guidelines on heating, ventilation and air …
TRANSCRIPT
Working document QAS/15.639/Rev.2
July 2017
Revised document for comment
1
GUIDELINES ON 2
HEATING, VENTILATION AND AIR-CONDITIONING 3
SYSTEMS FOR NON-STERILE PHARMACEUTICAL 4
PRODUCTS 5
6
(June 2017) 7
REVISED DRAFT FOR COMMENT 8
9
10
11
12
13
14
15
____________________________________________________________________________________________________________ 16
© World Health Organization 2017 17
All rights reserved. 18
This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 19 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 20 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 21 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 22 website. 23
Please send any request for permission to: 24
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Department of Essential 25 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; 26 email: [email protected] 27 28 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 29 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 30 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 31 border lines for which there may not yet be full agreement. 32
The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 33 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 34 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 35
All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 36 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 37 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 38 Organization be liable for damages arising from its use. 39
This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 40 41 42
Should you have any comments on the attached text, please send these to Dr S. Kopp, Group Lead,
Medicines Quality Assurance, Technologies, Standards and Norms ([email protected]) with a copy to
[email protected] by 15 September 2017.
Medicines Quality Assurance working documents will be sent out electronically only and will also
be placed on the Medicines website for comment under “Current projects”. If you do not already
receive our draft working documents please let us have your email address (to [email protected])
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Working document QAS/15.639/Rev.2
page 2
SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/15.639 43
GUIDELINES ON HEATING, VENTILATION AND AIR-CONDITIONING 44
SYSTEMS FOR NON-STERILE PHARMACEUTICAL PRODUCTS 45
Discussion of proposed need for revision in view of the current
trends in engineering and experience gained during the
implementation of this guidance in inspection during informal
consultation on data management, bioequivalence, GMP and
medicines’ inspection
29 June–
1 July
2015
Preparation of draft proposal for revision by Mr D. Smith, consultant
to the Medicines Quality Assurance group and Prequalification Team
(PQT)-Inspections, based on the feedback received during the
meeting and from PQT-Inspections
July–August 2015
Circulation of revised working document for public consultation September 2015
Preliminary consolidation of comments received and review of
feedback
10 October 2015
Presentation to the fiftieth meeting of the WHO Expert Committee
on Specifications for Pharmaceutical Preparations
12–16 October
2015
Final consolidation of comments received and review of feedback January–March
2016
Discussion at the informal consultation on good practices for health
products manufacture and inspection, Geneva
4–6 April 2016
Preparation of revision by Mr D. Smith, based on comments
provided by Mr A. Kupferman and Dr A.J. Van Zyl, both
participants at the above-mentioned consultation.
May 2016
Circulation of revised working document for public consultation May 2016
Consolidation of comments received and review of feedback August–
September 2016
Presentation to the fifty-first meeting of the WHO Expert Committee
on Specifications for Pharmaceutical Preparations
17–21 October
2016
Preparation of draft proposal for revision by Mr I. Thrussell,
consultant to the Medicines Quality Assurance group and
Prequalification Team (PQT)-Inspections, based on the feedback
received during the meeting and from PQT-Inspections for further
discussion at the informal consultation on good practices for health
products manufacture and inspection, Geneva, April 2017.
January–March
2017
Discussion at the informal consultation on good practices for health
products manufacture and inspection, Geneva, April 2017
April 2017
Preparation of the next version of the guidelines based on the feed-
back received prior to and during the informal consultation, by
Dr A.J. van Zyl, May 2017
May 2017
Circulation of revised working document for public consultation July 2017
Working document QAS/15.639/Rev.2
page 3
46
47 48
49
Consolidation of comments received and review of feedback September 2017
Presentation to the fifty-second meeting of the WHO Expert
Committee on Specifications for Pharmaceutical Preparations
October 2017
Working document QAS/15.639/Rev.2
page 4
BACKGROUND 50
The World Health Organization (WHO) published the first edition of the WHO Guidelines on 51
good manufacturing practices for heating, ventilation and air-conditioning systems for non-52
sterile pharmaceutical dosage forms in WHO Technical Report Series, No. 937, 2006. After 53
a revision, the second edition of the document was published in WHO Technical Report 54
Series, No. 961, 2011. Having considered various comments and questions related to good 55
manufacturing practices (GMP) for heating, ventilation and air-conditioning (HVAC) 56
systems, the document was opened for revision. After wide public consultation over the 57
recent years (see history of the process and timelines above), and considering comments 58
received from (but not limited to) various organizations, industry and individuals, the 59
document and comments were considered during an informal consultation in Geneva in 60
April 2017. 61
During this informal consultation the proposed changes based on comments received as well 62
as additional comments made during the consultation, were discussed. It was agreed that the 63
guidelines be amended to make provision for two documents. It was recommended that the 64
one document should consist of guidelines that contain recommendations for GMP for 65
HVAC systems for non-sterile products, while a second document should contain examples 66
and drawings that will clarify some of the recommendations included in the first document. 67
Therefore, the previous version of the WHO guidelines on good manufacturing practices for 68
heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage 69
forms as was published in WHO Technical Report Series, No. 961, Annex 5, 2011 is 70
proposed to be amended accordingly as set out in this draft guideline. 71
Summary of main changes 72
In accordance with the recommendation made during the informal consultation in April 2017, 73
the guidelines have been rewritten into two parts. This is the first part of the guidelines and 74
this part contains the recommendations that are to be considered as good practices in the 75
design, management, control and qualification over the life cycle of HVAC systems. 76
77
The second part will contain non-binding examples, clarifications and drawings in support of 78
Part one and is currently under preparation. 79
80
Due to the rewriting of the guidelines, a summary of changes is not provided here, as the 81
content in the previous guideline has been reorganized. In addition, all the comments received 82
during the last comment period were considered in rewriting the guidelines. 83
84
The illustrative guidance and explanations (Second part) will be published at a later stage. 85
86
87
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Contents 88
89
page 90
1. Introduction 91
2. Scope 92
3. Glossary 93
4. Premises 94
5. Design of HVAC systems and components 95
6. Full fresh air and recirculation systems 96
7. Air filtration, airflow direction and pressure differentials 97
8. Temperature and relative humidity 98
9. Dust, vapour and fume control 99
10. Protection of the environment 100
11. Commissioning 101
12. Qualification 102
13. Maintenance 103
References and further reading 104
105
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1. INTRODUCTION 106
107
Heating, ventilation and air-conditioning (HVAC) play an important role in ensuring the 108
manufacture of quality pharmaceutical products. The good manufacturing practice (GMP) 109
requirements of the prevention of contamination and cross-contamination are an essential 110
design consideration of an HVAC system. A well designed HVAC system also provides 111
environmental protection, operator protection as well as comfortable working conditions for 112
operators. 113
114
These guidelines mainly focus on recommendations for HVAC systems used in facilities for 115
the manufacture of non-sterile dosage forms which include tablets, capsules, powders, 116
liquids, creams and ointments. The general HVAC system design principles contained in the 117
guidelines may, however, also be applied to other dosage forms. 118
119
HVAC system design influences architectural building design and layouts with regard to, e.g. 120
airlock positions, doorways and lobbies. These in turn have an effect on room pressure, 121
pressure differential cascades, contamination and cross-contamination control. In view of 122
these aspects, the design of the HVAC system should be considered at the initial design stage 123
of a pharmaceutical manufacturing plant. 124
125
Temperature, relative humidity and ventilation should be appropriate and should not 126
adversely affect the quality of pharmaceutical products during their manufacture and storage, 127
or the accurate functioning of equipment and instruments. 128
129
A comprehensive science and risk-based approach should be followed throughout the 130
lifecycle of an HVAC system, including its design, qualification and maintenance. Risk 131
management principles should be applied throughout the life cycle. Risk assessment is 132
however not a substitute for GMP (WHO Technical Report Series, No. 957, Annex 3). 133
134
2. SCOPE 135
136
These guidelines focus primarily on GMP for the design, qualification, management and 137
maintenance of HVAC systems in facilities for the manufacture of non-sterile dosage forms. 138
139
These guidelines are intended to complement those provided for in GMP for pharmaceutical 140
products and should be read in conjunction with the parent guide. The additional standards 141
addressed in this guide should therefore be considered supplementary to the general 142
requirements set out in the main principles guide (WHO Technical Report Series, No. 961, 143
Annex 3). 144
145
Most of the system principles described in these guidelines may also be considered in 146
facilities manufacturing other dosage forms and products, including biological products, 147
herbal medicines, complimentary medicines and finishing processing steps for active 148
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pharmaceutical ingredients (APIs). Additional, specific requirements apply for air-handling 149
systems of pharmaceutical hazardous, sterile and biological products. Guidelines for these are 150
covered in separate WHO guidelines (WHO Technical Report Series, No. 957, Annex 3; 151
WHO Technical Report Series, No. 961, Annex 6; and working document 152
WHO/BS/2015.2253, intended to replace WHO Technical Report Series, No. 822, Annex 1, 153
1992, respectively). 154
155
3. GLOSSARY 156
157
The definitions given below apply to terms used in this document. They may have different 158
meanings in other contexts. 159
160
acceptance criteria. Measurable terms under which a test result will be considered 161
acceptable. 162
163
action limit. The action limit is reached when the acceptance criteria of a critical 164
parameter have been exceeded. Results outside these limits will require specified action and 165
investigation. 166
167
air changes per hour. The flow rate of air supplied to a room, in m3/hr, divided by 168
the room volume, in m3. 169
170
air-handling unit. The air-handling unit serves to condition the air and provide the 171
required airflow within a facility. 172
173
airflow protection booth. A booth or chamber, typically for purposes of carrying out 174
sampling or weighing, in order to provide product containment and operator protection. 175
176
airlock. An enclosed space with two or more doors, which is interposed between two 177
or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the 178
airflow between those rooms when they need to be entered. An airlock is designed for and 179
used by either people or goods (personnel airlock (PAL); material airlock (MAL)). 180
181
alert limit. The alert limit is reached when the normal operating range of a critical 182
parameter has been exceeded, indicating that corrective measures may need to be taken to 183
prevent the action limit being reached. 184
185
as-built. Condition where the installation is complete with all services connected and 186
functioning but with no production equipment, materials or personnel present. 187
188
at-rest. Condition where the installation is complete with equipment installed and 189
operating in a manner agreed upon by the customer and supplier, but with no personnel 190
present. 191
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192
central air-conditioning unit (see air-handling unit) 193
194
change control. A formal system by which qualified representatives of appropriate 195
disciplines review proposed or actual changes that might affect a validated status. The intent 196
is to determine the need for action that would ensure that the system is maintained in a 197
validated state. 198
clean area (cleanroom). An area (or room or zone) with defined environmental 199
control of particulate and microbial contamination, constructed and used in such a way as to 200
reduce the introduction, generation and retention of contaminants within the area. 201
202
clean-up (see recovery) 203
204
closed system. A system where the product or material is not exposed to the 205
manufacturing environment. 206
207
commissioning. Commissioning is the documented process of verifying that the 208
equipment and systems are installed according to specifications, placing the equipment into 209
active service and verifying its proper action. Commissioning takes place at various stages 210
during the project construction but prior to validation. 211
212
containment. A process or device to contain product, dust or contaminants in one 213
zone, preventing it from escaping to another zone. 214
215
contamination. The undesired introduction of impurities of a chemical or microbial 216
nature, or of foreign matter, into or onto a starting material or intermediate, during 217
production, sampling, packaging or repackaging, storage or transport. 218
219
controlled area (classified area). An area within the facility in which specific 220
procedures and environmental parameters, including viable and non-viable particles, are 221
defined, controlled and monitored to prevent degradation, contamination or cross-222
contamination of the product. 223
224
controlled not classified. An area where some environmental conditions are 225
controlled (such as temperature), but the area has no cleanroom classification. 226
227
critical parameter or component. A processing parameter (such as temperature or 228
relative humidity) that affects the quality of a product, or a component that may have a direct 229
impact on the quality of the product. 230
231
critical quality attribute. A physical, chemical, biological or microbiological 232
property or characteristic that should be within an appropriate limit, range or distribution to 233
ensure the desired product quality. 234
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235
cross-contamination. Contamination of a starting material, intermediate product or 236
finished product with another starting material or product during production. 237
238
cross-over-bench. Cross-over or step-over bench in change room to demarcate the 239
barrier between different garment change procedures. 240
241
design condition. Design condition relates to the specified range or accuracy of a 242
controlled variable used by the designer as a basis for determining the performance 243
requirements of an engineered system. 244
245
design qualification. Design qualification is the documented check of planning 246
documents and technical specifications for design conformity with the process, 247
manufacturing, good manufacturing practices and regulatory requirements. 248
249
differential pressure. The difference in pressure between two points such as the 250
pressure difference between an enclosed space and an independent reference point, or the 251
pressure difference between two enclosed spaces. 252
253
direct impact system. A system that is expected to have a direct impact on product 254
quality. These systems are designed and commissioned in line with good engineering practice 255
and, in addition, are subject to qualification practices. 256
257
exfiltration. Exfiltration is the egress of air from a controlled area to an external zone. 258
259
extract air. Air leaving a space, which could be either return air or exhaust air. 260
Return air means that the air is returned to the air-handling unit and exhaust air means that 261
the air is vented to atmosphere. 262
263
facility. The built environment within which the clean area installation and associated 264
controlled environments operate together with their supporting infrastructure. 265
266
good engineering practice. Established engineering methods and standards that are 267
applied throughout the project life cycle to deliver appropriate, cost-effective solutions. 268
269
hazardous substance or product. A product or substance that may present a 270
substantial risk of injury to health or to the environment. 271
272
HEPA filter. High efficiency particulate air filter. 273
274
HVAC. Heating, ventilation and air-conditioning. Also referred to as Environmental 275
control systems. 276
277
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indirect impact system. This is a system that is not expected to have a direct impact 278
on product quality, but typically will support a direct impact system. These systems are 279
designed and commissioned according to good engineering practice only. 280
281
infiltration. Infiltration is the ingress of air from an external zone into a controlled 282
area. 283
284
installation qualification. Installation qualification is documented verification that 285
the premises, HVAC system, supporting utilities and equipment have been built and installed 286
in compliance with their approved design specification. 287
288
ISO 14644.The International Standards Organization has developed a set of standards 289
for the classification and testing of cleanrooms. Where ISO 14644 is referenced it implies the 290
latest revision and all the separate parts thereof. 291
292
no-impact system. This is a system that will not have any impact, either directly or 293
indirectly, on product quality. These systems are designed and commissioned according to 294
good engineering practice only. 295
296
non-critical parameter or component. A processing parameter or component within 297
a system where the operation, contact, data control, alarm or failure will have an indirect 298
impact or no impact on the quality of the product. 299
300
normal operating range. The range that the manufacturer selects as the acceptable 301
values for a parameter during normal operations. This range must be within the operating 302
range. 303
304
out-of-specification (OOS). In relation to HVAC systems this could refer to any of 305
the environmental conditions being OOS, i.e. falling outside of alert or action limits. 306
307
operating limits. The minimum and/or maximum values that will ensure that product 308
and safety requirements are met. 309
310
operating range. Operating range is the range of validated critical parameters within 311
which acceptable products can be manufactured. 312
313
operational condition. This condition relates to carrying out room classification tests 314
with the normal production process with equipment in operation and the normal staff present 315
in the specific room. 316
317
operational qualification. Operational qualification is the documentary evidence to 318
verify that the equipment operates in accordance with its design specifications in its normal 319
operating range and performs as intended throughout all anticipated operating ranges. 320
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321
oral solid dosage. Usually refers to oral solid dosage medicinal products such as 322
tablets, capsules and powders to be taken orally. 323
324
pass-through-hatch or pass box. A cabinet with two or more doors for passing 325
equipment, material or product, whilst maintaining the pressure cascade and segregation 326
between two controlled zones. A passive pass-through-hatch (PTH) has no air supply or 327
extract. A dynamic PTH has an air supply into the chamber. 328
329
performance qualification. Performance qualification is the documented verification 330
that the process and/or the total process related to the system performs as intended throughout 331
all anticipated operating ranges. 332
333
point extraction. Air extraction to remove dust with the extraction point located as 334
close as possible to the source of the dust. 335
336
pressure cascade. A process whereby air flows from one area, which is maintained at 337
a higher pressure, to another area maintained at a lower pressure. 338
339
qualification. Qualification is the planning, carrying out and recording of tests on 340
equipment and a system, which forms part of the validated process, to demonstrate that it will 341
perform as intended. 342
343
quality critical process parameter. A process parameter which could have an impact 344
on the critical quality attribute. 345
346
recovery. Room recovery or clean-up tests are performed to determine whether the 347
installation is capable of returning to a specified cleanliness level within a finite time, after 348
being exposed briefly to a source of airborne particulate challenge. 349
350
relative humidity. The ratio of the actual water vapour pressure of the air to the 351
saturated water vapour pressure of the air at the same temperature expressed as a percentage. 352
More simply put, it is the ratio of the mass of moisture in the air, relative to the mass at 100% 353
moisture saturation, at a given temperature. 354
355
standard operating procedure. An authorized written procedure, giving instructions 356
for performing operations, not necessarily specific to a given product or material, but of a 357
more general nature (e.g. operation of equipment, maintenance and cleaning, validation, 358
cleaning of premises and environmental control, sampling and inspection). Certain standard 359
operating procedures may be used to supplement product-specific master and batch 360
production documentation. 361
362
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turbulent air flow. Turbulent flow, or non-unidirectional airflow, is air distribution 363
that is introduced into the controlled space and then mixes with room air by means of 364
induction. 365
366
unidirectional airflow. Unidirectional airflow is a rectified airflow over the entire 367
cross-sectional area of a clean zone with a steady velocity and approximately parallel 368
streamlines (see also turbulent flow). (Modern standards no longer refer to laminar flow, but 369
have adopted the term unidirectional airflow.) 370
371
validation. The documented act of proving that any procedure, process, equipment, 372
material, activity or system actually leads to the expected results. 373
374
validation master plan. Validation master plan is a high-level document which 375
establishes an umbrella validation plan for the entire project and is used as guidance by the 376
project team for resource and technical planning (also referred to as master qualification plan). 377
378
4. PREMISES 379
380
4.1. The manufacture of non-sterile pharmaceutical products should take place in a 381
controlled environment, as defined by the manufacturer. 382
383
4.2. The design of the HVAC system should be closely coordinated with the architectural 384
design of the building. 385
386
4.3. Infiltration of unfiltered air into a manufacturing facility should be prevented as this 387
can be a source of contamination. 388
389
4.4. Manufacturing facilities should normally be maintained at a positive pressure relative 390
to the outside, to prevent the ingress of contaminants. Where facilities are to be maintained at 391
negative pressures relative to the outside, special precautions should be taken to mitigate any 392
risks (see WHO Technical Report Series, No. 957, Annex 3). 393
394
4.5. Areas for the manufacture of products, or where open equipment is exposed, should 395
be of an appropriate level of cleanliness. The level of protection and air cleanliness for 396
different areas should be determined according to, but not limited to, the products 397
manufactured, the process used and product susceptibility to degradation. 398
399
Where a clean room classification is specified, the manufacturer should state whether the 400
classification is rated for the “as-built”, “at-rest” or “operational” condition. 401
402
4.6. HVAC systems should ensure that the specified room conditions are attained, e.g. 403
through heating, cooling, air filtration, air distribution, airflow rates and air exchange rates. 404
405
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4.7. Any area where pharmaceutical starting materials, products, primary packing 406
materials, utensils and equipment are exposed to the environment – should have the same 407
level of cleanliness or classification as that in which the products are produced. 408
409
4.8. Appropriate design and controls for the premises and HVAC systems should be in 410
place to achieve the required containment, cleanliness and the appropriate levels of product, 411
personnel and environmental protection. 412
(Note: For facilities where the highest level of containment is a requirement refer to the 413
WHO Technical Report Series, No. 957, Annex 3). 414
415
4.9. Containment, cleanliness and protection may be facilitated through, for example: 416
417
correct building layout; 418
building finishes; 419
the use of airlocks such as personnel airlocks (PAL) and/or material airlocks (MAL); 420
pass-through hatches (PTH); 421
change rooms and passages; 422
sufficient pressure cascades. 423
424
4.10. Detailed schematic diagrams should be maintained, indicating pressure cascades, 425
airflow directions and flow routes for personnel and materials. 426
427
4.11. Where possible, personnel and materials should not move from a higher cleanliness 428
zone to a lower cleanliness zone and back to a higher cleanliness zone. Where this is 429
unavoidable, risks should be identified and controlled. 430
431
4.12. The final change room should be at the same cleanliness level (at rest) as the area into 432
which it leads. 433
434
4.13. Where appropriate, such as where the simultaneous opening of airlock doors might 435
lead to a cross-contamination risk, airlock doors should not be opened at the same time. In 436
such cases, controls such as interlocking systems, warning systems and procedures should be 437
implemented. 438
439
4.14. Swing doors should normally open to the high-pressure side and be provided with 440
self-closers. Exceptions to the door swing direction should be justified and may include, e.g. 441
fire escapes or other health and safety constraints. In these cases, door closer mechanisms 442
should be carefully controlled and other controls should be in place to prevent any risk. 443
444
4.15. Sampling, weighing and dispensing areas should be appropriately designed with 445
required levels of containment, operator protection and product protection. 446
447
4.16. Sampling, weighing and dispensing should be performed under the same 448
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environmental conditions as specified in the areas for further processing of the product. 449
450
4.17. Factors such as airflow should not disrupt the accuracy of balances. 451
452
4.18. The position of the operator, equipment and containers should not obstruct airflow 453
patterns. 454
455
4.19. Once an area is qualified with a specific layout for operators, equipment and 456
processes, this configuration should be ensured during routine activity. 457
458
4.20. Return and exhaust filters and grilles selected and installed should be appropriate and 459
their design should facilitate cleaning and maintenance. 460
461
4.21. The impact and risk to the HVAC system should be considered when changes are 462
planned to an existing facility. This includes upgrades and retrofitting of facilities. 463
464
5. DESIGN OF HVAC SYSTEMS AND COMPONENTS 465
466
HVAC systems should be appropriately designed and managed throughout their life cycle. 467
Documentation such as schematic drawings should be maintained to reflect the current 468
situation, including but not limited to, air supply and extraction, air handling units, room 469
pressure cascades, air flow direction, personnel and material movement, and waste removal. 470
471
5.1. Risk management principles should be applied during the design of an HVAC system. 472
This includes, but is not limited to, appropriate controls of the climatic conditions and the 473
prevention of contamination and cross-contamination. 474
475
5.2. The HVAC system capacity should be sufficient to ensure that the required 476
performance is maintained during normal use. 477
478
5.3. Materials of construction for components of an HVAC system should not become a 479
source of contamination. 480
481
5.4. Where possible, ducting, piping, fittings, sensors and other components should be 482
clearly marked or labelled for ease of identification, location and direction of flow as 483
appropriate. 484
485
5.5. Air intake and exhaust air terminals should be positioned in a manner in relation to 486
one another that assist in preventing cross-contamination. 487
488
5.6. Air-handling units (AHUs) should be provided with adequate drains to remove 489
condensate that may form in the AHU. 490
491
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5.7. Conditions and limits for parameters such as temperature, relative humidity, air 492
cleanliness and recovery times should be specified and achieved, as needed, for the materials 493
and products handled, as well as process risks. 494
495
5.8. Room recovery rates should demonstrate that the HVAC system is capable of 496
returning an area to a specified level of cleanliness or classification, temperature, relative 497
humidity, room pressure and microbial limits, as appropriate, within the specified time. 498
499
5.9. Possible room pressure changes due to fan failure and partial system shut down with 500
an impact on ease of opening of doors for escape purposes should be considered. 501
502
5.10. The effectiveness of the air distribution and air flow patterns should be appropriate 503
and effective. 504
505
5.11. Air supply and extract grilles should be appropriately located to provide effective 506
room flushing and prevent zones of stagnant air. 507
508
5.12. The performance of HVAC systems should be controlled and monitored to ensure 509
ongoing compliance with defined parameters. Records should be maintained. Limits defined 510
should be justified. 511
512
5.13. Where automated monitoring systems are used, these should be capable of indicating 513
any out-of-specification (OOS) condition by means of an alarm or similar system. Where 514
these systems are identified as GXP systems, they should be appropriately validated. 515
516
5.14. Appropriate alarm systems should be in place to alert personnel in case a critical 517
component of the system fails, e.g. a fan. 518
519
5.15. The effect of fan failure on building and HVAC components should be assessed. 520
Where appropriate provision should be made for a fan interlock failure matrix. 521
522
5.16. Switching off of AHUs at intervals such as overnight or weekends, or reducing supply 523
air volumes during non-production hours, should not compromise product quality. Where this 524
is done, there should be appropriate justification and no risk to materials or products. The 525
procedure and acceptability should be proven through validation and qualification. 526
527
5.17. There should be procedures and records maintained for the start up and shut down 528
sequence of air handling units. 529
530
6. FULL FRESH AIR SYSTEMS AND RECIRCULATION SYSTEMS 531
532
6.1. Full fresh air, or recirculation type HVAC systems may be used. Where recirculation 533
systems are used, there should be no risk of contaminants in the return-air system. The 534
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recirculated air should be adequately filtered. 535
536
6.2. HEPA filters may be installed (in the supply air stream or return air stream) to remove 537
contaminants and thus prevent cross-contamination. The HEPA filters in such an application 538
should have an EN 1822 classification of at least H13 or equivalent. 539
540
6.3. HEPA filters may not be required to control cross-contamination where there is 541
evidence that cross-contamination would not be possible due to other robust technical means, 542
or where the air-handling system is serving a single product facility. 543
544
6.4. The amount of fresh air intake required should be determined. As a minimum, the 545
following criteria should be considered: 546
547
sufficient volume of fresh air to compensate for leakage from the facility and loss 548
through exhaust air systems; 549
operator occupancy; 550
regional or national legislation. 551
552
6.5. Air that might be contaminated with organic solvents or highly hazardous materials 553
should normally not be recirculated. 554
555
6.6. The required degree of filtration of the exhaust air should be considered based on risk, 556
exhaust air contaminants and local environmental regulations. 557
558
6.7. Where energy-recovery wheels are used in multiproduct facilities, controls should be 559
in place to ensure that these do not become a source of cross-contamination. 560
561
7. AIR FILTRATION, AIRFLOW DIRECTION AND PRESSURE DIFFERENTIALS 562
563
7.1. Where different products are manufactured at the same time, such as in different areas 564
or cubicles in a multiproduct manufacturing site, measures should be taken to ensure that dust 565
cannot move from one cubicle to another. Appropriate levels of filtration, airflow direction 566
and a pressure cascade systems can assist in preventing cross-contamination. 567
568
7.2. Filters selected should be appropriate for their intended use and classified according 569
to current international classification (see Table 1 below). 570
571
7.3. Airflow directions should be appropriate, taking operator and equipment locations 572
into consideration. 573
574
7.4. The pressure cascade for areas in a facility should be individually assessed according 575
to the products handled and level of protection required. The pressure cascade regime and the 576
direction of airflow should be appropriate to the product and processing method used, and 577
Working document QAS/15.639/Rev.2
page 17
should also provide operator and environmental protection. 578
579
7.5. The pressure cascade should be such that the direction of airflow is from the clean 580
area, resulting in dust containment, e.g. from the corridor to the cubicle. 581
582
7.6. The limits for the pressure differential between adjacent areas should be such that 583
there is no risk of overlap in the defined operating ranges. 584
585
7.7. Normally, for cubicles where dust is liberated, the corridor should be maintained at a 586
higher pressure than the cubicles and the cubicles at a higher pressure than atmospheric 587
pressure. (For negative pressure facilities refer to WHO Technical Report Series, No. 957, 588
Annex 3, for hazardous products guidelines and design conditions.) 589
590
Room pressure differential indication should be provided. The pressure indication gauges 591
should have a range and graduation scale which enables the reading to an appropriate 592
accuracy. The normal operating range, alert and action limits should be defined and displayed 593
at the point of indication. 594
595
Room pressure should be traced back to representative ambient pressure (by summation of 596
the room pressure differentials), in order to determine the room actual absolute pressure. 597
598
7.8. The pressure control and monitoring devices used should be calibrated. Compliance 599
with specifications should be regularly verified and the results recorded. 600
601
7.9. Pressure control devices should be linked to an alarm system which is set according to 602
the levels determined by a risk analysis and justified dead times. 603
604
7.10. Zero setting of gauges should be tamper proof. Zero setting should be checked at 605
regular intervals. 606
607
7.11. Where airlocks are used, the pressure cascade regimes selected should be appropriate. 608
In considering room pressure differentials, transient variations, such as machine extract 609
systems and their impact, should be taken into consideration. 610
611
612
613
614
615
Working document QAS/15.639/Rev.2
page 18
Table 1. Comparison of filter test standards* 616
617
Eurovent 4/5
rating
ASHRAE
52.2
Eurovent 4/5
ASHRAE
52.1
BS6540 Part
1
Eurovent
4/5
ASHRAE
52.1
BS6540
Part 1
EN 779 & EN 1822
ISO
29
46
3
(superseded) Merv
rating
Average
arrestance
Am (%) (superseded)
Average
dust spot
efficiency
Em (%) (superseded)
MPPS integral
overall
efficiency (%)
EN rating
99.999995 U17
EN
182
2:
200
9
75E
99.99995 U16 65E
EU 14
99.9995 U15 55E
EU 13 Merv 18
99.995 H14 45E
EU 12 Merv 17
99.95 H13 35E
EU 11
99.5 E12 25E
EU 10
95 E11 15E
EU 9 Merv 16
>95 85 E10
EU 9 Merv 15
95
F9
EN
779
: 20
12
EU 8 Merv 14
90
MPPS =
most
penetrating
particle size
F8
Merv 13 >98 85 F7
EU 7
>98 80
Merv 12 >95 75
EU 6
>95 70 M6
Merv 11 >95 65
>95 60
Merv 10 >95 55
EU 5 Merv 9 >95 50
M5
Merv 8 >95 45
>95 40
Merv 7 >90 35
EU 4
>90 30
G4
Merv 6 90 25
EU 3 Merv 5 85 20
G3
80 <20
Merv 4 75
EU 2 Merv 3 70
G2
Merv 2 65
EU 1 Merv 1 <65
G1
*Ensure that the classification is current. 618
Note: The filter classifications referred to above relate to the EN1822:2009 and EN779: 2012 619
test standards (EN779 relates to filter classes G1 to F9 and EN1822 relates to filter classes 620
E10 to U17). 621
622
8. TEMPERATURE AND RELATIVE HUMIDITY 623
624
8.1. Where appropriate, temperature and relative humidity should be controlled, monitored 625
and recorded to ensure that the conditions are maintained pertinent to the materials and 626
products as required, and provide a comfortable environment for the operators. 627
Working document QAS/15.639/Rev.2
page 19
628
8.2. Limits for minimum and maximum room temperatures and relative humidity should 629
be appropriate. Alert and action limits should be set appropriate to material and product 630
requirements, and to inhibit increased microbial loading. 631
632
8.3. Where steam or humidity is present, controls should be in place to ensure that the 633
HVAC system will remain effective. Precautions should be taken to prevent moisture 634
migration that may increase an uncontrolled load on the HVAC system. 635
636
Where humidification or dehumidification is required, this should be achieved by appropriate 637
means which does not become a source of contamination. 638
639
8.4. Dehumidification and cooling systems should be well drained. Condensate should not 640
accumulate in air-handling systems and should not become a source of contamination. 641
642
9. DUST, VAPOUR AND FUME CONTROL 643
644
The location of discharge exhaust points relative to air inlet points should be carefully 645
considered to prevent contamination and cross-contamination. 646
647
9.1. Dust, vapours and fumes could be possible sources of contamination and should be 648
appropriately controlled. Wherever possible, these should be removed at source. The HVAC 649
system should normally not serve as the primary mechanism of dust control. 650
651
9.2. Dust extraction systems should be appropriately designed and installed. Dust should 652
not flow back in the opposite direction, e.g. in the event of component failure or airflow 653
failure. The transfer velocity should be sufficient to ensure that dust is carried away and does 654
not settle in the ducting. 655
656
9.3. The positioning of dust extraction points should be appropriate to prevent dust and 657
powders dropping down from the extract point causing contamination or cross-658
contamination. 659
660
9.4. Air should not flow through the dust extraction ducting or return air ducting from the 661
room with the higher pressure to the room with the lower pressure. 662
663
9.5. Periodic checks should be performed to ensure that there is no build-up of the dust in 664
the ducting. 665
666
9.6. Dust extraction systems should be interlocked, where appropriate, to the relevant air-667
handling unit to avoid any risk and impact on pressure cascade imbalances. 668
669
670
Working document QAS/15.639/Rev.2
page 20
671
10. PROTECTION OF THE ENVIRONMENT 672
673
Where exhaust air from equipment such as fluid bed driers, dust extraction systems and 674
facilities carry dust loads, adequate filtration should be provided to prevent contamination of 675
the ambient air. 676
677
10.1. Waste from wet and dry scrubbers should be disposed of in an appropriate manner. 678
679
10.2. Dust-slurry should be removed by suitable means, e.g. a drainage system or waste 680
removal contractor. 681
682
11. COMMISSIONING 683
684
Commissioning 685
686
Note: Commissioning is a precursor to system qualification and validation, and is normally 687
associated with good engineering practice (GEP). 688
689
12. QUALIFICATION 690
691
Note: For general notes on qualification and validation, see WHO Guideline on Validation . 692
(See WHO Technical Report Series, No. 937, Annex 4). 693
694
12.1. HVAC systems, including recirculation and full fresh air systems, should be qualified 695
to ensure continued performance in accordance with specifications and achieving the 696
conditions as specified. 697
698
12.2. The scope and extent of qualification should be determined based on risk management 699
principles. 700
701
12.3. The qualification of the HVAC system should be described in a master plan. The 702
master plan should define the nature and extent of testing, the test procedures and protocols to 703
be followed. 704
705
12.4. Where relevant, the procedures followed for the conduct of tests should be in 706
accordance with the appropriate parts as mentioned in ISO 14644 and relevant WHO 707
guidelines. 708
709
12.5. The design condition, operating ranges, alert and action limits should be defined. 710
Alert limits should be based on system capability. 711
712
12.6. Performance parameters to be included in qualification for the HVAC system should 713
Working document QAS/15.639/Rev.2
page 21
be determined by means of a risk assessment. 714
715
12.7. Acceptable tolerances for system parameters, where appropriate, should be specified 716
prior to commencing the physical installation. 717
718
12.8. There should be standard operating procedures describing the action to be taken when 719
alert and action limits are reached. This may include, where relevant: 720
721
temperature; 722
relative humidity; 723
supply air quantities; 724
return air or exhaust air quantities; 725
room air-change rates; 726
room pressures and pressure differentials; 727
airflow pattern tests; 728
unidirectional air flow velocities; 729
containment system velocities; 730
HEPA filter penetration tests; 731
room particle count tests; 732
duct leakage tests; 733
materials of construction; 734
microbiological counts; 735
de-dusting and dust extraction systems. 736
737
12.9. Where routine or periodic revalidation is done, the frequency should be established 738
based on, e.g. risk, the type of facility, the level of product protection necessary, performance 739
of the system and the extent of routine ongoing monitoring activities. 740
741
12.10. Any change to the HVAC system should be handled according to a change control 742
procedure. The extent of qualification or requalification should be considered based on the 743
scope and impact of the change. 744
745
13. MAINTENANCE 746
747
13.1. Operation and maintenance (O&M) manuals, procedures and records should be 748
available and kept up to date, containing any system revisions made. 749
750
13.2. O&M manuals, schematic drawings, protocols and reports should be maintained as 751
reference documents for any future changes and upgrades to the system. 752
753
13.3. The O&M manuals may typically contain the following information: 754
Working document QAS/15.639/Rev.2
page 22
755
system description; 756
operating instructions; 757
trouble shooting; 758
commissioning data; 759
maintenance instructions; 760
list of equipment suppliers; 761
spare parts list; 762
equipment data/capacity schedules; 763
supplier’s literature; 764
control system description; e 765
electrical drawings; 766
as-built drawings. 767
768
13.4. There should be a planned preventive maintenance programme for the HVAC system. 769
The details of the maintenance programme should be commensurate with the criticality of the 770
system and components. 771
772
13.5. Maintenance activities should not have any negative impact on product quality and 773
should normally be scheduled to take place at appropriate times, e.g. outside production 774
hours. 775
776
In case of system stoppages, appropriate quality management system procedures should be 777
followed. Where necessary, the root cause and impact should be assessed and appropriate 778
corrective and preventive action taken. Where necessary, qualification or requalification 779
should be considered. 780
781
13.6. HEPA filters should be changed by a competent person followed by installed filter 782
leakage testing. 783
784
13.7. Records should be kept for a sufficient period of time. 785
786
787
REFERENCES AND FURTHER READING 788
789
1. Good manufacturing practices: quality assurance of pharmaceuticals. WHO guidelines, 790
good practices, related regulatory guidance and GXP training materials. CD-ROM, 791
update 2016. 792
793
2. ISO 14644 – Cleanrooms and Associated Controlled Environments Package, including 794
ISO 14644-1 to ISO 14644-10 (updated regularly). International Standard 795
Organization, Geneva. 796
797
Working document QAS/15.639/Rev.2
page 23
3. ICH Harmonised Tripartite Guideline on Quality Risk Management (Q9), 2005. 798
799
4. WHO guidelines on quality risk management, Annex 2, WHO Technical Report 800 Series, No. 981, 2013. 801
802
5. WHO GMP for sterile pharmaceutical products, WHO Technical Report Series, No. 803
961, Annex 6. 804
805
6. WHO good manufacturing practices for biological products, Annex 3, WHO 806 Technical Report Series, No. 996, 2016. 807
808
7. WHO Guideline on validation (see WHO Technical Report Series, No. 937, Annex 4) 809
(under revision). 810
***
811