Comments on the Supplementary Guidelines on Good Manufacturing Practices for Heating, Ventilation and Air-conditioning Systems for Non-sterile Pharmaceutical Dosage Forms are open

Working document QAS/15.639
August 2015
Draft document for comment
SUPPLEMENTARY GUIDELINES ON1
GOOD MANUFACTURING PRACTICES FOR HEATING,2
VENTILATION AND AIR-CONDITIONING SYSTEMS FOR3
NON-STERILE PHARMACEUTICAL DOSAGE FORMS4
(August 2015)5
DRAFT FOR COMMENT6
7
8
9
10
11
© World Health Organization 201512
All rights reserved.13
This draft is intended for a restricted audience only, i.e. the individuals and organizations having14
received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted,15
distributed, translated or adapted, in part or in whole, in any form or by any means outside these16
individuals and organizations (including the organizations' concerned staff and member17
organizations) without the permission of the World Health Organization. The draft should not be18
displayed on any website.19
Please send any request for permission to:20
Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms,21
Department of Essential Medicines and Health Products, World Health Organization, CH-121122
Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: kopps@who.int23
24
The designations employed and the presentation of the material in this draft do not imply the25
expression of any opinion whatsoever on the part of the World Health Organization concerning the26
legal status of any country, territory, city or area or of its authorities, or concerning the delimitation27
of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which28
there may not yet be full agreement.29
The mention of specific companies or of certain manufacturers’ products does not imply that they30
are endorsed or recommended by the World Health Organization in preference to others of a similar31
nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are32
distinguished by initial capital letters.33
All reasonable precautions have been taken by the World Health Organization to verify the34
information contained in this draft. However, the printed material is being distributed without35
warranty of any kind, either expressed or implied. The responsibility for the interpretation and use36
of the material lies with the reader. In no event shall the World Health Organization be liable for37
damages arising from its use.38
This draft does not necessarily represent the decisions or the stated policy of the World Health39
Organization.40
Should you have any comments on the attached text, please send these to Dr S. Kopp, Dr S. Kopp,
Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms
(kopps@who.int) with a copy to Ms Marie Gaspard (gaspardm@who.int) by 10 October 2015.
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
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page 2
SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF41
DOCUMENT QAS/15.63942
SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING43
PRACTICES FOR HEATING, VENTILATION AND AIR-44
CONDITIONING SYSTEMS FOR NON-STERILE45
PHARMACEUTICAL DOSAGE FORMS.46
PROPOSAL FOR REVISION47
48
49
50
51
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 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
Consolidation of comments received and review of
feedback
10 October 2015
Presentation to fiftieth meeting of the WHO Expert
Committee on Specifications for Pharmaceutical
Preparations
12–16 October 2015
Any other follow-up action as required …

page 3
BACKGROUND52
During the consultation on data management, bioequivalence, GMP and53
medicines’ inspection held in 2015 the possible revision of the guidance54
for (WHO Technical Report Series, No. 961, Annex 5, 2011) was55
discussed with the inspectors. It was suggested that in light of the new56
developments a draft for revision be prepared. This new proposal for57
revision was drafted based on the feedback received, the new, current58
trends in engineering and the experience gained during the implementation59
of this guidance in inspection.60
At the same time, the opportunity was used to improve the graphic images61
and make them more readable in e-version as well as in print.62
Summary of main changes63
Below is a list of the main changes that have been made to the WHO Technical64
Report Series, No. 961, 2011, Annex 5: Supplementary guidelines on good65
manufacturing practices for heating, ventilation and air-conditioning systems for66
non-sterile pharmaceutical dosage forms.67
68
1. The Premises section has been moved towards the beginning of the document69
due to its important impact on HVAC designs. In addition the text has been70
expanded and a number of sample layouts have been included.71
72
2. The HVAC sections have been re-arranged into a more logical sequence.73
74
3. The Commissioning, Qualification and Validation (C, Q & V) section has75
been aligned with the proposed revisions to the Supplementary GMP76
Validation TRS937 Annex4 guideline.77
78
4. Significant notes were added under the new Supplementary notes on test79
procedures section.80
81
5. The Maintenance section has been separated out of the C, Q & V section.82
83
6. All the diagrams have been revised (mainly to achieve better clarity).84
85
7. Throughout the document additional notes have been added and text revised86
to provide better understanding and avoid ambiguity.87
88
8. A list of abbreviations has been added.89
90

page 4
Contents91
page92
1. Introduction93
2. Scope of document94
3. Glossary95
4. Premises96
5. Design of HVAC systems and components97
5.1 General98
5.2 Air distribution99
5.3 Recirculation system100
5.4 Full fresh-air systems101
5.5 Additional system components102
6. Protection103
6.1 Products and personnel104
6.2 Air filtration105
6.3 Unidirectional airflow106
6.4 Infiltration107
6.5 Cross-contamination108
6.6 Displacement concept (low pressure differential,109
high airflow)110
6.7 Pressure differential concept (high pressure differential,111
low airflow)112
6.8 Physical barrier concept113
6.9 Temperature and relative humidity114
7. Dust control115
8. Protection of the environment116
8.1 General117
8.2 Dust in exhaust air118
8.3 Vapour and fume removal119
9. Commissioning, qualification and validation120
9.1 General121
9.2 Commissioning122
9.3 Qualification123
9.4 Supplementary notes on test procedures124
10. Maintenance125
11. Abbreviations126
References127
Further reading128
129

page 5
1. Introduction130
131
Heating, ventilation and air-conditioning (HVAC) play an important role in132
ensuring the manufacture of quality pharmaceutical products.A well designed133
HVAC system will also provide comfortable conditions for operators.134
135
These guidelines mainly focus on recommendations for systems for136
manufacturers of solid dosage forms. The guidelines also refer to other137
systems or components which are not relevant to solid dosage form138
manufacturing plants, but which may assist in providing a comparison139
between the requirements for solid dosage-form plants and other systems.140
141
HVAC system design influences architectural layouts with regard to items142
such as airlock positions, doorways and lobbies.The architectural components143
have an effect on room pressure, differential cascades and cross-144
contamination control. The prevention of contamination and cross-145
contamination is an essential design consideration of the HVAC system. In146
view of these critical aspects, the design of the HVAC system should be147
considered at the concept design stage of a pharmaceutical manufacturing148
plant.149
150
Temperature, relative humidity and ventilation should be appropriate and151
should not adversely affect the quality of pharmaceutical products during152
their manufacture and storage, or the accurate functioning of equipment.153
154
This document aims to give guidance to pharmaceutical manufacturers155
and inspectors of pharmaceutical manufacturing facilities on the design,156
installation, qualification and maintenance of the HVAC systems.157
These guidelines are intended to complement those provided in Good158
manufacturing practices for pharmaceutical products (1) and should be read159
in conjunction with the parent guide. The additional standards addressed by160
the present guidelines should, therefore, be considered supplementary to161
the general requirements set out in the parent guide.162
163
2. Scope of document164
165
These guidelines focus primarily on the design and good manufacturing166
practices (GMP) requirements for HVAC systems for facilities for the167
manufacture of solid dosage forms. Most of the system design principles168
for facilities manufacturing solid dosage forms also apply to facilities169
manufacturing other dosage forms and other classes of products including170
biological products, herbal medicines, complimentary medicines and171
finishing process steps for APIs . Additional specific requirements apply172
for handling of sterile products and hazardous products. Guidelines for173
hazardous, sterile and biological product facilities are covered in separate174

page 6
WHO guidelines (WHO Technical Report Series, No. 957, Annex 3,175
Technical Report Series, No. 961 Annex 6 and working document176
WHO/BS/2015.2253, intended to replace Technical Report Series, No.177
822, Annex 1, 1992, respectively).178
179
These guidelines are intended as a basic guide for use by pharmaceutical180
manufacturers and GMP inspectors.181
They are not intended to be prescriptive in specifying requirements and design182
parameters. There are many parameters affecting a clean area condition and it183
is, therefore, difficult to lay down the specific requirements for one particular184
parameter in isolation.185
186
Many pharmaceutical manufacturers have their own engineering design and187
qualification standards, and requirements may vary from one manufacturer188
to the next. Design parameters and user requirements should, therefore, be189
set realistically for each project, with a view to creating a cost-effective190
design, yet still complying with all regulatory standards and ensuring that191
product quality and safety are not compromised. The three primary aspects192
addressed in this manual are the roles that the HVAC system plays in product193
protection, personnel protection and environmental protection (Figure 2).194
195
Cognizance should be taken of the products to be manufactured when196
establishing system design parameters. A facility manufacturing multiple197
different products may have more stringent design parameters with respect198
to cross-contamination control, compared with a single product facility.199
200
Risk assessment studies should be an integral part of the facility design and201
implementation, from the URS stage right through to validation, as202
indicated in the diagram below (Figure 1). Validation protocols and criteria203
should be justified by links to a written risk assessment.204
205

page 7
Figure 1206
GMP compliance sequence diagram207
RISK
ASSESSMENT
STUDIES
USER
REQUIREMENT
SPECIFICATION
FACILITY
LAYOUTS
QUALIFICATION
&
VALIDATION
HVAC &
SERVICES
DESIGNS
PROJECT
INCEPTION
RISK
ASSESSMENT
STUDIES
ENERGY
EFFICIENCY
STUDIES
LOC
P
MG
M I
ECNAP
L
OCPMGM
I
EC
N A
P
L
OC
P
M
G
MIECNAP
Installations
208
209
210

page 8
Figure 2211
The guidelines address the various system criteria according to the212
sequence set out in this diagram213
214
215

page 9
3. Glossary216
217
The definitions given below apply to terms used in these guidelines. They218
may have different meanings in other contexts.219
220
acceptance criteria221
Measurable terms under which a test result will be considered acceptable.222
223
action limit224
The action limit is reached when the acceptance criteria of a critical225
parameter have been exceeded. Results outside these limits will require226
specified action and investigation.227
228
air changes per hour229
The volume of air supplied to a room, in m3/hr, divided by the room volume, in m3.230
231
air-handling unit232
The air-handling unit serves to condition the air and provide the required air233
movement within a facility.234
235
airflow protection booth236
A booth or chamber, typically for purposes of carrying out Sampling or237
Weighing, in order to provide product containment and operator protection.238
Similar to UDAF protection but not necessarily a Grade A condition.239
240
airlock241
An enclosed space with two or more doors, which is interposed between242
two or more rooms, e.g. of differing classes of cleanliness, for the purpose243
of controlling the airflow between those rooms when they need to be244
entered. An airlock is designed for and used by either people or goods245
(PAL, personnel airlock; MAL, material airlock).246
247
alert limit248
The alert limit is reached when the normal operating range of a critical249
parameter has been exceeded, indicating that corrective measures may need250
to be taken to prevent the action limit being reached.251
252
as-built253
Condition where the installation is complete with all services connected and254
functioning but with no production equipment, materials or personnel present.255
256
at-rest257
Condition where the installation is complete with equipment installed and258

page 10
operating in a manner agreed upon by the customer and supplier, but with259
no personnel present.260
261
central air-conditioning unit (see air-handling unit)262
263
change control264
A formal system by which qualified representatives of appropriate265
disciplines review proposed or actual changes that might affect a validated266
status. The intent is to determine the need for action that would ensure that267
the system is maintained in a validated state.268
269
clean area (cleanroom)11
270
An area (or room or zone) with defined environmental control of particulate271
and microbial contamination, constructed and used in such a way as to reduce272
the introduction, generation and retention of contaminants within the area.273
274
closed system275
A system where the product or material is not exposed to the manufacturing276
environment.277
278
commissioning279
Commissioning is the documented process of verifying that the equipment280
and systems are installed according to specifications, placing the equipment281
into active service and verifying its proper action. Commissioning takes282
place at the conclusion of project construction but prior to validation.283
284
containment285
A process or device to contain product, dust or contaminants in one zone,286
preventing it from escaping to another zone.287
288
contamination289
The undesired introduction of impurities of a chemical or microbial nature,290
or of foreign matter, into or on to a starting material or intermediate, during291
production, sampling, packaging or repackaging, storage or transport.292
293
controlled area294
An area within the facility in which specific environmental facility295
conditions and procedures are defined, controlled, and monitored to prevent296
degradation or cross-contamination of the product.297
1
Note: Clean area standards, such as ISO 14644-1, provide details on how to classify air cleanliness by
means of particle concentrations, whereas the GMP standards provide a grading for air cleanliness in
terms of the condition (at-rest or operational), the permissible microbial concentrations, as well as
other factors such as gowning requirements. GMP and clean area standards should be used in
conjunction with each other to define and classify the different manufacturing environments.

page 11
298
controlled-not classified299
An area where some environmental conditions are controlled (such as300
temperature), but the area has no cleanroom classification301
302
critical parameter or component303
A processing parameter (such as temperature or relative humidity) that304
affects the quality of a product, or a component that may have a direct305
impact on the quality of the product.306
307
critical quality attribute308
A physical, chemical, biological or microbiological property or characteristic309
that should be within an appropriate limit, range or distribution to ensure310
the desired product quality.311
312
cross-contamination313
Contamination of a starting material, intermediate product or finished314
product with another starting material or product during production.315
316
design condition317
Design condition relates to the specified range or accuracy of a controlled318
variable used by the designer as a basis for determining the performance319
requirements of an engineered system.320
321
design qualification322
Design qualification is the documented check of planning documents and323
technical specifications for conformity of the design with the process,324
manufacturing, GMP and regulatory requirements.325
326
direct impact system327
A system that is expected to have a direct impact on product quality. These328
systems are designed and commissioned in line with good engineering329
practice and, in addition, are subject to qualification practices.330
331
exfiltration332
Exfiltration is the egress of air from a controlled area to an external zone.333
334
facility335
The built environment within which the clean area installation and associated336
controlled environments operate together with their supporting infrastructure.337
338
good engineering practice339
Established engineering methods and standards that are applied throughout340
the project life-cycle to deliver appropriate, cost-effective solutions.341

page 12
342
hazardous substance or product343
A product or substance that may present a substantial risk of injury to health344
or to the environment345
346
HVAC347
Heating, ventilation and air-conditioning. Also referred to as Environmental348
control systems349
350
indirect impact system351
This is a system that is not expected to have a direct impact on product352
quality, but typically will support a direct impact system. These systems are353
designed and commissioned according to good engineering practice only.354
355
infiltration356
Infiltration is the ingress of air from an external zone into a controlled area.357
358
installation qualification359
Installation qualification is documented verification that the premises,360
HVAC system, supporting utilities and equipment have been built and361
installed in compliance with their approved design specification.362
363
Most penetrating particle size (MPPS)364
MPPS is a means of determining HEPA & ULPA filter efficiencies. The365
MPPS is the particle size with the highest penetration for a defined filter366
medium. (MPPS Integral overall efficiency is the efficiency, averaged over367
the whole superficial face area of a filter element under a given operating368
conditions of the filter. MPPS local efficiency is the efficiency, at a specific369
point of the filter element under given operating conditions of the filter)370
371
NLT372
Not less than373
374
NMT375
Not more than376
377
no-impact system378
This is a system that will not have any impact, either directly or indirectly, on379
product quality. These systems are designed and commissioned according380
to good engineering practice only.381
382
non-critical parameter or component383
A processing parameter or component within a system where the operation,384

page 13
contact, data control, alarm or failure will have an indirect impact or no385
impact on the quality of the product.386
387
normal operating range388
The range that the manufacturer selects as the acceptable values for a parameter389
during normal operations. This range must be within the operating range.390
391
OOS392
Out of specification393
394
operating limits395
The minimum and/or maximum values that will ensure that product and396
safety requirements are met.397
398
operating range399
Operating range is the range of validated critical parameters within which400
acceptable products can be manufactured.401
402
operational condition403
This condition relates to carrying out room classification tests with the404
normal production process with equipment in operation, and the normal405
staff present in the specific room.406
407
operational qualification (OQ)408
Operational qualification is the documentary evidence to verify that the equipment409
operates in accordance with its design specifications in its normal operating range410
and performs as intended throughout all anticipated operating ranges.411
412
oral solid dosage (OSD)413
Usually refers to an OSD plant that manufactures medicinal products such414
as tablets, capsules and powders to be taken orally.415
416
pass-through-hatch (PTH) or pass box (PB)417
A cabinet with two or more doors for passing equipment or product, whilst418
maintaining the pressure cascade and segregation between two controlled419
zones. A passive PTH has no air supply or extract. A dynamic PTH has an420
air supply into the chamber.421
422
performance qualification (PQ)423
Performance qualification is the documented verification that the process and/424
or the total process related to the system performs as intended throughout all425
anticipated operating ranges.426
427
428

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point extraction429
Air extraction to remove dust with the extraction point located as close as430
possible to the source of the dust.431
432
pressure cascade433
A process whereby air flows from one area, which is maintained at a higher434
pressure, to another area at a lower pressure.435
436
qualification437
Qualification is the planning, carrying out and recording of tests on438
equipment and a system, which forms part of the validated process, to439
demonstrate that it will perform as intended.440
441
quality critical process parameter (QCPP)442
A process parameter which could have an impact on the critical quality443
attribute.444
445
relative humidity446
The ratio of the actual water vapour pressure of the air to the saturated447
water vapour pressure of the air at the same temperature expressed as a448
percentage. More simply put, it is the ratio of the mass of moisture in449
the air, relative to the mass at 100% moisture saturation, at a given450
temperature.451
452
standard operating procedure (SOP)453
An authorized written procedure, giving instructions for performing454
operations, not necessarily specific to a given product or material, but of a455
more general nature (e.g. operation of equipment, maintenance and cleaning,456
validation, cleaning of premises and environmental control, sampling and457
inspection). Certain SOPs may be used to supplement product-specific458
master and batch production documentation.459
460
turbulent flow461
Turbulent flow, or non-unidirectional airflow, is air distribution that is462
introduced into the controlled space and then mixes with room air by means463
of induction.464
465
unidirectional airflow (UDAF)466
Unidirectional airflow is a rectified airflow over the entire cross-sectional467
area of a clean zone with a steady velocity and approximately parallel468
streamlines (see also turbulent flow).469
470
validation471

page 15
The documented act of proving that any procedure, process, equipment,472
material, activity or system actually leads to the expected results.473
474
validation master plan (VMP)475
Validation master plan is a high-level document which establishes an476
umbrella validation plan for the entire project, and is used as guidance by477
the project team for resource and technical planning (also referred to as478
master qualiﬁcation plan).479
480
4. Premises481
482
4.1. There is a close relationship between architectural design and HVAC483
design, as they both have an impact on the functionality of the other.484
HVAC system design influences architectural layouts with regard to items485
such as airlock positions, doorways and lobbies. The architectural layouts486
and building components have an effect on room pressure differential487
cascades and cross-contamination control. The prevention of contamination488
and cross-contamination is an essential design consideration of the HVAC489
system. In view of these critical aspects, the design of the HVAC system490
should be considered at the concept design stage of a pharmaceutical491
manufacturing plant, and the design should be closely co-ordinated with the492
architectural designers. In addition the architectural layout must ensure that493
the material flow is in a logical sequence, excluding material flow reversals494
where possible.495
496
4.2. As the efficient operation of the air-handling system and cleanliness levels497
attained are reliant on the correct building layout and building finishes, the498
following items should be considered.499
500
4.2.1. Adequate airlocks, such as personnel airlocks (PAL) and/or material501
airlocks (MAL), change rooms and passages should be provided to protect502
passage between different cleanliness conditions. These should have supply503
and extract air systems as appropriate.504
505
4.2.2. Areas such as airlocks, change rooms and passages, should be506
designed so that the required pressure cascades can be achieved.507
508
4.2.3. Detailed diagrams depicting pressure cascades, air flow directions509
and flow routes for personnel and materials should be prepared and510
maintained.511
512

page 16
4.2.4. Where possible, personnel and materials should not move from a513
higher cleanliness zone to a lower cleanliness zone and back to a higher514
cleanliness zone (if moving from a lower cleanliness zone to a higher515
cleanliness zone, changing /decontamination procedures should be516
followed).517
518
4.2.5. The final stage of the changing room should be the same GMP519
classification grade as the area into which it leads. Changing rooms should520
be of a sufficient size to allow for ease of changing. Changing rooms should521
be equipped with mirrors so that personnel can confirm the correct fit of522
garments before leaving the changing room. Appropriate hand wash and523
sanitizing facilities should be provided. Hand-wash basins should be524
provided with elbow taps or sensor operated taps.525
526
4.2.6. Door gaps around the door perimeter have a marked impact on the527
pressure differential across the doorway. The fit of the doors should be528
agreed upon between the architect and the HVAC designer to ensure that529
the correct leakages are allowed for. Likewise the maintenance of doors is530
a critical factor in room pressure control (a poorly fitting door can severely531
compromise a room pressure differential).532
533
4.2.7. Where the opening and closing of airlock doors could lead to cross-534
contamination, these airlock doors should not be opened simultaneously.535
An interlocking system and a visual and/or audible warning system should536
be operated to prevent the opening of more than one door at a time.537
538
4.2.8. Doors should be carefully designed to avoid un-cleanable recesses;539
sliding doors may be undesirable for this reason. Swing doors should open540
to the high-pressure side and be provided with self-closers. Exceptions are541
permitted based on egress and site environmental, fire, health and safety542
containment requirements.543
544
4.2.9. The choice of building finishes and materials also has an impact on545
air conditioning performance and air cleanliness. Materials should be546
selected that will provide a well-sealed building to facilitate room pressure547
control. Materials and paint finishes should also be non-dust and particle548
liberating as this impacts on room cleanliness. Finishes should be easy to549
clean and non-absorbent. To reduce the accumulation of dust and to550
facilitate cleaning, there should be no un-cleanable recesses and a minimum551
of projecting ledges, shelves, cupboards and equipment.552
553

page 17
4.3. The following diagrams illustrate some typical room and suite layouts with554
their associated room pressures. These are purely examples and other555
factors may dictate different room arrangements and room pressures.556
557
Figure 3558
Typical weigh booth layout559
560
SOB
Dispensary Pre-Staging Room
Change
Room
Weigh Booth
Wash Bay
ReturnAirShaft
Perforated Worktop
Airflow Protection
Plenum
Floor
Scale
BIN
BIN
Dispensary Post-Staging
Room
Pallet
MaterialFlowMaterialFlow
BIN
BIN BIN
BINBIN
25 Pa
35 Pa
35 Pa
35 Pa
15 Pa
Table Scale
561
562
563
564
565

page 18
Figure 4566
Typical dispensary suite567
568
Dispensary Pre-Staging Room
Weigh
Booth 1
ReturnAirShaft
Airflow
Protection
Plenum
Dispensary
Post-Staging
Room
Wash
Bay
MAL
MAL
Change
Room
Weigh
Booth 2
ReturnAirShaft
Airflow
Protection
Plenum
Wash
BayMAL
MAL
Change
Room
Production Passage
Warehouse
Area
Brocken
Bulk
Store
MAL
MAL
Material Flow
569
570
571

page 19
Figure 5572
Sampling booth for small volumes573
574
SOB
ReturnAirShaft
575
576
577
Figure 6578
Sampling Booth for larger volumes579
580
581
582

page 20
Figure 7583
Change rooms and ablution layouts584
585
Figure 8586
Compression cubicle with change room and MAL587
Passage
Low
Level
Return
A
ir
Low
Level
R
eturn
Air
SOB
588

page 21
Figure 9589
Compression cubicle without change room and MAL590
(inclusion of airlocks dependant on risk assessment)591
Compression
Cubicle
Passage
Low
Level
Return
Air
Low
Level
R
eturn
Air
30 Pa
15 Pa
Supply
Air
Grille
592
593

page 22
Figure 10594
Wash-bay suite595
Passage
MaterialFlow
596
597
5. Design of HVAC systems and components598
599
5.1. General600
601
5.1.1. The required degree of air cleanliness in most OSD manufacturing602
facilities can normally be achieved without the use of high-efficiency603
particulate air (HEPA) filters, provided the air is not recirculated or in the604
case of a single-product facility. Many open product zones of OSD form605
facilities are capable of meeting ISO 14644-1 Class 8 or Grade D, “at-rest”606
condition, measured against particle sizes of 0.5 µm and 5 µm, but607
cleanliness may not necessarily be classified as such by manufacturers.608
609
5.1.2. A risk assessment should be carried out to determine the cleanroom610
conditions required and the extent of validation required.611
612
5.1.3. There are two basic concepts of air delivery to pharmaceutical613
production facilities: a recirculation system, and a full fresh air system614

page 23
(100% outside air supply). For recirculation systems the amount of fresh air615
should not be determined arbitrarily on a percentage basis, but, for example,616
by the following criteria:617
618
• sufficient fresh air to compensate for leakage from the facility and619
loss through exhaust air systems;620
• sufficient fresh air to comply with national building regulations621
(depending on occupant density, between 1 and 2.5 ACPH will often622
satisfy occupancy requirements);623
• sufficient fresh air for odour control;624
• sufficient fresh air to provide the required building pressurization625
626
5.1.4. Where automated monitoring systems are used, these should be627
capable of indicating any out-of-specification (OOS) condition without628
delay by means of an alarm or similar system. Sophisticated computer-629
based data monitoring systems may be installed, which can aide with630
planning of preventive maintenance and can also provide trend logging.631
632
(This type of system is commonly referred to as a building management633
system (BMS), building automation system (BAS) or system control and634
data acquisition (SCADA) system. If these systems are used for critical635
decision-making, they should be validated. If the BMS is not validated in636
full (or in part for these critical parameters), an independent validated637
environmental monitoring system (EMS) should be provided, specifically638
for recording and alarming critical parameters. Critical parameters could639
include for example, room temperature in production areas, humidity,640
differential pressures, fan failure alarms, etc.)641
,642
5.1.5. Failure of a supply air fan, return air fan, exhaust air fan or dust643
extract system fan can cause a system imbalance, resulting in a pressure644
cascade malfunction with a resultant airflow reversal.645
646
5.1.6. A fan interlock failure matrix should be set up, such that if a fan647
serving a high pressure zone fails, then any fans serving surrounding lower648
pressure areas should automatically stop, to prevent an airflow reversal and649
possible cross-contamination. This fan stop-start matrix should apply to the650
switching on and switching off of systems to ensure that there is no flow651
reversal causing cross-contamination.652
653
5.1.7. Appropriate alarm systems should be in place to alert personnel if a654
critical fan fails All critical alarms should be easily identifiable and visible655
and/or audible to relevant personnel.656
657
658

page 24
5.2. Air distribution659
660
5.2.1. The positioning of supply and extract grilles should be such as to661
provide effective room flushing. Low-level return or exhaust air grilles are662
usually preferred. However, where this is not possible, a higher air change663
rate may be needed to achieve a specified clean area condition, e.g. where664
ceiling return air grilles are used.665
666
5.2.2. There may be alternative locations for return air. For example,667
referring to Figure 11, Room 1 (low-level return air) and Room 2 (ceiling668
return air)..669
670
671
Figure 11672
Air-handling system with high-efficiency particulate air filters in air-673
handling unit674
675
PrimaryFilter
SupplyAir
Fan
Secondary
Filter
HEPAFilter
CoolingCoil
676
677
The airflow schematics of the two systems (Figures 11 and 12) indicate678
air-handling units with return air or recirculated air, having a percentage679
of fresh air added. Depending on product characteristics and dust loading680
it is sometimes preferable to fit filters on return air outlets or in return air681
ducting.682
683

page 25
Figure 12 is a schematic diagram of an air-handling system serving684
rooms with horizontal unidirectional flow, vertical unidirectional flow and685
turbulent flow, for rooms 3, 4 and 5, respectively. In this case the HEPA686
filters are terminally mounted at the rooms, and not in the AHU.687
Terminally mounted HEPA filters can assist with preventing cross-688
contamination from room to room in the event of a fan failure condition.689
The decision whether to install terminal HEPA filters should be based on a690
risk-assessment study.691
692
693
694
Figure 12695
Horizontal unidirectional flow, vertical unidirectional flow and696
turbulent flow697
698
PrimaryFilter
SupplyAir
Fan
Secondary
Filter
HEPAFilters
CoolingCoil
699
700
5.3. Recirculation system701
702
5.3.1. There should be no risk of contamination or cross-contamination703
(including by fumes and volatiles) due to recirculation of air.704
705
5.3.2. Depending on the airborne contaminants in the return-air system706
it may be acceptable to use recirculated air, provided that HEPA filters707
are installed in the supply air stream (or return air stream) to remove708
contaminants and thus prevent cross-contamination. The HEPA filters for709
this application should have an EN 1822 classification of H13.710
711
5.3.3. HEPA filters may not be required where the air-handling system712
is serving a single product facility and there is evidence that cross-713
contamination would not be possible.714
715

page 26
5.3.4. Recirculation of air from areas where pharmaceutical dust is not716
generated such as secondary packing, may not require HEPA filters in the717
system.718
719
5.3.5. HEPA filters may be located in the air-handling unit or placed720
terminally. Where HEPA filters are terminally mounted they721
should preferably not be connected to the ducting by means of flexible722
ducting. Due to the high air pressure required for the terminal filter, this723
connection should preferably be a rigid duct connection. Where flexible724
ducting is used, it should be as short as possible and properly fixed to725
withstand duct pressure. When HEPA filters are terminally mounted, it726
should be possible to carry out filter integrity tests from within the room.727
The filter housings will therefore require ports for measuring appropriate728
upstream concentration (refer to ISO 14644.3) and penetration729
concentration from within the room. In addition it should be possible to730
monitor the filter pressure drop in individual HEPA filters.731
732
5.3.6. Air containing dust from highly toxic processes and/or solvents or733
flammable vapours should never be recirculated to the HVAC system.734
735
736
737
5.4. Full fresh-air systems738
739
740
5.4.1. The required degree of filtration of the exhaust air depends on the741
exhaust air contaminants and local environmental regulations. HEPA filters742
in the exhaust system would normally only be required when handling743
hazardous materials.744
745
Figure 13 indicates a system operating on 100% fresh air and would746
normally be used in a facility dealing with toxic products or solvents, where747
recirculation of air with contaminants should be avoided.748
749
750

page 27
Figure 13751
Full fresh-air system752
753
754
755
756
757

page 28
Figure 14758
Full fresh-air system with energy recovery759
760
PrimaryFilter
SupplyAir
Fan
Secondary
Filter
HEPAFilter
PrimaryFilter
Exhaust
AirFan
Secondary
Filter
HEPAFilter
FreshAir
CoolingCoil
761
762
5.4.2. Energy-recovery wheels if used in multiproduct facilities should763
have been subjected to a risk assessment to determine if there is any764
risk of cross-contamination. When such wheels are used they should765
not become a source of possible contamination (see Figure 14). Note:766
Alternatives to the energy-recovery wheels, such as crossover plate heat767
exchangers and water-coil heat exchangers, may be used in multiproduct768
facilities.769
770
5.4.3. The potential for air leakage between the supply air and exhaust air771
as it passes through the wheel should be prevented. The relative pressures772
between supply and exhaust air systems should be such that the exhaust air773
system operates at a lower pressure than the supply system.774
775
776
5.5. Additional system components777
778
5.5.1. A schematic diagram of the airﬂow for a typical system serving a779
low relative humidity suite is represented in Figure 15. Air can be dried780
with a chemical drier (e.g. a rotating desiccant wheel which is continuously781
regenerated by means of passing hot air through one segment of the wheel).782
Alternative methods of drying air are also available.783

page 29
Figure 15784
Air-handling system with chemical drying785
SupplyAir
Fan
Secondary
Filter
HEPAFilter
AIR HANDLING UNIT
LOW HUMIDITY
PRODUCTION
FACILITY
Process
AirFan
CHEMICAL DRIER UNIT
Reactivation
Air Fan
PrimaryFilter
PrimaryFilter
Fresh Air
Chemical Drier
Desiccant Wheel
S
R
F
= Supply Air
= Return Air
= Fresh Air
E = Exhaust Air
E
F
S
S
RR
R
R
CoolingCoil
-
+
+
Reactivation
Heater
786
787
5.5.2. The figure illustrates the chemical drier handling part of the fresh788
air/return air mixture on a bypass flow. The location of the chemical drier789
should be considered in the design phase. The practice of locating the790
complete chemical drier unit in the production cubicle is not recommended791
as this could be a source of contamination or cross-contamination. Examples792
of appropriate locations for the drying wheel could include:793
794
— full flow of fresh/return air;795
— partial handling of fresh/return air (bypass airflow);796
— return air only;797
— fresh air only; or798
— pre-cooled air with any of the above alternatives.799
800
5.5.3. Possible additional components that may be required in air handling801
should be considered depending on the climatic conditions and locations.802
These may include items such as:803
804
‒ frost coils on fresh air inlets in very cold climates to preheat the air;805
‒ reheaters for humidity control806
‒ automatic air volume control devices807
‒ sound attenuators808

page 30
‒ snow eliminators to prevent snow entering air inlets and809
blocking airflow810
‒ dust eliminators on air inlets in arid and dusty locations811
‒ moisture eliminators in humid areas with high rainfall812
‒ fresh air precooling coils for very hot or humid climates.813
814
815
6. Protection816
817
6.1. Products and personnel818
819
6.1.1. Areas for the manufacture of pharmaceuticals, where pharmaceutical820
starting materials and products, utensils, primary packing materials and821
equipment are exposed to the environment, should be defined as “clean822
areas”, “clean zones”, “controlled areas” or “cleanrooms”.823
824
6.1.2. The achievement of a particular clean area condition depends on a825
number of criteria that should be addressed at the design and qualification826
stages. A suitable balance between the different criteria will be required in827
order to create an efficient clean area.828
829
6.1.3. Some of the basic criteria to be considered which affects room830
cleanliness should include:831
832
• building finishes and structure• dust control and containment833
• air filtration834
• air change rate or flushing rate835
• room pressure836
• location of air terminals and directional airflow837
• temperature838
• relative humidity839
• material flow840
• personnel flow841
• gowning procedures842
• equipment movement843
• process being carried out (open or closed system)844
• outside air conditions845
• occupancy846
• type of product847
• cleaning standard operating procedures (SOPs).848
849
6.1.4. Air filtration and air change rates should be set to ensure that the850
defined clean area condition is attained.851
852

page 31
6.1.5. The air change rates should be determined by the manufacturer and853
designer, taking into account the various critical parameters using a risk854
based approach with due consideration of capital and running costs and855
energy usage. Primarily the air change rate should be set to a level that will856
achieve the required clean area condition.857
858
6.1.6. Air change rates are normally determined by the following859
considerations (could normallyvary between 6 and 20 air changes per hour):860
861
• area condition required: whether a specific room cleanliness862
condition is in fact required and whether the room condition is863
rated for an “at rest” condition or an “operational” condition (air864
change rate should be selected on need rather than tradition);865
• the product characteristics (e.g. odours, hygroscopicity, etc.);866
• the quality and filtration of the supply air;867
• particulates generated by the manufacturing process;868
• particulates generated by the operators;869
• configuration of the room and air supply and extract locations;870
• sufficient air to achieve containment effect and to clean up the area;871
• sufficient air to cope with the room heat load;872
• sufficient air to balance extract rates;873
• sufficient air to maintain the required room pressure.874
875
6.1.7. If a cleanroom classification is specified, the manufacturer should876
state whether this is achieved under “as-built” (Figure 16), “at-rest” (Figure877
17) or “operational” (Figure 18) conditions.878
879
6.1.8. Room classification tests in the “as-built” condition should be880
carried out on the bare room, in the absence of any equipment or personnel.881
882
6.1.9. Room classification tests in the “at-rest” condition should be carried883
out with the equipment operating where relevant, but without any operators.884
Because of the amounts of dust usually generated in a solid dosage facility,885
the clean area classifications would be rated for the “at-rest” condition.886
887
6.1.10. Room classification tests in the “operational” condition are888
normally carried out during the normal production process with equipment889
operating, and the normal number of personnel present in the room. When890
qualifying for the operational condition details of the process operating,891
number and positions of staff should be stipulated for each room, to enable892
future qualifications to duplicate the same conditions.893
894
6.1.11. Room clean-up or recovery tests are performed to determine895
whether the installation is capable of returning to a specified cleanliness896

page 32
level within a finite time, after being exposed briefly to a source of897
airborne particulate challenge. Room “clean-up” or “recovery” tests should898
demonstrate a change in particle concentration by a factor of 100 within899
the prescribed time (as per ISO 14644-3 clause B.12) (3). The guidance900
time period for clean-up or recovery is about 15 to 20 minutes.901
In some instances it is not possible to increase the concentration by a factor902
of 100 (such as for an ISO 14644 Class 8 condition) as the high particle903
concentration can damage the particle counter. In this instance the particle904
decay method can be used as per ISO 14644-3 clause B.12.3.2.905
906
6.1.12. Materials and products should be protected from contamination907
and cross-contamination during all stages of manufacture (see also section908
6.5 for cross-contamination control).909
910
Note: contaminants may result from inappropriate premises (e.g. poor design,911
layout or ﬁnishing), poor cleaning procedures, contaminants brought in by912
personnel, poor manufacturing process and a poor HVAC system.913
914
Figure 16915
“As-built” condition916
917
918
919
920

page 33
Figure 17921
“At-rest” condition922
923
924
Figure 18925
“Operational” condition926
927

page 34
928
929
6.1.13. Airborne contaminants should be controlled through effective930
ventilation and filtration.931
932
6.1.14. External contaminants should be removed by effective filtration of933
the supply air (see Figure 19 for an example of a shell-like building934
layout to enhance containment and protection from external935
contaminants).936
937
6.1.15. Internal contaminants should be controlled by dilution and938
flushing of contaminants in the room, or by displacement airflow (See939
Figures 20 and 21 for examples of methods for the flushing of airborne940
contaminants).941
942
6.1.16. Airborne particulates and the degree of filtration should be943
considered critical parameters with reference to the level of product944
protection required.945
946
6.1.17. Personnel should not be a source of contamination.947
948
6.1.18. The level of protection and air cleanliness for different areas should949
be determined according to the product being manufactured, the process950
being used and the product’s susceptibility to degradation (Table 3).951

page 35
Figure 19952
Shell-like containment control concept953
954
WasteExit
PersonnelMovement
PersonnelMovement
955
956
957
6.2. Air filtration958
959
Note: The degree to which air is filtered plays an important role in the960
prevention of contamination and the control of cross-contamination.961
962
6.2.1. The type of filters required for different applications depends on963
the quality of the ambient air and the return air (where applicable) and964
also on the air change rates. Table 4 gives the recommended filtration965
levels for different levels of protection in a pharmaceutical facility.966
Manufacturers should determine and prove the appropriate use of967
filters.968
969
6.2.2. Filter classes should always be linked to the standard test method970
because referring to actual filter efficiencies can be very misleading (as971
different test methods each result in a different efficiency value for the972
same filter). (Referring to filter classifications such as an 85% filter or a 5 µm973
filter are not valid classifications and should not be used, as this can lead to974
the incorrect filter being installed. Only the EN 779 and EN 1822 or ISO975
29463 classifications, as per Tables 1 and 2, should be used.)976

page 36
977
978
Table 1979
Comparison of filter test standards980
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
ISO29463
(supersede
d)
Merv rating
Average
arrestance
Am (%)
Average
dust spot
efficiency
Em (%)
MPPS integral
overall
efficiency (%)
EN Rating
99.999995 U17
EN1822:2009
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
EN1822:2009
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 F6
Merv 11 >95 65
>95 60
Merv 10 >95 55
EU 5 Merv 9 >95 50 F5
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
981

page 37
Table 2982
Comparison of ISO and EN Filter Standards983
ISO 29463
EN 1822Global or Integral
Values for MPPS
Local Values for
MPPS
Filter
Class
Collection
Efficiency
(%)
Penetrat
ion (%)
Collection
Efficiency
(%)
Penetrat
ion (%)
MPPS
Integral
Overall
Efficiency
(%)
EN
Rating
ISO 75 E
≥
99.999995
≤
0.000005
≥ 99.9999 ≤ 0.0001 99.999995 U17
ISO 70 E
≥
99.99999
≤
0.00001
≥ 99.9999 ≤ 0.0001 - -
ISO 65 E
≥
99.99995
≤
0.00005
≥ 99.99975
≤
0.00025
99.99995 U16
ISO 60 E ≥ 99.9999 ≤ 0.0001 ≥ 99.9995 ≤ 0.0005 - -
ISO 55 E
≥
99.99995
≤ 0.0005 ≥ 99.9975 ≤ 0.0025 99.9995 U15
ISO 50 E ≥ 99.999 ≤ 0.001 ≥ 99.995 ≤ 0.005 - -
ISO 45 E ≥ 99.995 ≤ 0.005 ≥ 99.975 ≤ 0.025 99.995 H14
ISO 40 E ≥ 99.99 ≤ 0.01 ≥ 99.95 ≤ 0.05 - -
ISO 35 E ≥ 99.95 ≤ 0.05 ≥ 99.75 ≤ 0.25 99.95 H13
ISO 30 E ≥ 99.9 ≤ 0.1 - -
ISO 25 E ≥ 99.5 ≤ 0.5 99.5 E12
ISO 20 E ≥ 99 ≤ 1 - -
ISO 15 E ≥ 95 ≤ 5 95 E11
The above all tested for MPPS (most penetrating
particle size)
Note: The filter classifications referred to above relate to the EN984
1822:2009 and EN 779: 2002 test standards (EN 779 relates to filter985
classes G1 to F9 and EN1822 relates to filter classes E10 to U17).986

page 38
987
6.2.3. In selecting filters, the manufacturer should have considered other988
factors, such as particularly contaminated ambient conditions, local989
regulations and specific product requirements. Good prefiltration extends990
the life of the more expensive filters downstream.991
992
6.2.4. Filters have an impact on the cleanroom class or Level of993
Protection. The different levels of protection and recommended filters994
grades are given in Tables 3 and 4 below.995
996
Table 3997
Examples of levels of protection (based on ISPE oral solid dosage998
(OSD) guideline criteria)9991000
Level Condition Example of area
Level 1 General Area with normal housekeeping and
maintenance where there is no potential for
product contamination, e.g. warehousing.
Level 2 Protected Area in which steps are taken to protect
the pharmaceutical starting material or
product from direct or indirect
contamination or degradation, e.g.
secondary packing, warehousing, first
stage change rooms.
Level 3 Controlled Area in which specific environmental
conditions are defined, controlled and
monitored to prevent contamination or
degradation of the pharmaceutical starting
material or product, e.g. where product,
starting materials and components are
exposed to the room environment; plus
equipment wash and storage areas for
equipment product contact parts.
1001
1002

page 39
Table 41003
Levels of protection and recommended filtration10041005
Level of protection Recommended filtration
Level 1 Primary filters only (e.g. EN 779 G4 filters)
Level 2 Protected areas operating on 100% outside air:
primary plus secondary filters (e.g. EN 779 G4
plus F8 or F9 filters)
Level 3 Production facility operating on recirculated
plus ambient air, where potential for cross-
contamination exists: Primary plus secondary
plus tertiary filters (e.g. EN 779 G4 plus F8 plus
EN 1822 H13 filters) (for full fresh air system,
without recirculation, G4 and F8 or F9 filters are
acceptable)
1006
6.2.5. Materials for components of an HVAC system should be selected1007
with care so that they do not become a source of contamination. Any1008
component with the potential for liberating particulate or microbial1009
contamination into the airstream should be located upstream of the final1010
filters.1011
1012
6.2.6. Where possible ventilation dampers, filters and other services should1013
be designed and positioned so that they are accessible from outside the1014
manufacturing areas (service voids or service corridors) for maintenance1015
purposes.1016
1017
6.2.7. Directional airflow within production or primary packing areas1018
should assist in preventing contamination. Airflows should be planned in1019
conjunction with operator locations, so as to minimize contamination of the1020
product by the operator and also to protect the operator from dust inhalation.1021
Different airflow patterns are indicated in Figures 20 & 21 below.1022
1023
1024

page 40
Figure 201025
Turbulent dilution of dirty air1026
1027
1028
1029
1030
Low-level extract is ideal for dust suppression purposes, but is not1031
essential. (Low-level extract is essential for Grade A, B & C classified1032
areas.)1033
1034
1035

page 41
Figure 211036
Unidirectional displacement of dirty air1037
1038
10391040
1041
1042
6.2.8. HVAC air distribution components should be designed, installed1043
and located to prevent contaminants generated within the room from being1044
spread.1045
1046
6.2.9. Supplyair diffusers should be selected with care taking consideration1047
of, e.g. room requirements and positions of equipment and operators in the1048
room. Supply air diffusers of the high induction type (e.g. those typically1049
used for ofﬁce-type air-conditioning) should where possible not be used1050
in clean areas where dust is liberated. Air diffusers should be of the non-1051
induction type, introducing air with the least amount of induction so as to1052
maximize the ﬂushing effect. In rooms where the process results in high1053
dust liberation; perforated plates or low induction swirl diffusers with1054
low level extract or return should be used (to contain the dust at the lower1055
level of the room) (see Figures 22–24 for illustrations of the three types of1056
diffuser). In cases where dust liberation is low, ceiling return air grilles may1057
be acceptable.1058
1059
1060
1061

page 42
6.2.10. Induction and certain swirl diffusers induce room air vertically1062
up to the diffuser to mix with the supply air. These diffusers create good1063
dilution of contaminants in the room and may be used in rooms where there1064
is low dust liberation. However, if used in rooms where excessive dust is1065
generated, the distribution of dust in the room could be hazardous for the1066
operators in the room, as dust is drawn up into the supply air stream and1067
then spread throughout the room. Airflow patterns for different diffuser1068
types are indicated in figures 22, 23 & 24 below.1069
1070
Figure 221071
Induction diffuser1072
1073
1074
1075
1076

page 43
Figure 231077
Perforated plate diffuser1078
1079
1080
1081

page 44
Figure 241082
Swirl diffuser1083
1084
1085
1086
6.3. Unidirectional airflow1087
1088
6.3.1. Unidirectional airflow (UDAF) should be used for weighing booths1089
or sampling booths to provide operator and product protection and should1090
also have a slight air in-flow from the room to enhance containment. Dust1091
containment at the weigh booth should be demonstrated by smoke airflow1092
pattern tests, or other appropriate tests. UDAF can also be used to provide1093
protection of other dusty processes.1094
1095
6.3.2. Sampling of materials such as starting materials, primary packaging1096
materials and products, should be carried out in the same environmental1097
conditions that are required for the further processing of the product.1098
1099
6.3.3. In a weighing booth situation, the aim of the UDAF is to provide1100
dust containment and operator protection.1101
1102
Example: in Figure 25 the dust generated at the weighing station is1103
immediately extracted through the perforated worktop, thus protecting the1104
operator from dust inhalation, but at the same time protecting the product1105
from contamination by the operator by means of the vertical unidirectional1106
airflow stream.1107

page 45
Figure 251108
Operator protection at weighing station1109
1110
6.3.4 The unidirectional flow velocity should be such that it does not1111
disrupt the sensitivity of balances in weighing areas. Where necessary the1112
velocity may be reduced to prevent inaccuracies during weighing,1113
provided that sufficient airflow is maintained to provide containment.1114
Conventional unidirectional airflow systems, where a Grade A condition is1115
required, have a guidance airflow velocity of 0.36 to 0.54 m/s. However, in1116
a weigh booth or sampling booth a lower velocity can be used as a Grade1117
A condition is not required. It is often necessary to reduce velocities to a1118
lower level in order not to influence balance readings. The airflow velocity1119
and directional flow should still ensure product containment. For this type1120
of application it is sometimes better to refer to the unit as an airflow1121
protection booth (APB) rather than a UDAF, in order to avoid confusion,1122
with a Grade A requirement. To assist with containment for weighing and1123
sampling operations there should be a slight inflow of air into the UDAF1124
protected zone from the surrounding room in order to prevent dust1125
escaping. Thus the amount of air extracted from below the UDAF/APB1126
should exceed the amount of air supplied. (Unless the hazardous or sterile1127
nature of the product dictates otherwise.)1128

page 46
6.3.5 The position in which the operator stands relative to the source of1129
dust liberation and airflow should be determined to ensure that the operator1130
is not in the path of an airflow that could lead to contamination of the1131
product (Figure 26).1132
Figure 261133
Operator protection by horizontal airflow1134
1135
1136
1137
6.3.6 Once the system has been designed and qualified with a specific1138
layout for operators and processes, this should be maintained in accordance1139
with an SOP.1140
1141
6.3.7 There should be no obstructions in the path of a unidirectional flow1142
air stream that may cause the operator to be exposed to dust.1143
1144
Figure 27 illustrates the incorrect use of a weighing scale which has a solid1145
back. The back of the weighing scale should not block the return air path1146
as this obstructs the airflow and causes air to rise vertically carrying dust,1147
resulting in a hazardous situation for the operator.1148
1149
Figure 28 illustrates a situation where an open bin is placed below a vertical1150
unidirectional flow distributor. The downward airflow should be prevented1151
from entering the bin, and then being forced to rise again, as this would1152
carry light dust up towards the operator’s face. In such an occurrence it1153

page 47
may be necessary to add a partial cover over the bin to limit the entry of1154
air. Point extraction could also be used but this can result in the excessive1155
loss of product.1156
1157
Figure 29 shows that a solid worktop can sometimes cause deflection of1158
the vertical unidirectional airflow resulting in a flow reversal. A possible1159
solution would be to have a 100 mm gap between the back of the table and1160
the wall, with the air being extracted here.1161
1162
Figure 271163
Operator subject to powder inhalation due to obstruction1164
1165
1166
1167
1168
1169
1170

page 48
Figure 281171
Operator subject to powder contamination due to airﬂow reversal in1172
bin1173
1174
1175
1176
1177

page 49
Figure 291178
Operator subject to powder inhalation due to worktop obstruction1179
1180
1181
6.3.8 The manufacturer should select either vertical or horizontal1182
unidirectional airﬂow (Figure 30) and an appropriate airﬂow pattern to1183
provide the best protection for the particular application.1184
1185
1186

page 50
Figure 301187
Diagram indicating horizontal and vertical unidirectional ﬂow1188
1189
1190
1191
1192
1193
1194

page 51
6.3.9 Return or exhaust air grilles in rooms or at weigh or sampling booths1195
should preferably be of the perforated grille types, which are easy to clean.1196
Return/exhaust air filters can either be installed at the room terminal or in1197
the air-handling unit. Maintenance and cleaning of filters and ducts should1198
be addressed to ensure constant airflow.1199
1200
1201
6.4. Infiltration1202
1203
6.4.1. Air infiltration of unfiltered air into a pharmaceutical plant should1204
not be a source of contamination.1205
1206
6.4.2. Manufacturing facilities should normally be maintained at a positive1207
pressure relative to the outside, to limit the ingress of contaminants. Where1208
facilities are to be maintained at negative pressures relative to the ambient1209
pressure, special precautions should be taken. Refer to the WHO1210
guidelines for hazardous products, for further guidance on negative1211
pressure facilities.1212
1213
6.4.3. The location of the negative pressure facility should be carefully1214
considered with reference to the areas surrounding it, particular attention1215
being given to ensuring that the building structure is well sealed.1216
1217
6.4.4. Negative pressure zones should, as far as possible, be encapsulated1218
by surrounding areas with clean air supplies, so that only clean air can1219
infiltrate into the controlled zone.1220
1221
6.5. Cross-contamination1222
1223
6.5.1. Where different products are manufactured at the same time, in1224
different areas or cubicles, in a multiproduct OSD manufacturing site,1225
measures should be taken to ensure that dust cannot move from one cubicle1226
to another.1227
1228
6.5.2. Correct directional air movement and a pressure cascade system1229
can assist in preventing cross-contamination. The pressure cascade should1230
be such that the direction of airflow is from the clean corridor into the1231
cubicles, resulting in dust containment.1232
1233
6.5.3. For cubicles where dust is liberated, the corridor should be1234
maintained at a higher pressure than the cubicles and the cubicles at a1235
higher pressure than atmospheric pressure.1236
1237

page 52
6.5.4. Containment can normally be achieved by application of the1238
displacement concept (low pressure differential, high airflow), or the1239
pressure differential concept (high pressure differential, low airflow), or the1240
physical barrier concept.1241
1242
6.5.5. The pressure cascade regime and the direction of airflow should be1243
appropriate to the product and processing method used.1244
1245
6.5.6. Highly potent products should be manufactured under a pressure1246
cascade regime that is negative relative to atmospheric pressure.1247
1248
6.5.7. The pressure cascade for each facility should be individually1249
assessed according to the product handled and level of protection required.1250
1251
6.5.8. Building structure should be given special attention to accommodate1252
the pressure cascade design.1253
1254
6.5.9. Ceilings and walls, close fitting doors and sealed light fittings should1255
be in place, to limit ingress or egress of air.1256
1257
6.6. Displacement concept (low pressure differential, high airflow)1258
1259
Note: This method of containment is not the preferred method, as the1260
measurement and monitoring of airflow velocities in doorways is difficult.1261
This concept is commonly found in production processes where large1262
amounts of dust are generated.1263
1264
6.6.1. Under this concept the air should be supplied to the corridor,1265
flow through the doorway, and be extracted from the back of the cubicle.1266
Normally the cubicle door should be closed and the air should enter the1267
cubicle through a door grille, although the concept can be applied to an1268
opening without a door. (With the door open the pressure differential will1269
effectively be zero.)1270
1271
6.6.2. The velocity should be high enough to prevent turbulence within the1272
doorway resulting in dust escaping.1273
1274
6.6.3. This displacement airflow should be calculated as the product of1275
the door area and the velocity through the doorway, which generally1276
results in fairly large air quantities.1277
1278
Note: Although this method of containment may still exist on older facilities,1279
it is not the preferred method, as the measurement and monitoring of doorway1280
velocities is difficult. In addition, simultaneously maintaining the correct1281
room pressure and the correct room air change rate is often not achieved.1282

page 53
1283
1284
6.7. Pressure differential concept (high pressure differential, low airflow)1285
1286
Note:The pressure differential concept may normally be used in zones where1287
little or no dust is being generated. It may be used alone or in combination1288
with other containment control techniques and concepts, such as a double1289
door airlock.1290
1291
6.7.1. The high pressure differential between the clean and less clean1292
zones should be generated by leakage through the gaps of the closed doors1293
to the cubicle.1294
1295
6.7.2. The pressure differential should be of sufficient magnitude to ensure1296
containment and prevention of flow reversal, but should not be so high as to1297
create turbulence problems.1298
1299
6.7.3. In considering room pressure differentials, transient variations, such1300
as machine extract systems, should be taken into consideration.1301
1302
6.7.4. A pressure differential of 15 Pa is often used for achieving1303
containment between two adjacent zones, but pressure differentials of1304
between 5 Pa and 20 Pa may be acceptable. Where the design pressure1305
differential is too low and tolerances are at opposite extremities, a flow1306
reversal can take place. For example, where a control tolerance of ± 3 Pa1307
is specified, the implications of adjacent rooms being operated at the upper1308
and lower tolerances should be evaluated. It is important to select pressures1309
and tolerances such that a flow reversal is unlikely to occur.1310
1311
6.7.5. The pressure differential between adjacent rooms could be1312
considered a critical parameter, depending on the outcome of risk analysis.1313
The limits for the pressure differential between adjacent areas should be1314
such that there is no risk of overlap in the acceptable operating range, e.g.1315
5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting1316
in the failure of the pressure cascade, where the first room is at the maximum1317
pressure limit and the second room is at its minimum pressure limit.1318
1319
6.7.6. Low p r e s s u r e d i f f e r e n t i a l s m a y b e a c c e p t a b l e1320
w h e n a i r l o c k s (pressure sinks or pressure bubbles) are used to1321
segregate areas.1322
1323
6.7.7. The effect of room pressure tolerances are illustrated in Figure 31.1324
If one room is at the higher side of the tolerance and the other at the lower1325
side of the tolerance, it could result in either a high or a low pressure1326
differential. When setting tolerances it is also important to specify if the1327
tolerance is applicable to the absolute room pressures or the pressure1328
differentials. In the diagram below the tolerances have been based on a ±1329

page 54
3 Pa tolerance on absolute room pressures, resulting in pressure1330
differential variances of between 21 and 9 Pa. . For a room pressure1331
differential of 15 Pa and a tolerance based on ± 3 Pa of differential1332
pressure, then the resultant variances would only be between 12 and 18 Pa.1333
1334
Figure 311335
Examples of pressure cascades1336
1337
AirLeakage
AirLeakage
AirLeakage
AirLeakage
AirLeakage
AirLeakage
AirLeakage
AirLeakage
AirLeakage
Image of room pressure gauge
indicatingcolour coded normal,
alert & action parameters
1338
1339
6.7.8. The pressure control and monitoring devices used should be1340
calibrated and qualified. Compliance with specifications should be regularly1341
verified and the results recorded. Pressure control devices should be linked1342
to an alarm system set according to the levels determined by a risk analysis.1343
1344
6.7.9. Manual control systems, where used, should be set up during1345
commissioning, with set point marked, and should not change unless other1346
system conditions change.1347
1348
6.7.10. Airlocks can beimportant components in settingup and maintaining1349
pressure cascade systems and also to limit cross-contamination.1350
1351
6.7.11. Airlocks with different pressure cascade regimes include the1352
cascade airlock, sink airlock and bubble airlock (Figures 32–34):1353
1354
• cascade airlock: higher pressure on one side of the airlock and1355
lower pressure on the other;1356
• sink airlock: lower pressure inside the airlock and higher pressure on1357

page 55
both outer sides;1358
• bubble airlock: higher pressure inside the airlock and lower1359
pressure on both outer sides.1360
1361
Figure 321362
Example of cascade airlock1363
(In most cases the internal pressure of the airlock is not critical. The1364
pressure differential between the two outer sides is the important criteria.)1365
1366
1367
1368
1369

page 56
Figure 331370
Example of sink airlock1371
1372
1373
1374

page 57
1375
Figure 341376
Example of bubble airlock1377
1378
Material Airlock
Bubble Airlock
Air LeakageAir Leakage
30 Pa
15 Pa15 Pa
13791380
Note: The diagrams above and the differential pressures shown here are1381
for illustration purposes only. Pressures indicated in these examples are1382
absolute pressures, whereas the local pressure indication would most likely1383
be pressure differential from room to room.1384
1385
6.7.12. Doors should open to the high pressure side, so that room pressure1386
assists in holding the door closed and in addition be provided with self-1387
closers. Should the doors open to the low pressure side, the door closer1388
springs should be sufﬁcient to hold the door closed and prevent the pressure1389
differential from pushing the door open. There should be a method to1390
indicate if both doors to airlocks are open at the same time, or alternatively1391
these should be interlocked. The determination of which doors should be1392
interlocked should be the subject of a risk assessment study.1393
1394
6.7.13. Central dust extraction systems should be interlocked with the1395
appropriate air-handling systems, to ensure that they operate simultaneously.1396
1397
6.7.14. Room pressure differential between adjacent cubicles, which are1398
linked by common dust extraction ducting, should be avoided.1399
1400

page 58
6.7.15. Air should not flow through the dust extraction ducting or return1401
air ducting from the room with the higher pressure to the room with the1402
lower pressure (this would normally occur only if extract or return systems1403
were inoperative). Systems should be designed to prevent dust flowing back1404
in the opposite direction in the event of component failure or airflow failure.1405
1406
6.7.16. Adequate room pressure differential indication should be provided1407
so that each critical room pressure can be traced back to ambient pressure1408
(by summation of the room pressure differentials), in order to determine the1409
room actual absolute pressure, such as a pressure gauge installed to1410
indicate the pressure differential from a central corridor to the outside.1411
Room pressure indication gauges should have a range and graduation scale1412
which enables the reading to an appropriate accuracy. Normal operating1413
range, alert and action limits should be defined and displayed at the point of1414
indication.A colour coding of these limits on the gauge may be helpful.1415
1416
Room pressure indication may be either analogue or digital, and may be1417
represented as either pressure differentials or absolute pressures.1418
Whichever system is used any out-of-specification condition should be1419
easily identifiable.1420
1421
6.7.17. Material pass-through-hatches (PTH) or pass boxes (PB) can also1422
be used for separating two different zones. PTHs fall into two categories,1423
namely a dynamic PTH or a passive PTH. Dynamic PTHs have an air1424
supply to or extraction from them, and can then be used as bubble, sink or1425
cascade PTHs.1426
1427
6.7.18. Room pressure differential tolerances should always be set with a1428
maximum and minimum tolerance. Setting tolerances as NMT or NLT can1429
easily lead to an OOS condition.1430
1431
6.8. Physical barrier concept1432
1433
6.8.1. Where appropriate, an impervious barrier to prevent cross-1434
contamination between two zones, such as closed systems, pumped or1435
vacuum transfer of materials, should be used.1436
1437
1438
6.9. Temperature and relative humidity1439
1440
6.9.1. Where appropriate, temperature and relative humidity should be1441
controlled, monitored and recorded, where relevant, to ensure compliance1442
with requirements pertinent to the materials and products and provide a1443
comfortable environment for the operator where necessary.1444
1445

page 59
6.9.2. Maximum and minimum room temperatures and relative humidity1446
should be appropriate. Alert and action limits on temperatures and1447
humidities should be set, as appropriate.1448
1449
6.9.3. The operating band, or tolerance, between the acceptable minimum1450
and maximum temperatures should not be made too close. Tight control1451
tolerances may be difficult to achieve and can also add unnecessary1452
installation and running costs.1453
1454
6.9.4. Cubicles, or suites, in which products requiring low relative humidity1455
are processed, should have well-sealed walls and ceilings and should also1456
be separated from adjacent areas with higher relative humidity by means of1457
suitable airlocks.1458
1459
6.9.5. Precautions should be taken to prevent moisture migration that1460
increases the load on the HVAC system.1461
1462
6.9.6. Humidity control should be achieved by removing moisture from1463
the air, or adding moisture to the air, as relevant.1464
1465
6.9.7. Dehumidification (moisture removal) may be achieved by means of1466
either refrigerated dehumidifiers or chemical dehumidifiers.1467
1468
6.9.8. Appropriate cooling media for dehumidification such as low1469
temperature chilled water/glycol mixture or refrigerant should be used.1470
1471
6.9.9. Humidifiers should be avoided if possible as they may become a1472
source of contamination (e.g. microbiological growth). Where humidification1473
is required, this should be achieved by appropriate means such as the injection1474
of steam into the air stream. A product-contamination assessment should be1475
done to determine whether pure or clean steam is required for the purposes1476
of humidification.1477
1478
6.9.10. Where steam humidifiers are used, chemicals such as corrosion1479
inhibitors or chelating agents, which could have a detrimental effect on1480
the product, should not be added to the boiler system. Only appropriate1481
additives should be added to the boiler system.1482
1483
6.9.11. Humidification systems should be well drained. No condensate1484
should accumulate in air-handling systems.1485
1486
6.9.12. Other humidification appliances such as evaporative systems,1487
atomizers and water mist sprays, should not be used because of the potential1488
risk of microbial contamination.1489
1490
6.9.13. Duct material in the vicinity of the humidifier should not add1491
contaminants to air that will not be removed by filtration further downstream.1492
1493

page 60
6.9.14. Air filters should not be installed immediately downstream of1494
humidifiers, as moisture on the filters could lead to bacterial growth.1495
1496
6.9.15. Cold surfaces should be insulated to prevent condensation within1497
the clean area or on air-handling components.1498
1499
6.9.16. When specifying relative humidity, the associated temperature1500
should also be specified.1501
1502
6.9.17. Chemical driers using silica gel or lithium chloride are acceptable,1503
provided that they do not become sources of contamination.1504
1505
7. Dust control1506
1507
7.1. Wherever possible, dust or vapour contamination should be1508
removed at source. Point-of-use extraction, i.e. as close as possible to the1509
point where the dust is generated, should be employed. Spot ventilation or1510
capture hoods may be used as appropriate. The HVAC system should not1511
serve as the primary mechanism of dust control.1512
1513
7.2. Point-of-use extraction should be either in the form of a fixed,1514
high-velocity extraction point or an articulated arm with movable hood or a1515
fixed extraction hood.1516
1517
7.3. Dust extraction ducting should be designed with sufficient transfer1518
velocity to ensure that dust is carried away, and does not settle in the ducting.1519
Periodic checks should be performed to ensure that there is no build-up of1520
the dust in the ducting.1521
1522
7.4. The required transfer velocity should be determined: it is dependent1523
on the density of the dust (the denser the dust, the higher the transfer1524
velocity should be, e.g. 15–20 m/s).1525
1526
7.5. Airflow direction should be carefully chosen, to ensure that the1527
operator does not contaminate the product, and also so that the operator is1528
not put at risk by the product.1529
1530
7.6. Point extraction alone is usually not sufficient to capture all of1531
the contaminants, and general directional airflow should be used to assist1532
in removing dust and vapours from the room.1533
1534
7.7. Typically, in a room operating with turbulent airflow, the air should1535
be introduced from ceiling diffusers, located at the door entry side of the1536
room and extracted from the rear of the room at low level to help give a1537
flushing effect in the room. Correct flushing of the rooms may be verified1538
by airflow visualization smoke tests.1539
1540

page 61
7.8. When dealing with particularly harmful products, additional steps,1541
such as handling the products in glove boxes or using barrier isolator1542
technology, should be used.1543
1544
8. Protection of the environment1545
1546
8.1. General1547
1548
8.1.1. It should be noted that protection of the environment is not addressed1549
in this guideline, and discharges into the atmosphere should be compliant1550
with relevant local and national environmental legislation and standards.1551
1552
8.1.2. Dust, vapours and fumes could be possible sources of contamination;1553
therefore, care should be taken when deciding on the location of the inlet1554
and exhaust points relative to one other.1555
1556
8.2. Dust in exhaust air1557
1558
8.2.1. Exhaust air discharge points on pharmaceutical equipment and1559
facilities, such as from fluid bed driers and tablet-coating equipment, and1560
exhaust air from dust extraction systems, carry heavy dust loads and should be1561
provided with adequate filtration to prevent contamination of the ambient air.1562
1563
8.2.2. Where the powders are not highly potent, final filters on a dust1564
exhaust system should be fine dust filters with a filter classification of F91565
according to EN 779 filter standards.1566
1567
8.2.3. Where reverse-pulse dust collectors are used for removing dust from1568
dust extraction systems, they should usually be equipped with cartridge1569
filters containing a compressed air lance, and be capable of continuous1570
operation without interrupting the airflow.1571
1572
8.2.4. Alternative types of dust collectors (such as those operating with a1573
mechanical shaker, requiring that the fan be switched off when the mechanical1574
shaker is activated) should be used in such a manner that there is no risk1575
of cross-contamination. There should be no disruption of airflow during a1576
production run as the loss of airflow could disrupt the pressure cascade.1577
1578
8.2.5. Mechanical-shakerdustcollectorsshouldnotbeusedforapplications1579
where continuous airflow is required, in order to avoid unacceptable1580
fluctuations in room pressures, except in the case where room pressures are1581
automatically controlled.1582
1583
8.2.6. When wet scrubbers are used, the dust-slurry should be removed by1584
a suitable means, e.g. a drainage system or waste removal contractor.1585
1586

page 62
8.2.7. The quality of the exhaust air should be determined to see whether the1587
filtration efficiency is adequate with all types of dust collectors and wet1588
scrubbers.1589
1590
8.2.8. Where necessary, additional filtration may be provided downstream1591
of the dust collector.1592
1593
8.3. Vapour and fume removal1594
1595
8.3.1. Vapour should be extracted at the point of generation.When planning1596
the system for the extraction of residual vapours, the density of the vapour1597
should be taken into account. If the vapour is lighter than air, the extract1598
grilles should be at a high level, or possibly at both high and low levels.1599
1600
8.3.2. The systems for fume, dust and effluent control should be designed,1601
installed and operated in such a manner that they do not become possible1602
sources of contamination or cross-contamination, e.g. an exhaust-air1603
discharge point located close to the HVAC system fresh air inlet.1604
1605
8.3.3. Fumes should be removed by means of wet scrubbers or dry1606
chemical scrubbers (deep-bed scrubbers).1607
1608
8.3.4. Wet scrubbers for fume removal normally require the addition of1609
various chemicals to the water to increase the adsorption efficiency.1610
1611
8.3.5. Deep-bed scrubbers should be designed with activated carbon filters1612
or granular chemical adsorption media. The chemical media for deep-bed1613
scrubbers should be specific to the effluent being treated.1614
1615
8.3.6. The type and quantity of the vapours to be removed should be1616
known to enable the appropriate filter media, as well as the volume of media1617
required to be determined.1618
1619
1620
9. Commissioning, qualification and validation1621
1622
9.1. General1623
9.2.1624
9.2.1. The heating, ventilation and air-conditioning (HVAC) system plays1625
an important role in the protection of the product, the personnel and the1626
environment.1627
1628
9.2.2. For all HVAC installation components, subsystems or parameters,1629
critical parameters and non-critical parameters should be determined.1630
1631
9.2.3. Some of the parameters of a typical HVAC system that should be1632
qualified include:1633

page 63
1634
• room temperature and humidity;1635
• supply air and return air quantities;1636
• room pressure, air change rate, flow patterns, particle count and clean-up1637
rates;1638
• unidirectional flow velocities and HEPA filter penetration tests; and1639
• critical alarms, etc.1640
1641
9.3. Commissioning1642
1643
9.3.1. Commissioning should involve the setting up, balancing,1644
adjustment and testing of the entire HVAC system, to ensure that the1645
system meets all the requirements, as specified in the user requirement1646
specification, and capacities as specified by the designer or developer. The1647
commissioning plan should start at the early stages of a project so that it1648
can be integrated with qualification and verification procedures.1649
1650
9.3.2. Acceptable tolerances for all system parameters should be specified1651
and agreed by the user prior to commencing the physical installation.1652
These tolerances should be specified in the User Requirement1653
Specifications1654
1655
9.3.3. Acceptance criteria should be set for all system parameters. The1656
measured data should fall within the acceptance criteria.1657
1658
9.3.4. System installation records should provide documented evidence1659
of all measured capacities of the system.1660
1661
9.3.5. The i n s t a l l a t i o n r e c o r d s should include items such as the1662
design and measured figures for airflows, water flows, system pressures1663
electrical amperages, etc. These should be contained in the operating1664
and maintenance manuals (O & M manuals). The installation records of1665
the system should provide documented evidence of all measured capacities1666
of the system.1667
1668
9.3.6. Typical information that should be contained in the O&M1669
manuals is the following:1670
1671
• system description;1672
• operating instructions,1673
• trouble shooting;1674

page 64
• commissioning data schedules;1675
• maintenance instructions;1676
• list of equipment suppliers;1677
• spare parts lists;1678
• equipment capacity and data schedules;1679
• supplier’s literature;1680
• control system operation;1681
• electrical drawings;1682
• as-built drawings;1683
• maintenance records.1684
1685
9.3.7. O & M manuals, schematic drawings, protocols and reports should1686
be maintained as reference documents for any future changes and upgrades1687
to the system. As-built drawings should be available and should be kept up1688
to date with all the latest system changes. Any changes from the originally1689
approved system should be covered by change control documentation and1690
risk assessment studies where deemed necessary.1691
1692
9.3.8. Training should be provided to personnel after installation of the1693
system, and should include how to perform operation and maintenance.1694
1695
9.3.9. Commissioning should be a precursor to system qualification and1696
validation.1697
9.4.1698
9.5. Qualification1699
9.6.1700
9.6.1. Manufacturers should qualify HVAC systems using a risk-based1701
approach. The basic concepts of qualification of HVAC systems are set out1702
in Figure 35 below.1703
1704
1705

page 65
Figure 351706
Qualification is a part of validation1707
1708
9.6.2. The qualification of the HVAC system should be described in a1709
validation master plan (VMP), or a subsection of the VMP.1710
1711
9.6.3. The validation master plan should define the nature and extent of1712
testing and the test procedures and protocols to be followed.1713
1714
9.6.4. Stages of the qualification of the HVAC system should include1715
design qualification (DQ), installation qualification (IQ), operational1716
qualification (OQ) and performance qualification (PQ). The relationship1717
between the development stage of a project and the qualification/validation1718
stage is given in the V-Diagram (Figure 36) below.1719
1720

page 66
Figure 361721
User Requirement
Specification
Functional Design
Specification
Detail Design and
Configuration
Specifications
Build & Project
Implementation
Installation
Qualification
Operational
Qualification
Performance
Qualification
V-Model for Direct Impact Systems
PQ Test Plan
(incl. UAT)
OQ Test Plan
(incl. FAT)
IQ Test Plan
(incl. PDI)
Design
Qualification
DQ Test Plan
1722
9.6.5. Critical and non-critical parameters for all HVAC installation1723
components, subsystems and controls should be determined by means of a1724
risk analysis.1725
1726
9.6.6. Any parameter that may affect the quality of the pharmaceutical1727
product should be considered a critical parameter.1728
1729
9.6.7. All critical parameters should be included in the qualification1730
process.1731
1732
Note: A realistic approach to differentiating between critical and1733
noncritical parameters, systems or components is required, to avoid1734
making the validation process unnecessarily complex.1735
Example1736
• The humidity of the room where the product is exposed should be1737
considered a critical parameter when a humidity-sensitive product1738
is being manufactured. The humidity sensors and the humidity1739
monitoring system should, therefore, be qualified. Components or1740
equipment such as the heat transfer system, chemical drier or1741
steam humidifier, which is producing the humidity-controlled air, is1742

page 67
further removed from the product and may not require operational1743
qualification.1744
• A room cleanliness classification is a critical parameter and,1745
therefore, the room air-change rates and high-efficiency particulate1746
air (HEPA) filters should be considered critical parameters and1747
components, and therefore require qualification. Items such as the1748
fan generating the airflow and the primary and secondary filters1749
are considered non-critical components, and may not require1750
operational qualification.1751
1752
9.6.8. Non-critical systems and components should be subject to1753
verification by good engineering practice (GEP) and may not necessarily1754
require full qualification.1755
1756
9.6.9. A change control procedure should be followed when changes are1757
planned to the HVAC system, its components and controls, that may affect1758
critical parameters.1759
1760
9.6.10. The design condition, normal operating ranges, operating range1761
and alert and action limits should be defined and be realistic. Alert limits1762
should be based on system capability.1763
.1764
9.6.11. All parameters should fall within the design condition range1765
during system operational qualification. Conditions may go out of the1766
design condition range during normal operating procedures but they should1767
remain within the operating range.1768
1769
9.6.12. Out-of-limit results (e.g. alert or action limit deviations) should be1770
recorded and form part of the batch manufacturing records, and their1771
impact should be investigated.1772
1773
9.6.13. The relationships between design conditions, operating range and1774
qualified acceptance criteria are given in Figure 37. There should be SOPs1775
to determine action to be taken when alert and action limits are reached.1776
1777

page 68
Figure 371778
System operating ranges1779
1780
1781
9.6.14. A narrow range of relative humidities coupled with a wide range of1782
temperatures is unacceptable as changes in temperature will automatically1783
give rise to variations in the relative humidity.1784
1785
9.6.15. Some of the typical HVAC system parameters, based on a risk1786
assessment, that should be qualified for a pharmaceutical facility may1787
include:1788
1789
— temperature1790
— relative humidity1791
— supply air quantities for all diffusers1792
— return air or exhaust air quantities1793
— room air-change rates1794
— room pressures (pressure differentials)1795
— room airflow patterns1796
— unidirectional flow velocities1797
— containment system velocities1798
— HEPA filter penetration tests1799
— room particle counts1800
— room clean-up or recovery rates1801
— microbiological air and surface counts where appropriate1802
— operation of de-dusting1803
— warning/alarm systems where applicable.1804
1805
9.6.16. The maximum time interval between tests and re-qualification1806
should be defined by the manufacturer. The type of facility under test and1807
the product level of protection should be considered.1808
1809

page 69
Note: Table 5 gives intervals for reference purposes only. The actual test1810
periods may be more or less frequent, depending on the product and process1811
and subject to risk assessment.1812
Table 51813
Strategic tests to demonstrate continued compliance1814
(Time intervals given for re-qualification are for reference purposes only.1815
The actual tests required will depend on specific facility requirements)1816
Test parameter Max. time
interval
between tests
(all classes)
Test procedure
Particle count test
(verification of
cleanliness)
6 months
(ISO 5)
12 months
(>ISO 5)
Dust particle counts to be carried
out and result printouts produced.
No. of readings and positions of
tests to be in accordance with ISO
14644-1 Annex B.2
Air pressure
difference (to verify
absence of cross-
contamination)
12 months
Log of pressure differential
readings to be produced - critical
plants should be logged daily,
preferably continuously. In
accordance with ISO 14644-3
Airflow volume
(to verify air change
rates)
12 months
Airflow readings for supply air and
return air grilles to be measured
and air change rates to be
calculated. In accordance with
ISO 14644-3 Annex B.4
Airflow velocity
(to verify
unidirectional flow or
containment
conditions)
12 months
Air velocities for containment
systems and unidirectional flow
protection systems to be measured.
In accordance with ISO 14644-3
Annex B.4

page 70
HEPA filter leakage
tests
(to verify filter
integrity)
12 months
Filter penetration tests to be carried
out by a competent person to
demonstrate filter media, filter seal
and filter frame integrity.. In
Annex B.6
Containment leakage
(to verify absence of
cross-contamination)
12 months
Demonstrate that contaminant is
maintained within a room by
means of:
• airflow direction smoke tests
• room air pressures. In
Annex B.13
Recovery
(to verify clean-up
time)
12 months
Test to establish time that a
cleanroom takes to recover from a
contaminated condition to the
specified cleanroom condition. In
Room temperatures
(to verify temperature
tolerance adherence) 12 months
Demonstrate that room
temperatures at determined
locations comply with specified
tolerances. In accordance with
ISO 14644-3 Annex B.8.2
Warehouse and store
temperatures
(to verify temperature
mapping conditions)
36 months
Demonstrate that store
temperatures are uniform within
specified tolerances
In accordance with WHO 45th
report (WHO Technical Report
Series, No. 961), Annex 9 and
WHO 49th report (WHO Technical
Report Series, No. 992), Annex 5
plus Supplements 1 to 16
Room Humidities
(To verify humidity
tolerance adherence)
12 months
Demonstrate that room humidities
at determined locations comply
with specified tolerances. In
Annex B.9.2

page 71
9.6.17. Requalification should also be done when any change, which could1817
affect system performance, takes place.1818
1819
9.6.18. Room clean-up or recovery tests are performed to determine1820
whether the installation is capable of returning to a specified cleanliness1821
level within a finite time, after being exposed briefly to a source of1822
airborne particulate challenge.1823
1824
Room clean-up or recovery tests should demonstrate a change in particle1825
concentration by a factor of 100 within the prescribed time (as per ISO1826
14644-3 clause B.12) (3). The guidance time period for clean-up or1827
recovery is about 15 to 20 minutes.1828
In some instances it is not possible to increase the concentration by a1829
factor of 100 (such as for an ISO 14644 Class 8 condition) as the high1830
particle concentration can damage the particle counter. In this instance the1831
particle decay method can be used as per ISO 14644-3 clause B.12.3.2.1832
9.6.19. If energy-saving procedures such as reducing the airflow during1833
non-production hours are used, precautionary measures should be in place1834
to ensure that the systems are not operated outside the defined relevant1835
environmental conditions.1836
1837
These precautionary measures should be based on a risk assessment to1838
ensure that there is no negative impact on the quality of the product.1839
Qualification tests should be carried out to demonstrate that there are no1840
flow reversals, loss of room pressurisation cascade, temperature, humidity1841
excursions, etc.1842
9.6.20. Additional documents that should be included in the qualification1843
manuals should include system airflow schematics, room pressure cascade1844
drawings, zone concept drawings, air-handling system allocation drawings,1845
particle count mapping drawings, etc.1846
1847
1848

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