ispe good practice guide - hvac

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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DRAFT FOR REVIEW 13

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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

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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

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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

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This guide addresses HVAC requirements in the following areas of 161

facility lifecycle. 162

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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

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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

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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

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The guide discusses the impact of external conditions on HVAC design. 189

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This guide attempts to give information in I/P and SI units. 191

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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

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1.3 OBJECTIVES OF THIS GUIDE 197 198

Provide the Pharmaceutical Engineering Community with common language 199

and understanding of critical HVAC issues. 200

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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

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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

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1.5 REFERENCES 218 219

a. ISO Standards for Cleanrooms and Associated Controlled Environments 220

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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

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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

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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

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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

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f. US FDA Guidance for Industry Sterile Drug Products Produced by 265

Aseptic Processing- Current Good Manufacturing Practice (2004) 266

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g. EudraLex Volume 4 EU Guidelines to Good Manufacturing Practice 268

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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

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i. WHO document on HVAC- proposed draft, does not apply to this 277

document. 278

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j. CFR Title 21 Food & Drugs 280

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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

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k. FDA Guidance for Industry/ICH Guidelines 288

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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

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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

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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

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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

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Four criteria are commonly considered for people comfort: 344

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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

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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

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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

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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

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2.2.1.2 Air Movement 372

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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

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2.2.1.3 Air Quality 379

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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

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Table2-1 Oxygen Consumption by activity Level 387

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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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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



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


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



20

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



21

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


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



22

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



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


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



24

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



25

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


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



26

control of parameters (T, RH, etc) 998

999


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


1021

Simple to operate. Makeup air is pulled from surrounding spaces. 1022 1023


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



27

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



28

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



29

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



30

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



31

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



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



33

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



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



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



36

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



37

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



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

ispe good practice guide - hvac

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