ISPE Good Practice Guide - HVAC
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ISPE GOOD PRACTICE GUIDE HVAC
DRAFT FOR REVIEW JULY 2008
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ISPE GOOD PRACTICE GUIDE 7
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HVAC 9
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2008 ISPE. ALL RIGHTS RESERVED. 40
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TABLE OF CONTENTS 45
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1 INTRODUCTION ...................................................... 5 47 1.1 BACKGROUND .................................................... 5 48 1.2 SCOPE OF THIS GUIDE ........................................... 5 49 1.3 OBJECTIVES OF THIS GUIDE ...................................... 6 50 1.4 DEFINITIONS ................................................... 6 51 1.5 REFERENCES .................................................... 6 52
2 FUNDAMENTALS OF HVAC .............................................. 9 53 2.1 INTRODUCTION .................................................. 9 54 2.2 WHAT IS HVAC? ................................................. 9 55 2.3 AIRFLOW FUNDAMENTALS ......................................... 13 56 2.4 PSYCHROMETRICS ............................................... 19 57 2.5 EQUIPMENT .................................................... 21 58 2.6 HVAC SYSTEM CONFIGURATION .................................... 23 59 2.7 HVAC CONTROLS AND MONITORING ................................. 39 60 2.8 SYSTEM ECONOMICS ............................................. 51 61 2.9 SUSTAINABILITY (TO BE WRITTEN LATER) ........................ 58 62
3 THE DESIGN PROCESS ............................................... 59 63 3.1 INTRODUCTION ................................................. 59 64 3.2 DEVELOPING THE USER REQUIREMENTS SPECIFICATION (URS) ......... 61 65 3.3 HVAC SYSTEM RISK ASSESSMENT .................................. 69 66
4 HVAC APPLICATIONS BY PROCESS AND CLASSIFICATION .................. 73 67 4.1 INTRODUCTION ................................................. 73 68 4.2 SYSTEM APPLICATIONS .......................................... 73 69 4.3 ROOM LEVEL EXAMPLES .......................................... 78 70 4.4 ACTIVE PHARMACEUTICAL INGREDIENTS (API) - (WET END) .......... 83 71 4.5 ACTIVE PHARMACEUTICAL INGREDIENTS (API) - (DRY END) .......... 84 72 4.6 BIOLOGICS .................................................... 85 73 4.7 ORAL SOLID DOSAGE (NON-POTENT COMPOUNDING) ................... 86 74 4.8 ORAL SOLID DOSAGE (POTENT COMPOUNDING) ....................... 89 75 4.9 ASEPTIC PROCESSING FACILITY .................................. 91 76 4.10 PACKAGING/LABELING ........................................... 94 77 4.11 LABS ......................................................... 95 78 4.12 SAMPLING/DISPENSING .......................................... 99 79 4.13 ADMINISTRATIVE AND GENERAL BUILDING ......................... 100 80 4.14 WAREHOUSE ................................................... 101 81 4.15 PROCESS EQUIPMENT CONSIDERATIONS ............................ 102 82
5 DESIGN QUALIFICATION / DESIGN REVIEW (DQ/DR) .................... 106 83 5.1 DESIGN REVIEW/ DESIGN VERIFICATION/DESIGN QUALIFICATION ..... 106 84 5.2 INTRODUCTION ................................................ 108 85
6 EQUIPMENT FUNCTION, INSTALLATION, AND OPERATION ................. 117 86 6.1 EQUIPMENT FUNCTION AND MANUFACTURE .......................... 117 87 6.2 EQUIPMENT INSTALLATION AND STARTUP .......................... 147 88 6.3 EQUIPMENT OPERATION AND MAINTENANCE ......................... 156 89
7 VERIFICATION AND TESTING ........................................ 165 90 7.1 INTRODUCTION ................................................ 165 91 7.2 PHILOSOPHY .................................................. 165 92 7.3 PRINCIPLES .................................................. 166 93 7.4 REGULATORY EXPECTATIONS ..................................... 167 94
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7.5 KEY CONCEPTS OF VERIFICATION ................................ 167 95 7.6 DESIGN, SPECIFICATION, VERIFICATION, AND ACCEPTANCE PROCESS . 169 96 7.7 SUPPORTING PROCESSES ........................................ 170 97
8 DOCUMENTATION REQUIREMENTS ...................................... 172 98 8.1 INTRODUCTION ................................................ 172 99 8.2 ENGINEERING DOCUMENT LIFECYCLE .............................. 172 100 8.3 DOCUMENTS FOR MAINTENANCE AND OPERATIONS (NON-GMP) .......... 173 101 8.4 MASTER/RECORD DOCUMENTS ..................................... 173 102 8.5 GMP HVAC DOCUMENTS .......................................... 174 103
9 PSYCHROMETRICS .................................................. 176 104 9.1 DRY-BULB TEMPERATURE ........................................ 176 105 9.2 WET-BULB TEMPERATURE ........................................ 176 106 9.3 DEW-POINT TEMPERATURE ....................................... 177 107 9.4 BAROMETRIC OR TOTAL PRESSURE ................................ 179 108 9.5 SPECIFIC ENTHALPY ........................................... 179 109 9.6 SPECIFIC VOLUME ............................................. 180 110 9.7 EIGHT FUNDAMENTAL VECTORS ................................... 183 111
10 COMMISSIONING AND QIUALIFICATION PROCESS ...................... 185 112 10.1 COMMISSIONING AND QUALIFICATION ............................. 185 113 10.2 IMPACT RELATIONSHIPS ........................................ 186 114 10.3 RISK ASSESSMENT MATRIX ...................................... 187 115
11 MISCELLANEOUS HVAC INFORMATION ................................ 188 116 11.1 GLOSSARY OF TERMS ........................................... 188 117 11.2 EQUATIONS USED IN HVAC AND THEIR DERIVATION ................. 188 118
12 REFERENCES .................................................... 195 119 12.1 SUMMARY OF USEFUL CLEANROOM EQUATIONS ....................... 195 120 12.2 PRESSURE CONTROL WHEN AIRLOCKS ARE NOT POSSIBLE ............. 196 121 12.3 HEPA FILTERS FOR HOT ZONES (DEPYROGENATION) ................. 196 122 12.4 USEFUL REFERENCE MATERIALS .................................. 196 123 12.5 HVAC EXAMPLES AND WORKBOOK (???) ............................ 196 124 12.6 EXAMPLE DOCUMENTS ........................................... 196 125
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1 INTRODUCTION 130 131
1.1 BACKGROUND 132 133
The heating, ventilating, and air conditioning (HVAC) system is one of 134
the more critical systems affecting the ability of a pharmaceutical 135
facility to meet its key objectives. HVAC systems which are properly 136
designed, built, operated, and maintained can help ensure the quality 137
of product manufactured in that facility, improve reliability, and 138
reduce both first cost and ongoing operating costs of the facility. The 139
design of HVAC systems for the pharmaceutical industry requires special 140
considerations beyond those for most other industries, particularly in 141
regards to cleanroom applications. 142
143
Each of the previously published ISPE Baseline Guides for facilities 144
(Active Pharmaceutical Ingredients, Oral Solid Dosage, Sterile Products 145
Manufacture, Biopharmaceuticals, etc.) have included some discussion of 146
the considerations for HVAC systems for facilities of that type. This 147
Good Practice Guide is intended to supplement those sections with more 148
detailed information and recommended practices for implementation of 149
HVAC systems in pharmaceutical facilities. 150
151
1.2 SCOPE OF THIS GUIDE 152 153
The Guide provides supporting information and HVAC practices for 154
facility types covered by Baseline Guides. 155
156
The Guide provides an overview of the basic principles of HVAC only to 157
the extent required to facilitate a common understanding and consistent 158
nomenclature. 159
160
This guide addresses HVAC requirements in the following areas of 161
facility lifecycle. 162
163
Establishing User Requirements 164
Design 165
Construction 166
Commissioning / Qualification 167
Operation / Maintenance 168
Redeployment for other use 169
Decommissioning 170 171
The guide does NOT serve as a handbook for HVAC design (e.g. it does 172
not discuss the details of sizing and selection of equipment. It does 173
go into boring detail on the physics of air and humidity.) 174
175
The guide clarifies HVAC issues critical to the Safety, Identity, 176
Strength, Purity and Quality (SISPQ) for the production of bulk and 177
finished pharmaceuticals and biopharmaceuticals, and it considers the 178
requirements for HVAC control and monitoring systems. 179
180
This guide addresses how to implement the recommendations in the 181
Baseline guides to meet FDA and EMEA regulatory expectations for HVAC 182
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design. 183
184
This guide references but does NOT reiterate the issues or content from 185
the Baseline guides. The appropriate Baseline Guide should be consulted 186
for regulatory expectations. 187
188
The guide discusses the impact of external conditions on HVAC design. 189
190
This guide attempts to give information in I/P and SI units. 191
192
The user of this guide should apply good engineering practice in 193
assessing which of the recommended practices is most applicable to a 194
situation. 195
196
1.3 OBJECTIVES OF THIS GUIDE 197 198
Provide the Pharmaceutical Engineering Community with common language 199
and understanding of critical HVAC issues. 200
201
Provide guidance on accepted industry practices to address these 202
issues. 203
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Provide a single common resource for HVAC information currently 205
included in appendices of the various Baseline guides. 206
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Target a global audience, with particular focus on US (FDA) and 208
European (EMEA) regulated facilities. 209
210
1.4 DEFINITIONS 211 212
This GPG uses terms as defined in the ISPE Glossary of Pharmaceutical 213
Engineering Terminology and will not repeat these definitions here. 214
Only new terms or terms specific to the content of this GPG are defined 215
in the Glossary. 216
217
1.5 REFERENCES 218 219
a. ISO Standards for Cleanrooms and Associated Controlled Environments 220
221
ISO 14644-1 Classification of air cleanliness 222
ISO 14644-2 Specifications for testing and monitoring to prove 223 continued compliance with ISO 14644-1 224
ISO 14644-3 Test methods 225
ISO 14644-4 Design, construction and start-up 226
ISO 14644-5 Operations 227
ISO 14644-6 Vocabulary 228
ISO 14644-7 Separative devices (clean air hoods, glove boxes, 229 isolators, and mini-environments) 230
ISO 14644-8 Classification of airborne molecular contamination 231
ISO 14698-1 Biocontamination control, Part 1: General principles and 232 methods 233
ISO 14698-2 Biocontamination control Part 2: Evaluation and 234 interpretation of biocontamination data. 235
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b. IEST Recommended Practices 237
238
RP-CC034.2- HEPA and ULPA Filter Leak Tests 239
RP-CC006.3- Testing Cleanrooms 240
RP-CC012.1- Considerations in Cleanroom Design 241 242
c. ISPE Baseline Guides 243
244
Vol. 1- Active Pharmaceutical Ingredients 245
Vol. 2- Oral Solid Dosage Forms 246
Vol. 3- Sterile Manufacturing Facilities 247
Vol. 4- Water and Steam Systems 248
Vol. 5- Commissioning and Qualification 249
Vol. 6- Biopharmaceuticals 250 251
d. ASHRAE- specific ASHRAE documents which are used in this GPG: 252
253
ASHRAE standard 62.1 - Ventilation for Acceptable Indoor Air Quality 254
ASHRAE standard 90.1 - Energy Standard for Buildings Except Low-Rise 255 Residential Buildings 256
ASHRAE standard 110 - Method of Testing Performance of Laboratory 257 Fume Hoods 258
ASHRAE Handbooks - Fundamentals; Applications; Systems & Equipment 259 260
e. ASTM Standard E2500-07 - Standard Guide for Specification, Design, 261
and Verification of Pharmaceutical and Biopharmaceutical Manufacturing 262
Systems and Equipment 263
264
f. US FDA Guidance for Industry Sterile Drug Products Produced by 265
Aseptic Processing- Current Good Manufacturing Practice (2004) 266
267
g. EudraLex Volume 4 EU Guidelines to Good Manufacturing Practice 268
269
Medicinal Products for Human and Veterinary Use 270
Annex 1: Manufacture of Sterile Medicinal Products 271
Annex 2: Manufacture of Biological Medicinal Products for Human Use 272 273
h. The Good Automated Manufacturing Practice (GAMP) Guide for 274
Validation of Automated Systems in Pharmaceutical Manufacture 275
276
i. WHO document on HVAC- proposed draft, does not apply to this 277
document. 278
279
j. CFR Title 21 Food & Drugs 280
281
Part 11: Electronic records 282
Part 210: Current good manufacturing practice in manufacturing, 283 processing, packing or holding of drugs; general 284
Part 211: Current good manufacturing practice for finished 285 pharmaceuticals 286
287
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k. FDA Guidance for Industry/ICH Guidelines 288
289
Q7A: Good manufacturing practice guidance for active pharmaceutical 290 ingredients 291
Q8: Pharmaceutical Development 292
Q9: Quality Risk Management 293
Q10: Quality Systems 294 295
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2 FUNDAMENTALS OF HVAC 296 297
2.1 INTRODUCTION 298 299
Most people live in homes with equipment incorporated into the building 300
to keep them comfortable. They have windows to allow natural 301
ventilation and heating and cooling systems to maintain desired 302
temperatures. 303
304
We have the same goal in our pharmaceutical manufacturing workplace 305
to make people comfortable, but we also have the more exacting 306
requirement to control the impact of the environment on the finished 307
product (i.e., product SISPQ). 308
309
This guide introduces the fundamentals of the HVAC systems that control 310
the GMP workplace environment. Only three room environment variables 311
may have an effect on product and processes (at the critical 312
locations): 313
314
Air temperature at the critical location may affect product or 315 product contact surfaces 316
Relative humidity of the air at the critical location may affect 317 product moisture content, or may affect product contact surfaces 318
(via corrosion, etc.) 319
Airborne contamination at the critical location (may affect product 320 purity or product contact surfaces) 321
322
Some variables, such as local contaminants, depend on other HVAC 323
variables such as room pressure, air changes, airflow volume, airflow 324
direction and velocity, and air filter efficiency. 325
326
2.2 WHAT IS HVAC? 327 328
HVAC (Heating, Ventilation and Air Conditioning) is the generic name 329
given to a system that provides the conditioning of the environment 330
through the control of Temperature, Relative Humidity, Air Movement and 331
air quality - including fresh air, airborne particles, and vapors. 332
HVAC systems can increase or decrease temperature, increase or reduce 333
the moisture or humidity in the air, decrease the level of particulate 334
or gaseous contaminants in the air. These abilities are employed for 335
comfort and to protect people and product. 336
337
2.2.1 People Comfort 338 339
The first role of HVAC systems is to make people comfortable. We notice 340
the HVAC systems performance when we are uncomfortable, but what 341
conditions are actually required to make people comfortable? 342
343
Four criteria are commonly considered for people comfort: 344
345
Temperature 346
Humidity 347
Air quality (contaminants, both particles and odors) 348
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Air movement (airflow direction and speed to control drafts) 349 350
2.2.1.1 Temperature and Humidity 351
352
The following drawing shows two boxes which define "comfort" conditions 353
(Temperature and Humidity) that Americans find comfortable in winter 354
and summer (from the ASHRAE Handbook). This standard varies across the 355
world - for example, in parts the tropics people prefer an office at 75 356
degrees F (24 degrees C) to one at 72 F (22C). 357
358
It should also be noted that these are general guidelines, as many 359
things affect these conditions apart from individual preferences - the 360
type and consistency of work being performed, for example. 361
362
This is apparent in the office workplace, with the different levels of 363
clothing people wear, some people dressed more heavily than others in 364
order to be comfortable 365
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Figure 2-1 Standard Effective Temperature and ASHRAE Comfort Zones 369
courtesy of ______________________ 370
371
2.2.1.2 Air Movement 372
373
Some people prefer a light sensation of air movement and some prefer 374
still air, so a typical design figure of 0.1 m/s (3 ft/sec) is used in 375
an office environment. Greater air velocities are usually needed for 376
product protection. 377
378
2.2.1.3 Air Quality 379
380
People need fresh air to dilute exhaled carbon dioxide and other 381
environmental contaminants. The amount of fresh air required depends on 382
the activity; the table below shows typical oxygen use for different 383
levels of activity. 384
385
Level of exertion Oxygen consumed L/min
Light work LT 0.5
Moderate work 0.5 to 1.0
Heavy work 1.0 to 1.5
Very heavy work 1.5 to 2.0
Extremely heavy work GT 2.0
386
Table2-1 Oxygen Consumption by activity Level 387
388
The amount of fresh air required to dilute environmental contaminants 389
is a minimum of 15 to 20 cubic feet per minute (cfm) or 24 to 32 cubic 390
meters per hour per person . 391
392
2.2.2 Product and Process Considerations 393 394
Product may be sensitive to temperature and humidity and to airborne 395
contamination - from outside sources or cross-contamination between 396
products. Process operators may need protection from exposure to 397
hazardous or potent materials 398
399
It is usually possible to find the products environmental 400
requirements, as they will be listed in the NDA when they are 401
considered critical. The impact of conditions outside these ranges 402
will depend on the duration of exposure prolonged exposure time may 403
reduce the efficacy of the product. 404
405
Control of airborne cross contamination and contamination are always 406
major issues. These requirements are often interlinked with temperature 407
and humidity consider the effect of temperature for example; 408
409
Comfortable people work more efficiently they are more 410
productive, and make fewer mistakes. They also produce fewer 411
environmental contaminants: A typical person will give off 100,000 412
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particles a minute doing relatively sedentary work (particles sized 413
0.3 micron and larger a human hair is approximately 100 micron in 414
diameter). A worker who is hot and uncomfortable may shed several 415
million particles per minute in this size range, including more 416
bacteria. 417
418
Environmental conditions inside a building can influence the product in 419
other ways higher temperatures and humidity tend to increase 420
microbial growth rates, particularly with regard to mold. 421
422
If building conditions are significantly different from those outside 423
and the fabric of the building does not have sufficient integrity, 424
condensation in interstitial spaces can occur and can lead to microbial 425
contamination problems and deterioration of the building. 426
427
Operator protection also depends on air flow direction both within and 428
between rooms. Airflow can entrain particles of product, product in 429
other rooms, or other hazardous materials harmful to operators. Though 430
differential pressure is commonly used as a control of contamination 431
between two rooms, it is the airflow generated by the differential 432
pressure that contains the product 433
434
2.2.3 How does the HVAC system control these parameters? 435 436
2.2.3.1 Temperature and Humidity 437
438
The HVAC system controls the temperature and humidity in the room using 439
the mechanism of supplying the room with air at a condition that, when 440
mixed with the room air, will yield the desired temperature and 441
humidity. 442
443
The heat gains and losses to and from the space are through the usual 444
mechanisms of heat transfer - Radiant, conductive and convective heat 445
transfer. These may be due to solar gain, external temperature outside 446
the facility, and internal heat gains due to the process, equipment, 447
people and lighting. 448
449
The changes in humidity are due to the process, people and the 450
environment. Moisture migration into the controlled space from 451
surrounding areas is governed by the difference in vapor pressure, as 452
defined by Daltons law, and can sometimes migrate against an air 453
pressure differential 454
455
2.2.3.2 Air velocity 456
457
In a working environment, air velocity is not as critical in terms of 458
human comfort as it is in an office environment. Velocity is critical 459
to proper mixing of air within the room and transport of airborne 460
particulates. 461
462
2.2.3.3 Particulate/fume and vapor control 463
464
The control of the particulate levels in the room, and in some cases 465
vapors/fumes, may be by dilution and displacement, controlling the 466
particulate levels in the supply air through filtration, and vapor/fume 467
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level by the use of exhaust and replacement (makeup) fresh air where 468
necessary. 469
470
2.2.4 What cant the HVAC System do? 471 472
HVAC systems are not a substitute for good process, facilities and 473
equipment design and good operating procedures. HVAC can not clean 474
surfaces that are already contaminated, and as a practical matter, it 475
cannot control processes that generate an excess of contaminants or 476
compensate for improperly designed or maintained facilities. HVAC, 477
while a common suspect area for investigation, is rarely the cause - or 478
the solution - for persistent contamination problems. 479
480
2.3 AIRFLOW FUNDAMENTALS 481 482
2.3.1 Introduction 483 484
As was discussed in section 2.1, HVAC can contribute to the control of 485
temperature, humidity, and particulates within a space. In order to 486
understand what equipment is needed to achieve this at the HVAC system 487
level, we must first define what the air is intended to do at the room 488
level. 489
490
Both the quality (temperature, humidity, filtration) and quantity of 491
air introduced into a room affect its ability to maintain environmental 492
conditions. This explores the effects of physical layout (geometry), 493
air velocity and air volume in assuring effective ventilation. 494
495
2.3.2 Ventilation Fundamentals 496 497
Ventilation is the movement and replacement of air for the purpose of 498
maintaining a desired environmental quality within a space. Ventilation 499
is responsible for the transport of airborne particles, the movement of 500
masses of hot or cold air, the removal of airborne contaminants (e.g., 501
vapors and fumes) and the supply of fresh O2 rich air. 502
503
Although the layman may be conscious of the term air change rates 504
(more properly called ventilation rate), successful pharmaceutical 505
HVAC design can be attributed to proper filtration and attention to the 506
physical geometry of airflow in a space. The layout of inlets and 507
outlets with relation to the sources of contamination/heat and 508
accommodation for expected obstructions are key to controlling 509
contamination and yielding effective HVAC design. The relationship 510
between these factors is expressed in the effective ventilation rate 511
for a space. This measure expresses the efficiency of the HVAC system 512
at removing contaminants expressed as a % of the theoretical 513
performance of perfect dilution. When comparing the effective 514
ventilation rates of various designs, it becomes clear that good 515
layout and filtration can produce desired airborne particulate levels 516
and recovery rates at lower than expected air change rates. 517
518
2.3.3 Contamination Control 519 520
The primary factor that separates pharmaceutical HVAC from comfort HVAC 521
is the need to control contamination. This stems from the need to 522
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assure the purity, identity and quality of the product (21CFR211). 523
Pharmaceutical HVAC is one tool in preventing unwanted environmental 524
contaminants from adversely affecting a product and to prevent products 525
from contaminating one another. It can also assist in limiting operator 526
exposure to potent pharmaceutical compounds, ingredients or reagent 527
vapors. Contamination control is generally achieved by filtering the 528
incoming air, to assure that it does not carry particulates, and then 529
introducing the air to the work space at sufficient velocity and volume 530
to transport unwanted particulate out of the work zone. The orientation 531
of these airflows can aligned so as to protect product or personnel by 532
sweeping across one or the other (or both) on its way from the supply 533
terminal to the extract point. Local supply or extraction can also 534
assist in contamination control by creating a local environment that 535
excludes or removes particulate. 536
537
Pharmaceutical HVAC can help control contaminants within a space, but 538
these facilities must be designed with several additional features that 539
contribute to this mission of limiting the migration of contaminants. 540
541
2.3.4 Airlocks 542 543
In order to minimize the amount of air that is needed to maintain 544
particle transport velocities (typically over 100fpm times 21 square 545
feet of open door area equals 2100 cfm) it is desirable that the doors 546
of a contamination controlled space remain closed. One way to do this 547
is to provide airlocks or ante rooms. These rooms control traffic 548
into and out of a space through a series of interlocked doors to assure 549
that a door to the space is always closed. 550
551
Airlocks serve other purposes as well: 552
553
they maintain some differential pressure between the two areas they 554 serve, such that the DP can not drop to zero 555
they provide a location for gowning/de-gowning prior to 556 entering/exiting a classified space 557
they provide a location for sanitizing / decontamination of incoming 558 or outgoing materials and equipment 559
they can be designed with a small volume and high air change rate to 560 allow them to recover quickly and function to minimize the 561
particulate introduced to a classified space by door openings. 562
they provide can provide a high or low pressure buffer to control 563 the ingress and egress of contaminants. 564
565
2.3.5 Classified Space 566 567
A key measurement of room environmental conditions for pharmaceutical 568
operations is the concentration of total airborne particulate and/or 569
microbial contamination within the space; this is referred to as the 570
classification of the space. Several systems have been promulgated 571
for the classification of space; however there is not consensus between 572
international regulators on a single best standard for classification. 573
To bridge the gap between the various standards, this guide provides 574
the following reference to be used across facility types requiring air 575
classification, (primarily facilities for sterile/aseptic manufacture 576
and for controlled bioburden processing, such as bulk 577
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biopharmaceuticals). It should not be used for other facilities, such 578
as bulk chemical intermediates or oral dosage finishing. See the 579
appropriate Baseline Guide for specific air quality information. 580
581
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582
REFERENCE DESCRIPTION CLASSIFICATION
ISPE STERILE BASELINE
GUIDE
Draft 2008
ENVIRONMENTAL CLASSIFICATION GRADE 5 GRADE 7 GRADE 8 Controlled
Not
Classified
with local
monitoring
Controlled
Not
Classified
European Commission
EU GMP, Annex 1,
Volume lV,
Manufacture of
Sterile Medicinal
Products (1997) also
PIC/S GMP Annex 1
2002
Descriptive Grade A
(Note1) B C D Not defined
At
Res
t
(No
te
2)
Maximum no.
particles
permitted
per m3 the
stated size
0.5 3 500 3 500 350 000 3 500 000 -
5 1 1 2 000 20 000 -
In
Ope
rat
ion
Maximum no.
particles
permitted
per m3 the
stated size
0.5 3 500
(Note
3)
350 000 3 500
000
Not stated -
5 1 2 000 20 000 Not stated -
Maximum permitted
number of viable
organisms cfu / m3
< 1 < 10 < 100 < 200 -
FDA, October 2004,
Guidance for Industry
Sterile Drug Products
Produced by
In
Ope
rat
ion
Maximum
particl
es
permitt
ed
stated
size
no.
the
0.5 ISO 5
Class
100
ISO 7
(Class
10 000)
ISO 8
(Class
100
000)
- -
583
Table 2-2 Comparison of Classified Spaces 584
585
586
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587
Pharmaceutical HVAC can help control contaminants within a space, but 588
these facilities must be designed with several additional features that 589
contribute to this mission of limiting the migration of contaminants. 590
591
2.3.6 Total Airflow Volume and Ventilation Rate 592 593
Much has been made of the importance of air change rate (volume of 594
air/hour room volume) or ventilation rate, the number of times in 595
an hour that the air volume of a room is replaced. Little is said about 596
the relationship between these rates and the classification of the 597
space, recovery rates and the more important issue of total volume of 598
ventilation. 599
600
When considering the design of classified space, designers will often 601
first consider the requirement for 20 Air Changes/hour (AC/hr), 602
expressed in the 1987 FDA Sterile Guide. In lieu of calculating the 603
airflow required by the process, many will default to rules of thumb 604
for ventilation rate by the class of space, typically in the ranges: 605
606
15-20 AC/hr for Controlled, Not Classified (CNC) spaces 607
20-40 AC/hr for Grade 8 (EU Grade C) 608
40-60 AC/hr for Grade 7 (EU Grade B) 609
300-600 AC/hr for Grade 5 (EU Grade A) 610 611
As seen below, these rules of thumb may be overkill, or may prove to be 612
insufficient. The airborne particle levels depend more on a number of 613
factors. 614
615
2.3.6.1 Air change or Air Flow? 616
617
These air change rates often drive decisions regarding room size and 618
airflows, and can have significant cost implications, but do not 619
relate directly to the particle count in the room. Air change rates are 620
related to the rooms ability to recover from an upset, not the room 621
classification as is commonly assumed. To explain this difference: 622
623
Assume a 1 cubic foot volume with a process inside it that generates 624
10,000 particles per minute. If we purge the volume with 1 cubic foot 625
per minute of clean air, the steady state (equilibrium) airborne 626
particle level will be 10,000 particle per cubic foot (see the Appendix 627
for equations). This 1 CFM creates an air change every minute, or 60 628
air changes per hour. This value (60/hr) is often assumed to be more 629
than enough to keep a space well below 10,000 particles per cubic foot 630
(PCF). 631
632
Now put the same process into a 100 cubic foot volume and keep the 633
airflow at 1 cfm, assuming good mixing inside the room. Now the room 634
sees an air change every 100 minutes, or about 0.67 ac/hr. Yet, when we 635
calculate the dilution, the equilibrium airborne particle counts are 636
still 10,000 PCF (10,000 particles per minute divided by 1 cubic foot 637
per minute = 100 particles per cubic foot). If we would supply 1 air 638
change per hour (100 CFM) of clean air, the room airborne counts drop 639
to 100 PCF !!! So its not air changes that determine airborne particle 640
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ISPE GOOD PRACTICE GUIDE HVAC
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counts, but three factors (referring to the Appendix): 641
642
1. Particles generated inside the space 643 2. Quantity of dilution air supplied to the space (cubic volume 644
per time) 645
3. Cleanliness of dilution air (assumed to be negligible in 646 pharma due to HEPA filtration) 647
648
As is demonstrated elsewhere, a room receiving only 1 air change per 649
hour will take hours to recover from in-use to at-rest conditions. 650
With clean air supply of 20 air changes per hour, a 100-fold recovery 651
in particle levels can happen in less than 20 minutes (see the ISPE 652
Sterile Baseline Guide). So when it comes to RECOVERY, air changes ARE 653
important, 20/hr often being the minimum for classified spaces. 654
655
Although the layman is conscious of the importance of air change rate 656
(more properly called ventilation rate) successful pharmaceutical 657
HVAC design can be attributed to proper filtration and attention to the 658
physical geometry of airflow in a space. 659
660
2.3.6.2 Impact of UDF (UFH) hoods on air change rates 661
662
Later sections will discuss mixed flow rooms with clean air supplied 663
at the ceiling through terminal filters as well as clean air being 664
introduced to the room from Unidirectional Flow Hoods (UFH or UDF, once 665
called Laminar Flow) operating inside the room. Since air leaving the 666
space served by the hood is often orders of magnitude cleaner than the 667
room it leaks into, the relatively clean hood air serves to dilute 668
airborne particles in the room, along with the supply air from the 669
HVAC. In many respects the added flow from the hood not only reduces 670
airborne particles in its path, but can also accelerate the recovery 671
time of the room from in-use to at-rest conditions. The entire flow 672
from the hood will likely not be available to add into air change 673
calculations, however, due to: 674
675
Short circuiting of the hood air back to the hood inlet. Only areas 676 near the airflow path will see the added dilution. 677
Hood air is not as clean as HVAC supply air. Even though the hood 678 might be rated as Grade 5 (class 100) the air leaving the work space 679
has collected additional contaminants from equipment and people 680
outside the critical zone. 681
682
2.3.7 Room Distribution and Quality of incoming air 683 684
The layout of inlets and outlets with relation to the sources of 685
contamination and accommodation for expected obstructions are key to 686
controlling contamination and yielding effective HVAC design. The 687
relationship between these factors is expressed in the effective 688
ventilation rate for a space. This measure recognizes that good layout 689
and filtration can produce desired airborne particulate levels and 690
recovery rates at lower than expected air change rates. 691
692
Taking the example above, good air mixing (dilution) and faster 693
recovery can be accomplished in a room where clean air supply is 694
distributed over a high percentage of the ceiling and not just from one 695
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ISPE GOOD PRACTICE GUIDE HVAC
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19
air outlet. Although its not necessary to create a laminar flow 696
ceiling, numerous air outlets equally spaced with equal flow rates can 697
create a plug flow for faster recovery (often less than 10 minutes 698
for 20 ac/hr) and also prevent hot spots of high particle count in 699
the room. 700
701
2.3.8 Airflow Direction and Pressurization 702 703
Since constructing a space that is totally airtight is not practical is 704
normal construction, other means must be provided to assure that 705
particulate can be prevented from migrating into or out of a space. 706
Assuring that air is always flowing in the desired direction through 707
the cracks in building construction (door gaps, wall penetrations, 708
conduits, etc.) can influence contamination through the transport of 709
airborne particulates. A velocity of 1-200 FPM will contain light 710
powders and bioburden 711
712
One method to control this direction of airflow is by controlling the 713
relative pressurization of adjacent spaces or the Differential Pressure 714
(DP) between the spaces. 715
716
A simplified method (neglecting the orifice coefficient for the 717
opening) to calculate the expected velocity of airflow from a given 718
pressure is: 719
720
V = 4005 (sqrt VP) or VP =(V/4005) (where V is velocity in ft/min, 721
VP is pressure difference in inches w.g., A is area of the opening 722
in square feet, Q is airflow in CFM) 723
724
We can breakdown velocity as being volume divided by area, giving 725
V = Q/A, or 726
727
VP = (CFM/4005A) 2 728
729
Assuming room DP converts fully to Velocity Pressure thru an 730
opening (a conservative assumption), calculating the opening area, 731
such as the crack area around a closed door between rooms, allows 732
calculation of the airflow (CFM) required to create a pressure, or 733
the velocity that results from a known DP. 734
735
For A=1 sq foot (0.1 sq.M) opening, 890 CFM (about 1500 CuM/hr or 736
0.45 CuM/sec) will create 0.05" w.g. (12.5 Pa) differential 737
pressure (V = Q/A = 890 FPM = 4.5 M/s) 738
739
2.4 PSYCHROMETRICS 740 741
2.4.1 Introduction 742 743
Psychrometrics is the science that involves the properties of moist air 744
(a mixture of dry air and water vapor) and the process in which the 745
temperature and/or the water vapor content of the mixture are changed. 746
Psychrometrics psychro means moisture and metrics means to 747
measure. A psychrometric chart is used to identify conditions of air 748
and to illustrate the process of achieving the desired state of the 749
controlled space. An in-depth knowledge of psychrometrics is impossible 750
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ISPE GOOD PRACTICE GUIDE HVAC
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to impart in this document; the reader is referred to other sources 751
such as the ASHRAE Fundamentals Handbook. 752
753
2.4.2 Basic Properties of Air 754 755
2.4.2.1 Dry air is comprised of 78.1% nitrogen, 21% oxygen, and has 756
trace amounts of ten additional elements totaling 0.9%. The air around 757
us is a mixture of dry air and water vapor. When this moist air 758
reaches a level at which it can not hold any more moisture, it is said 759
to be, saturated. The colder the air, the less moisture which can be 760
held in the air while warmer air can hold larger quantities of moisture 761
in the air. 762
763
2.4.2.2 The moisture in dry air (its specific humidity) is measured in 764
grains of moisture per pound of air (7,000 grains equal 1 pound). Air 765
at 75F and 60% RH has a specific humidity of 78 grains of water per 766
pound (7000 grains) of dry air. Therefore, one pound of this air 767
contains 77 grains of water and 6923 grains of dry air. 768
769
2.4.2.3 A psychrometric chart provides an overview of thermodynamic 770
properties of air-water mixtures, and shows the relationships of air at 771
different conditions. If any two properties of the air mixture are 772
known, the chart allows an engineer to determine all its other 773
properties. Air-water vapor mixtures have interrelated psychrometric 774
properties that can be plotted on a psychrometric chart. (See Appendix 775
for psychrometric chart discussion). 776
777
2.4.2.4 Sensible heat causes a change in the temperature of a 778
substance. Sensible heat can be sensed or felt and quantified by 779
measurement with a dry bulb thermometer. Addition or removal of 780
sensible heat will cause the measured temperature to rise or fall. 781
Sensible heat shows on the psychrometric chart as a horizontal line; 782
there is no resulting change in the amount of water vapor in the air. 783
784
2.4.2.5 Latent Heat comes from the Latin word meaning hidden. 785
Changes in latent heat are neither sensed or felt; however they will 786
cause a change of state in the substance. Latent heat is the heat 787
required to evaporate the moisture which the air contains. 788
789
For example, if sufficient latent heat is added to water in the liquid 790
state, it will change state into a vapor or steam. The change of state 791
from a liquid to steam is called the latent heat of vaporization and 792
from a steam to a liquid is called the latent heat of condensation. 793
The change of state from a liquid to a solid is called the latent heat 794
of fusion and from a solid to liquid the latent heat of melting. 795
Latent heat appears on the psychrometric chart as a vertical line. 796
797
2.4.3 Psychrometric Properties of Air 798 799
See the Appendix for a discussion of the terms used in Psychrometrics 800
and for an explanation of the Psychrometric Chart. 801
802
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Dry-bulb temperature tDB Specific enthalpy h
Wet-bulb temperature tWB Specific volume v
Dew-point temperature tDP Humidity ratio W
Relative humidity RH Water vapor pressure p WV
Barometric pressure PBAR
Measurable Psychrometric Properties Calculable Psychrometric Properties
803 Table 2-3 Psychrometric Terminology 804
805
2.5 EQUIPMENT 806 807
2.5.1 Introduction 808 809
Each piece of HVAC equipment helps contribute to sustaining the user 810
requirements for room environmental conditions. HVAC equipment serving 811
GMP areas are intended to work in conjunction with associated controls 812
and sequences of operation systems to: 813
814
Maintain room temperature 815
Maintain room pressurization and differential pressure cascades 816
Provide make up air for ventilation and room pressurization 817
Condition the air stream to remove and/or add moisture content of 818 the air 819
Minimize airborne contamination to the condition space 820
Provide required air change rates to maintain room cleanliness 821 classification when required 822
823
The following major components of an HVAC system for GMP spaces are 824
discussed in more depth in Chapter 6. 825
826
2.5.2 Air Handling Unit (Ahu) 827 828
An equipment package that includes a fan or blower, heating and/or 829
cooling coils, air filtration, etc. for providing heating, ventilation, 830
and air conditioning (HVAC) to a building. 831
832
2.5.3 Fan 833 834
An electrically driven air moving device used to supply, return or 835
exhaust/extract air to or from a room through ductwork to generate air 836
in sufficient amounts to provide ventilation, heating, cooling or to 837
overcome air pressure losses. 838
839
2.5.4 Fume Exhaust/Extraction System 840 841
A system made up of ductwork, fans and possibly filters that discharges 842
unwanted air outside into the atmosphere to a safe distance from 843
buildings and people. 844
845
2.5.5 Heating Coil 846 847
A heat transfer device consisting of a coil of piping which increases 848
the sensible heat into an air stream, using steam or hot water or 849
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glycol as the heating medium. And electric air-heating element can also 850
be called a heating coil. 851
852
2.5.6 Cooling Coil 853 854
A heat transfer device consisting of a coil of piping, which reduces 855
the sensible heat and possibly latent heat (via condensation of water 856
vapor) from the airstream using chilled liquid or refrigeration as the 857
cooling medium. 858
859
2.5.7 Humidifier 860 861
A device to increase the humidity within a controlled space by means of 862
the discharge of water vapor into the supply air stream or directly 863
into the room. 864
865
2.5.8 Dehumidifier 866 867
A special device that removes water vapor from the air to reduce 868
humidity. 869
870
2.5.9 Air Filtration 871 872
Devices to remove particulate material from an airstream by means of 873
various media types. 874
875
2.5.10 Ductwork 876 877
A network of air conduits distributed throughout a building, connected 878
to a fan to supply, return or exhaust/extract air to or from zones in a 879
building. 880
881
2.5.11 Damper And Louver 882 883
2.5.11.1 Found in ductwork, a damper consists of a movable plate(or 884
numerous plates), plunger, or bladder that opens and closes to 885
regulate airflow. Dampers are used to regulate airflow to certain 886
rooms. 887
888
2.5.11.2 A louver is an assembly of sloping vanes intended to permit 889
air to pass through and to inhibit transfer of water droplets from 890
outdoors into air systems. A louver may also be found in return air 891
ductwork at room interfaces. 892
893
2.5.12 Diffuser And Register 894 895
Air distribution outlet or grille designed to introduce air to a space 896
using direct airflow in desired patterns. Air diffusers are usually 897
located to distribute the air as uniformly as possible through out a 898
space. 899
900
2.5.13 Ultraviolet (UV) Light 901 902
A UV light uses precise ultraviolet light wavelength to destroy 903
microorganisms. 904
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23
905
Equipment
Heating
Cooling
Humidification
Dehumidification
Room
Static
Pressure
Airflow
Air Quality
Air Handler X X X X X X
Fan X X
Fume Exhaust/Extract
Systems X X
Heating Coil X
Cooling Coil X X
Air Filter X
Humidifier X
Dehumidifier X
Ductwork X X
Damper & Louver X X
Diffuser & Register X
UV Light X
906
TABLE 2-4 System components and their primary function relating to 907
environmental parameters 908
909
2.6 HVAC SYSTEM CONFIGURATION 910 911
2.6.1 Introduction 912 913
This section gives a brief overview of the key factors to consider, the 914
options available to an HVAC system designer, and the factors 915
influencing the decision to choose a particular system type. 916
917
This section should be read in conjunction with section 4 HVAC 918
APPLICATIONS BY PROCESS AND CLASSIFICATION. 919
920
One question to answer is how many Air Handling Units should be used? 921
922
It is common practice to divide a manufacturing area into zones, and 923
use a separate Air Handling Unit per zone a zone in general Building 924
Services design would be an area with similar heat gains and losses, a 925
similar approach is used within the pharmaceutical industry and is 926
usually considered as an area with one type of manufacturing process or 927
area classification, e.g. a tablet compression suite or all Grade 7 928
areas, as the area requirements will be similar. Other factors that are 929
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ISPE GOOD PRACTICE GUIDE HVAC
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considered when dividing a facility into zones include: 930
931
Use of multiple units improves reliability of the area it would be 932 unusual for all of the units to fail. 933
The use of multiple smaller units might make air balancing easier 934
The use of multiple smaller units means that the main distribution 935 ducts are smaller, making then easier to route in small ceiling 936
voids. 937
It is easier to make modifications to parts of the facility in 938 future and upgrade a small unit than change a large single unit 939
Use of multiple units allows for easier separation of areas within a 940 multi-product concurrent manufacturing plant. 941
942
The decisions regarding AHU system zoning are very important as a 943
factor in subsequent facility commissioning, qualification and related 944
documentation. 945
946
2.6.2 Basic System Types 947 948
There are three basic categories of HVAC system; 949
950
2.6.2.1 Once through - uses treated outside air to provide the design 951
internal conditions, this air is then extracted from the space and 952
discarded. 953
954
Air Handler Unit
(AHU)
Room
Outdoor
air
Supply air
Exhaust Infiltration
Exfiltration 955
956
Figure 2-2 Once-through HVAC 957
958
Advantages of this system: 959
960
This system provides an abundance of O2 rich fresh air to dilute 961 contaminants 962
The system can handle hazardous materials, though the extracted air 963
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may need treatment before it is discarded. 964
Lower risk of cross contamination of products from another room via 965 HVAC 966
Exhaust fan may be located remote from the AHU making duct routing 967 simpler 968
As there are less concerns about the ductwork noise in the extract 969 ductwork, it can usually be sized for a high velocity, making it 970
easier to route as high velocity = smaller diameter 971
972
Disadvantages of this system: 973
974
More expensive to operate than an equivalent recirculating system, 975 especially when cooling and heating. 976
Filter loading very high = frequent replacement 977
Potential need for exhaust air treatment (scrubbers, dust 978 collectors, filters) 979
Room conditions more difficult to maintain 980 981
2.6.2.2 Recirculating systems - This category is much more common the 982
room supply air is made up of a percentage of treated outside air mixed 983
with some of the air extracted from the space. A percentage of the air 984
is either discarded or lost through leakage to adjacent areas, due to 985
local area pressurization. 986
987
Air Handler Unit
(AHU)
Room
Makeup
(Fresh)
air
Return air
Supply air
Exfiltration
Infiltration
Possible extract
988 989
Figure 2-3 Recirculated HVAC 990
991
Advantages of this system: 992
993
Usually less air filter loading = lower filter maintenance and lower 994 cost opportunity for higher grade air filtration 995
Lower energy cost than once through 996
Less challenge to HVAC means that it is simpler to obtain better 997
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control of parameters (T, RH, etc) 998
999
Disadvantages of this system: 1000
1001
Return air ductwork routing to air handler may complicate above 1002 ceiling 1003
Chance of cross contamination via HVAC = Requires adequate supply 1004 air filtration (and sometimes return air filtration to prevent 1005
contamination of the air handler) 1006
Chance of recirculation of odors and vapors and of inadequate fresh 1007 air supply 1008
1009
2.6.2.3 Exhaust (Extract) system sometimes a stand-alone system that 1010
removes airborne contaminants, either solid particles or gasses/vapors. 1011
It may be interlinked to a once-through or recirculated air supply 1012
system. Used alone, the extract/exhaust system will create a negative 1013
differential pressure in the room or enclosure it serves 1014
1015
"Space" with airborne contaminants
Space may be a room, a glovebox or an exhaust hood
Fan
Air cleanerStack
(follow 1.3x
rule of thumb
if "foul air"see ASHRAE)
Ductwork
Infiltration
duct leakageExfiltration
duct leakage
1016 1017
Figure 2-4 Exhaust System 1018
1019
Advantages of this system: 1020
1021
Simple to operate. Makeup air is pulled from surrounding spaces. 1022 1023
Disadvantages of this system: 1024
1025
If used to capture large quantities of contaminants, such as from 1026 open processes, a large energy cost will be associated with 1027
conditioned air being thrown away (see once-through system above). 1028
1029
2.6.2.1 Use of Air Handling Units in parallel or series 1030
1031
It is possible to put units in series, for example if a higher air 1032
pressure is required to offset the pressure drop through HEPA filters 1033
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in one area served by an HVAC system. 1034
1035
The use of parallel units is common practice where large areas are 1036
being conditioned, for example warehouses and large research 1037
laboratories, where this approach may make it possible to maintain 1038
acceptable conditions in the area should one unit fail. When 1039
configuring units in parallel, care must be taken to assure that the 1040
fans can be isolated and started independently. Automatic isolation 1041
dampers and variable fan drives assist in managing these factors. 1042
1043
2.6.2.2 Configurations and combinations 1044
1045
The basic components and concepts outlined above can be assembled in an 1046
infinite variety of ways. Shown below are a few examples of design 1047
concepts commonly used. 1048
1049
(Note: Add some basic block diagram schematics to illustrate these 1050
combinations.) 1051
1052
2.6.3 Air Handling Unit Configurations 1053 1054
There are two basic types of AHU configuration blow through or draw 1055
through. The term describes the relationship of the fan to the coils in 1056
the air handling unit. The two approaches have distinctive 1057
characteristics; 1058
1059
2.6.3.1 Blow through units 1060
1061
Air is drawn into the unit, typically through a set of pre-filters used 1062
to reduce the dirt load on the (usually more expensive) final filters, 1063
and to prevent build up of dirt onto the heating and cooling coils, 1064
which would quickly reduce their efficiency. 1065
1066
One advantage of this type of unit is that it allows the AHU discharge 1067
temperature to be at the cooling coil discharge air temperature, 1068
because the fan heat is removed in the cooling coil. This is 1069
particularly useful when heat loads are particularly high and supply 1070
air temperature must be as cold as possible. It is not advisable to 1071
follow a blow through unit immediately with a set of HEPA filters 1072
unless special precautions are included to prevent moisture carryover 1073
from the cooling coil. Another advantage is that if the drain trap on 1074
the cooling coil runs dry, then air will blow out through the trap 1075
wasting a small amount of treated air. 1076
1077
The disadvantage - the unit typically needs to be longer to allow a 1078
diffuser to be installed after the fan to ensure that the airflow is 1079
spread over the entire coil area, and not concentrated on the middle, 1080
which would cause a drop in system performance. 1081
1082
2.6.3.2 Draw through units 1083
1084
These units are typically arranged with the pre-filters and coils 1085
before the fan. The advantage of this is that the unit is often 1086
smaller, and the motor and fan provide a small amount of reheat 1087
(usually 1-2 degrees F) to the air coming off the cooling coil. This 1088
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lowers the RH of the air and prevents the problems with wetting final 1089
AHU HEPA filter banks. One precaution with draw through units is that 1090
if the drain trap is dry, then untreated air can be drawn into the unit 1091
through the trap, with only the final filter to protect the conditioned 1092
environment. The design must include provisions for maintaining a 1093
wetted drain trap, which can be several inches in height. 1094
1095
2.6.3.3 Air Handling Unit Design variations 1096
1097
A design variation worth considering is the use of a face and bypass 1098
damper the concept is shown below a portion of the air passing 1099
through the AHU is redirected through a treatment stage, with the 1100
volume altered to vary the condition of the resulting output air. This 1101
is a useful concept to use to gain improved accuracy, particularly if 1102
the treatment process is not easily controllable e.g. chemical 1103
desiccant dehumidification. 1104
1105
Dehumidifier
_
1106 1107
Figure 2-5 Face and bypass control with a packaged dehumidifier and 1108
cooling coil (-) 1109
1110
A similar concept is often employed in the first mixing box of the AHU 1111
when enthalpy control is used in all cases careful sizing of the 1112
dampers, to ensure adequate velocity for control, is necessary to 1113
obtain proper operation of these systems, maintaining constant system 1114
volume as the proportions of the air streams are varied. 1115
1116
2.6.3.4 Air Handling Unit Components 1117
1118
Numerous design options are possible within the 2 basic types. Here 1119
will establish a lexicon of design components, or modules, that can be 1120
assembled into an AHU design and discuss the motivations that drive the 1121
selection of each. To illustrate the possible options, the following 1122
demonstration uses a draw-through, Recirculating AHU: 1123
1124
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Mixing Box HumidifierDehumidifier Reheating Coil
Supply Fan
Energy
Recovery
Coil
1125 1126
Figure 2-6 Air Handler Unit Components 1127
1128
Return Fan 1129
1130
Most recirculating air systems will utilize a return fan. This fan 1131
allows return pressure and flow to be managed independently from the 1132
supply. This is particularly important if the downstream system has 1133
volume control boxes on both the supply and return. It also allows the 1134
return air to be diverted to exhaust when outside air conditions are 1135
closer to desired discharge conditions than return air. This function 1136
is referred to as an economizer and is generally employed in offices 1137
or other spaces that are not pressure controlled. 1138
1139
Mixing Box 1140
1141
This pieced of equipment is also common in recirculating air systems. 1142
The return air can be directed to exhaust or to recirculate, it is then 1143
mixed with outside air for pressurization and/or ventilation. The 1144
resulting air stream is referred to as mixed air. In very cold 1145
environments the mixed air may be subjected to a turbulence inducing 1146
device to assure thorough mixing and avoid stratification. 1147
1148
Prefilter or Prefilter and Intermediate Filter 1149
1150
Filters are typically provided upstream of coils in an air handler to 1151
protect the coils from fouling with dirt or debris. The system 1152
typically employs a low efficiency dust stop (MERV 7) filter followed 1153
by a medium or high efficiency intermediate filter (MERV 7-14). 1154
1155
Energy Recovery Coil 1156
1157
Once through air systems, or other systems with high amounts of exhaust 1158
may employ an energy recovery coil to return a portion of the energy 1159
employed in conditioning the exhausted air to the incoming air. These 1160
coils are typically upstream of all other coils and may be placed 1161
upstream of the filters if used to melt snow in cold climates. These 1162
systems may also employ a bypass damper to decrease pressure drop 1163
across the coil when energy recovery is not advantageous. 1164
1165
Preheat Coil 1166
1167
Once through air systems, or other systems with high amounts of outside 1168
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air in cold climates may employ a preheat coil to condition the 1169
incoming or mixed air. These coils are always upstream of cooling 1170
coils, to protect them from freezing and may be placed upstream of the 1171
filters if used to melt snow in cold climates. These coils do not 1172
typically impose a large pressure drop, so a bypass damper is not 1173
common. 1174
1175
Humidifier 1176
1177
Once through air systems, or other systems with high amounts of outside 1178
air in cold climates may employ a humidifier to inject water vapor to 1179
condition the incoming or mixed air. These devices are typically 1180
downstream of the heating coil and may even be mounted in ductwork 1181
where turbulence and high velocity promote absorption of water vapor. 1182
When employed in an AHU, mounting upstream of cooling coils provides a 1183
natural baffle to prevent carryover of liquid water droplets. 1184
1185
Cooling Coil 1186
1187
Cooling to maintain environmental conditions is common, if not always 1188
required in Pharmaceutical applications. These coils can eliminate both 1189
sensible and latent heat and can be upstream or downstream of the fan. 1190
If latent cooling is expected drainage of these coils is a key design 1191
issue and mist eliminators may be employed to eliminate carryover of 1192
liquid water droplets that condense on the coil. These coils do impose 1193
a large pressure drop so a bypass damper can be employed, but can pose 1194
a risk of unconditioned air leakage and non-attainment of humidity 1195
goals. 1196
1197
Dehumidifier 1198
1199
Dehumidifiers employ a chemical desiccant to remove moisture from the 1200
supply air stream when humidity below 30-40% is required. The 1201
dehumidifier is often located downstream of the cooling coil as they 1202
work most efficiently when airstream relative humidity is high (but 1203
within desired limits). However care must be taken to assure that 1204
excessive relative humidity or liquid water droplets do not damage the 1205
dehumidifier. The choice of desiccant may vary, depending on the 1206
application but all desiccants are regenerated using heat; therefore, 1207
air leaving the dehumidifier is both dryer and hotter than upon 1208
entering. 1209
1210
Recool Coil 1211
1212
These coils are only commonly installed downstream of dehumidifiers to 1213
eliminate sensible heat from the supply air. They are also employed 1214
downstream of cooling coils to provide additional latent heat removal. 1215
In this second application they operate below chilled water temperature 1216
and are typically filled with refrigerant or a low temperature brine of 1217
water and glycol (ethylene or propylene). If latent cooling is expected 1218
drainage of these coils is a key design issue and mist eliminators may 1219
be employed to eliminate carryover of liquid water droplets that 1220
condense on the coil. These coils do not typically impose a large 1221
pressure drop so a bypass damper would be unusual. 1222
1223
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Reheat Coil 1224
1225
Systems that require over-cooling to achieve humidity control (in lieu 1226
of dehumidification) may also employ a preheat coil to condition the 1227
air leaving the cooling coil. These coils are always downstream of 1228
cooling coils, to increase the discharge temperature of the air handler 1229
and avoid condensation in the ductwork or overcooling of the space. 1230
1231
Supply Fan 1232
1233
All air systems will utilize a supply fan. This fan provides the motive 1234
force for distribution of air throughout the air handling system. 1235
1236
Final Filter 1237
1238
Filters may be provided as the last treatment step in an air handler. 1239
These filters provide assurance of air quality (with reference to 1240
particulate) downstream of all air handling operations and are 1241
particularly valuable in protecting terminal filters from fouling with 1242
dirt or debris and in providing filtration for classified spaces. This 1243
is of particular interest in systems that employ fan drive belts which 1244
shed particulate into the airstream. Systems typically employs a high 1245
efficiency filter in this location (MER V 14+). 1246
1247
2.6.4 AIRLOCK STRATEGIES 1248 1249
2.6.4.1 PRESSURIZATION 1250
1251
Airlocks are usually interposed between areas if airflow between the 1252
spaces needs to be controlled when they are entered or exited. 1253
Airlocks may also serve as material transfer / decontamination rooms, 1254
and gown or degown rooms. Three types of airlock pressure arrangements 1255
are indicated below: 1256
1257
Airlock
"Cascade" "Sink"
AirlockAirlock
"Bubble" 1258
1259
Figure 2-7 Airlock configurations 1260
1261
The cascade pressurization scheme should be used when there are area 1262
cleanliness classification requirements but no containment issues, or 1263
where there are containment issues but no cleanliness classification 1264
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32
requirements. (i.e., cascade outward from the room for aseptic 1265
operations, but cascade into the room for hazardous compounds.) Doors 1266
are usually interlocked to allow only one to be open at a time. The 1267
normal differential from one air class to the next (ACROSS the airlock) 1268
is 10-15 Pa (0.04 to 0.06 w.g.). The pressure INSIDE the airlock is 1269
somewhere between the two classes, depending on which door is open. It 1270
is not necessary to have 10-15 Pa between a room and its airlock (see 1271
Not required in the drawing below). 1272
1273
If there are requirements for both area cleanliness classification and 1274
product containment, then the use of pressure sinks and bubbles may be 1275
necessary. Pressure bubbles are usually used for clean operations 1276
(i.e., such as gowning or material entry airlock) and pressure sinks 1277
are usually used for dirty operations (i.e., de-gowning material 1278
decontamination/exit airlock). Normal design pressure differential 1279
between classifications should be 0.06 w.g. (15 Pa) with the doors 1280
closed. Pressure differential will drop momentarily while one door is 1281
opened, but will not drop to zero (as it would with no airlock or if 1282
all airlock doors were opened). In no case should pressure differential 1283
reverse. 1284
1285
For unclassified areas the minimum suggested pressure differential is 1286
0.02 w.g. (5 Pa), being the minimum reliably detectable by current 1287
pressure sensor technologies. 1288
1289
The pressure differential is measured across the airlock, not across 1290
each door. 1291
1292
Airlock Airlock
0.06" w.g.
Acceptable Not Required
0.06" w.g. 0.06" w.g.
"Cascade" Pressure Relationships 1293
1294
Figure 2-8 Example of Cascade Pressure Relationships 1295
1296
When using the bubble pressurization scheme, the normal design 1297
pressure target, with doors closed, between classifications should be 1298
0.06 w.g. (15 Pa). There may be different pressure drops across each 1299
door due to building tolerances, or adjacent room conditions, this is 1300
not considered a problem. If protecting non-sterile processing (areas 1301
not classified) a lower pressure is acceptable, but should be 1302
measurable. The pressure of the very clean airlock bubble is usually 1303
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designed to be about 0.02 to 0.03 in. w.g (about 5-8 Pa) above the 1304
higher of the two room pressures. 1305
1306
The positive pressure airlock provides a robust means of segregating 1307
areas using positive airflow. 1308
1309
Bubble
Airlock
@ 0.09" w.g.
"Bubble" Pressure Relationships
0.09" w.g. 0.03" w.g.
Unclassified Space
@ 0" w.g.
Clean-Contained Space
@ 0.06" w.g.
0.06" w.g. across GMP boundary
1310 1311
Figure 2-9 Example of Bubble pressure relationships 1312
1313
Similarly, with the sink pressurization scheme, the normal design 1314
pressure between classifications should be 0.04 to 0.06 w.g. (10-15 1315
Pa) with doors closed. As with the bubble there may be different 1316
pressure drops across each door. The pressure of the contaminated 1317
airlock sink is usually designed to be about 0.02 to 0.03 in. w.g (5-1318
8 Pa) below the lesser of the two room pressures. 1319
1320
Bubble
Airlock
@ (-) 0.03" w.g.
"Sink" Pressure Relationships
0.03" w.g. 0.09" w.g.
Unclassified Space
@ 0" w.g.
Clean-Contained Space
@ 0.06" w.g.
0.06" w.g. across GMP boundary
1321 1322
Figure 2-10 Pressure sink relationships 1323
1324
It is often necessary to have pressure differentials at boundaries 1325
within the same air class area for operational reasons. The minimum 1326
operational differential between areas of the same classification 1327
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34
(where required) is suggested to be 0.02 w.g. (5 Pa), with a design 1328
target of 0.04 (10Pa) suggested. It is also sometimes necessary to 1329
have directional air flows for operational reasons without a measurable 1330
pressure differential, such as may be found in non-classified areas, 1331
such as oral dosage manufacture. 1332
1333
Pressure may be maintained across doors between air classes when no 1334
airlocks are present. However, without the added protection provided by 1335
the airlock, significant airflow volumes and pressure actuated dampers 1336
are required. (See the Appendix) This scheme should be adopted only 1337
when airlocks are not possible. 1338
1339
The airflow leakage rate should be calculated for each room. This 1340
calculation must be based on the design pressure differential 1341
established in the project documents and not on some rule of thumb 1342
method, e.g., percentage of supply air. Door seals are the primary 1343
path of room air leakage. Therefore, doors and doorframes are crucial 1344
components of the facility construction, as more leakage air must be 1345
designed into the system for doors with poor seals. The HVAC design 1346
engineer should consult with the facility architect to assure 1347
specifications are adequate for pressurization requirements. Door 1348
frames may include continuous seals which would reduce leakage required 1349
to maintain the desired pressure, as well as provide isolation in case 1350
of airflow failure. Doors may be provided with a provision for 1351
operable floor sweeps which drop down as the door closes, but these may 1352
present cleaning problems. Where double doors are used in the 1353
facility, gasketed astragals are required. Door grilles should be 1354
avoided unless part of a pressure scheme without airlocks (as discussed 1355
in the Appendix). Figure 14, Chapter 27 of the 2005 ASHRAE Handbook- 1356
Fundamentals should be used in calculating the air leakage rate of 1357
doors. Common practice is to design for a 0.10 average crack between 1358
the door and frame on sides, top, and bottom. Note that corrections 1359
are to be applied for design pressure differentials using the formula 1360
contained in Figure 14. A similar leakage calculation is discussed in 1361
the article, Airlocks for Biopharmaceutical Plants, del Valle, 1362
Pharmaceutical Engineering , Volume 21, Number 2, March/April 2001 1363
1364
Material transfer openings are another key room air leakage path. To 1365
calculate leakage through these and other fixed openings use the 1366
formula, 1367
1368
Q = A x 4005sqrt (VP) (Sqrt = square root) 1369
1370
Q = airflow (CFM) 1371
1372
A = area of opening (sq. ft.) 1373
1374
VP = velocity pressure the velocity pressure at the opening (in. w.g.) 1375
is roughly the same as the differential pressure across the opening, 1376
(or the, room differential pressure), 1377
1378
This method provides a conservative leakage number. In most cases, a 1379
slightly smaller leakage airflow will produce the desired pressure 1380
differential for a given leakage path. Because of this, during 1381
commissioning there may be more return air leaving the room than 1382
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35
designed, so return air dampers should have some extra capacity. 1383
1384
In some cases the calculated room leakage may exceed the minimum air 1385
change rate for small rooms such as airlocks. In these instances the 1386
total supply air to the space must match the calculated leakage. 1387
However, provisions should be made in the design for some return air 1388
from the space in case the actual leakage is less than calculated. A 1389
good rule-of-thumb is to size the return for half the supply air flow 1390
into the room. In applying this approach, care should be taken in 1391
sizing any volume control (damper or CV box) on the return air side to 1392
ensure that the actual flow rate is with the operable range of the 1393
control device. 1394
1395
For this reason it is a good engineering practice to put a tighter 1396
specification on the supply air volume, being more critical to maintain 1397
the room conditions, and a larger design range on the return, which 1398
will be whatever value is needed to maintain desired differential 1399
pressures. 1400
1401
Two methods of measurement are commonly applied to monitor room 1402
pressure relationships; room-to-room and common reference point. While 1403
both have been used successfully, the preferred is the common reference 1404
point method in order to minimize compounded error. Here, one port of 1405
the differential pressure transmitter (usually, but not always, the 1406
High side) is piped to the room being monitored and the other side 1407
(usually, but not always, the Low side) is piped to a common 1408
reference in the interstitial space. 1409
1410
PDTH L
PDTH L
Interstitial Space- common reference
Space A Space B
PDTH L
PDTH L
Space A Space B Space C
Room-to-Room Monitoring Common Reference Monitoring 1411
1412
Figure 2-11 Differential Pressure Sensor Locations 1413
1414
The common reference point should not be outdoors, as the effect of 1415
wind direction may give unstable readings. Where room to room 1416
monitoring is used it is a good practice to confirm through the system 1417
balancing that net airflow into the facility is greater than the 1418
extract/exhaust. 1419
1420
All signals are sent to the control system where differentials are 1421
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calculated by means of an algorithm. In the event that the reference 1422
(interstitial) space is partitioned by fire walls or other means, it 1423
may be necessary to provide multiple common reference points by 1424
building zone. In this case the pressure relationship across a 1425
zone will need to be room-to-room or the use of two differential 1426
pressure transmitters, one to each reference point, will be required. 1427
1428
For information on monitoring system see section 2.7 Control and 1429
monitoring. 1430
1431
2.6.5 Ventilation/supply strategies 1432 1433
2.6.5.1 Room Air Distribution: 1434
1435
There are two basic types of room air distribution: dilution and 1436
displacement air distribution. 1437
1438
In a dilution design, room air is mixed continuously with supply air to 1439
help achieve uniform air temperatures within the space. In areas where 1440
temperature uniformity is the only factor, aspirating-type diffusers 1441
are used to allow turbulent mixing of room air with supply air. From a 1442
particulates perspective, dilution also mixes less clean room air 1443
with the clean supply air. Aspirating-type diffusers are not acceptable 1444
in any of the clean classified rooms. Even though non-aspirating 1445
diffusers do not eliminate turbulent air patterns in the room, using 1446
non-aspirating diffusers in clean rooms reduces the mixing effect. The 1447
particulate level in the room can be reduced with dilution by 1448
increasing the air-change rate of clean air supply. Dilution 1449
distribution with non-aspirating diffusers (typically perforated face 1450
plate over the terminal HEPA media) is acceptable to clean classified 1451
areas up to ISPE-7. 1452
1453
In a displacement design, room particulates are displaced by clean 1454
terminal HEPA filtered unidirectional air. This design requires 1455
continuous HEPA coverage at the ceiling and properly sized and located 1456
low level return or exhaust grills. ISPE-Grade 5 should use 1457
displacement air distribution (typically a unidirectional flow hood 1458
UFH). 1459
1460
2.6.5.2 Room Air Distribution options 1461
1462
Conventional air distribution techniques are generally acceptable for 1463
administrative, warehouse, and unclassified spaces. Large warehouse 1464
spaces, however, may see hot and cold spots with poor air distribution. 1465
GMP spaces and cleanrooms require more stringent methods. Supply air 1466
should be introduced at the ceiling level and return/exhaust air should 1467
be extracted near the floor. The use of non-aspirating diffusers on 1468
the face on terminal HEPA filters may improve airflow patterns. 1469
1470
Within mixed airflow rooms, airflow patterns should be from clean side 1471
of the space to the less clean. For example, within a space that 1472
contains an ISO 5 micro-environment/zone with an ISO 7 background, 1473
airflow should always be from the cleaner zone into the less clean 1474
background area. 1475
1476
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Mixed Airflow GMP Space
ISO Class 5 ISO Class 7
1477 1478
Figure 2-12 Mixed Airflow Space 1479
1480
Some process operations, i.e., centrifugation, are inherently particle 1481
generating. Airflow patterns within the spaces that contain these 1482
processes should take this into account by locating returns/exhausts at 1483
floor level near the particle generating operation. 1484
1485
Airlocks and gown rooms are usually divided, often by a physical line 1486
on the floor, into clean and dirty zones in accordance with the flow 1487
of personnel, material, and equipment. Within such spaces, the air 1488
pattern should from the clean to the dirty side of the airlock. 1489
Therefore, HEPA supplies should be located on the clean side and low 1490
wall returns should be located on the opposite side of the room. 1491
1492
Low wall returns should be located no more than 12 above the floor. 1493
Returns should be generously sized with a maximum grille face velocity 1494
of no more that 400 FPM. Ductwork should be sized for a maximum 1495
pressure drop or 0.1 per 100 or a maximum velocity of 850 FPM, 1496
whichever is more restrictive. The heel of the connecting elbow should 1497
have a minimum 6 radius to facilitate cleaning. The elbow and 1498
connecting ductwork, up to an elevation of 5 feet above the floor, 1499
should be Type 304 or 304L stainless steel. 1500
1501
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38
6" Radius
1'-
0" m
ax
imu
m
Typical Low Wall Return
1502 1503
Figure 2-13 Typical Low Wall Return 1504
1505
Return air ducts located in stud wall spaces need not be insulated 1506
within the walls. Insulation shall terminate at the top of the wall. 1507
The mechanical engineer should consult with the facility Architect to 1508
assure that, where needed, wall cavities are adequate to contain low 1509
wall returns. 1510
1511
2.6.6 EXTRACT (EXHAUST AND / OR RETURN) STRATEGIES 1512 1513
Why we use low level or high level extract, the area affected by an 1514
extract point do we want to cover dust extract systems at all here?? 1515