of this document is to discuss the different possible approaches – including methods that 97

account for pharmacological and toxicological data (Health-Based Exposure Limits {HBEL}) – that could 98

be used when establishing safe Carryover limits when manufacturing in shared facilities. 99

100

This document further provides clarification on cleaning validation and presents points to consider 101

when reviewing the current status and approaches to cleaning validation in multiproduct facilities. It 102

reflects the current regulatory guidance and expectations. It further focuses on approaches where 103

HBELs setting need to be considered in cleaning and cleaning validation approaches. 104

105

The principles should be applied in manufacturing facilities with active pharmaceutical ingredients 106

(APIs) and finished pharmaceutical products (FPPs). 107

108

This document should be read in conjunction with the main GMP text and supplementary texts on 109

validation (1-10). 110

111

3. Glossary 112

113

cleaning validation. Documented evidence to establish that cleaning procedures are removing residues 114

to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, 115

toxicology and equipment size. 116

117

contamination. The undesired introduction of impurities of a chemical or microbiological nature, or of 118

foreign matter, into or on to a starting material or an intermediate or pharmaceutical product during 119

handling, production, sampling, packaging, repackaging, storage or transport. 120

121

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cross-contamination. Contamination of a starting material, intermediate product or finished product 122

with another starting material or product during production. 123

124

margin of safety. The margin of safety is the distance between a calculated acceptance limit and the 125

actual residues after cleaning. It indicates the probability that a patient has to be exposed to the API 126

residues resulting from cleaning. 127

128

maximum safe Carryover (MSC). Mathematically calculated quantity of residue from a previous product 129

when carried over into a different product that can represent potential harm to the patients. 130

131

maximum safe surface residue (MSSR). The maximum safe surface residue is mathematically calculated 132

dividing the quantity of residue on a contact surface by the total area of contact (Maximum Safe 133

Carryover/Total Equipment Surface Area). 134

135

verification. The application of methods, procedures, tests and other evaluations, in addition to 136

monitoring, in order to determine compliance with GMP principles. 137

138

4. Traditional approach 139

140

For details on the traditional approaches in cleaning validation, see the WHO Technical Report Series, 141

No. 1019, Annexure 3, Appendix 3, 2019 (5). 142

143

One traditional approach is that cleaning validation is performed and the appropriateness of the 144

cleaning procedure was based on acceptance criteria suggested in GMP texts. This approach may no 145

longer be acceptable and justifiable as HBELs were not considered. 146

147

Where traditional acceptance limits are used, the decision should be discussed and justified as an 148

alternative to new approaches in setting acceptance criteria. 149

150

In view of the risks of contamination and cross-contamination, the new approaches, as described 151

below, should be implemented without delay. 152

153

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5. New approaches 154

155

Traditional cleaning validation approaches were often based on verifying that a cleaning procedure was 156

effective. However, in many instances, no development work or cleanability studies were performed 157

for these cleaning procedures. 158

159

Manufacturers should ensure that their cleaning is effective and appropriate and that their cleaning 160

validation provides scientific evidence that identified products can be manufactured in shared facilities 161

– with control measures implemented to mitigate the risks of contamination and cross-contamination. 162

163

This approach should include at least the following points which are further described in the text below: 164

• cleanability studies; 165

• risk assessment and risk control; 166

• technical and organizational controls; 167

• HBELs setting; 168

• analytical procedures; and 169

• cleaning verification with proven capability through statistical evaluation. 170

171

Manufacturers should describe their policy and approaches, including the points mentioned above, in 172

a document such as a master plan. 173

174

It is strongly recommended that manufacturers review their existing technical and organizational 175

measures, suitability of cleaning procedures and appropriateness of cleaning validation. Genotoxic and 176

carcinogenic substances, degradants and other contaminants should be identified and the appropriate 177

action should be taken in order to ensure that materials and products are not contaminated when 178

produced in shared facilities. 179

180

5.1 Documentation 181

182

Risk management principles, as described in other WHO guidelines on quality risk management 183

(10), should be applied to assist in identifying risks and controls to mitigate contamination and 184

cross-contamination. 185

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Procedures, protocols, reports and other related and supportive documentation should be 186

prepared, used and maintained. 187

188

The policy and approaches in cleaning and cleaning validation may be described in a Cleaning 189

Validation Master Plan. Experiments and validation should be performed in accordance with 190

predefined, authorized standard operating procedures, protocols and reports. 191

192

The design and layout of documents, and the reporting of data and information, should be in 193

compliance with the principles of good documentation practices (11) and should also meet 194

data integrity requirements (12). 195

196

5.2 Equipment 197

198

Consideration for cleaning validation should cover contact surfaces, as well as non-contact 199

surfaces, where the latter have been identified as areas of risk. 200

201

Authorized drawings of equipment should be current, accurate and available. These should be 202

used when equipment surface areas are calculated. Source data for these calculations should 203

be available. The calculated values should be used in the calculations in cleaning validation. 204

205

Equipment and components that are difficult to clean, such as sieves, screens and bags, should 206

also be included in the cleaning validation and calculations. 207

208

5.3 Detergents and solvents 209

210

Solvents and detergents used in cleaning processes should be selected with care. They should 211

also be appropriate for their intended use. The selection of the relevant solvent and detergent 212

should be justified. 213

214

There should be proof of effectiveness and appropriateness of the selected solvent and 215

detergent. 216

217

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Other points to consider include the concentration in which these are used, their composition, 218

and removal of their residues after cleaning. 219

220

The use of solvents and detergents should be included in cleanability studies. 221

222

5.4 Sampling 223

224

Traditionally, cleaning validation included the sampling of equipment and other areas in order 225

to determine whether or not there was any residue remaining on the surfaces. The focus was 226

mainly on contact surface areas. Non-contact surface areas were sometimes considered by 227

some manufacturers. 228

229

A combination of at least two or three sampling methods should be used. These include a 230

combination of swab samples, rinse samples and visual inspection. 231

232

The appropriate sampling procedures and techniques should be selected and used to collect 233

samples. These should be clearly described in procedures and protocols. The location (swab 234

sample) and the manner in which the samples are collected should be clearly described and be 235

scientifically justifiable. 236

237

The manner in which a rinse sample is collected should be described in detail. The procedure 238

should be clear and unambiguous. 239

240

The manner in which samples collected are prepared for analysis should be appropriate and 241

described in detail. 242

243

5.5 Cleanability studies 244

245

Before a cleaning procedure is validated and adopted for routine use, a cleanability study 246

should be performed in order to determine the appropriateness of the procedure for removing 247

material, product residue, cleaning agents and microorganisms. 248

249

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The lowest concentration of a substance that can be removed by following the cleaning 250

procedure should be established for different materials, intermediates and products on 251

different materials of construction. The concentration can be expressed in mg/m2. 252

253

Cleanability studies should be described in authorised documents, such as protocols and 254

procedures. The method should be scientific and may include spiking on coupons made from 255

different materials of construction. The so-called beaker method, or other appropriate 256

method, may be used. 257

258

Consideration should be given to all substances and different procedures where different 259

processes or solvents are used, including different surface materials. 260

261

The results should be documented in authorized reports and used in further determinations, 262

such as Maximum Safe Residue. 263

264

5.6 Risk assessment and risk control 265

266

Risk identification should be performed with a focus on the assessment of risks and defining 267

and implementing controls to mitigate the risk of contamination and cross-contamination. 268

269

These should include technical and organization controls, including but not limited to, 270

premises, equipment, utilities, containment, closed systems, cleaning and cleaning validation. 271

272

5.7 Technical and organizational controls 273

274

The appropriate technical and organizational controls should be defined and implemented. 275

276

Their appropriateness and effectiveness should be evaluated. Note: Cleaning and cleaning 277

validation are considered additional and supplementary controls to technical and 278

organizational controls. 279

280

Technical and organizational controls should be justifiable and clearly documented. 281

282

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Technical controls, such as the design of the premises and utilities (e.g. heating, ventilation and 283

air-conditioning {HVAC}, water and gas), should be appropriate for the range of products 284

manufactured (e.g. pharmacological classification, activities and properties). 285

286

Organizational controls, such as dedicated equipment, procedural control, and campaign 287

production, should be considered where appropriate as a means to reduce the risk of cross-288

contamination. 289

290

5.8 Health Based Exposure Limits (HBELs) setting 291

292

Manufacturers should establish, document and implement a company-wide policy on HBELs 293

setting for shared facilities. 294

295

APIs and products manufactured in shared facilities should be reviewed based on scientific 296

evidence in order to determine whether production and control activities in shared facilities 297

may be considered acceptable or whether dedicated facilities are required for the production 298

and control of identified products. 299

300

This is applicable to legacy products as well as the introduction of new products introduced 301

into a facility through a change control procedure. 302

303

Procedures should be established and implemented describing how scientific data and 304

toxicological information on HBELs should be obtained. 305

306

Data and information should be gathered and presented in a report. The data should be free 307

from bias. Where this service is outsourced, the appropriate measures should be put in place 308

in order to ensure that the data obtained are reliable. GMP requirements, such as vendor 309

qualification, agreements and other related aspects, should be considered. 310

311

The report should include scientific detail, including information on: 312

• chemical structure; 313

• hazard identification; 314

• mode of action; 315

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• identification of critical effects; 316

• establishing NOAELs (no-observed-adverse-effect level); 317

• adjustment factors; 318

• pre-clinical, clinical and non-clinical data; 319

• pharmacokinetics and pharmacodynamics; 320

• expert assessment; 321

• identification of the critical effect; 322

• assignment of adjustment factors (AF); 323

• argumentation for the selected HBEL; 324

• routes of administration; 325

• point of departure (POD); 326

• justification for critical effect of POD; and 327

• justification for factor. 328

329

The Permitted Daily Exposure (PDE) should be calculated based on the data and information 330

obtained. For example: 331

332

PDE = NOAEL x weight adjustment 333

F1 x F2 x F3 x F4 x F5 334

335

Where NOAEL is no-observed adverse event level, and 336

F represents various factors. The value selected should be justifiable. 337

338

The report should be reviewed by the manufacturer’s in-house team for completeness and 339

appropriateness. Team members should have the appropriate qualifications and experience in 340

the field of toxicology. A summary report should be prepared for each product and contain 341

information on the PDE value, genotoxicity and carcinogenicity (13). 342

343

These scientific reports should be used when considering the cleaning validation control 344

measures. 345

346

Manufacturers should periodically review and update PDE reports. The appropriate action 347

should be taken where such a report needs to be updated. 348

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5.9 Acceptance criteria 349

350

Limits established in cleaning validation should be justifiable. 351

352

Manufacturers often specified acceptance limits based on historical GMP texts. These 353

traditional limits may no longer be acceptable as HBELs (PDE) and cleanability studies were not 354

performed in many cases. 355

356

Criteria such as Margin of safety, Maximum Safe Carryover (MSC) and Maximum Safe Surface 357

Residue (MSSR) values should be calculated. Calculations and data should be available and 358

comply with data integrity principles. The calculation should include values of PDE, maximum 359

daily dose, batch size and equipment surface areas. 360

361

Maximum Safe Surface Residue (MSSR) should be calculated and presented, for example, in 362

table form listing preceding and following product values. The cleanability value obtained 363

should be considered in determining the acceptability of the procedure(s) and whether other 364

controls including separate, dedicated facilities are required. (See Annex 1 as an example.) 365

366

5.10 Grouping by therapeutic use 367

368

The risk associated with contamination and cross-contamination from one product to another 369

product in one therapeutic group, and between products in different therapeutic groups in 370

shared facilities, should be considered. For example, due to the risk, certain products should 371

be manufactured in dedicated or segregated self-contained facilities, including certain 372

antibiotics, certain hormones, certain cytotoxics and certain highly-active drugs – even though 373

these are in the same therapeutic class. 374

375

The risk assessment should include, for example, PDE values, batch size, maximum daily dose 376

of the next product, as well as other criteria associated with cleaning. 377

378

The higher the PDE value, the lower the risk. The products and therapeutic groups considered 379

for manufacturing should be plotted based on an identified scale of risk (14, 15). An illustration 380

is presented in figure 1 where hazard is plotted against risk 381

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Figure 1. Increasing hazard and PDE values 382

383

5.11 Analytical procedures 384

385

Samples obtained in cleaning validation should be analyzed by using specific, validated 386

procedures. The procedures should be developed, validated and appropriate for their intended 387

use. 388

389

Specific methods, such as HPLC, should be used where possible. Non-specific methods 390

including UV spectrophotometry should only be used where specific methods cannot be 391

employed. 392

393

Testing for total organic carbon (TOC) may be used where indicated and where justified. 394

395

Analytical procedures validation should be done on-site. Where analytical procedures were 396

developed and validated off-site, the scope and extent of validation should be defined and 397

justified. This includes procedures that are transferred from research and development 398

laboratories to site laboratories. (For analytical procedure validation, see reference 6). 399

400

Manufacturers should ensure that the procedures remain in a validated state. 401

402

403

404

405

406

Increasing hazard

Health Based Exposure Limit (HBEL) – PDE

>10 000ug/day <10ug/day

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5.12 Data integrity 407

408

Data, information and results pertaining to, for example, HBELs, PDE reports, results obtained 409

from cleaning validation and calculations should be scientific and should be in compliance with 410

the principles as contained in data integrity guidelines (12). 411

412

5.13 Cleaning validation and cleaning verification 413

414

The cleaning procedure should be validated after the cleaning procedure had been developed 415

and the cleanability study had been done. 416

417

Cleaning validation should include proof of, for example, the applicability of the procedure to 418

clean equipment that: 419

• had been kept in an unclean state for a period of time (dirty equipment hold time); 420

• are used after product change-over; 421

• are used in a campaign, where multiple batches of a product are produced one after 422

the other; and/or 423

• are stored in a clean state for defined periods of time (clean equipment hold time). 424

425

Cleaning validation should include consideration of HBELs when the appropriate method used 426

in establishing Carryover limits. Where HBELs are not used, scientific justification should be 427

provided. 428

429

The company should describe the policy and approach to cleaning verification. The 430

effectiveness of the validated cleaning procedure should be routinely verified. The approach 431

may include swab or rinse samples. The results obtained from testing on a routine basis should 432

be reviewed and subjected to statistical trending. 433

434

5.14 Visually clean 435

436

Visually clean is an important criterion in cleaning validation and should be one of the 437

acceptance criteria used on a routine basis. 438

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Visible residue limits (VRLs) should be determined. The process to determine the limit should 439

be appropriately described in procedures and protocols including concentrations, method of 440

spiking, surface areas, material of construction and other conditions such as light and angles. 441

442

VRLs should be quantitatively established for APIs, excipients, detergents and pharmaceutical 443

products. 444

445

Visual Detection Index (VDI) may be calculated using MSSR. 446

447

5.15 Cleaning verification and process capability 448

449

The cleaning procedure should remain in a validated state. Cleaning verification and process 450

capability may be used to provide data to support this. For example, the results from cleaning 451

verification sample analysis could be statistically trended. The capability of the cleaning 452

process is then calculated through an appropriate statistical process. 453

454

The presentation of individual results and data used in the calculation, such as with a Central 455

Processing Unit (Cpu) and acceptable daily exposure (ADE) base limit, should meet ALCOA 456

principles. 457

458

Data should be presented, for example, in graph form, and the capability of the process in 459

relation to control limits and the margin of safety should be discussed as part of continuous 460

improvement. 461

462

5.16 Personnel 463

464

Personnel should be trained in the principles of cleaning validation, with an emphasis on 465

contamination and cross-contamination control, HBELs setting, equipment disassembly, 466

sampling, testing and statistical calculations. 467

468

469

470

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5.17 Quality metrics and performance indicators 471

472

Aspects of HBELs setting, cleanability studies, cleaning validation and cleaning verification, as 473

well as process capability, should be considered in quality metrics, with performance indicators 474

identified and to be monitored. 475

476

5.18 Life cycle 477

478

HBEL reports, protocols, cleaning validation and cleaning verification should be included in a 479

company policy and life cycle approach in preventing cross-contamination in shared facilities. 480

481

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References 482

483

1. Guidelines on good manufacturing practices for pharmaceutical products: main principle. In: 484

WHO Expert Committee on Specifications for Pharmaceutical Preparations, forty-eighth report. 485

Geneva: World Health Organization; 2013: Annex 2 (WHO Technical Report Series, No. 986; 486

https://www.who.int/medicines/areas/quality_safety/quality_assurance/TRS986annex2.pdf?487

ua=1, accessed 4 May 2020). 488

2. Good Manufacturing Practices: Guidelines on Validation. In: WHO Expert Committee on 489

Specifications for Pharmaceutical Preparations, fifty-third report. Geneva: World Health 490

Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019; 491

http://digicollection.org/whoqapharm/documents/s23430en/s23430en.pdf, accessed 5 May 492

2020). 493

3. Guidelines on heating ventilation and air-conditioning systems for non-sterile pharmaceutical 494

products and Part 2: interpretation of guidelines on heating ventilation and air-conditioning 495

systems for non-sterile pharmaceutical products. In: WHO Expert Committee on Specifications 496

for Pharmaceutical Preparations: fifty-third report. Geneva: World Health Organization; 2019: 497

Annex 2 (WHO Technical Report Series, No. 1019; https://www.who.int/ 498

medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1, 499

accessed 4 May 2020). 500

4. Good manufacturing practices: guidelines on validation. Appendix 4. Validation of water 501

systems for pharmaceutical use. In: WHO Expert Committee on Specifications for 502

Pharmaceutical Preparations, fortieth report. Geneva: World Health Organization; 2006: Annex 503

3 (WHO Technical Report Series, No. 937; https://www.who.int/medicines/areas/ 504

quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1 accessed 4 May 2020). 505

5. Good manufacturing practices: guidelines on validation. Appendix 3. Cleaning validation. In: 506

WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report. 507

Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, No. 1019; 508

https://www.who.int/medicines/areas/quality_safety/quality_assurance/WHO_TRS_1019_An509

nex3.pdf?ua=1, accessed 4 May 2020). 510

6. Good manufacturing practices: guidelines on validation. Appendix 4. Analytical procedure 511

validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty- 512

third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report Series, 513

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No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/ 514

WHO_TRS_1019_Annex3.pdf?ua=1, accessed 4 May 2020). 515

7. Good manufacturing practices: guidelines on validation. Appendix 5. Validation of 516

computerized systems. In: WHO Expert Committee on Specifications for Pharmaceutical 517

Preparations: fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO 518

Technical Report Series, No. 1019; https://www.who.int/medicines/areas/ 519

quality_safety/quality_assurance/WHO_TRS_1019_Annex3.pdf?ua=1, accessed 4 May 2020). 520

8. Good manufacturing practices: guidelines on validation. Appendix 6. Guidelines on 521

qualification. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: 522

fifty-third report. Geneva: World Health Organization; 2019: Annex 3 (WHO Technical Report 523

Series, No. 1019; https://www.who.int/medicines/areas/quality_safety/quality_assurance/ 524

WHO_TRS_1019_Annex3.pdf?ua=1, accessed 4 May 2020). 525

9. Guidelines on good manufacturing practices: validation, Appendix 7: non-sterile process 526

validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: 527

forty-ninth report. Geneva: World Health Organization; 2015: Annex 3 (WHO Technical Report 528

Series, No. 992; https://www.who.int/medicines/areas/quality_safety/quality_assurance/ 529

Annex3-TRS992.pdf?ua=1, accessed 4 May 2020). 530

10. WHO guidelines on quality risk management. In: WHO Expert Committee on Specifications for 531

Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013: 532

Annex 2 (WHO Technical Report Series, No. 981; https://www.who.int/ 533

medicines/areas/quality_safety/quality_assurance/Annex2TRS-981.pdf, accessed 4 May 534

2020). 535

11. Guidance on good data and record management practices. In: WHO Expert Committee on 536

Specifications for Pharmaceutical Preparations: fiftieth report. Geneva: World Health 537

Organization; 2016: Annex 5 (WHO Technical Report Series, No. 996; 538

https://www.who.int/medicines/publications/pharmprep/WHO_TRS_996_annex05.pdf, 539

accessed 4 May 2020). 540

12. Guideline on data integrity. Draft for comments. Geneva: World Health Organization; 2019 541

(working document QAS/19.819; https://www.who.int/medicines/areas/quality_safety/ 542

quality_assurance/QAS19_819_data_integrity.pdf?ua=1, accessed 4 February 2020). 543

13. Guideline on setting health based exposure limits for use in risk identification in the 544

manufacture of different medicinal products in shared facilities, European Medicines Agency, 545

November 2014. 546

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14. ISPE Baseline, Pharmaceutical Engineering Guide, Volume 7 – Risk-based manufacture of 547

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