Working document QAS/13.

527
April 2013
RESTRICTED

1
PROPOSAL FOR REVISION OF THE 2
SUPPLEMENTARY GUIDELINES ON 3
GOOD MANUFACTURING PRACTICES: VALIDATION, 4
APPENDIX 7: NON-STERILE PROCESS VALIDATION 5
6
(APRIL 2013) 7
8
DRAFT FOR COMMENT 9
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12
World Health Organization 2013 13
All rights reserved. 14
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this 15
draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or 16
adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including 17
the organizations' concerned staff and member organizations) without the permission of the World Health 18
Organization. The draft should not be displayed on any web site. 19
Please send any request for permission to: 20
Dr Sabine Kopp, Medicines Quality Assurance Programme, Quality Assurance and Safety: Medicines, 21
Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, 22
Switzerland. Fax: (41-22) 791 4730; e-mail: kopps@who.int. 23
The designations employed and the presentation of the material in this draft do not imply the expression of any 24
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territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted 26
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The mention of specific companies or of certain manufacturers products does not imply that they are endorsed 28
or recommended by the World Health Organization in preference to others of a similar nature that are not 29
mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital 30
letters. 31
All reasonable precautions have been taken by the World Health Organization to verify the information 32
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This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 36
37
Please address any comments on this proposal by 24 May 2013 to Dr S. Kopp, Medicines Quality
Assurance Programme, World Health Organization, 1211 Geneva 27, Switzerland, fax: (+41 22) 791 4730
or e-mail: kopps@who.int with a copy to gaspardm@who.int.
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Working document QAS/13.527
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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/13.527: 38
PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON 39
GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE 40
PROCESS VALIDATION 41
42
43
44
Need for revision of published good manufacturing
practices: validation identified by Prequalification of
Medicines Programme
March 2013
Wide circulation of draft document for comment April 2013
Compilation of feedback received June 2013
Discussion of feedback during informal consultation on
quality assurance guidelines
July 2013
Mailing of revision for comment August 2013
Presentation to forty-eighth meeting of the WHO Expert
Committee on Specifications for Pharmaceutical
Preparations
October 2013
Any further action as necessary

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PROPOSAL FOR REVISION OF THE SUPPLEMENTARY GUIDELINE ON 45
GOOD MANUFACTURING PRACTICES: VALIDATION, APPENDIX 7: NON-STERILE 46
PROCESS VALIDATION 47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
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63
64
65
The Appendixes of the Supplementary Guideline on Good Manufacturing Practices: 66
Validation are currently as follows: 67
68
Appendix 1- Validation of heating, ventilation and air-conditioning systems 69
70
Appendix 2 -Validation of water systems for pharmaceutical use 71
72
Appendix 3 - Cleaning validation need for revision? 73
74
Appendix 4 - Analytical method validation 75
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Appendix 5 - Validation of computerized systems 77
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Appendix 6 - Qualification of systems and equipment 79
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Appendix 7 - Non-sterile process validation proposed to be revised 81
82
Note from Secretariat:
The current text of the Supplementary Guideline on Good Manufacturing Practices:
Validation (Ref: World Health Organization, WHO Technical Report Series, No. 937,
2006, Annex 4) is available on the following web site:
http://www.who.int/medicines/areas/quality_safety/quality_assurance/production/en/index.html
Moreover, comments are being sought at the same time, if the Appendix 3 on Cleaning
validation be revised in line with the current developments on setting health based
exposure limits for use in risk identification in the manufacture of different medicinal
products in shared facilities; if yes concrete proposals for revision would be
appreciated.
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Proposal for revision of the 83
Supplementary Guideline on Good Manufacturing Practices: Validation, 84
Appendix 7: Non-sterile process validation 85
86
87
Contents 88
page 89
1. Background and scope 90
2. Glossary 91
3. Introduction 92
4. Phase I. Process design 93
5. Phase II. Qualification and process verification 94
6. Phase III. Continued process verification 95
7. Change control 96
References 97
98
1. BACKGROUND AND SCOPE 99
100
Further to the Supplementary Guideline on good manufacturing practices: validation, as 101
published in the World Health Organization (WHO) Technical Report, No. 937,
1
additional 102
guidelines to support current approaches in GMP are published herewith to further support 103
the scope of process validation (also referred to as process qualification) linked to quality risk 104
management and quality by design principles as described by WHO and the International 105
Conference on Harmonisation (ICH). 106
107
This guideline allows for different approaches in process validation. The principles described 108
in this guideline are applicable to non-sterile finished pharmaceutical dosage forms. 109
Thorough knowledge of product and process development studies; previous manufacturing 110
experience; and quality risk management (QRM) principles are essential in the all approaches 111
to process validation as the focus is now on the life-cycle approach. The life-cycle approach 112

1
Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert Committee on
Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization. WHO
Technical Report Series, No. 937 (Annex 5), 2006.

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links product and process development, validation of the commercial manufacturing process 113
and maintenance of the process during routine commercial production. 114
115
A risk based approach to validation is recommended, linked to in-line or on-line controls and 116
monitoring to ensure that a process is in a state of control during routine manufacture. 117
118
2. GLOSSARY 119
120
control strategy 121
A planned set of controls, derived from current product and process understanding that assures 122
process performance and product quality. The controls can include parameters and attributes related to 123
drug substance and pharmaceutical product materials and components, facility and equipment 124
operating conditions, in-process controls, finished product specifications, and the associated methods 125
and frequency of monitoring and control. 126
127
continued process verification (CPV) 128
Continued process verification (CPV) can be defined as continuous monitoring of 129
manufacturing performance by using extensive in-line, on-line or at-line monitoring and/or 130
controls to evaluate process performance. It is a science and risk-based real-time approach to 131
verify and demonstrate that a process that operates within the predefined specified parameters 132
consistently produces material which meets all its critical quality attributes (CQAs) and 133
control strategy requirements. 134
135
continuous process verification 136
An alternative approach to process validation in which manufacturing process performance is 137
continuously monitored and evaluated. 138
139
critical process parameter (CPP) 140
A process parameter whose variability has an impact on a critical quality attribute 141
and therefore should be monitored or controlled to ensure the process produces the 142
desired quality. 143
144
145
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critical quality attribute (CQA) 146
A physical, chemical, biological or microbiological property or characteristic that should be 147
within an appropriate limit, range or distribution to ensure the desired product quality. 148
149
life-cycle 150
All phases in the life of a product from the initial development through marketing until the 151
products discontinuation (ICH Q8). 152
153
pharmaceutical quality system (PQS) 154
Management system to direct and control a pharmaceutical company with regard to 155
quality. 156
157
process validation 158
Documented evidence which provides a high degree of assurance that a specific process will 159
consistently result in a product that meets its predetermined specifications and quality 160
characteristics. 161
162
3. INTRODUCTION 163
164
Process validation data should be generated for all products to demonstrate the adequacy of 165
the manufacturing process at each site of manufacture. The validation should be carried out in 166
accordance with good manufacturing practices (GMP) and data should be held at the 167
manufacturing location and made available for inspection. Manufacturers should confirm that 168
a manufacturing process is under control before a product is placed on the market. 169
170
Process validation is associated with the collection and evaluation of data, from the process 171
design stage through commercial production, which provides scientific evidence that a 172
process is capable of consistently delivering a quality product. Process validation provides 173
documented evidence that a process is capable of reliably and repeatedly rendering a product 174
of the required quality. 175
176
A risk assessment approach should be used to determine the scope and extent to which 177
process(es) and starting material variability may affect product quality. The critical steps and 178

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parameters (e.g. those that may have an impact on the quality of the product) in the process of 179
manufacturing a pharmaceutical product and other relevant studies demonstrating that the 180
process is capable of delivering the desired product, quality should be identified and 181
documented and be based on knowledge of the product or processes concerned, according to 182
the stage of the product life-cycle. Process validation should cover at least these critical steps 183
and parameters. 184
185
Where necessary, a flow diagram may be helpful, covering all operations and controls in the 186
process to be validated. When applying QRM to a given operation, the steps preceding and 187
following that operation should also be considered. Amendments to the flow diagram may be 188
made where appropriate and should be documented as part of the validation documentation. 189
190
Different approaches can be followed when validating a process. 191
192
Manufacturers should ensure that the principles of process validation described in this 193
guideline are implemented. These include and cover phases of validation during process 194
design, scale up, qualification of premises, utilities and equipment, process performance 195
verification and ongoing monitoring of batches manufactured for commercial supply to 196
ensure that the process remains in a state of control. 197
198
The objectives of process validation include ensuring that: 199
200
the process design is evaluated to show that it is reproducible, 201
the commercial manufacturing process is defined and controlled, 202
ongoing assurance is gained to show that the process remains in a state of control. 203
204
The validation should cover all manufactured strengths and all manufacturing sites used for 205
production of the marketed product. A matrix approach may be acceptable based on 206
appropriate risk assessment. 207
208
There are different approaches to process validation which include traditional process 209
validation with prospective and concurrent validation, continuous process performance 210
verification (where an enhanced approach to development has been employed or where a 211
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substantial amount of product and process knowledge and understanding has been gained 212
through historical data and manufacturing experience) and a combination of traditional 213
process validation and continuous process verification. 214
215
Continued process verification is considered as a third phase in process validation. 216
217
Manufacturers should plan towards implementing the new approach in process validation that 218
should consist of three phases in the product life-cycle. 219
220
Phase I. Process design 221
Phase II. Qualification and process verification 222
Phase IIA. Qualification 223
Phase IIB. Continuous process performance verification 224
Phase III. Continued process verification 225
226
4. PHASE I. PROCESS DESIGN 227
228
As part of the process validation life-cycle some process validation studies may be conducted 229
on pilot-scale batches (corresponding to at least 10% or 100 000 units whichever is the 230
greater) of the production scale. 231
232
In certain cases, however, it may be necessary to provide production-scale validation data. 233
The number of batches (minimum of three) should be based on the variability of the process, 234
the complexity of the process/product and the experience of the manufacturer. 235
236
The number of batches produced in this validation exercise should be sufficient to allow the 237
normal extent of variation and trends to be established and to provide sufficient data for 238
evaluation. Extensive testing should be performed on the product at various stages during the 239
manufacturing process of the batches. 240
241
Manufacturers should define the stage at which the product is considered to be validated and 242
the basis on which that decision was made. It should include a justification for the number of 243
batches used based on the complexity and expected variability of the process. 244

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245
Validation should be done in accordance with process validation protocols. Data should be 246
collected and reviewed against predetermined acceptance criteria, and reflected in process 247
validation reports. 248
249
The protocol should include: 250
a description of the process; 251
a description of the experiment; 252
details of the equipment and/or facilities to be used (including measuring or recording 253
equipment) together with its calibration status; 254
the variables to be monitored; 255
the samples to be taken where, when, how, how many and how much (sample size); 256
the product performance characteristics/attributes to be monitored, together with the test 257
methods; 258
the acceptable limits; 259
time schedules; 260
personnel responsibilities; 261
details of methods for recording and evaluating results, including statistical analysis. 262
263
The results should be documented in the validation report which reflects the validation 264
protocol. 265
266
A conclusion and recommendation should be made on the extent of monitoring and the in- 267
process controls necessary for routine production, on the basis of the results obtained. 268
269
The planned commercial production and control records, which contain the operational limits 270
and overall strategy for process control, should be carried forward to the next phase for 271
confirmation. 272
273
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5. PHASE II. QUALIFICATION AND PROCESS VERIFICATION 274
275
Process verification is divided into two phases. These phases include qualification of 276
premises, utilities and equipment where commercial scale batches will be manufactured and 277
continuous process performance verification. 278
279
Phase IIA. Qualification 280
281
Premises, utilities, support systems and equipment should be appropriately qualified before 282
process performance verification (as part of validation) is started. 283
284
In a traditional approach, stages of qualification may include design, installation, operational 285
and performance qualification. 286
287
In some cases process validation may be conducted concurrently with performance 288
qualification. 289
290
Phase IIB. Continuous process performance verification 291
292
After completion of qualification, commercial batches should be subjected to continuous 293
process performance verification as part of process validation. It should confirm that scale up 294
in batch size did not adversely affect the characteristics of a product. 295
296
CPV demonstrates that a process that operates within the predefined specified parameters 297
consistently produces a product which meets all its critical quality attributes (CQAs) and 298
control strategy requirements. 299
300
The process should be verified on commercial-scale batches prior to marketing of the product. 301
Extensive in-line or at-line controls should be used to monitor process performance and 302
product quality in a timely manner. Relevant process quality attributes of incoming materials 303
or components, in-process material and finished products should be collected. This should 304
include the verification of attributes, parameters and end points, and assessment of CQA and 305

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critical process parameter (CPP) trends. Process analytical technology applications and 306
multivariate statistical process control (MSPC) can be used. 307
308
The scope and extent of continuous process verification will be influenced by a number of 309
factors including: 310
prior development and manufacturing knowledge from similar products and/or processes; 311
the extent of process understanding gained from development studies and commercial 312
manufacturing experience; 313
the complexity of the product and/or manufacturing process; 314
the level of process automation and analytical technologies used; 315
process robustness and manufacturing history since point of commercialization as 316
appropriate. 317
318
Manufacturers should describe the appropriateness and feasibility of the CPV strategy 319
including the process parameters and material attributes that will be monitored as well as the 320
analytical methods that will be employed. 321
322
Continuous process verification can be introduced at any time of the life-cycle of the product: 323
it can be used to design process validation protocols for the initial commercial production; 324
to revalidate commercialized products as part of process changes; 325
to support continual improvement throughout the remainder of the life-cycle. 326
327
It is expected that additional monitoring for the first commercial batches should be done 328
where continuous process verification is implemented. 329
330
Manufacturers should define: 331
the number of batches for which additional monitoring is proposed; 332
the type of testing/monitoring to be performed; 333
the acceptance criteria to be applied; 334
how the data will be evaluated. 335
336
Statistical models or tools used should be described. 337
338
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6. PHASE III. CONTINUED PROCESS VERIFICATION 339
340
Manufacturers should monitor product quality of commercial batches after completion of 341
Phase I and Phase II of process validation. This will provide evidence that a state of control is 342
maintained throughout the product life-cycle. 343
344
Periods of enhanced sampling and monitoring may help to increase process understanding as 345
part of continuous improvement. 346
347
Process trends such as the quality of incoming materials or components, in-process and 348
finished product results and non-conformances should be collected and assessed in order to 349
verify the validity of the original process validation or to identify required changes to the 350
control strategy. 351
352
The extent and frequency of ongoing process validation should be reviewed periodically and 353
modified if appropriate throughout the product life-cycle. 354
355
Continued process validation (CdPV) should not be confused with product quality review. 356
357
Table 2 provides a summary of the new approach to process validation. 358
359
Table 2. New approach to process validation 360
Product life-cycle
Process validation
Phase I Phase II Phase III
Process design Qualification Continuous process
verification
Continued process
verification
- Pilot scale (and
scale-up batches
where appropriate)
- Risk assessment to
identify critical
quality attributes and
process control
parameters
- Premises
- Utilities
- Equipment
- Commercial-scale
batches
- In-line or on-line
monitoring (e.g. PAT)
- Defined number of
batches
- Periodic review of
trends
- May include
sampling and testing

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- Protocols and
reports
- Validate process
- Define CQA and
CPPs to be
monitored in Phase II
Change control
GMP
361
7. CHANGE CONTROL 362
363
Changes during the life-cycle of a product should be managed through a change control 364
procedure. Sufficient data should be generated to demonstrate that the revised process will 365
result in a product of the desired quality, consistent with the approved specification. 366
367
The change control procedure and records should ensure that all aspects are thoroughly 368
documented and approved including regulatory approval where appropriate (variation). 369
Manufacturers should follow change control procedures when changes are planned to 370
existing systems or processes. 371
372
Validation should be considered when changes are planned to production and/or control 373
procedures. 374
375
Changes that are likely to require revalidation may include: 376
changes in the manufacturing process (e.g. mixing times, drying temperatures); 377
changes in the equipment (e.g. addition of automatic detection systems); 378
production area and support system changes (e.g. rearrangement of areas or a new water 379
treatment method); 380
transfer of processes to another site; 381
unexpected changes (e.g. those observed during self-inspection or during routine analysis 382
of process trend data). 383
384
Based on risk assessment, revalidation should be considered in the case of: 385
changes in the master formula, methods, starting material manufacturer, equipment and/or 386
instruments; 387
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equipment calibrations and preventive maintenance carried out; 388
changes to standard operating procedures (SOPs); 389
changes to cleaning and hygiene programmes. 390
391
REFERENCES 392
393
1. Guideline on Process Validation, 29 March 2012 394
EMA/CHMP/CVMP/QWP/70278/2012-Rev1 , Committee for Medicinal Products for 395
Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP) 396
www.ema.europa.eu/uideline/2012/04/WC500125399.pdf. 397
398
2. Guidance for Industry, Process Validation: General Principles and Practices, U.S. 399
Department of Health and Human Services, Food and Drug Administration, 400
Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation 401
and Research (CBER), Center for Veterinary Medicine (CVM), January 2011, 402
Current Good Manufacturing Practices (CGMP) Revision 1. 403
404
3. ICH Harmonised Tripartite Guideline, Pharmaceutical Development Q8(R2), Current 405
Step 4 version, dated August 2009. 406
407
4. ICH Harmonised Tripartite Guideline, Quality Risk Management, Q9, Current Step 4 408
version, dated 9 November 2005. 409
410
5. ICH Harmonised Tripartite Guideline, Pharmaceutical Quality System, Q10, Current 411
Step 4 version, dated 4 June 2008 412
http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html 413
414
6. Quality Assurance of pharmaceuticals. WHO guidelines, related guidance and 415
GXP training materials. Geneva, World Health Organization, 2013 (CD-ROM). 416
417
418

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7. WHO good manufacturing practices: main principles for pharmaceutical products. In: 419
WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty- 420
fifth report. Geneva, World Health Organization. WHO Technical Report Series, No. 421
961 (Annex 3), 2011 (WHO good manufacturing practices: main principles for 422
pharmaceutical products). 423
424
8. WHO guidelines on quality risk management. In: WHO Expert Committee on 425
Specifications for Pharmaceutical Preparations. Forty-seventh report. Geneva, World 426
Health Organization. WHO Technical Report Series, No. 981 (Annex 2), 2013 (in 427
press). 428
429
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