ISPE- HVAC.pdf

8/20/2019 ISPE- HVAC.pdf

http://slidepdf.com/reader/full/ispe-hvacpdf 1/199

ISPE GOOD PRACTICE GUIDE HVAC

DRAFT FOR REVIEW JULY 2008

1

12345

6ISPE GOOD PRACTICE GUIDE7

8

HVAC9

101112

DRAFT FOR REVIEW13

1415

16171819202122232425262728

293031323334

353637

3839

© 2008 ISPE. ALL RIGHTS RESERVED.4041424344





2

TABLE OF CONTENTS45

461

INTRODUCTION ...................................................... 5

47

1.1 BACKGROUND .................................................... 5 48

1.2

SCOPE OF THIS GUIDE ........................................... 5

491.3 OBJECTIVES OF THIS GUIDE ...................................... 6 501.4

DEFINITIONS ................................................... 6

511.5

REFERENCES .................................................... 6 522

FUNDAMENTALS OF HVAC .............................................. 9 53

2.1 INTRODUCTION .................................................. 9 54

2.2 WHAT IS HVAC? ................................................. 9 552.3 AIRFLOW FUNDAMENTALS ......................................... 13 562.4 PSYCHROMETRICS ............................................... 19 572.5 EQUIPMENT .................................................... 21 582.6 HVAC SYSTEM CONFIGURATION .................................... 23 592.7 HVAC CONTROLS AND MONITORING ................................. 39 60

2.8

SYSTEM ECONOMICS ............................................. 51

612.9 SUSTAINABILITY (TO BE WRITTEN LATER) ........................ 58 62

3

THE DESIGN PROCESS ............................................... 59 63

3.1 INTRODUCTION ................................................. 59 643.2

DEVELOPING THE USER REQUIREMENTS SPECIFICATION (URS) ......... 61

653.3

HVAC SYSTEM RISK ASSESSMENT .................................. 69 664 HVAC APPLICATIONS BY PROCESS AND CLASSIFICATION .................. 73 67

4.1 INTRODUCTION ................................................. 73 684.2 SYSTEM APPLICATIONS .......................................... 73 694.3 ROOM LEVEL EXAMPLES .......................................... 78 704.4 ACTIVE PHARMACEUTICAL INGREDIENTS (API) - (WET END) .......... 83 714.5 ACTIVE PHARMACEUTICAL INGREDIENTS (API) - (DRY END) .......... 84 724.6

BIOLOGICS .................................................... 85

73 4.7

ORAL SOLID DOSAGE (NON-POTENT COMPOUNDING) ................... 86

744.8 ORAL SOLID DOSAGE (POTENT COMPOUNDING) ....................... 89 754.9 ASEPTIC PROCESSING FACILITY .................................. 91 764.10

PACKAGING/LABELING ........................................... 94

774.11

LABS ......................................................... 95 784.12

SAMPLING/DISPENSING .......................................... 99 794.13

ADMINISTRATIVE AND GENERAL BUILDING ......................... 100 804.14 WAREHOUSE ................................................... 101 814.15 PROCESS EQUIPMENT CONSIDERATIONS ............................ 102 82

5 DESIGN QUALIFICATION / DESIGN REVIEW (DQ/DR) .................... 106 83

5.1 DESIGN REVIEW/ DESIGN VERIFICATION/DESIGN QUALIFICATION ..... 106 845.2 INTRODUCTION ................................................ 108 85

6

EQUIPMENT FUNCTION, INSTALLATION, AND OPERATION ................. 117

866.1 EQUIPMENT FUNCTION AND MANUFACTURE .......................... 117 876.2 EQUIPMENT INSTALLATION AND STARTUP .......................... 147 886.3

EQUIPMENT OPERATION AND MAINTENANCE ......................... 156

897

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





3

7.5 KEY CONCEPTS OF VERIFICATION ................................ 167 95

7.6 DESIGN, SPECIFICATION, VERIFICATION, AND ACCEPTANCE PROCESS . 169 967.7 SUPPORTING PROCESSES ........................................ 170 97

8 DOCUMENTATION REQUIREMENTS ...................................... 172 98

8.1 INTRODUCTION ................................................ 172 99

8.2

ENGINEERING DOCUMENT LIFECYCLE .............................. 172

1008.3 DOCUMENTS FOR MAINTENANCE AND OPERATIONS (NON-GMP) .......... 173 1018.4 MASTER/RECORD DOCUMENTS ..................................... 173 1028.5 GMP HVAC DOCUMENTS .......................................... 174 103

9

PSYCHROMETRICS .................................................. 176 104

9.1 DRY-BULB TEMPERATURE ........................................ 176 1059.2

WET-BULB TEMPERATURE ........................................ 176 1069.3

DEW-POINT TEMPERATURE ....................................... 177 1079.4 BAROMETRIC OR TOTAL PRESSURE ................................ 179 1089.5 SPECIFIC ENTHALPY ........................................... 179 1099.6 SPECIFIC VOLUME ............................................. 180 1109.7 EIGHT FUNDAMENTAL VECTORS ................................... 183 111

10

COMMISSIONING AND QIUALIFICATION PROCESS ...................... 185

11210.1 COMMISSIONING AND QUALIFICATION ............................. 185 11310.2 IMPACT RELATIONSHIPS ........................................ 186 11410.3 RISK ASSESSMENT MATRIX ...................................... 187 115

11

MISCELLANEOUS HVAC INFORMATION ................................ 188

116

11.1 GLOSSARY OF TERMS ........................................... 188 11711.2

EQUATIONS USED IN HVAC AND THEIR DERIVATION ................. 188 11812 REFERENCES .................................................... 195 11912.1

SUMMARY OF USEFUL CLEANROOM EQUATIONS ....................... 195 12012.2

PRESSURE CONTROL WHEN AIRLOCKS ARE NOT POSSIBLE ............. 196 12112.3

HEPA FILTERS FOR HOT ZONES (DEPYROGENATION) ................. 196 12212.4 USEFUL REFERENCE MATERIALS .................................. 196 12312.5

HVAC EXAMPLES AND WORKBOOK (???) ............................ 196

124 12.6

EXAMPLE DOCUMENTS ........................................... 196

125126127128129





5

1 INTRODUCTION130

131

1.1 BACKGROUND132133

The heating, ventilating, and air conditioning (HVAC) system is one of134 the more critical systems affecting the ability of a pharmaceutical135facility to meet its key objectives. HVAC systems which are properly136designed, built, operated, and maintained can help ensure the quality137of product manufactured in that facility, improve reliability, and138reduce both first cost and ongoing operating costs of the facility. The139design of HVAC systems for the pharmaceutical industry requires special140considerations beyond those for most other industries, particularly in141regards to cleanroom applications.142

143Each of the previously published ISPE Baseline® Guides for facilities144(Active Pharmaceutical Ingredients, Oral Solid Dosage, Sterile Products145Manufacture, Biopharmaceuticals, etc.) have included some discussion of146the considerations for HVAC systems for facilities of that type. This147

Good Practice Guide is intended to supplement those sections with more148detailed information and recommended practices for implementation of149HVAC systems in pharmaceutical facilities.150

151

1.2 SCOPE OF THIS GUIDE152153

The Guide provides supporting information and HVAC practices for154facility types covered by Baseline Guides.155

156The Guide provides an overview of the basic principles of HVAC only to157the extent required to facilitate a common understanding and consistent158nomenclature.159

160

This guide addresses HVAC requirements in the following areas of161facility lifecycle.162

163

Establishing User Requirements164

Design165

Construction166

Commissioning / Qualification167

Operation / Maintenance168

Redeployment for other use169

Decommissioning170171

The guide does NOT serve as a handbook for HVAC design (e.g. it does172not discuss the details of sizing and selection of equipment. It does173go into boring detail on the physics of air and humidity.)174

175The guide clarifies HVAC issues critical to the Safety, Identity,176Strength, Purity and Quality (SISPQ) for the production of bulk and177finished pharmaceuticals and biopharmaceuticals, and it considers the178requirements for HVAC control and monitoring systems.179

180This guide addresses how to implement the recommendations in the181Baseline guides to meet FDA and EMEA regulatory expectations for HVAC182





6

design.183184

This guide references but does NOT reiterate the issues or content from185the Baseline guides. The appropriate Baseline Guide should be consulted186for regulatory expectations.187

188 The guide discusses the impact of external conditions on HVAC design.189190

This guide attempts to give information in I/P and SI units.191192

The user of this guide should apply good engineering practice in193assessing which of the recommended practices is most applicable to a194situation.195

196

1.3 OBJECTIVES OF THIS GUIDE197198

Provide the Pharmaceutical Engineering Community with common language199and understanding of critical HVAC issues.200

201 Provide guidance on accepted industry practices to address these202issues.203

204Provide a single common resource for HVAC information currently205included in appendices of the various Baseline© guides.206

207Target a global audience, with particular focus on US (FDA) and208European (EMEA) regulated facilities.209

210

1.4 DEFINITIONS211212

This GPG uses terms as defined in the ISPE Glossary of Pharmaceutical213Engineering Terminology and will not repeat these definitions here.214Only new terms or terms specific to the content of this GPG are defined215in the Glossary.216

217

1.5 REFERENCES218219

a. ISO Standards for Cleanrooms and Associated Controlled Environments220221

ISO 14644-1 Classification of air cleanliness222

ISO 14644-2 Specifications for testing and monitoring to prove223continued compliance with ISO 14644-1224

ISO 14644-3 Test methods225

ISO 14644-4 Design, construction and start-up226

ISO 14644-5 Operations227 ISO 14644-6 Vocabulary228

ISO 14644-7 Separative devices (clean air hoods, glove boxes,229isolators, and mini-environments)230

ISO 14644-8 Classification of airborne molecular contamination231

ISO 14698-1 Biocontamination control, Part 1: General principles and232methods233

ISO 14698-2 Biocontamination control‘ Part 2: Evaluation and234interpretation of biocontamination data.235





7

236b. IEST Recommended Practices237

238

RP-CC034.2- HEPA and ULPA Filter Leak Tests239

RP-CC006.3- Testing Cleanrooms240

RP-CC012.1- Considerations in Cleanroom Design241242

c. ISPE Baseline Guides243244

Vol. 1- Active Pharmaceutical Ingredients245

Vol. 2- Oral Solid Dosage Forms246

Vol. 3- Sterile Manufacturing Facilities247

Vol. 4- Water and Steam Systems248

Vol. 5- Commissioning and Qualification249

Vol. 6- Biopharmaceuticals250251

d. ASHRAE- specific ASHRAE documents which are used in this GPG:252

253 ASHRAE standard 62.1 - Ventilation for Acceptable Indoor Air Quality254

ASHRAE standard 90.1 - Energy Standard for Buildings Except Low-Rise255Residential Buildings256

ASHRAE standard 110 - Method of Testing Performance of Laboratory257Fume Hoods258

ASHRAE Handbooks - Fundamentals; Applications; Systems & Equipment259260

e. ASTM Standard E2500-07 - Standard Guide for Specification, Design,261and Verification of Pharmaceutical and Biopharmaceutical Manufacturing262Systems and Equipment263

264f. US FDA Guidance for Industry ―Sterile Drug Products Produced by265

Aseptic Processing- Current Good Manufacturing Practice‖ (2004) 266267g. 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 Products271

Annex 2: Manufacture of Biological Medicinal Products for Human Use272273

h. The Good Automated Manufacturing Practice (GAMP) Guide for274Validation of Automated Systems in Pharmaceutical Manufacture275

276i. WHO document on HVAC- proposed draft, does not apply to this277document.278

279 j. CFR Title 21 Food & Drugs280281

Part 11: Electronic records282

Part 210: Current good manufacturing practice in manufacturing,283processing, packing or holding of drugs; general284

Part 211: Current good manufacturing practice for finished285pharmaceuticals286

287





8

k. FDA Guidance for Industry/ICH Guidelines288289

Q7A: Good manufacturing practice guidance for active pharmaceutical290ingredients291

Q8: Pharmaceutical Development292

Q9: Quality Risk Management293 Q10: Quality Systems294

295





9

2 FUNDAMENTALS OF HVAC296

297

2.1 INTRODUCTION298299

Most people live in homes with equipment incorporated into the building300 to keep them comfortable. They have windows to allow natural301ventilation and heating and cooling systems to maintain desired302temperatures.303

304We have the same goal in our pharmaceutical manufacturing workplace – 305to make people comfortable, but we also have the more exacting306requirement to control the impact of the environment on the finished307product (i.e., product SISPQ).308

309This guide introduces the fundamentals of the HVAC systems that control310the GMP workplace environment. Only three room environment variables311may have an effect on product and processes (at the ―critical312locations‖): 313

314 Air temperature at the critical location may affect product or315

product contact surfaces316

Relative humidity of the air at the critical location may affect317product moisture content, or may affect product contact surfaces318(via corrosion, etc.)319

Airborne contamination at the critical location (may affect product320purity or product contact surfaces)321

322Some variables, such as local contaminants, depend on other HVAC323variables such as room pressure, air changes, airflow volume, airflow324direction and velocity, and air filter efficiency.325

326

2.2 WHAT IS HVAC?327328

HVAC (Heating, Ventilation and Air Conditioning) is the generic name329given to a system that provides the conditioning of the environment330through the control of Temperature, Relative Humidity, Air Movement and331air quality - including fresh air, airborne particles, and vapors.332HVAC systems can increase or decrease temperature, increase or reduce333the moisture or humidity in the air, decrease the level of particulate334or gaseous contaminants in the air. These abilities are employed for335comfort and to protect people and product.336

3372.2.1 People Comfort338

339

The first role of HVAC systems is to make people comfortable. We notice340the HVAC system‘s performance when we are uncomfortable, but what341conditions are actually required to make people comfortable?342

343Four criteria are commonly considered for people comfort:344

345

Temperature346

Humidity347

Air quality (contaminants, both particles and odors)348





10

Air movement (airflow direction and speed to control ―drafts‖) 349350

2.2.1.1 Temperature and Humidity351

352The following drawing shows two boxes which define "comfort" conditions353

(Temperature and Humidity) that Americans find comfortable in winter354and summer (from the ASHRAE Handbook). This standard varies across the355world - for example, in parts the tropics people prefer an office at 75356degrees F (24 degrees C) to one at 72 F (22°C).357

358It should also be noted that these are general guidelines, as many359things affect these conditions apart from individual preferences - the360type and consistency of work being performed, for example.361

362This is apparent in the office workplace, with the different levels of363clothing people wear, some people dressed more heavily than others in364order to be comfortable365

366

367





11

368Figure 2-1 Standard Effective Temperature and ASHRAE Comfort Zones369courtesy of ______________________370

3712.2.1.2 Air Movement372

373Some people prefer a light sensation of air movement and some prefer374still air, so a typical design figure of 0.1 m/s (3 ft/sec) is used in375an office environment. Greater air velocities are usually needed for376product protection.377

3782.2.1.3 Air Quality379

380People need fresh air to dilute exhaled carbon dioxide and other381environmental contaminants. The amount of fresh air required depends on382the activity; the table below shows typical oxygen use for different383levels 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 2.0386

Table2-1 Oxygen Consumption by activity Level387388

The amount of fresh air required to dilute environmental contaminants389

is a minimum of 15 to 20 cubic feet per minute (cfm) or 24 to 32 cubic390 meters per hour per person .391392

2.2.2 Product and Process Considerations393394

Product may be sensitive to temperature and humidity and to airborne395contamination - from outside sources or cross-contamination between396products. Process operators may need protection from exposure to397hazardous or potent materials398

399It is usually possible to find the product‘s environmental400requirements, as they will be listed in the NDA when they are401considered critical. The impact of conditions outside these ranges402will depend on the duration of exposure – prolonged exposure time may403

reduce the efficacy of the product.404405

Control of airborne cross contamination and contamination are always406major issues. These requirements are often interlinked with temperature407and humidity – consider the effect of temperature for example;408

409Comfortable people work more efficiently – they are more410productive, and make fewer mistakes. They also produce fewer411environmental contaminants: A typical person will give off 100,000412





12

particles a minute doing relatively sedentary work (particles sized4130.3 micron and larger – a human hair is approximately 100 micron in414diameter). A worker who is hot and uncomfortable may shed several415million particles per minute in this size range, including more416bacteria.417

418 Environmental conditions inside a building can influence the product in419other ways – higher temperatures and humidity tend to increase420microbial growth rates, particularly with regard to mold.421

422If building conditions are significantly different from those outside423and the fabric of the building does not have sufficient integrity,424condensation in interstitial spaces can occur and can lead to microbial425contamination problems and deterioration of the building.426

427Operator protection also depends on air flow direction both within and428between rooms. Airflow can entrain particles of product, product in429other rooms, or other hazardous materials harmful to operators. Though430differential pressure is commonly used as a control of contamination431

between two rooms, it is the airflow generated by the differential432pressure that contains the product433

4342.2.3 How does the HVAC system control these parameters?435

4362.2.3.1 Temperature and Humidity437

438The HVAC system controls the temperature and humidity in the room using439the mechanism of supplying the room with air at a condition that, when440mixed with the room air, will yield the desired temperature and441humidity.442

443The heat gains and losses to and from the space are through the usual444

mechanisms of heat transfer - Radiant, conductive and convective heat445transfer. These may be due to solar gain, external temperature outside446the facility, and internal heat gains due to the process, equipment,447people and lighting.448

449The changes in humidity are due to the process, people and the450environment. Moisture migration into the controlled space from451surrounding areas is governed by the difference in vapor pressure, as452defined by Dalton‘s law, and can sometimes migrate against an air453pressure differential454

4552.2.3.2 Air velocity456

457

In a working environment, air velocity is not as critical in terms of458 human comfort as it is in an office environment. Velocity is critical459to proper mixing of air within the room and transport of airborne460particulates.461

4622.2.3.3 Particulate/fume and vapor control463

464The control of the particulate levels in the room, and in some cases465vapors/fumes, may be by dilution and displacement, controlling the466particulate levels in the supply air through filtration, and vapor/fume467





13

level by the use of exhaust and replacement (makeup) fresh air where468necessary.469

4702.2.4 What can‘t the HVAC System do? 471

472

HVAC systems are not a substitute for good process, facilities and473 equipment design and good operating procedures. HVAC can not clean474surfaces that are already contaminated, and as a practical matter, it475cannot control processes that generate an excess of contaminants or476compensate for improperly designed or maintained facilities. HVAC,477while a common suspect area for investigation, is rarely the cause - or478the solution - for persistent contamination problems.479

480

2.3 AIRFLOW FUNDAMENTALS481482

2.3.1 Introduction483484

As was discussed in section 2.1, HVAC can contribute to the control of485

temperature, humidity, and particulates within a space. In order to486 understand what equipment is needed to achieve this at the HVAC system487level, we must first define what the air is intended to do at the room488level.489

490Both the quality (temperature, humidity, filtration) and quantity of491air introduced into a room affect its ability to maintain environmental492conditions. This explores the effects of physical layout (geometry),493air velocity and air volume in assuring effective ventilation.494

4952.3.2 Ventilation Fundamentals496

497Ventilation is the movement and replacement of air for the purpose of498maintaining a desired environmental quality within a space. Ventilation499

is responsible for the transport of airborne particles, the movement of500masses of hot or cold air, the removal of airborne contaminants (e.g.,501vapors and fumes) and the supply of ―fresh‖ O2 rich air. 502

503Although the layman may be conscious of the term ―air change rates‖504(more properly called ―ventilation rate‖), successful pharmaceutical505HVAC design can be attributed to proper filtration and attention to the506physical geometry of airflow in a space. The layout of inlets and507outlets with relation to the sources of contamination/heat and508accommodation for expected obstructions are key to controlling509contamination and yielding effective HVAC design. The relationship510between these factors is expressed in the ―effective ventilation rate‖511for a space. This measure expresses the efficiency of the HVAC system512

at removing contaminants expressed as a % of the theoretical513 performance of perfect dilution. When comparing the effective514ventilation rates of various designs, it becomes clear that good515layout and filtration can produce desired airborne particulate levels516and recovery rates at lower than expected air change rates.517

5182.3.3 Contamination Control519

520The primary factor that separates pharmaceutical HVAC from comfort HVAC521is the need to control contamination. This stems from the need to522





14

assure the ―…purity, identity and quality…‖ of the product (21CFR211).523Pharmaceutical HVAC is one tool in preventing unwanted environmental524contaminants from adversely affecting a product and to prevent products525from contaminating one another. It can also assist in limiting operator526exposure to potent pharmaceutical compounds, ingredients or reagent527

vapors. Contamination control is generally achieved by filtering the528 incoming air, to assure that it does not carry particulates, and then529introducing the air to the work space at sufficient velocity and volume530to transport unwanted particulate out of the work zone. The orientation531of these airflows can aligned so as to protect product or personnel by532sweeping across one or the other (or both) on its way from the supply533terminal to the extract point. Local supply or extraction can also534assist in contamination control by creating a local environment that535excludes or removes particulate.536

537Pharmaceutical HVAC can help control contaminants within a space, but538these facilities must be designed with several additional features that539contribute to this mission of limiting the migration of contaminants.540

541

2.3.4 Airlocks542543

In order to minimize the amount of air that is needed to maintain544particle transport velocities (typically over 100fpm times 21 square545feet of open door area equals 2100 cfm) it is desirable that the doors546of a contamination controlled space remain closed. One way to do this547is to provide airlocks or ―ante rooms‖. These rooms control traffic548into and out of a space through a series of interlocked doors to assure549that a door to the space is always closed.550

551Airlocks serve other purposes as well:552

553

they maintain some differential pressure between the two areas they554

serve, such that the DP can not drop to zero555 they provide a location for gowning/de-gowning prior to556

entering/exiting a classified space557

they provide a location for sanitizing / decontamination of incoming558or outgoing materials and equipment559

they can be designed with a small volume and high air change rate to560allow them to recover quickly and function to minimize the561particulate introduced to a classified space by door openings.562

they provide can provide a high or low pressure buffer to control563the ingress and egress of contaminants.564

5652.3.5 Classified Space566

567

A key measurement of room environmental conditions for pharmaceutical568operations is the concentration of total airborne particulate and/or569microbial contamination within the space; this is referred to as the570―classification‖ of the space. Several systems have been promulgated571for the classification of space; however there is not consensus between572international regulators on a single best standard for classification.573To bridge the gap between the various standards, this guide provides574the following reference to be used across facility types requiring air575classification, (primarily facilities for sterile/aseptic manufacture576and for controlled bioburden processing, such as bulk577





15

biopharmaceuticals). It should not be used for other facilities, such578as bulk chemical intermediates or oral dosage finishing. See the579appropriate Baseline Guide for specific air quality information.580

581





16

582

REFERENCE DESCRIPTION CLASSIFICATION

ISPE STERILE BASELINEGUIDE

Draft 2008

ENVIRONMENTAL CLASSIFICATION GRADE 5 GRADE 7 GRADE 8 ControlledNotClassifiedwith localmonitoring

ControlledNotClassified

European CommissionEU GMP, Annex 1,Volume lV,Manufacture ofSterile MedicinalProducts (1997) alsoPIC/S GMP Annex 12002

Descriptive GradeA(Note1)

B C D Not defined

AtRest(Note2)

Maximum no.particlespermittedper m3 ≥ thestated size

0.5μ 3 500 3 500 350 000 3 500 000 -

5μ 1 1 2 000 20 000 -

InOperation

Maximum no.particlespermittedper m3 ≥ the

stated size

0.5μ 3 500(Note3)

350 000 3 500000

Not stated -

5μ 1 2 000 20 000 Not stated -

Maximum permittednumber of viableorganisms cfu / m3

< 1 < 10 < 100 < 200 -

FDA, October 2004,Guidance for IndustrySterile Drug ProductsProduced by

InOperation

Maximumparticlespermittedstatedsize

no.≥

the

0.5 μ ISO 5Class100

ISO 7(Class10 000)

ISO 8(Class100000)

- -

583Table 2-2 Comparison of Classified Spaces584

585586





17

587Pharmaceutical HVAC can help control contaminants within a space, but588these facilities must be designed with several additional features that589contribute to this mission of limiting the migration of contaminants.590

591

2.3.6 Total Airflow Volume and Ventilation Rate592593Much has been made of the importance of ―air change rate‖ (volume of594air/hour ’ room volume) or ―ventilation rate‖, the number of times in595an hour that the air volume of a room is replaced. Little is said about596the relationship between these rates and the classification of the597space, recovery rates and the more important issue of total volume of598ventilation.599

600When considering the design of classified space, designers will often601first consider the requirement for 20 Air Changes/hour (AC/hr),602expressed in the 1987 FDA Sterile Guide. In lieu of calculating the603airflow required by the process, many will default to ―rules of thumb‖604for ventilation rate by the class of space, typically in the ranges:605

606 15-20 AC/hr for Controlled, Not Classified (CNC) spaces607

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)610611

As seen below, these rules of thumb may be overkill, or may prove to be612insufficient. The airborne particle levels depend more on a number of613factors.614

6152.3.6.1 Air change or Air Flow?616

617

These air change rates often drive decisions regarding room size and618 airflows, and can have significant cost implications, but do not619relate directly to the particle count in the room. Air change rates are620related to the room‘s ability to recover from an upset, not the room621classification – as is commonly assumed. To explain this difference:622

623Assume a 1 cubic foot volume with a process inside it that generates62410,000 particles per minute. If we purge the volume with 1 cubic foot625per minute of clean air, the steady state (equilibrium) airborne626particle level will be 10,000 particle per cubic foot (see the Appendix627for equations). This 1 CFM creates an air change every minute, or 60628air changes per hour. This value (60/hr) is often assumed to be more629than enough to keep a space well below 10,000 particles per cubic foot630(PCF).631

632Now put the same process into a 100 cubic foot volume and keep the633airflow at 1 cfm, assuming good mixing inside the room. Now the room634sees an air change every 100 minutes, or about 0.67 ac/hr. Yet, when we635calculate the dilution, the equilibrium airborne particle counts are636still 10,000 PCF (10,000 particles per minute divided by 1 cubic foot637per minute = 100 particles per cubic foot). If we would supply 1 air638change per hour (100 CFM) of clean air, the room airborne counts drop639to 100 PCF !!! So it‘s not air changes that determine airborne particle640





18

counts, but three factors (referring to the Appendix):641642

1. Particles generated inside the space6432. Quantity of dilution air supplied to the space (cubic volume644

per time)645

3. Cleanliness of dilution air (assumed to be negligible in646 pharma due to HEPA filtration)647648

As is demonstrated elsewhere, a room receiving only 1 air change per649hour will take hours to ―recover‖ from in-use to at-rest conditions.650With clean air supply of 20 air changes per hour, a 100-fold recovery651in particle levels can happen in less than 20 minutes (see the ISPE652Sterile Baseline Guide). So when it comes to RECOVERY, air changes ARE653important, 20/hr often being the minimum for classified spaces.654

655Although the layman is conscious of the importance of ―air change rate‖656(more properly called ―ventilation rate‖) successful pharmaceutical657HVAC design can be attributed to proper filtration and attention to the658physical geometry of airflow in a space.659

6602.3.6.2 Impact of UDF (UFH) hoods on air change rates661

662Later sections will discuss ―mixed flow‖ rooms with clean air supplied663at the ceiling through terminal filters as well as clean air being664introduced to the room from Unidirectional Flow Hoods (UFH or UDF, once665called ―Laminar Flow‖) operating inside the room. Since air leaving the666space served by the hood is often orders of magnitude cleaner than the667room it leaks into, the relatively clean hood air serves to dilute668airborne particles in the room, along with the supply air from the669HVAC. In many respects the added flow from the hood not only reduces670airborne particles in its path, but can also accelerate the recovery671time of the room from in-use to at-rest conditions. The entire flow672

from the hood will likely not be available to add into air change673calculations, however, due to:674

675

Short circuiting of the hood air back to the hood inlet. Only areas676near the airflow path will see the added dilution.677

Hood air is not as clean as HVAC supply air. Even though the hood678might be rated as Grade 5 (class 100) the air leaving the work space679has collected additional contaminants from equipment and people680outside the critical zone.681

6822.3.7 Room Distribution and Quality of incoming air683

684The layout of inlets and outlets with relation to the sources of685

contamination and accommodation for expected obstructions are key to686controlling contamination and yielding effective HVAC design. The687relationship between these factors is expressed in the ―effective688ventilation rate‖ for a space. This measure recognizes that good layout689and filtration can produce desired airborne particulate levels and690recovery rates at lower than expected air change rates.691

692Taking the example above, good air mixing (dilution) and faster693recovery can be accomplished in a room where clean air supply is694distributed over a high percentage of the ceiling and not just from one695





19

air outlet. Although it‘s not necessary to create a ―laminar flow696ceiling‖, numerous air outlets equally spaced with equal flow rates can697create a ―plug flow‖ for faster recovery (often less than 10 minutes698for 20 ac/hr) and also prevent ―hot spots‖ of high particle count in699the room.700

701 2.3.8 Airflow Direction and Pressurization702703

Since constructing a space that is totally airtight is not practical is704normal construction, other means must be provided to assure that705particulate can be prevented from migrating into or out of a space.706Assuring that air is always flowing in the desired direction through707the cracks in building construction (door gaps, wall penetrations,708conduits, etc.) can influence contamination through the transport of709airborne particulates. A velocity of 1-200 FPM will contain light710powders and bioburden711

712One method to control this direction of airflow is by controlling the713relative pressurization of adjacent spaces or the Differential Pressure714

(DP) between the spaces.715716

A simplified method (neglecting the orifice coefficient for the717opening) to calculate the expected velocity of airflow from a given718pressure is:719

720V = 4005 (sqrt VP) or VP =(V/4005) (where V is velocity in ft/min,721VP is pressure difference in inches w.g., A is area of the opening722in square feet, Q is airflow in CFM)723

724– We can breakdown velocity as being volume divided by area, giving725V = Q/A, or726

727

VP = (CFM/4005A) 2728729– Assuming room DP converts fully to Velocity Pressure thru an730opening (a conservative assumption), calculating the opening area,731such as the crack area around a closed door between rooms, allows732calculation of the airflow (CFM) required to create a pressure, or733the 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 or7360.45 CuM/sec) will create 0.05" w.g. (12.5 Pa) differential737pressure (V = Q/A = 890 FPM = 4.5 M/s)738

739

2.4 PSYCHROMETRICS740

741 2.4.1 Introduction742743

Psychrometrics is the science that involves the properties of moist air744(a mixture of dry air and water vapor) and the process in which the745temperature and/or the water vapor content of the mixture are changed.746Psychrometrics – ―psychro‖ means moisture and ―metrics‖ means to747measure. A psychrometric chart is used to identify conditions of air748and to illustrate the process of achieving the desired state of the749controlled space. An in-depth knowledge of psychrometrics is impossible750





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 pWV

Barometric pressure PBAR

Measurable Psychrometric Properties Calculable Psychrometric Properties

803Table 2-3 Psychrometric Terminology804

805

2.5 EQUIPMENT806807


Each piece of HVAC equipment helps contribute to sustaining the user810requirements for room environmental conditions. HVAC equipment serving811GMP areas are intended to work in conjunction with associated controls812and sequences of operation systems to:813

814 Maintain room temperature815

Maintain room pressurization and differential pressure cascades816

Provide make up air for ventilation and room pressurization817

Condition the air stream to remove and/or add moisture content of818the air819

Minimize airborne contamination to the condition space820

Provide required air change rates to maintain room cleanliness821classification when required822

823The following major components of an HVAC system for GMP spaces are824discussed in more depth in Chapter 6.825

826

2.5.2 Air Handling Unit (Ahu)827828

An equipment package that includes a fan or blower, heating and/or829cooling coils, air filtration, etc. for providing heating, ventilation,830and air conditioning (HVAC) to a building.831

8322.5.3 Fan833

834An electrically driven air moving device used to supply, return or835exhaust/extract air to or from a room through ductwork to generate air836in sufficient amounts to provide ventilation, heating, cooling or to837overcome air pressure losses.838

839

2.5.4 Fume Exhaust/Extraction System840841

A system made up of ductwork, fans and possibly filters that discharges842unwanted air outside into the atmosphere to a safe distance from843buildings and people.844

8452.5.5 Heating Coil846

847A heat transfer device consisting of a coil of piping which increases848the sensible heat into an air stream, using steam or hot water or849





22

glycol as the heating medium. And electric air-heating element can also850be called a ―heating coil‖. 851

8522.5.6 Cooling Coil853

854

A heat transfer device consisting of a coil of piping, which reduces855 the sensible heat and possibly latent heat (via condensation of water856vapor) from the airstream using chilled liquid or refrigeration as the857cooling medium.858

8592.5.7 Humidifier860

861A device to increase the humidity within a controlled space by means of862the discharge of water vapor into the supply air stream or directly863into the room.864

8652.5.8 Dehumidifier866

867A special device that removes water vapor from the air to reduce868

humidity.869870

2.5.9 Air Filtration871872

Devices to remove particulate material from an airstream by means of873various media types.874

8752.5.10 Ductwork876

877A network of air conduits distributed throughout a building, connected878to a fan to supply, return or exhaust/extract air to or from zones in a879building.880

881

2.5.11 Damper And Louver8828832.5.11.1 Found in ductwork, a damper consists of a movable plate(or884numerous plates), plunger, or bladder that opens and closes to885regulate airflow. Dampers are used to regulate airflow to certain886rooms.887

8882.5.11.2 A louver is an assembly of sloping vanes intended to permit889air to pass through and to inhibit transfer of water droplets from890outdoors into air systems. A louver may also be found in return air891ductwork at room interfaces.892

8932.5.12 Diffuser And Register894

895

Air distribution outlet or grille designed to introduce air to a space896using direct airflow in desired patterns. Air diffusers are usually897located to distribute the air as uniformly as possible through out a898space.899

9002.5.13 Ultraviolet (UV) Light901

902A UV light uses precise ultraviolet light wavelength to destroy903microorganisms.904





23

905

Equipment

H e a t i n g

C o o l i n g

H u m i d i f i c

a t i o n

D e h u m i d i f

i c a t i o n

R o o m

S t a t i c

P r e s s u r e

A i r f l o w

A i r Q u a l i

t y

Air Handler X X X X X X

Fan X X

Fume Exhaust/ExtractSystems

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 to907environmental parameters908

909

2.6 HVAC SYSTEM CONFIGURATION910911


This section gives a brief overview of the key factors to consider, the914options available to an HVAC system designer, and the factors915influencing the decision to choose a particular system type.916

917This section should be read in conjunction with section 4 ―HVAC918APPLICATIONS BY PROCESS AND CLASSIFICATION‖. 919

920One question to answer is ‗how many Air Handling Units should be used‘? 921

922It is common practice to divide a manufacturing area into zones, and923use a separate Air Handling Unit per zone – a zone in general Building924Services design would be an area with similar heat gains and losses, a925similar approach is used within the pharmaceutical industry – and is926usually considered as an area with one type of manufacturing process or927area classification, e.g. a tablet compression suite or all Grade 7928areas, as the area requirements will be similar. Other factors that are929





24

considered when dividing a facility into zones include:930931

Use of multiple units improves reliability of the area – it would be932unusual for all of the units to fail.933

The use of multiple smaller units might make air balancing easier934

The use of multiple smaller units means that the main distribution935ducts are smaller, making then easier to route in small ceiling936voids.937

It is easier to make modifications to parts of the facility in938future and upgrade a small unit than change a large single unit939

Use of multiple units allows for easier separation of areas within a940multi-product concurrent manufacturing plant.941

942The decisions regarding AHU system zoning are very important as a943factor in subsequent facility commissioning, qualification and related944documentation.945

9462.6.2 Basic System Types947

948There are three basic categories of HVAC system;949

9502.6.2.1 Once through - uses treated outside air to provide the design951internal conditions, this air is then extracted from the space and952discarded.953

954

Air Handler Unit

(AHU)

Room

Outdoor

air

Supply air

Exhaust Infiltration

Exfiltration 955956

Figure 2-2 Once-through HVAC957958

Advantages of this system:959960

This system provides an abundance of O2 rich fresh air to dilute961contaminants962

The system can handle hazardous materials, though the extracted air963





25

may need treatment before it is discarded.964

Lower risk of cross contamination of products from another room via965HVAC966

Exhaust fan may be located remote from the AHU making duct routing967simpler968

As there are less concerns about the ductwork noise in the extract969ductwork, it can usually be sized for a high velocity, making it970easier to route as high velocity = smaller diameter971

972Disadvantages of this system:973

974

More expensive to operate than an equivalent recirculating system,975especially when cooling and heating.976

Filter loading very high = frequent replacement977

Potential need for exhaust air treatment (scrubbers, dust978collectors, filters)979

Room conditions more difficult to maintain980981

2.6.2.2 Recirculating systems - This category is much more common – the982room supply air is made up of a percentage of treated outside air mixed983with some of the air extracted from the space. A percentage of the air984is either discarded or lost through leakage to adjacent areas, due to985local area pressurization.986

987

Air Handler Unit

(AHU)

Room

Makeup

(Fresh)

air

Return air

Supply air

Exfiltration

Infiltration

Possible extract

988989

Figure 2-3 Recirculated HVAC990991


Usually less air filter loading = lower filter maintenance and lower994cost opportunity for higher grade air filtration995

Lower energy cost than once through996

Less challenge to HVAC means that it is simpler to obtain better997





26

control of parameters (T, RH, etc)998999

Disadvantages of this system:10001001

Return air ductwork routing to air handler may complicate above1002

ceiling1003 Chance of cross contamination via HVAC = Requires adequate supply1004

air filtration (and sometimes return air filtration to prevent1005contamination of the air handler)1006

Chance of recirculation of odors and vapors and of inadequate fresh1007air supply1008

10092.6.2.3 Exhaust (Extract) system – sometimes a stand-alone system that1010removes airborne contaminants, either solid particles or gasses/vapors.1011It may be interlinked to a once-through or recirculated air supply1012system. Used alone, the extract/exhaust system will create a negative1013differential pressure in the room or enclosure it serves1014

1015

"Space" with airborne contaminants

Space may be a room, a glovebox or an exhaust hood

Fan

Air cleaner Stack

(follow 1.3x

rule of thumb

if "foul air"…

see ASHRAE)

Ductwork

Infiltration

duct leakageExfiltration

duct leakage

10161017

Figure 2-4 Exhaust System10181019


Simple to operate. Makeup air is pulled from surrounding spaces.10221023

Disadvantages of this system:1024

1025 If used to capture large quantities of contaminants, such as from1026

open processes, a large energy cost will be associated with1027conditioned air being thrown away (see once-through system above).1028

10292.6.2.1 Use of Air Handling Units in parallel or series1030

1031It is possible to put units in series, for example if a higher air1032pressure is required to offset the pressure drop through HEPA filters1033





27

in one area served by an HVAC system.10341035

The use of parallel units is common practice where large areas are1036being conditioned, for example warehouses and large research1037laboratories, where this approach may make it possible to maintain1038

acceptable conditions in the area should one unit fail. When1039 configuring units in parallel, care must be taken to assure that the1040fans can be isolated and started independently. Automatic isolation1041dampers and variable fan drives assist in managing these factors.1042

10432.6.2.2 Configurations and combinations1044

1045The basic components and concepts outlined above can be assembled in an1046infinite variety of ways. Shown below are a few examples of design1047concepts commonly used.1048

1049(Note: Add some basic block diagram schematics to illustrate these1050combinations.)1051

10522.6.3 Air Handling Unit Configurations1053

1054There are two basic types of AHU configuration – blow through or draw1055through. The term describes the relationship of the fan to the coils in1056the air handling unit. The two approaches have distinctive1057characteristics;1058

10592.6.3.1 Blow through units1060

1061Air is drawn into the unit, typically through a set of pre-filters used1062to reduce the dirt load on the (usually more expensive) final filters,1063and to prevent build up of dirt onto the heating and cooling coils,1064which would quickly reduce their efficiency.1065

1066One advantage of this type of unit is that it allows the AHU discharge1067temperature to be at the cooling coil discharge air temperature,1068because the fan heat is removed in the cooling coil. This is1069particularly useful when heat loads are particularly high and supply1070air temperature must be as cold as possible. It is not advisable to1071follow a blow through unit immediately with a set of HEPA filters1072unless special precautions are included to prevent moisture carryover1073from the cooling coil. Another advantage is that if the drain trap on1074the cooling coil runs dry, then air will blow out through the trap – 1075wasting a small amount of treated air.1076

1077The disadvantage - the unit typically needs to be longer to allow a1078

diffuser to be installed after the fan to ensure that the airflow is1079 spread over the entire coil area, and not concentrated on the middle,1080which would cause a drop in system performance.1081

10822.6.3.2 Draw through units1083

1084These units are typically arranged with the pre-filters and coils1085before the fan. The advantage of this is that the unit is often1086smaller, and the motor and fan provide a small amount of reheat1087(usually 1-2 degrees F) to the air coming off the cooling coil. This1088





28

lowers the RH of the air and prevents the problems with wetting final1089AHU HEPA filter banks. One precaution with draw through units is that1090if the drain trap is dry, then untreated air can be drawn into the unit1091through the trap, with only the final filter to protect the conditioned1092environment. The design must include provisions for maintaining a1093

wetted drain trap, which can be several inches in height.109410952.6.3.3 Air Handling Unit Design variations1096

1097A design variation worth considering is the use of a face and bypass1098damper – the concept is shown below – a portion of the air passing1099through the AHU is redirected through a treatment stage, with the1100volume altered to vary the condition of the resulting output air. This1101is a useful concept to use to gain improved accuracy, particularly if1102the treatment process is not easily controllable – e.g. chemical1103desiccant dehumidification.1104

1105

Dehumidifier

_

11061107

Figure 2-5 Face and bypass control with a packaged dehumidifier and1108cooling coil (-)1109

1110A similar concept is often employed in the first mixing box of the AHU1111when enthalpy control is used – in all cases careful sizing of the1112dampers, to ensure adequate velocity for control, is necessary to1113obtain proper operation of these systems, maintaining constant system1114volume as the proportions of the air streams are varied.1115

11162.6.3.4 Air Handling Unit Components1117

1118Numerous design options are possible within the 2 basic types. Here1119will establish a lexicon of design components, or modules, that can be1120

assembled into an AHU design and discuss the motivations that drive the1121selection of each. To illustrate the possible options, the following1122demonstration uses a draw-through, Recirculating AHU:1123

1124





29

Mixing Box Humidifier Dehumidifier Reheating Coil

Supply Fan

Energy

Recovery

Coil

11251126

Figure 2-6 Air Handler Unit Components11271128

Return Fan11291130

Most recirculating air systems will utilize a return fan. This fan1131

allows return pressure and flow to be managed independently from the1132 supply. This is particularly important if the downstream system has1133volume control boxes on both the supply and return. It also allows the1134return air to be diverted to exhaust when outside air conditions are1135closer to desired discharge conditions than return air. This function1136is referred to as an ―economizer‖ and is generally employed in offices1137or other spaces that are not pressure controlled.1138

1139 Mixing Box1140

1141This pieced of equipment is also common in recirculating air systems.1142The return air can be directed to exhaust or to recirculate, it is then1143mixed with outside air for pressurization and/or ventilation. The1144resulting air stream is referred to as ―mixed air‖. In very cold1145

environments the mixed air may be subjected to a turbulence inducing1146device to assure thorough mixing and avoid stratification.1147

1148Prefilter or Prefilter and Intermediate Filter1149

1150Filters are typically provided upstream of coils in an air handler to1151protect the coils from fouling with dirt or debris. The system1152typically employs a low efficiency ―dust stop‖ (MERV 7) filter followed1153by a medium or high efficiency intermediate filter (MERV 7-14).1154

1155Energy Recovery Coil1156

1157Once through air systems, or other systems with high amounts of exhaust1158

may employ an energy recovery coil to return a portion of the energy1159 employed in conditioning the exhausted air to the incoming air. These1160coils are typically upstream of all other coils and may be placed1161upstream of the filters if used to melt snow in cold climates. These1162systems may also employ a bypass damper to decrease pressure drop1163across the coil when energy recovery is not advantageous.1164

1165Preheat Coil1166

1167Once through air systems, or other systems with high amounts of outside1168





30

air in cold climates may employ a preheat coil to condition the1169incoming or mixed air. These coils are always upstream of cooling1170coils, to protect them from freezing and may be placed upstream of the1171filters if used to melt snow in cold climates. These coils do not1172typically impose a large pressure drop, so a bypass damper is not1173

common.11741175Humidifier1176

1177Once through air systems, or other systems with high amounts of outside1178air in cold climates may employ a humidifier to inject water vapor to1179condition the incoming or mixed air. These devices are typically1180downstream of the heating coil and may even be mounted in ductwork1181where turbulence and high velocity promote absorption of water vapor.1182When employed in an AHU, mounting upstream of cooling coils provides a1183natural baffle to prevent carryover of liquid water droplets.1184

1185Cooling Coil1186

1187

Cooling to maintain environmental conditions is common, if not always1188required in Pharmaceutical applications. These coils can eliminate both1189sensible and latent heat and can be upstream or downstream of the fan.1190If latent cooling is expected drainage of these coils is a key design1191issue and mist eliminators may be employed to eliminate carryover of1192liquid water droplets that condense on the coil. These coils do impose1193a large pressure drop so a bypass damper can be employed, but can pose1194a risk of unconditioned air leakage and non-attainment of humidity1195goals.1196

1197Dehumidifier1198

1199Dehumidifiers employ a chemical desiccant to remove moisture from the1200

supply air stream when humidity below 30-40% is required. The1201 dehumidifier is often located downstream of the cooling coil as they1202work most efficiently when airstream relative humidity is high (but1203within desired limits). However care must be taken to assure that1204excessive relative humidity or liquid water droplets do not damage the1205dehumidifier. The choice of desiccant may vary, depending on the1206application but all desiccants are regenerated using heat; therefore,1207air leaving the dehumidifier is both dryer and hotter than upon1208entering.1209

1210Recool Coil1211

1212These coils are only commonly installed downstream of dehumidifiers to1213eliminate sensible heat from the supply air. They are also employed1214

downstream of cooling coils to provide additional latent heat removal.1215In this second application they operate below chilled water temperature1216and are typically filled with refrigerant or a low temperature brine of1217water and glycol (ethylene or propylene). If latent cooling is expected1218drainage of these coils is a key design issue and mist eliminators may1219be employed to eliminate carryover of liquid water droplets that1220condense on the coil. These coils do not typically impose a large1221pressure drop so a bypass damper would be unusual.1222

1223





31

Reheat Coil12241225

Systems that require over-cooling to achieve humidity control (in lieu1226of dehumidification) may also employ a preheat coil to condition the1227air leaving the cooling coil. These coils are always downstream of1228

cooling coils, to increase the discharge temperature of the air handler1229 and avoid condensation in the ductwork or overcooling of the space.12301231

Supply Fan12321233

All air systems will utilize a supply fan. This fan provides the motive1234force for distribution of air throughout the air handling system.1235

1236Final Filter1237

1238Filters may be provided as the last treatment step in an air handler.1239These filters provide assurance of air quality (with reference to1240particulate) downstream of all air handling operations and are1241particularly valuable in protecting terminal filters from fouling with1242

dirt or debris and in providing filtration for classified spaces. This1243is of particular interest in systems that employ fan drive belts which1244shed particulate into the airstream. Systems typically employs a high1245efficiency filter in this location (MER V 14+).1246

12472.6.4 AIRLOCK STRATEGIES1248

12492.6.4.1 PRESSURIZATION1250

1251Airlocks are usually interposed between areas if airflow between the1252spaces needs to be controlled when they are entered or exited.1253Airlocks may also serve as material transfer / decontamination rooms,1254and gown or degown rooms. Three types of airlock pressure arrangements1255

are indicated below:12561257

Airlock

"Cascade" "Sink"

Airlock Airlock

"Bubble" 12581259

Figure 2-7 Airlock configurations12601261

The ―cascade‖ pressurization scheme should be used when there are area1262cleanliness classification requirements but no containment issues, or1263where there are containment issues but no cleanliness classification1264





32

requirements. (i.e., cascade outward from the room for aseptic1265operations, but cascade into the room for hazardous compounds.) Doors1266are usually interlocked to allow only one to be open at a time. The1267normal differential from one air class to the next (ACROSS the airlock)1268is 10-15 Pa (0.04 to 0.06‖ w.g.). The pressure INSIDE the airlock is1269

somewhere between the two classes, depending on which door is open. It1270 is not necessary to have 10-15 Pa between a room and its airlock (see1271―Not required‖ in the drawing below). 1272

1273If there are requirements for both area cleanliness classification and1274product containment, then the use of pressure sinks and bubbles may be1275necessary. Pressure bubbles are usually used for ‗clean‘ operations1276(i.e., such as gowning or material entry airlock) and pressure sinks1277are usually used for ‗dirty‘ operations‘ (i.e., de-gowning material1278decontamination/exit airlock). Normal design pressure differential1279between classifications should be 0.06― w.g. (15 Pa) with the doors1280closed. Pressure differential will drop momentarily while one door is1281opened, but will not drop to zero (as it would with no airlock or if1282all airlock doors were opened). In no case should pressure differential1283

reverse.12841285

For unclassified areas the minimum suggested pressure differential is12860.02‖ w.g. (5 Pa), being the minimum reliably detectable by current1287pressure sensor technologies.1288

1289The pressure differential is measured across the airlock, not across1290each 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 Relationships12951296

When using the ―bubble‖ pressurization scheme, the normal design1297pressure target, with doors closed, between classifications should be12980.06‖ w.g. (15 Pa). There may be different pressure drops across each1299door due to building tolerances, or adjacent room conditions, this is1300not considered a problem. If protecting non-sterile processing (areas1301not classified) a lower pressure is acceptable, but should be1302measurable. The pressure of the very clean airlock ‗bubble‘ is usually1303





33

designed to be about 0.02 to 0.03 in. w.g (about 5-8 Pa) above the1304higher of the two room pressures.1305

1306The positive pressure airlock provides a robust means of segregating1307areas 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

13101311

Figure 2-9 Example of “Bubble” pressure relationships 13121313

Similarly, with the ―sink‖ pressurization scheme, the normal design1314pressure between classifications should be 0.04 to 0.06‖ w.g. (10-151315Pa) with doors closed. As with the ―bubble‖ there may be different1316pressure drops across each door. The pressure of the contaminated1317airlock ‗sink‘ is usually designed to be about 0.02 to 0.03 in. w.g (5-13188 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

13211322

Figure 2-10 Pressure “sink” relationships 13231324

It is often necessary to have pressure differentials at boundaries1325within the same air class area for operational reasons. The minimum1326operational differential between areas of the same classification1327





34

(where required) is suggested to be 0.02― w.g. (5 Pa), with a design1328target of 0.04‖ (10Pa) suggested. It is also sometimes necessary to1329have directional air flows for operational reasons without a measurable1330pressure differential, such as may be found in non-classified areas,1331such as oral dosage manufacture.1332

1333 Pressure may be maintained across doors between air classes when no1334airlocks are present. However, without the added protection provided by1335the airlock, significant airflow volumes and pressure actuated dampers1336are required. (See the Appendix) This scheme should be adopted only1337when airlocks are not possible.1338

1339The airflow leakage rate should be calculated for each room. This1340calculation must be based on the design pressure differential1341established in the project documents and not on some rule of thumb1342method, e.g., percentage of supply air. Door seals are the primary1343path of room air leakage. Therefore, doors and doorframes are crucial1344components of the facility construction, as more leakage air must be1345designed into the system for doors with poor seals. The HVAC design1346

engineer should consult with the facility architect to assure1347specifications are adequate for pressurization requirements. Door1348frames may include continuous seals which would reduce leakage required1349to maintain the desired pressure, as well as provide isolation in case1350of airflow failure. Doors may be provided with a provision for1351operable floor sweeps which drop down as the door closes, but these may1352present cleaning problems. Where double doors are used in the1353facility, gasketed astragals are required. Door grilles should be1354avoided unless part of a pressure scheme without airlocks (as discussed1355in the Appendix). Figure 14, Chapter 27 of the 2005 ASHRAE Handbook-1356Fundamentals should be used in calculating the air leakage rate of1357doors. Common practice is to design for a 0.10‖ average crack between1358the door and frame on sides, top, and bottom. Note that corrections1359

are to be applied for design pressure differentials using the formula1360 contained in Figure 14. A similar leakage calculation is discussed in1361the article, Airlocks for Biopharmaceutical Plants, del Valle,1362Pharmaceutical Engineering , Volume 21, Number 2, March/April 20011363

1364Material transfer openings are another key room air leakage path. To1365calculate leakage through these and other fixed openings use the1366formula,1367

1368Q = A x 4005sqrt (VP) (―Sqrt‖ = square root) 1369

1370Q = airflow (CFM)1371

1372A = area of opening (sq. ft.)1373

1374VP = velocity pressure — the velocity pressure at the opening (in. w.g.)1375is roughly the same as the differential pressure across the opening,1376(or the, room differential pressure),1377

1378This method provides a conservative leakage number. In most cases, a1379slightly smaller leakage airflow will produce the desired pressure1380differential for a given leakage path. Because of this, during1381commissioning there may be more return air leaving the room than1382





35

designed, so return air dampers should have some extra capacity.13831384

In some cases the calculated room leakage may exceed the minimum air1385change rate for small rooms such as airlocks. In these instances the1386total supply air to the space must match the calculated leakage.1387

However, provisions should be made in the design for some return air1388 from the space in case the actual leakage is less than calculated. A1389good rule-of-thumb is to size the return for half the supply air flow1390into the room. In applying this approach, care should be taken in1391sizing any volume control (damper or CV box) on the return air side to1392ensure that the actual flow rate is with the operable range of the1393control device.1394

1395For this reason it is a good engineering practice to put a tighter1396specification on the supply air volume, being more critical to maintain1397the room conditions, and a larger design range on the return, which1398will be whatever value is needed to maintain desired differential1399pressures.1400

1401

Two methods of measurement are commonly applied to monitor room1402pressure relationships; room-to-room and common reference point. While1403both have been used successfully, the preferred is the common reference1404point method in order to minimize compounded error. Here, one port of1405the differential pressure transmitter (usually, but not always, the1406―High‖ side) is piped to the room being monitored and the other side1407(usually, but not always, the ―Low‖ side) is piped to a common1408reference 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

1412Figure 2-11 Differential Pressure Sensor Locations1413

1414The common reference point should not be outdoors, as the effect of1415wind direction may give unstable readings. Where room to room1416monitoring is used it is a good practice to confirm through the system1417balancing that net airflow into the facility is greater than the1418extract/exhaust.1419

1420All signals are sent to the control system where differentials are1421





36

calculated by means of an algorithm. In the event that the reference1422(interstitial) space is partitioned by fire walls or other means, it1423may be necessary to provide multiple common reference points by1424building ―zone‖. In this case the pressure relationship across a1425―zone‖ will need to be room-to-room or the use of two differential1426

pressure transmitters, one to each reference point, will be required.14271428For information on monitoring system see section 2.7 Control and1429monitoring.1430

14312.6.5 Ventilation/supply strategies1432

14332.6.5.1 Room Air Distribution:1434

1435There are two basic types of room air distribution: dilution and1436displacement air distribution.1437

1438In a dilution design, room air is mixed continuously with supply air to1439help achieve uniform air temperatures within the space. In areas where1440temperature uniformity is the only factor, aspirating-type diffusers1441are used to allow turbulent mixing of room air with supply air. From a1442particulates perspective, dilution also mixes ―less clean‖ room air1443with the clean supply air. Aspirating-type diffusers are not acceptable1444in any of the clean classified rooms. Even though non-aspirating1445diffusers do not eliminate turbulent air patterns in the room, using1446non-aspirating diffusers in clean rooms reduces the mixing effect. The1447particulate level in the room can be reduced with dilution by1448increasing the air-change rate of clean air supply. Dilution1449distribution with non-aspirating diffusers (typically perforated face1450plate over the terminal HEPA media) is acceptable to clean classified1451areas up to ISPE-7.1452

1453

In a displacement design, room particulates are displaced by clean1454terminal HEPA filtered unidirectional air. This design requires1455continuous HEPA coverage at the ceiling and properly sized and located1456low level return or exhaust grills. ISPE-Grade 5 should use1457displacement air distribution (typically a unidirectional flow hood – 1458UFH).1459

14602.6.5.2 Room Air Distribution options1461

1462Conventional air distribution techniques are generally acceptable for1463administrative, warehouse, and unclassified spaces. Large warehouse1464spaces, however, may see hot and cold spots with poor air distribution.1465GMP spaces and cleanrooms require more stringent methods. Supply air1466

should be introduced at the ceiling level and return/exhaust air should1467 be extracted near the floor. The use of non-aspirating diffusers on1468the face on terminal HEPA filters may improve airflow patterns.1469

1470Within mixed airflow rooms, airflow patterns should be from clean side1471of the space to the less clean. For example, within a space that1472contains an ISO 5 micro-environment/zone with an ISO 7 background,1473airflow should always be from the cleaner zone into the less clean1474background area.1475

1476





37

Mixed Airflow GMP Space

ISO Class 5 ISO Class 7

14771478

Figure 2-12 Mixed Airflow Space14791480

Some process operations, i.e., centrifugation, are inherently particle1481generating. Airflow patterns within the spaces that contain these1482processes should take this into account by locating returns/exhausts at1483floor level near the particle generating operation.1484

1485Airlocks and gown rooms are usually divided, often by a physical line1486on the floor, into clean and ―dirty‖ zones in accordance with the flow1487of personnel, material, and equipment. Within such spaces, the air1488pattern should from the clean to the ―dirty‖ side of the airlock.1489

Therefore, HEPA supplies should be located on the clean side and low1490 wall returns should be located on the opposite side of the room.14911492

Low wall returns should be located no more than 12‖ above the floor.1493Returns should be generously sized with a maximum grille face velocity1494of no more that 400 FPM. Ductwork should be sized for a maximum1495pressure drop or 0.1‖ per 100‘ or a maximum velocity of 850 FPM,1496whichever is more restrictive. The heel of the connecting elbow should1497have a minimum 6‖ radius to facilitate cleaning. The elbow and1498connecting ductwork, up to an elevation of 5 feet above the floor,1499should be Type 304 or 304L stainless steel.1500

1501





38

6" Radius

1 ' - 0 " m a x i m u m

Typical Low Wall Return

15021503

Figure 2-13 Typical Low Wall Return15041505

Return air ducts located in stud wall spaces need not be insulated1506within the walls. Insulation shall terminate at the top of the wall.1507The mechanical engineer should consult with the facility Architect to1508assure that, where needed, wall cavities are adequate to contain low1509wall returns.1510

1511

2.6.6 EXTRACT (EXHAUST AND / OR RETURN) STRATEGIES15121513

Why we use low level or high level extract, the area affected by an1514extract point – do we want to cover dust extract systems at all here??1515

15162.6.7 DISTRIBUTION1517

1518Design concepts for ductwork distribution systems – equal velocity,1519static regain etc are covered in the ASHRAE Handbooks. Such1520calculations should be performed by only qualified HVAC professionals,1521





39

who should be familiar with ASHRAE.15221523

2.7 HVAC CONTROLS AND MONITORING15241525


1527This section will give a brief overview of the options available for1528controlling and monitoring HVAC systems and the environments that they1529provide, providing guidance on the points to consider when designing a1530new system or reviewing an existing installation.1531

1532An important early decision is to decide if the control system will1533also be the quality ―system of record‖ providing the alarms and1534recording that the environment is being maintained within the specified1535limits, or if there will be an independent system to do this, with the1536HVAC control system providing only ―engineering‖ information and1537alarms.1538

1539

2.7.2 Controls15401541

There are many types of equipment that can be used to control an HVAC1542system, each with advantages and disadvantages, three of the more1543common variations are described below;1544

15452.7.2.1 Basic control system1546

1547A basic system may use packaged controllers (Packaged ―PID‖ units) for1548each of the controlled variables. There may be independent control1549units – e.g. temperature, humidity, or a single combined unit, with the1550sensors and controlled items – dampers, valves etc connected to the1551controller. The controller may also have the capability of providing1552alarms.1553

1554This option provides a low purchase and installation cost, control1555panels in a large installation can be standardized and complete panels1556held as spares.1557

1558However there is no ability to monitor the system performance, or1559analyze trends or component performance with this system, hence it is1560rarely used. A picture of a typical control unit is shown below.1561

1562

15631564

Figure 2-14 Typical Single Loop Control (Courtesy of __________)1565





41

1608

1609 Figure 2-16 Field Bus system (courtesy of _________)16101611

2.7.3 Actuation methods16121613

There are two common means of actuating components – electrical and1614pneumatic.1615

16162.7.3.1 Electrical/Electronic1617

1618The actuator will use a low voltage control signal, to control an1619electric motor, the units can be on off, or proportional1620

1621These systems are used where the speed of actuation can be slower,1622typical times for a valve to go from fully open to fully closed are in1623the range of 1-2 minutes.1624

1625Installation is simple, as all signals are by cable – e.g. control1626signal, power supply, and any feedback, such as valve position, or1627open/closed signals.1628

1629The actuators can be supplied as fail open, fail closed, or with a1630manual override facility.1631

16322.7.3.2 Pneumatic1633

1634The control signal is used to vary the output pressure from a pneumatic1635

controller, which is fed to a pneumatic actuator on the controlled1636component.1637

1638The system requires the use of an I/P (control signal to pneumatic)1639converter, with an instrument quality air supply, then local tubing to1640the actuator. In order to get the best response time the converter1641should be as close as possible to the actuator. Fully pneumatic1642controls are available but seldom used with large installations and1643BMS.1644





42

1645The units use air pressure one way, with an opposing spring to return1646the controlled item to the fail position. The system is naturally1647proportional control – i.e. the controlled item position is1648proportional to the control signal.1649

1650 These units typically have a faster response time than an electric or1651electronic unit. The pneumatic system is also ideal for hazardous areas1652requiring intrinsically safe installations.1653

1654

16551656

Figure 2-17 I/P transmitter16571658

For HVAC applications response time is not usually critical, as the1659response time of the overall system is slow, e.g. if the full equipment1660heat load is added instantaneously, the room temperature will rise1661slowly, not instantaneously, similarly the rate of change of external1662conditions is typically slow.1663

16642.7.4 Instrumentation1665

1666It is important to consider the requirements for the instrumentation to1667be used, in order to select the most cost effective type, and to define1668the appropriate calibration/verification regime. There is a lot of1669difference between domestic and commercial building type sensors and1670industrial type units, the latter being in general more reliable, and1671certainly more robust – for this reason on this grade of instrument1672should be considered.1673

1674

For some instruments accuracy and repeatability are important, e.g.1675measuring room temperature, for others accuracy is not important, but1676repeatability is, e.g. measuring a system flow rate in order to1677maintain constant flow through the control of a variable speed fan.1678

1679Thus three point calibration may be required, or single point1680verification may be justifiable.1681

1682The parameters usually requiring monitoring include:1683

1684





43

2.7.4.1 Airflow1685

1686Measurement of airflow is typically done to allow control of airflow in1687a system. For classified spaces, airflow should be kept constant to1688assure that particle counts, recovery, and room pressure are in1689

control.16901691

This may be done using a flow grid – The Grid consists of a row of1692tubes with closed ends, some of the tubes are perforated with small1693holes facing upstream sensing total pressure, while others have holes1694facing downstream to sense throat sub-static pressure the tubes are1695connected by manifolds with the distribution designed to compensate for1696non uniform flow profile in the duct . The difference in pressure1697signal between the two sets of tubes is proportional to the square of1698the mean velocity in the airway. By connecting the output tubes to a1699suitable instrument, the pressure difference and hence the volume flow1700rate can be easily measured. In order to get an accurate reading the1701installation should have straight duct runs equivalent 2-3 times the1702duct diameter upstream and downstream of the flow grid.1703

1704A similar grid system uses hot wire anemometer elements. Because flow1705sensing is not dependent on the square root of pressure, better1706accuracy at low flows is possible.1707

1708Another system gaining popularity is the fan venturi meter, either1709retrofitted to or an integral part of the system fan inlet (evase) – 1710with the advantage of established accuracy. Its performance is1711independent of the ductwork design - hence is a useful commissioning1712aid. The wiring is all local to the fan/AHU, simplifying installation.1713

1714It should be noted that the usual function of the grid is not to get an1715accurate reading, but to maintain a preset reading determined during1716

system commissioning, whether actual flow or not. Due to the square law1717operating principle, differential pressure flow measurements have a1718limited turndown capability.1719

1720For specialized applications such as the monitoring of unidirectional1721air flow protection devices (laminar flow hoods) hot wire anemometers1722are used. Vane anemometers are commonly used for commissioning as they1723tend to have an averaging affect over the fan area compared to the spot1724reading from the hot wire unit.1725

17262.7.4.2 Flow control1727

1728The most common form of flow control is the damper – these can be1729

manually adjusted, or actuated, use a single blade, or be multi blade1730 parallel or opposed blade17311732

These items are fairly basic, and the relationship between air flow and1733position is non linear improved control is available using devices1734such as a ―pneumatic‖ damper – this uses a bladder inflated with low1735pressure compressed air to open aerodynamically shaped blades. These1736provide more linear control with better pressure recovery and turndown.1737

17381739





44

1740

17411742

Figure 2-18 Pneumatic (“Bladder”) dampers 17431744

Another device that may be used to provide better control is a variable1745orifice, such as the item shown below:1746

1747Figure 2-19 Variable Orifice (Venturi) Damper GRAPHIC MISSING1748

17492.7.4.3 Control Valves1750

1751The correct selection of fluid (liquids or steam) control valve is1752critical for good system performance, together with tuning of the1753control loop.1754

1755

There are two types of control valve; the three port valve, which can1756 be used as a mixing or diverting valve to supply the controlled1757equipment, or the two port valve, which directly controls flow to the1758equipment.1759

1760The three port valve was once the industry standard , however the use1761of two port valves with variable flow rate systems is becoming far more1762common, as a well designed system is as effective, and has a lower1763capital and operating cost.1764

1765





45

Correct valve selection is important for the correct operation of a1766system, a brief over view of the process follows, but for readers who1767require more information references are given in the references1768section.1769

1770

Valve characteristic17711772The valve characteristic is the ratio of flow through the valve to the1773valve lift (opening) at a constant differential pressure.1774

1775There are three main types of valve characteristic:1776

1777

17781779

Figure 2-20 Valve Characteristics (Courtesy of _____________)17801781

These are shown graphically as in a globe valve;1782

1783 The fast opening valve is typically used for on / off control.1784

The Linear valve has a flow rate directly proportional to the amount1785it is open, and is commonly used for diverting applications in HVAC1786supplying water to heating or cooling coils..1787

The equal percentage valve is more commonly used in two port1788applications.1789

1790The characteristic should be chosen with respect to the application of1791the valve. The installed characteristic is the relationship between the1792flow and valve lift in the system where it is installed. Where the1793pressure drop across the valve decreases with increasing flow the EP1794valve will produce a more desirable linear characteristic.1795

1796 Simple Flow coefficient calculation or Cv for liquids17971798

Cv= design flowrate (gpm) x sqrt (Specific Gravity of the fluid/1799Allowable pressure drop1)1800

1 Calculation should be based on the allowable pressure drop to determine the CVneeded. Selected valve should have that CV at 90% opening or less.





46

1801Select a valve where the required Cv is in the 10-80% range of the1802stroke – use of a valve that is too small (typically less than half the1803line size) or too large (line size or greater) would be wrong – the1804valve will not have the ability to control the flow accurately, i.e.1805

not have adequate authority. If the valve normal operating condition1806 results in operation in a near closed condition control can be erratic,1807particularly if installed where flow tends to close the valve.1808

1809 Valve Authority1810

1811This is defined as the percentage of total system pressure drop1812assigned to the valve, i.e. in a circulation system the pump will1813deliver some head to overcome pipe and heat exchanger losses and some1814to overcome valve resistance. If the latter is small in comparison to1815the former the valve will have less ability to control effectively.1816

1817Differential Pressure1818

1819

There are three applications for the measurement of differential1820pressure:1821

1822

The use of a differential pressure monitor to interpret the readings1823from a flow measuring device.1824

The use of a pressure switch to detect:18251826

Flow failure of a fan (not usually necessary if the system has flow1827monitoring)1828

Detection of high pressure across a filter or filter set, to1829provide an indication that the filters require changing.1830

The detection of low differential pressure between rooms to provide1831an indication of the incorrect airflow direction (non sterile1832areas), or failure of a design differential pressure (sterile1833areas).1834

18352.7.4.4 Differential Pressure sensing/Indication1836

1837There are a number of options here;1838

1839One of the most basic instruments is the Magnehelic gauge, a robust1840device based on the measurement of the deflection of a metal diaphragm1841which provides a visual indication of differential pressure. This1842device is also available with a switch output, or a variable output.1843

1844An alternative is a simple device using a colored ball mounted in an1845inclined tube, as shown below – this type of unit operates from first1846principles, so does not require calibration, the disadvantage is that1847there is airflow through the unit, so it requires routine cleaning.1848

1849





47

18501851

Figure 2-21 Visual DP indicator (courtesy of _____)18521853

Where greater sensitivity is required, or a control function based on a1854

differential pressure an electronic pressure transducer can be used – 1855these are available with or without indicator LEDs to allow an operator1856to see if conditions are acceptable or not. The most sophisticated DP1857sensors are pressure diaphragms with an accuracy of +/- 0.005‖ (0.251858Pa). Output is commonly 4-20 mA.1859

1860When specifying these units be careful to consider the operating1861pressure range, and ensure that the device is robust enough to handle1862the occasional pressure spike.1863

18642.7.4.5 Temperature sensor1865

1866The almost universal industrial sensor used to monitor temperature is1867

the resistance thermometer (RTD). Liquid and gas expansion systems are1868 used for self acting controllers and switches. 100 Ohm RTDs with a 38.51869Ohm fundamental interval are the industry standard and are available1870with different accuracy standards, some as accurate as ________. Some1871HVAC systems may utilize 1000 Ohm sensors of a lower accuracy.1872

18732.7.4.6 Humidity sensor1874

1875It is far more common to monitor relative humidity, though there are1876applications where it may be advantageous to monitor absolute humidity,1877for example in a system used to supply multiple areas, each equipped1878with a local branch re-heater, so that the moisture reading is1879independent of the temperature (in the example given the supply1880

temperature would be reset to minimize the use of the re-heaters, thus1881 each change in supply temperature would require the supply RH to be1882reset, whereas the humidity would be constant).1883

1884The sensors used industrially to monitor relative humidity now are1885generally units which measure the change in capacitance between two1886plates due to the variation in humidity. Accuracy is in the range of1887__________.1888

1889





49

This is an area of great discussion, let us consider temperature and1943humidity (typically Relative Humidity – the most important thing to1944remember is that conditions are very rarely uniform throughout a room – 1945see fundamentals of HVAC systems.1946

1947

The traditional location for the monitoring sensor was in the common1948 return air duct – this is still a good location, giving an average of1949the conditions in the space, assuming that the supply diffusers are1950doing a good job of mixing the supply with the room air.1951

1952It may be necessary to study the relationship between worst case1953conditions in the room and the mixed condition in the return duct.1954

1955If there are any significant heat or humidity gains then the local1956conditions near the source will be different.1957

1958When considering sensor locations also consider the process as seen by1959the product – for example consider a typical tablet compression room;1960

1961

The raw material sits in a hopper typically near a supply register, so1962that the area is flushed with clean air, it is then fed into the dies,1963where it is compressed – the process generating a significant amount of1964heat – the compressed tablet is then released into a de-duster/metal1965detector, into a collection bin, where it is cooling and exposed to the1966room conditions – due to the localized heat, the local RH will be1967lower.1968

1969As the equipment generates a significant amount of heat the air change1970rate is high – typically around 20 times per hour, to keep the supply1971air temperature differential reasonable – circa 0.5 degrees.1972

1973The most critical area is the feed hopper, which is covered by the1974

supply air – thus in this instance it could be argued that this would1975 be the location to monitor.19761977

There are also a number of options to consider for Differential1978Pressure, it is common practice to measure across the doors of the1979airlock, though the requirement it maintain the difference between the1980rooms, as it is usually desirable to maintain a positive pressure in1981the manufacturing area where there is any risk of ingress of outside1982air, hence some may prefer to monitor the room pressure compared to an1983external reference point.1984

19852.7.5.5 Alarm requirements1986

1987

It is important to consider the desired response to an alarm state.1988 Many alarms will provide early warning to the facility engineering1989staff of an unusual state requiring some attention or adjustment, but1990not indicating any transgression of required operating conditions.1991Other alarms often for the same variable at a worse condition may1992indicate that operating conditions have exceeded the specified states1993and production need to take action with the process to ensure product1994quality is not compromised. These alarms need to be relayed to the1995appropriate business unit.1996

1997





50

The regulatory requirement is for a local alarm, notifying the operator1998when the conditions are outside the defined limits.1999

2000This may be by an audible and or visual indication – e.g. a horn and2001flashing light mounted in a common area of the production suite, where2002

it can be seen or heard from the whole suite.20032004It is a good practice to set this action alarm at the extreme2005conditions, and have an engineering ―alert‖ alarm at conditions just2006outside the normal operating range, to alert the engineering staff of a2007potentially unusual condition as soon as possible, so that action may2008be taken to prevent an action alarm.2009

2010This engineering alarm may come from the validated monitoring system,2011or the GEP control system.2012

20132.7.5.6 Record requirements2014

2015Every company has its own standards – it may be acceptable to just have2016a record of any alarms during manufacturing – or lack thereof! – 2017recorded on the batch record sheet.2018

2019It may be preferred to have an actual record.2020

2021With current data logging systems this may be in the form of a2022continuous chart, or a daily printout of min, max average, Standard2023Deviation.2024

20252.7.6 Equipment monitoring2026

2027There are a number of ways that HVAC equipment can be monitored;2028consider a fan motor:2029

2030 The control contactor can be wired so that an alarm is given if the2031

unit goes into overload.2032

The motor current can be monitored2033

The motor temperature can be monitored2034

Vibration or acoustic output may be monitored.2035

The airflow from the fan can be monitored using an in duct device,2036or a in fan device2037

2038The unit which measures the flow is the unit which will detect all of2039the fan failure modes, the others have potential limitations, depending2040on the fan drive arrangement, this measurement is also likely to be the2041most sensitive.2042

2043With the new generation of accelerometers it is cost effective to2044monitor the performance of rotating equipment to ensure early detection2045of system wear (due to vibration). The sensors can be wired to a BMS,2046or be wireless, transmitting data to a base station for monitoring.2047

20482.7.5.1 Other equipment parameters may also be monitored, primarily as2049part of GEP to ensure lowest life cycle cost:2050Fan speed (or current draw, to indicate added pressure drop due to2051





51

filter loading)2052Supply duct pressure2053Damper actuator positions (to predict need for re-balancing of the2054HVAC)2055Filter pressure drop (where filters tend to load quickly)2056

Cooling coil leaving temperature2057 Other HVAC parameters, to aid in predicting maintenance and in2058troubleshooting performance problems2059

20602.7.5.2 Sensor mounting considerations2061

2062The things to consider when selecting where to mount a sensor are:2063

2064The instrument needs to be mounted so that it is easy to calibrate.2065

2066The instrument specification and mounting need to consider any local2067cleaning required2068

2069It is best to keep pneumatic control lines as short as possible.2070

20712.8 SYSTEM ECONOMICS2072


2075The pharmaceutical industry is unusual in that the potential impact of2076an HVAC system failure could be financially very significant, for2077example causing loss of a batch of product, or the loss of control of2078the conditions in a research laboratory, potentially invalidating the2079results of a long term test. Thus the risk assessment of a system‘s2080failure must encompass the product quality issues as well as the2081potential business issues. The benefit of providing a clear definition2082of the potential impact of system failure is that it can influence and2083

justify the allowable budget for the system.20842085

If the cost and likelihood of failure is high, duplication of2086systems/equipment may be viable. But a better recourse is to redesign2087the system or process to reduce the risk. The potential impact of2088redundancy will not only influence the HVAC system design and2089maintenance but also the design requirements for the supporting2090utilities – for example, there may be no sense having duplex air2091conditioning systems if there is only one chiller and one circulating2092pump for the chilled water supply to the HVAC cooling coil.2093

2094There is another ―softer‖ consideration – appearance. The industry is2095open for audit, typically by internal as well as external agencies, and2096

there is a strong desire to maintain the appearance of the facility.2097 Thus the cost of the equipment installed may be higher than in2098equivalent plant in other industries.2099

2100These requirements present Engineers with a unique set of challenges2101which vary from system to system. The engineer needs to review the risk2102and potential impact of system failure considering all of the potential2103modes of failure, for example;2104

2105

Airflow failure2106





52

Filter failure (loss of control of airborne particles or cross-2107contamination)2108

Failure of temperature control2109

Failure of humidity control21102111

This risk analysis assessing the potential impact of system failure can2112significantly influence the HVAC system design, and maintenance, as2113well as the design of the supporting utilities. The scope of the2114analysis may include business as well as quality aspects – 2115simplistically put if the system fails, and the qualified (verified)2116monitoring system advises quality that the area is not within2117specifications, there is no patient risk, but the coat to the business2118could be considerable.2119

2120These considerations are on top of the conventional economical2121considerations balancing capital and operating costs.2122

2123The user requirements have serious implications on the design, and need2124

to be carefully considered and defined, they should include the2125 following:21262127

Internal conditions - How much variation is acceptable, - a wider2128operating range will mean a lower cost system, both to install and2129operate. Many believe that if they specify closer operating ranges,2130they will get a ―better‖ i.e. more robust system, this is not2131necessarily the case, in order to maintain closer tolerances the2132plant may be selected with greater capacity and faster responding2133sensors, and actuators, which are more sensitive and require careful2134tuning, and maintenance. Having specified these closer tolerances2135the system must be commissioned to operate to meet these2136specifications. The capital and operating costs of this more complex2137system are likely to be higher.2138

External conditions - If the facility is to kept operable 365 days a2139year then the plant needs to be sized to handle the peak external2140design conditions. If it is acceptable to have a a few percent2141downtime during peak seasons, then the HVAC system and supporting2142utilities can be downsized to suit, or a system of load shedding2143incorporated into the design of the support utilities, with the HVAC2144system components being sized to suit the extremes.2145

2146Other factors will affect the system economics:2147

2148

Building envelope - A low cost poorly insulated facility will mean a2149corresponding increase in the operating cost and capital cost of the2150HVAC system, for a given set of internal conditions. Similarly a2151

review of the facility construction/insulation may be beneficial – 2152for example improving the insulation may allow a warehouse facility2153to require only a heating system, rather than air conditioning.2154

Internal layout/design - A well developed design will keep the2155influence of major heat loads outside the conditioned area, or use2156the other utilities required to minimize the internal loads, for2157example a dust extract unit can also extract heat from a motor in2158the room, reducing space heat gains. There may be benefits from2159grouping the environmentally critical areas within the building,2160





54

2.8.2.4 Energy costs and trends2213

2214The cost of energy must be considered not only from the system design2215concepts, but the perspective of component selection, for example:2216

2217

AHU housing – low cost units may be made of pre-finished steel, and2218have minimal insulation. The unit may suffer from high air leakage,2219causing increased operating costs, and sweating, causing external2220corrosion and a shorter working life.2221

Fan – the fan may be direct drive, with a variable frequency supply2222to vary the fan speed to maintain a constant supply volume. It may2223use a high efficiency flat belt drive instead of the traditional V-2224belts to improve energy efficiency.2225

Filter selection – the optimum selection of pre-filtration systems2226will balance labor cost, filter cost, the contaminants in the local2227environment, the capacity of the filter, energy costs and the cost2228of cleaning the AHU during changing of the filter – this may be the2229conventional panel / bag, or may be a bag / bag filter combination.2230

Chillers cooled using cooling tower water rather than air cooled2231condensers.2232

Chilled water cooling vs. direct expansion22332234

Energy Recovery22352236

The potential risk of cross contamination means that some of the2237simpler means of heat recovery, such as the rotating wheel are not2238acceptable, however other systems such as heat pipes, and run around2239coils are and should be reviewed to see if there is a payback.2240

2241Similarly systems which use the measurement of enthalpy to vat the2242amount of fresh air may be economic, though the design and sizing of2243

the dampers needs to be more carefully considered for an application2244 where it is important to maintain system volumes, and room pressure2245differentials.2246

22472.8.2.5 Consumables Costs2248

2249The life and cost of each consumable component must be considered -2250filters are an obvious example – the optimum selection of pre-2251filtration systems will balance labor cost (for the actual replacement2252and the cleaning required when a filter is removed prior to installing2253the new filter), filter cost, the contaminants in the local2254environment, the capacity of the filter, rate of change of pressure2255drop, energy costs in order to recommend an optimum selection – this2256

may be the conventional panel / bag arrangement or may show a bag / bag2257 filter combination to be more cost effective.22582259

Another example would be the drive belt – V-belts have a significantly2260shorter life than a flat belt, but cost less. They are not as energy2261efficient as a flat belt though, thus the savings in maintaining a2262stock of spare belts, energy savings, and saving in labor costs to2263replace the belts, and re-tension them may make them cheaper over the2264plant operating life.2265

2266





55

2.8.2.6 Impact of system failure2267

2268If the cost and likelihood of failure is very high, and product value2269and risk are also high, duplication of systems/equipment may be2270advisable.2271

2272The potential impact of system failure will not only potentially2273influence the HVAC system design and maintenance but affect design of2274the supporting utilities.2275

22762.8.2.7 Appearance is another factor many believe influences plant2277room, system and equipment design and specification. The industry is2278open for audit, typically by internal as well as external agencies, and2279there is a strong desire to maintain the appearance of the facility – 2280in addition to complying with the GMP requirements, ensuring that not2281only the equipment but the plant room area and is easily cleanable.2282

22832.8.2.7 Reliability / Maintenance Costs2284

2285 The life cycle cost analysis must also consider reliability /2286maintenance aspects.2287

2288Consider the lowest cost material used for a cooling coil, aluminum2289fins on copper tube. In a poor environment there will be corrosion on2290the fin material, reducing the efficiency of the unit, with the fins2291eventually corroding to the extent that the unit will not perform2292adequately.2293

2294There are options for the specification of this item, each increasing2295the first cost, but increasing the operating life: Copper tube with2296polyester coated aluminum fins or Copper tube with electro tinned2297copper fins2298

2299A fan specification with a long design bearing life will allow for2300extended operating periods without maintenance. Grouped lubrication2301points will minimize costs, and allow lubrication when the plant is in2302operation.2303

2304The cost of routinely calibrating instrumentation should not be2305overlooked – it may be cost effective to have one calibrated2306differential pressure switch across a bank of filters, with un-2307calibrated ―engineering information‖ pressure gauges across each2308filter.2309

23102.8.2.9 As well as the obvious factors there are other ―political‖2311

factors to consider to vary the ratio of direct (capital) vs. indirect2312 (operating) cost;23132314

There may be grants available to assist with capital costs2315

There may be incentives to make the system more energy efficient23162317

2.8.3 User Requirements Specification23182319

As a project is considered justifiable, before the design details are2320developed the quality critical environmental requirements must be2321





57

The tasks the occupants are doing2376

The clothing (gowning level) of the occupants2377

The process2378

The cleanliness of the supply air2379

The means and efficiency of coverage of distributing the supply air2380

The means and location of extracting the air from the conditioned2381space2382

Where the control and monitoring sensors are located2383

The locations where the specified conditions are critical – e.g. in2384a tablet compression room the process will add a considerable amount2385of heat to the product – the critical area is likely to be where the2386raw material is exposed.2387

The cost of putting in a system capable of higher air change rates2388than those actually required is significant both in terms of the2389capital and system operating costs. As discussed earlier, a process2390that generates low volumes of particles, in a large room, may need2391fewer air changes to maintain desirable particle levels.2392

2393 2.8.4 Life Time Operating Costs23942395

These are the total costs of building and operating the installation,2396including design, purchasing, installing, commissioning, operating and2397maintaining (including labor, energy and spare parts) the system during2398the working life of the asset, and its dismantling. Cleaning and2399disposal cost. Refer to 2.8.2, and 2.8.4 for the factors affecting2400this.2401

24022.8.5 Comparing Options2403

2404Most companies have internal accounting systems that will facilitate2405the evaluation of different design concepts, evaluating payback against2406

the cost of the different design options, (investment analysis)2407considering the design life of the facility e.g. chemical2408dehumidification vs. chilled water or DX systems, humidification using2409suitably treated plant steam, local electric boilers, water spray2410injection (ultrasonic or air blown), or clean steam, water cooled vs.2411air cooled chillers.2412

2413Some of the areas to consider are provided below:2414

2415

Energy sources2416

Airflow management – through the use of flow measurement and fan2417speed control2418

Energy efficient ductwork design based on low velocity static2419

regain, requiring minimum balancing2420 Night setback of temperature and or humidity, reduction in airflow2421

if no production2422

Fume hood velocity control and fume hood diversity2423

Minimizing the use of local heating/cooling batteries2424

Energy recovery systems – air to air or air to fluid to air (e.g.2425rotary wheels, heat pipes, run around coils).2426

Recovery and use of cooling coil condensate2427

Reuse of cooling tower blow down water2428





58

Use of non storage water heater (calorifier)24292430

2.9 SUSTAINABILITY (TO BE WRITTEN LATER)24312432





59

3 THE DESIGN PROCESS2433

2434


The HVAC engineer is responsible for the development of a GMP compliant2437 design for that particular application which also meets other key2438customer requirements such as reliability, maintainability,2439sustainability, flexibility, and safety and which complies with local2440codes and standards. In the pharmaceutical industry, the role of the2441HVAC design engineer requires not only an understanding of both basic2442and advanced HVAC system design, but also a thorough understanding of2443the most current requirements of the regulatory authorities which will2444govern that particular facility‘s operations. This includes cGMPs of2445the countries where the facility‘s product will be sold as well as2446where the facility is located. To be successful in delivering such a2447design, the HVAC engineer must also understand how those systems2448integrate into and are affected by other aspects of the facility design2449and operation. People, equipment and material flow patterns,2450

architectural layout, finishes and tightness of room construction, air2451locks, spatial requirements for HVAC equipment an d ductwork, intake2452locations and exhaust locations are all examples of where the HVAC2453engineer must coordinate the HVAC design with other disciplines for a2454successful project.2455

24563.1.1 System Design Process2457

2458The engineer responsible for HVAC system design follows a process that2459includes first defining and documenting the key requirements of the end2460user (process and quality criteria, maintainability, etc.). This will2461require collaboration with the user and the quality unit in determining2462which are the critical operating parameters and thus the environmental2463

requirements which must be provided by the facility design, including2464 the HVAC systems. This defining of user requirements is the most2465critical step in the design process and has the greatest impact on the2466size and complexity of the facility, and ultimately the cost to2467construct, commission, qualify, operate and maintain it. Even small2468incremental increases in the level of cleanliness and the amount of2469classified space can result in relatively large increases in the2470initial cost of the facility and ongoing operating costs. It is2471important to clearly establish the required levels of cleanliness for2472any particulate, biological and/or chemical contamination for the2473processes, equipment and personnel in the facility. The HVAC engineer2474plays a key role throughout the design process in helping the project2475team understand the implications of excessive requirements on the cost2476of the project and the ongoing operating costs of the facility.2477

2478Once user requirements are established, the HVAC engineer must use his2479knowledge of HVAC systems to work with other disciplines to develop a2480functional (or schematic) design. This includes a risk assessment of2481alternative engineering solutions that can meet the user requirements.2482The risk assessment can be combined with an economic analysis to arrive2483at a facility and HVAC system which will have the lowest total cost of2484ownership. In addition to the cGMP related user requirements, the2485following are some additional issues that the HVAC engineer and the2486project team need to address in order to develop the functional design2487





60

for the facility:24882489

Flow patterns of people, product, equipment and other materials2490

Potential sources and risks of contamination2491

Hierarchy of cleanliness classification to control contamination2492

risks2493 Procedures to control contamination (i.e., cleaning, sanitization)2494

Requirements for redundancy of equipment and/or systems2495

Requirements for flexibility of the facility and/or systems2496

Economics of facility first cost and operational costs24972498

In developing the functional design, the HVAC engineer must also2499consider the design in light of the need to construct, commission,2500qualify, operate and maintain the facility and its HVAC systems.2501

2502At certain points in the design process, often at the end of2503functional design and before detailed design begins, the HVAC engineer2504will be involved in a formal design review/design qualification which2505is intended to verify that the project as designed will deliver a2506facility, including an HVAC system, which will meet the user2507requirements. After detailed design is completed, the HVAC engineer2508will often remain involved in the project by helping to resolve2509construction questions from the field and performing on-site2510construction reviews. He/she may also be involved in activities related2511to the receipt and installation of equipment and systems intended to2512verify that they were delivered and installed in a manner consistent2513with the design. The HVAC engineer is also often involved in the2514commissioning and qualification of the HVAC systems to verify that they2515perform as designed. This could include involvement in developing the2516Commissioning and Qualification (C&Q) protocols and/or executing the2517C&Q verification activities. The HVAC engineer is often involved in2518

Factory Acceptance Testing (FAT) and/or Site Acceptance Testing (SAT)2519 of major HVAC equipment and systems. The engineer is well advised to2520include planning for C&Q activities on the project during the design2521phase. Multiple past projects have proven that failure to consider C&Q2522requirements during the design phase may have a negative impact to the2523project in scope, cost and schedule.2524

25253.1.2 Regulatory Considerations2526

2527To be an effective member of the design team, the HVAC engineer needs2528an understanding of the regulatory requirements which will govern the2529facility and its processes. This requires an understanding of the cGMPs2530where the facility is located and those where the facility‘s products2531will be marketed, and the implications on the design of the facility2532and its HVAC systems. ISPE‘s Baseline Guide series provides practical2533advice for understanding and meeting regulatory requirements for2534various types of facilities (Parenteral, OSD, API, etc.) and their2535systems (maintenance, water & steam systems, etc.) and should be2536consulted in conjunction with this Good Practice Guide.2537

2538These regulatory requirements identified in the Baseline Guides from2539such governing bodies as the FDA, EMEA, USP, ASTM, ICH, ISO, WHO, etc.2540will impact the project design at the HVAC system design level in such2541





61

areas as:25422543

pressure differentials2544

temperatures2545

air change rates2546

specific alert and alarm ranges2547 facility layout (cleanliness classification hierarchy strategy,2548

airlock strategy, etc)2549

monitoring and control platforms (BMS, DCS, PLC, etc.)2550

Commissioning & Qualification25512552

In addition to the cGMP quality regulatory requirements, the HVAC2553engineer must also be knowledgeable about other compliance related2554codes and standards which apply to the design of facilities and HVAC2555systems where the facility is located. These include applicable local2556building, mechanical, electrical, fire and energy codes. Other2557compliance related requirements will usually apply which govern2558employee health & safety and process safety. The owner‘s insurance2559representative may also have additional requirements for their clients2560beyond those of the local codes.2561

2562

3.2 DEVELOPING THE USER REQUIREMENTS SPECIFICATION (URS)25632564


User requirements provide key information that defines the processes,2567activities, and environments needed for an operating facility.2568Assembling programming data for a facility early in the design process2569is critical to the successful operation, not only in terms of2570production output and efficiency, but also in delivering the asset at2571the right time to maximize Return On Investment (ROI) and provide the2572

lowest Total Cost of Ownership(TCO).25732574

Decisions and commitments made in the early phase of project planning2575are often too costly to change as the project advances to final design2576and then to execution phase. Therefore, developing the user2577requirements that drive HVAC criteria early in the design process is2578critical in setting the overall HVAC strategy for the facility. HVAC2579costs, both operating and initial capital costs, can account for a2580significant portion of a facilities cost.2581

2582It is important to ensure that user requirements are well understood2583and properly applied.2584

2585

For HVAC systems in a pharmaceutical environment, user requirements are2586 developed as a result of gathering relevant data with regards to the2587following:2588

2589Process – Critical environmental parameters that must be achieved and2590maintained.2591

2592Quality – Regulatory guidance and quality principles to guide decision2593making on HVAC parameters that can have product impact.2594

2595





62

Operations – Proper environment for the working conditions that impact2596the HVAC design.2597

2598Maintenance – Provide input on critical aspects of the HVAC design that2599would ensure a low TCO2600

2601 User requirements have often been associated with qualification, that2602is, critical HVAC parameters (e.g., temperature, humidity, differential2603pressure, air quality) are segregated from non critical HVAC2604parameters. Critical HVAC parameters are part of direct impact systems2605while non-critical HVAC parameters are either indirect or no impact2606systems. In either case, all HVAC systems are commissioned following2607GEP while direct impact systems are further qualified.2608

2609User requirements can either be in the form of performance based2610information that describes an operation and sets expectations or strict2611criteria where critical HVAC parameters are well defined, e.g.,2612Temperature, Relative Humidity, etc.2613

2614

In the case of performance based information, the HVAC designer would2615gather relevant information and propose the necessary criteria that2616would meet the user requirements. It is accepted practice to copy HVAC2617criteria from one facility to another (similar) facility – as long as2618the rationale for the original criteria is well understood. For2619example, determining temperature and relative humidity criteria in an2620aseptic environment is dependent on, type of process (closed or open,2621powder or liquid), local regulatory expectations, gowning procedures,2622environmental monitoring procedures, the level and type of activity in2623the area, and alert and alarm limits,. The HVAC designer should2624carefully consider each of these variables when proposing criteria and2625avoid using "industry norms" or "accepted industry practices" without2626an understanding of the variables involved.2627

2628 Once user requirements are established, the HVAC designer should begin2629to consider design strategies and impact. It is desirable to segregate2630HVAC parameters that are critical and non-critical under different HVAC2631systems rather than mix critical and non-critical HVAC parameters under2632the same system. Although there may not be any restrictions from a2633process viewpoint, segregating HVAC system components between direct2634and indirect impact adds to the complexity of commissioning and2635qualification. It could unnecessarily drive up qualification and on-2636going maintenance costs.2637

2638The flow diagrams shown below are a simple model segregating critical2639HVAC parameters with separate HVAC systems versus combining critical2640and non-critical HVAC parameters, by virtue of a single HVAC system.2641

Both design approaches would meet user requirements but it illustrates2642the potential complexity when using a single HVAC system to serve2643direct and indirect/no-impact areas.2644

2645





63

The impact assessment methodology evaluates the HVAC system at the2646component level to separate out critical and non-critical components,2647thus making it possible to have a single HVAC system. Well defined and2648accepted procedures should be in-place or agreed upon when defining the2649user requirements that would allow the single HVAC system to have a2650

lower total cost of ownership. If these concepts are not well2651 understood or established procedures or practices do not recognize this2652methodology, the HVAC design may increase the total cost of ownership.2653

2654Figure 3-1 User Requirements drive HVAC critical parameters2655

26563.2.2 References for User Requirements2657

2658ISPE Baseline Guides provide a framework to understand the different2659products and processes within pharmaceutical and biopharmaceutical2660manufacturing facility. The baseline guides that would apply to this2661section include the following:2662

2663

Bulk Pharmaceutical Chemicals2664

Oral Solid Dosage Forms2665

Sterile Manufacturing Facilities2666

Biopharmaceuticals2667

Packaging, Labeling & Warehousing Operations (under development)2668





64

Laboratories (draft)26692670

(Include a chart with a timeline and activities to illustrate?.... no)26712672

The following section describes HVAC parameters as covered in the2673

Baseline Guides listed above and the importance of each parameter in2674each type of facility.2675

26763.2.3 HVAC Parameters2677

2678HVAC parameters that may have impact on product generally include:2679

2680

Temperature2681

Relative Humidity2682

Airborne contamination (viable and non-viable particles), which is2683affected by:2684

2685

Room Relative Pressure2686

Airflow patterns2687 Air Changes2688

Air Filtration26892690

Within the context of the baseline guides listed, some parameters are2691common to all facility types while other parameters only apply to2692specific facilities. The following chart depicts at-a-glance the2693typical HVAC parameters that would generally apply to each facility2694type.2695

2696

HVAC Parameter

Facility Type TemperatureRelativeHumidity

Room

RelativePressure

AirborneParticles

AirChanges

Bulk PharmaceuticalChemicalsOral Solid DosageForms

Airdirection

SterileManufacturingFacilitiesBiopharmaceuticalsPack., Labeling &WarehousingLaboratories

2697 Table 3-1 Typical HVAC Critical Parameters by facility type26982699

Hatched areas represent the HVAC parameter used to set criteria that2700normally would have product impact or is required for creature comfort.2701Non-shaded areas are HVAC parameters that do not normally have product2702impact and are not used to set criteria. However, there may be other2703requirements such as local codes or regulations that may require2704certain parameters be considered in the design. For example, room2705relative pressure may not have product impact in a Bulk Pharmaceutical2706





65

facility, but due to governing codes, the design may implement room2707pressurization controls in order to sustain certain safety requirements2708due to the high presence of flammable liquids or vapors.2709

2710Individual HVAC parameters are discussed in the following section with2711

an emphasis on establishing the minimum requirements to achieve2712 "compliance", the importance of the parameter, the impact on design,2713and the challenges faced in determining these requirements.2714

27153.2.3.1 Temperature2716

2717General2718

2719Temperature requirements will vary depending on the application,2720product impact, and operator comfort. …………… 2721

2722This looks to be light… why discuss just temperature?2723

27243.2.4 Critical Parameters2725

2726Provide typical critical HVAC parameters under a given process or2727classification; i.e., Product Type, Solvent Issues, Environmental2728Classification, Open/Closed processes, Terminally Sterilized, Oral2729Solid Dosage Forms. Discuss assumptions or clarifications2730

2731The risk assessment process is used to determine which HVAC system2732components are critical to the SISPQ of the product. These components2733will require additional attention via qualification and may require2734higher levels of redundancy to avoid business impact.2735

2736This logic could be extended to determine which components should be2737under cGMP change control, with the remainder of the system under GEP2738

change control.27392740

There are a number of ways to address this. One suggested method will2741be provided in the form of a matrix in which the individual components2742of the HVAC system (preheat coil, fan, temperature sensor, etc.) are2743listed on one axis and a series of challenge questions which will aid2744in determining the GMP-critical nature of that component are listed on2745the other axis.2746

2747Managing HVAC Parameters (Monitoring) – Accountability for alerts and2748alarms. Methodology in determining appropriate alarm delays. Guidance2749on how to monitor - BAS, procedural means or manual monitoring.2750Determining what should be monitored – every room or select rooms.2751

2752 Table 3-2 (HVAC System Impact Matrix) See Appendix for graphic27532754

3.2.5 Programming and Layout Considerations27552756

The following is a listing of issues and considerations regarding HVAC2757systems and how they may affect the programming and layout of the2758facility design. These are areas in which the HVAC engineer and the2759project programmer must coordinate their knowledge and experience to2760avoid future problems in the construction, verification, operation and2761





66

maintenance of the facility. The impact of HVAC on programming and2762layout will vary by the type of facility, generally increasing as the2763complexity of the facility increases from general administrative office2764areas to more complex facilities for aseptic and/or potent compound2765processing.2766

2767 It is important to establish User Requirements before beginning layout2768and design. It is especially important to identify critical parameters2769versus controlled parameters, as this is a major factor determining2770environmental cleanliness classifications. In general, the larger the2771classified area and the more stringent the environmental cleanliness2772class the more complex and costly the HVAC system, both first cost and2773the ongoing operating cost. Determine if there are there special2774requirements for temperature or RH for specific rooms (freezers, chill2775rooms, stability storage chambers, R&D suites, etc.).2776

2777The flow of materials, equipment and people (unidirectional flow;2778gravity flow, etc.) must be understood by the HVAC engineer in2779determining area classifications, pressurization strategies, airlock2780

strategies (the use of airlocks to separate areas of different2781requirements for cleanliness, pressure, temperature, and/or RH) and2782their classification, HVAC system zoning, etc.2783

2784Area functionalities and adjacencies (both horizontal and vertical)2785

2786Determine functional/relational adjacencies (i.e., don‘t put large air2787compressors adjacent to a laboratory with vibration-sensitive precision2788analytical equipment.)2789

2790There may be special considerations in the layout and adjacencies for2791projects employing prefabricated modular construction.2792

2793

The locations and considerations for HVAC and utilities equipment,2794 ducting/piping routing, supply/exhaust/return diffusers/grilles.2795Outside air intakes and exhaust stacks must be located to avoid2796entrainment/re-entrainment of noxious fumes and odors such as lab fume2797hood exhausts, process vents and diesel fumes from idling trucks near2798docks and other loading/unloading facilities. Will major equipment be2799located in basement, penthouse, roof or elsewhere? Building2800configuration (H x W x L) may affect the location of central services2801and how they are distributed.2802

2803Understand the requirements for maintenance, testing, repair and/or2804replacement. This includes the locations for access doors/panels for2805HVAC system inspection, testing and maintenance, including HEPA filter2806scan testing and maintenance. Access to field instruments for2807

calibration, testing, and repair must also be considered. For AHU2808maintenance, consider how to remove/replace large motors & fans, DH2809wheels, coils, filters. You not only need access around the AHU for2810equipment removal, but must consider how large equipment will be2811removed from the area and replacements moved into the area (clear2812pathways, hoists/elevators, etc.). Identify the locations and need for2813access to BMS/EMS data and control, and what local indications and/or2814control features are needed. What are the maintenance philosophies for2815the facility (i.e., maintain from inside or outside of room)?2816





67

2817What are the materials to be used in the process (i.e., potent,2818solvents, cytotoxic, sterile) and the approaches & technologies for2819product containment and for clean/sterile processing. The use of mini-2820environments (barrier isolators, RABS, biosafety cabinets, etc.) will2821

usually reduce both the required amount and grade of classified space2822 compared to traditional ‗ballroom‘ cleanroom processing. The location2823of hazardous equipment & ductwork and the need to maintain them may2824affect the facility layout.2825

2826Issues related to codes and standards:2827

2828

What codes and standard apply to this jurisdiction? (ADA, Fire,2829OSHA, Energy, IMC, etc.)2830

Egress and other safety considerations2831

Must understand risks associated with various layout and programming2832issues (i.e., area electrical classification, blowout panels, SISPQ2833risks…) 2834

Special considerations with hydrogen operations28352836

The requirements of local codes and standards may need special2837attention in the design and construction of prefabricated modules.2838When facility modules are fabricated in a different jurisdiction than2839the location of the facility, this may become a major problem if not2840identified early in the design process.2841

2842Within the room: Consider the locations of people, processes and2843product with respect to HVAC supplies and exhaust/returns. Consider the2844equipment heat loads (where is heat generated and how is it cooled or2845extracted?) Consider the location of utilities connection with respect2846to the operations to be performed. Room HVAC system must be designed as2847an integrated system in rooms with fume hoods, BSCs, LEV systems and2848process equipment HVAC systems. The decision of whether to use a2849manifold exhaust system versus one fan per hood may affect facility2850layout.2851

28523.2.6 Architectural Considerations2853

2854Similar to the previous section, the following is a listing of issues2855and considerations regarding HVAC and how they may affect the2856architectural portion of the project and vice versa. All of the2857previously identified issues for consideration in the programming and2858layout of the facility (Section 3.2.4) are areas in which the project2859HVAC engineer and project architect need to coordinate their designs.2860The following are additional areas in which the HVAC engineer and the2861

project architect must also coordinate their knowledge and experience2862to avoid future problems in the construction, verification, operation2863and maintenance of the facility.2864

2865The materials of construction of the facility is a major area to2866address.2867

2868

Room Finishes: Must be cleanable, resistant to cleaning and2869sanitization chemicals, suitable for the environment, and be2870wear/bump resistant.2871





68

2872

Flooring: The same considerations as for Room Finishes. Selection of2873the flooring material for the application is important, but equally2874important is verifying the technique and skills of the flooring2875installer. Often, installing test patches of the materials and the2876

techniques being considered is the best method to evaluate their2877performance in a specific application.2878

2879The construction methodology for the facility is another key area in2880which the architect and the HVAC design engineer must coordinate their2881designs.2882

2883

Room tightness. Use floor to ceiling walls where pressure2884differential is important. If RH is important, then address reducing2885moisture migration through unsealed penetrations, door seals, and2886porous wall materials. Considerations in the door specifications2887need to address seals, windows, interlocks, construction of the2888door, actuation and hardware.2889

2890 Consider a commissioning test to verify room tightness (i.e., room2891leakage test or room integrity test).2892

2893

The use of prefabricated modular construction techniques might2894impose additional restrictions on the HVAC design (design might be2895limited to equipment vendors with which the module contractor has an2896established relationship; the size of AHUs might be limited to the2897size of a standard module; etc.)2898

2899Impact of HVAC on programming and layout will vary by the type of2900facility. (some of this is redundant)2901

2902

Flow of materials, equipment and people (unidirectional flow;2903gravity flow, etc.)2904

Area functionalities and adjacencies (both horizontal and vertical)2905

Determine functional/relational adjacencies (i.e., don‘t put large2906air compressors adjacent to a laboratory with vibration-sensitive2907precision analytical equipment.2908

Locations and considerations for HVAC and utilities equipment,2909ducting/piping routing, supply/exhaust/return diffusers/grilles.2910Major equipment in basement, penthouse, roof or ????2911

Requirements for testing, repair and/or replacement (i.e., HEPA2912filter scan testing and maintenance)2913

Access doors/panels for HVAC system inspection, testing and2914maintenance2915

For AHU maintenance- how to remove/replace large motors & fans, DH2916 wheels, coils, filters,2917

Environmental cleanliness classifications2918

Materials to be used in the process: Potent, solvents, cytotoxic,2919sterile?2920

Determining User Requirements (critical parameters versus controlled2921parameters)2922

What codes and standard apply? (ADA, Fire, OSHA, ??)2923

Egress and other safety considerations2924





69

Building configuration (H x W x L) may affect the location of2925central services and how they are distributed.2926

Approaches and technologies for product containment.2927

Routing of ductwork & utilities2928

Location of Hazardous equipment and ductwork2929

Manifolded exhaust systems versus one fan per hood.2930

In general, the larger the classified area and the higher the2931environmental cleanliness class, the more complex and costly the2932HVAC system, both first cost and the ongoing operating cost.2933

Room HVAC system must be designed as an integrated system in rooms2934with fume hoods, biosafety cabinets (BSCs), LEV systems and process2935equipment HVAC systems.2936

Must understand risks associated with various layout and programming2937issues (i.e., area electrical classification, blowout panels, SISPQ2938risks…) 2939

Special considerations with hydrogen operations2940

Location of HVAC inlet air and exhaust stacks2941

Special temperature (or RH) rooms (freezers, chill rooms, stability2942storage chambers, R&D suites, etc.)2943

Use of airlocks to separate areas of different requirements2944(cleanliness, pressure, temperature, RH) and their classification2945

Location and need for access to BMS/EMS data and control; what local2946indications and/or control features are needed2947

Access to field instruments (calibration, testing, and repair)2948

Special considerations for prefabricated modular construction2949

Locations of people, processes and product within the space with2950respect to HVAC supplies and exhaust/returns2951

Consideration of equipment heat loads (where is heat generated and2952how is it cooled or extracted?)2953

Location of utilities connection29542955

3.3 HVAC SYSTEM RISK ASSESSMENT29562957


Risk assessment is a process for determining the impact of systems or2960components on product SISPQ. Risk assessment is performed by organizing2961or dividing the components into systems and evaluating the impact of2962those systems/components on Critical Quality Attributes and/or2963Parameters. As the components included within a system can2964significantly impact results, the definition of system boundaries is a2965critical step in a successful risk assessment.2966

2967The risk assessment process may be used to determine:2968

2969The testing requirements for the system and associated controls2970

2971

The level of documentation that is appropriate2972

The components that should be verified (commissioned/qualified)2973

The necessary level of change control to apply for the system2974components2975

2976





70

From a patient safety perspective the key data is typically kept in an2977environmental monitoring file to facilitate quality review:2978

2979The contents of this file would include as applicable:2980

2981

Typical HVAC performance parameters that impact CQA/CQP are:2982 HEPA filter test data2983

Air change rates/airflow volumes2984

Area differential pressures2985

Temperature2986

Relative humidity2987

Particle count2988

Typical HVAC-related room performance parameters which impact2989CQA/CQP are:2990

Clean up & Room recovery time2991

Total particle count (area classification)2992

Microbial Viable particulate test results – in air2993

Microbial Viable particulate test results – swab tests29942995

The ―package‖ of data produced should be critiqued to ensure that it is2996adequate to minimize risk to quality.2997

2998There are a number of approaches to performing a risk assessment; one2999approach is described below:3000

30011.0 Define the Critical Quality Attributes/Parameters (CQA/CQP) for the3002area served by the HVAC system, together with the supporting rationale.3003Some examples may be:3004

3005

Humidity is not a critical factor for the product as it is an3006

aqueous liquid.30073008

Temperature is not a critical factor as the product is contained in3009temperature controlled vessels.3010

3011

Air quality is considered a critical factor – the room supplied is3012categorized classified as ISPE Grade 8 because product is exposed3013

3014

Room pressure differentials are considered a critical factor in3015order to maintain the room environment, minimizing the risk of3016contamination/cross contamination, because the room is classified3017ISPE Grade 8.3018

3019

2.0 Define system boundaries for HVAC system:30203021

Systems can be organized by components of like type (i.e., system3022that is all one type of components, such as only HEPA filters)3023

3024

Systems can be organized geographically (i.e., at room level)30253026

Systems can be organized by connected components (i.e., an AHU3027system)3028

3029





71

Control and monitoring system can be either a separate system, or3030may be included as part of another system.3031

30323.0 Define how the Critical Quality Attributes/Parameters (CQA/CQP) are3033monitored. Some examples may be:3034

3035 Humidity is monitored by an independent SCADA based environmental3036

monitoring system.30373038

Temperature is monitored by an independent SCADA based environmental3039monitoring system.3040

3041

Air quality is monitored by a routine test using a particle counter3042to per ISO CEN 14644 for all particles., and microbial3043

3044

Microbial monitoring for viable particles is tested per local SOP.30453046

Room pressure differentials are monitored by an independent SCADA3047

based environmental monitoring system30483049

4.0 Define how the Critical Quality Attributes/Parameters (CQA/CQP) are3050achieved, and any associated equipment risks of failure and the3051probability of detection of those failures. Some examples may be:3052

3053

Humidity control is achieved by either dehumidifying the air through3054cooling below its dew point to remove moisture, or by adding3055moisture with a steam humidifier. As humidity is continuously3056monitored by a verified system it is considered adequate to3057commission the humidifier/dehumidifier system, and maintain it under3058engineering change control3059

3060

Temperature control is obtained through the use of the heating or3061cooling coils. As temperature is continuously monitored by a3062verified system it is considered adequate to commission the heat3063system, and maintain it under engineering change control.3064

3065

Air quality is obtained through the final HEPA grade filter which is3066leak tested annually, with a particle count conducted periodically.3067As the HEPA filter integrity is not continuously monitored, and is3068directly responsible for this aspect of the system performance it3069will be verified and maintained under quality change control.3070

3071

Room pressure differentials are achieved through the leakage from3072and to the conditioned space from adjacent areas and via the HVAC3073

system balance. As pressure is continuously monitored by a verified3074 system it is considered adequate to commission the duct/damper3075system and maintain it under engineering change control.3076

3077Based on the above examples, the equipment to be verified and3078maintained under Quality Change Control is therefore shown is a shaded3079box in the system drawing shown below:3080

3081(Note: the editor has issues with the items shown as being under change3082control. Don‘t be surprised if the drawing below changes in the final3083





72

version, as fans and control valves are usually NOT critical devices.3084The monitoring systems for airflow, DP, and temperature/RH are. The3085shading is in the wrong place, and I can‘t change it.)3086

30873088

30893090

Figure 3-2 A Typical schematic of critical devices30913092

Examples of other methods for performing an HVAC risk assessment,3093including some typical for risk assessments of HVAC components, are3094included in the appendix.3095

30963097





73

4 HVAC APPLICATIONS BY PROCESS AND CLASSIFICATION3098

3099


There are many types of facilities, each with its own type of HVAC3102 system, but design philosophies remain the same. The following are key3103design steps during the design:3104

3105

Identify product and process critical HVAC parameters and acceptance3106criteria.3107

Define the type of facility and the operational requirements of each3108area within the facility.3109

Define the design criteria for each area within the facility.3110

Identify potential paths of product/process contamination and3111evaluate risks.3112

Develop a set of HVAC systems that meets the design criteria with an3113appropriate balance of cost and risk.3114

Provide a means to control the systems so that design criteria are3115met.3116

Assure that the systems meet the design criteria.31173118

Certain parts of a facility may be subject to regulatory compliance. It3119is imperative that HVAC systems that affect regulated operations are3120designed to an end result that repeatedly meets the expectations of the3121regulatory body.3122

3123Air handling systems should be designed to achieve physical separation3124in order to prevent cross contamination. Product separation guidelines3125should be consulted when determining the boundaries of air handling3126systems. Separate air handling units are often used to segregate3127

different building functions such as production, production support,3128 warehouse, administration, mechanical areas, etc. Within production3129areas, further segregation is often advisable for various unit3130operations, e.g., upstream cell culture vs. downstream purification,3131pre- vs. post-viral, filling, etc. Manufacturing areas supporting key3132unit operations require maximum on-stream reliability. The air handling3133units supporting these areas may be configured for partial operation3134during routine maintenance operations to support this requirement for3135areas still in production. Shutdowns for routine maintenance are3136permissible for certain product forms, with classified spaces requiring3137continuous service. Therefore, air handling units serving these less3138rigorous spaces may be designed accordingly.3139

3140

4.2 SYSTEM APPLICATIONS31413142

Typical AF&ID (air flow and Instrument diagrams) are included in the3143Appendix and referenced in this section.3144

31454.2.1 ISPE Grade 7 or ISPE Grade 8 With local protection or ISPE grade3146

531473148





74

31493150

Figure 4-1 GRAPHIC31513152





76

4.2.3 LAB31593160

31613162

Figure 4-3 Typical Lab AF&ID31633164





77

4.2.4 Warehouse:31653166

31673168

Figure 4-4 Typical Warehouse AF&ID31693170





78

4.2.5 Administrative:31713172

31733174

Figure 4-5 Typical Admin area AF&ID31753176

4.3 ROOM LEVEL EXAMPLES317731783179

FacilityType

System Type Notes Product andProcessRequirements

API - Wetend

Once Through If solvents are present -consider erc

EHS

CentralStation

Economics

Fixed Balance Airflow Tracking or pressure

control are possible

Economics

CentralFiltration

Merv 7, 13/14 Economics

Draw Through Unless load requires airnear dew point

Humidification In cold climates for staticcontrol

EHS

31803181

Facility System Type Notes





79

Type

API - Dryend

Once Through If solvents are present - consider erc

Recirc is

possible

with LEL detection, or if no solvents

CentralStationFixed Balance Airflow Tracking or pressure control are

possibleCentralFiltration

Merv 7, 13/14

FinalFiltrationHEPA or ULPA

for final API steps or potent compoundcontainment

Draw Through Unless load requires air near dew pointHumidification In cold climates for static controlReturn or ExhFiltration

For potent compounds, cross contaminationcontrol or as a dust stop for equip/personnel

Grade must be appropriate to paricle size andrisk

31823183

FacilityType

System Type Notes

OSD Recirculated Once through may be used for Multi-product orsolvent use

CentralStationDistributedunits

Distributed units work well for multi-productconcurrent

Makeup /Recirc

Excellent for multi-product concurrent

Fixed Balance Airflow Tracking or pressure control arepossible

CentralFiltration

Merv 7, 13/14

Draw Through Unless load requires air near dew pointHumidification In cold climates for static controlReturn or ExhFiltration

For cross-contamination Control

31843185

FacilityType

System Type Notes

Biologics Recirculated Once through may be used for Multi-product orsolvent use



Makeup /Recirc


Fixed Balance Airflow Tracking or pressure control are





80

possibleCentralFiltration

Merv 7, 13/14

FinalFiltration

May be used if CNC / Grade D / ISO 8 or 9

Draw Through Unless load requires air near dew pointHumidification/Dehumidification

In cold climates for static control / Iscommon, especially for hygroscopic products.

Return or ExhFiltration


31863187

FacilityType

System Type Notes

AsepticProcessing

Recirculated Once through may be used for Multi-product orsolvent use

Central

StationDistributedunits


Makeup /Recirc


Fixed Balance active pressure control is commonCentralFiltration

Merv 7, 13/14

FinalFiltration

May be used if CNC / Grade D / ISO 8 or 9.Double for A&B (AHU and Terminal) are notuncommon.

Draw Through Unless load requires air near dew pointHumidification/Dehumidification

In cold climates for static control / Iscommon, especially for hygroscopic productsand micro control, operator comfort andcondensation control

Return or ExhFiltration


31883189

FacilityType

System Type Notes

Packaging/ Labeling

Recirculated Once through may be used for Multi-product orsolvent use



Makeup /Recirc


Fixed Balance Airflow Tracking or pressure control arepossible

CentralFiltration

Merv 7, 13/14

FinalFiltration

May be used if CNC / Grade D / ISO 8 or 9





82

PressureControl

Room level active control of supply and/or exh/return tomaintain pressure differential

VolumetricAirflowControl

Room level active control of supply and/or exh/return tomaintain flow differential

ActiveFixedBalanceFixedBalance

31963197





83

3198

4.4 ACTIVE PHARMACEUTICAL INGREDIENTS (API) - (WET END)31993200

4.4.1 System Schematic (Sample)32013202

32033204

4.4.2 System Design Considerations32053206

Bulk biotech products may require area classification (see the3207Biopharmaceutical Baseline Guide for requirements)3208

Air systems should be once through where solvents or potent3209compounds are handled.3210

Air systems may recirculate with the OA necessary to maintain3211pressure relationships, in support areas, where no solvents or3212potent compounds are handled.3213

Manufacturing rooms should be fitted with low or combination3214

high/low returns.3215 Manufacturing rooms should be protected from migration of3216

contaminants or solvent vapors via the use of pressure or tracking3217differentials.3218

Where solvents are handled, closed processing or capture exhaust3219systems are strongly recommended. Oxygen depletion and LEL monitors3220may be employed as appropriate to assure that dangerous conditions3221do not occur, especially when recirculated air is used, in3222accordance with fire and building codes.3223





84

Provide LEV for dry product addition; drum handling, manways and3224spills in wet areas.3225

Provide LEV for containment devices.3226

Provide all spark-proof exhaust equipment serving process areas.3227

Provide explosion proof or intrinsically safe electrical components3228in the exhaust air stream.3229

Heating coils may not be required for systems in warm climates.3230

Dehumidification and post cooling coils should be considered for low3231humidity room control or for facilities with limited cooling3232capacity.3233

Humidification should be considered for cold climates where static3234control is a concern.3235

Risk assessment should be performed to determine need for fan3236redundancy (parallel fans or fan walls)3237

If required, Unidirectional flow hoods (UFH) that have recirculation3238should be supplied with a small percentage of fresh air to offset3239fan heat.3240

32414.5 ACTIVE PHARMACEUTICAL INGREDIENTS (API) - (DRY END)3242


3245

324632473248





85


Oral dosage (―dry‖) product handling areas (i.e. centrifuge, dryer, 3251blender, mill, pack-off rooms) do not require classified cleanrooms;3252however, they should be designed in a manner consistent with ISPE3253

CNC practices. Areas serving bulk product that will be sterile3254products (including bulk Biopharm) should meet ISPE Grade 8. This3255corresponds to: HEPA filtration on the inlet air, low returns with3256local filtration on the outlet, high-pressure airlock,3257instrumentation for verification of room conditions. When in doubt,3258final bulk API areas should meet the requirements for dispensing of3259API in the finishing facility.3260

Air systems should be once through where solvents or potent3261compounds are handled.3262

Air systems may recirculate with the minimum Outdoor Air necessary3263to maintain pressure relationships, in support areas, where no3264solvents or potent compounds are handled.3265

Manufacturing rooms should be fitted with low or combination3266

high/low returns.3267 Manufacturing rooms should be protected from migration of3268

contaminants or solvent vapors via the use of pressure or tracking3269differentials.3270

Where solvents are handled, 100% exhaust (once-through) systems are3271strongly recommended. Oxygen depletion and LEL monitors may be3272employed as appropriate to assure that dangerous conditions do not3273occur, especially when using recirculated systems. Such systems3274should also comply with fire and building codes.3275

Provide LEV for dry product addition; drum handling, manways and3276spills in wet areas.3277

Provide LEV for any containment devices.3278

Provide spark-proof exhaust equipment serving process areas.3279

Provide explosion proof or intrinsically safe electrical components3280in the exhaust air stream.3281

Heating coils may not be required for systems in warm climates.3282

Dehumidification and post cooling coils should be considered for low3283humidity room control or for facilities with limited cooling3284capacity.3285


Risk assessment should be performed to determine fan redundancy3288(parallel fans or fan walls)3289

Unidirectional flow modules (LFU) that have recirculation should be3290supplied with a small percentage of fresh air to offset fan heat.3291

3292 4.6 BIOLOGICS32933294






86

32973298


See requirements for API above. Also refer to the ISPE3301 Biopharmaceutical Facility Baseline Guide for area classification3302requirements.3303

3304

4.7 ORAL SOLID DOSAGE (NON-POTENT COMPOUNDING)33053306






87

33093310


Further discussion for Oral Solids Dosage facilities is covered in3313the ISPE Baseline Guide for OSD.3314

Oral dosage facilities do not require areas with assigned3315cleanliness classifications.3316

Process and process support areas, however, require critical3317parameters to be controlled and maintained to protect the product3318from contamination, whether from another product in a multi-product3319facility or from external or personnel contamination.3320

Low returns in CNC (w/local monitoring) areas are recommended and3321should be located behind process equipment where applicable and3322where clearance is sufficient to allow proper air extraction from3323the space. CNC (airflow filtration with access control) areas do not3324require low level returns but can be used if deemed necessary by the3325

design team.3326 AHU filtration – min 30% followed by 85% filtration is recommended.3327

Final filtration - 95% DOP efficiency is recommended in exposed Oral3328Solid Dose and dry bulk (non-Aseptic) product areas, but terminal3329HEPA filters may be more practical. Where terminal HEPA filters are3330employed for cross-contamination control, 95% pre-filtration will3331maximize terminal filter life.3332

HEPA filtration may be considered to prevent cross-contamination and3333limit operator exposure in all recirculation systems.3334





88

Non-recirculation systems do not require HEPA filtration for cross-3335contamination control.3336

All return or exhaust air grilles should be equipped with 30% ―dust3337stop‖ filters. 3338

Recirculation systems may be applied in multi-product areas, where3339

solvents are not present.3340 Recirculation of room air is not recommended when solvents are3341

present. Recirculation of room air is not allowed when solvents may3342be present above 25% of LEL.. Where solvents are occasional and in3343small volume, return air duct should be equipped with hydrocarbon3344sensors to switch the system to 100% outdoor air in the event of a3345spill.3346

Recirculation of return air from production areas to supply non-3347production areas without treatment is not acceptable.3348

Cleanliness of open processing areas should be maintained via3349control of airflow between product handling area or airlock and3350surrounding spaces.3351

Isolation via airflow from a clean airlock (pressure bubble or3352pressure sink) or corridor into the area of highest contamination is3353strongly recommended. Where solvents are used, this configuration is3354required.3355

Monitoring and alarming of direction of airflow (through3356differential pressure, hotwire velocity sensors, or flow tracking)3357to surrounding rooms is strongly recommended.3358

Airflow and makeup air delivery should be directed to flow from the3359operator‘s breathing zone and the room entrance, toward the source3360of airborne dust.3361

Non-aspirating diffusers are recommended to minimize air3362disturbances, eddies and re-entrainment of dust.3363

Provide LEV for control of fugitive emissions at open operation or3364equipment break point.3365

LEV for open operation should be designed and engineered according3366to ACGIH standards.3367

Recirculation of LEV exhaust within a production room requires HEPA3368filtration. Consult the ACGIH Ventilation Manual decision analysis3369and design criteria for guidance on when recirculation is3370acceptable.3371

Recirculation of LEV exhaust to the AHU is not acceptable.3372

Filtration of LEV through HEPA filters, scrubbers, or other3373equivalent treatment methods prior to release outdoors is required.3374

For operations that generate or have the potential to generate3375active dusts or aerosols – LEV must be provided at all emission3376points. Leak free connections are recommended.3377

A testing and preventative maintenance program will ensure the3378integrity of HEPA filtration system and LEV performance.3379

Dust collection systems designed to allow removal of contaminated3380media without contact or exposure with these compounds (e.g. bag3381in/bag out HEPA filters) should be considered.3382

Heating coils may be required for systems in cold climates with3383higher percentages of outside air.3384

Dehumidification and post cooling coils should be considered for low3385humidity room control or for facilities with limited cooling3386





89

capacity.3387


Risk assessment should be performed to determine the need for fan3390redundancy (parallel fans or fan walls)3391

Unidirectional flow hoods (UFH) that have recirculation should be3392supplied with a small percentage of fresh air to offset fan heat.3393

3394

4.8 ORAL SOLID DOSAGE (POTENT COMPOUNDING)33953396


33993400


Potent OSD facilities should follow the guides above for OSD, with the3403

following exceptions34043405

A minimum, filtration of ASHRAE 85% (MERV 13 or 14) shall be3406provided to the Supply Air if 100% once-through.3407

Closed containment is the primary means of control for this class of3408material. If processes are proven closed, recirculated air should3409include HEPA filtration.3410

Local Exhaust Vents (LEV) should be provided at points in which3411containment is broken and as needed, in conjunction with other3412





90

technologies.3413

LEV should be used for solvent extraction only where containment is3414not technically feasible (i.e. maintenance activities, etc.). Where3415LEV is used with any possibility of duct contamination, HEPA filters3416should be installed near the room, before the AHU.3417

Isolation via active control of direction of airflow (using3418differential pressure, hotwire velocity sensor, or flow tracking)3419into the area of highest contamination from surrounding areas is3420strongly recommended.3421

Monitoring and alarm of direction of airflow is required. Alarms3422should be recorded at a manned workstation (control room or3423maintenance center).3424

Audio and visual alert on loss of airflow containment should be3425transmitted to the controlled space3426

Room air locks/anterooms are recommended for powder handling areas3427to provide a barrier that maintains a positive airflow differential3428with respect to the corridor and the processing room (this may also3429serve as a gowning area).3430

Airflow into de-gowning areas should be negative with respect to the3431corridor and processing area to contain particles shed from3432clothing.3433

A secondary control against the spread of active materials is3434direction of airflow within the room. Supply air should be directed3435to flow across the operator‘s breathing zone before crossing the3436source of dust. Wherever possible, supply air should be directed to3437flow from a location near the room entrance toward the source of3438dust and finally out low returns mounted on the far wall.3439

A dedicated HVAC system is recommended for the controlled area.3440

It is strongly recommended that any air leaving the processing room3441boundary NOT be recirculated. Design main air systems for 100%3442exhaust, once-through supply. However if air recirculation within3443

the controlled area is required, – employ double HEPA filtration3444(supply and return) combined with semiannual filter integrity test.3445

Recirculation of air from the controlled space into other areas is3446not acceptable.3447

Recirculation of local exhaust (LEV) from equipment is not3448acceptable.3449

Filtration of exhaust from dry product handling areas and LEV3450through HEPA filters, scrubbers, or other equivalent treatment3451methods prior to release outdoors is required.3452

It is recommended that exhaust/return filters be located as near to3453processing area as possible to reduce length of potentially3454contaminated air ducts.3455

Where containment equipment is provided and PPE is not required,3456HEPA filters are intended to protect the AHU and facility in case of3457an accidental release. These should be a room-accessible type – Bag-3458In/Bag-Out is not required, PPE can be used for change-out if3459needed.3460

Exhaust/Return HEPA filters not located within the room, or where3461airborne powders are expected, should be safe-change type with BI/BO3462housing and bubble tight dampers.3463

Terminal HEPA supply filters are required for protection against3464backflow if product containment should fail during AHU failure.3465





91

A testing and preventative maintenance program to ensure the3466integrity of HEPA filtration systems is required, on no less than an3467annual basis. Filters on processes requiring PPE should be tested3468more frequently.3469

Appropriate monitoring and interlocking with process equipment3470

should be considered to maintain containment integrity and to3471control cross contamination and emissions.3472

3473

4.9 ASEPTIC PROCESSING FACILITY34743475


34783479


Considerable background on the design of HVAC systems is covered in3482

the ISPE Baseline Guide for Sterile Manufacturing Facilities.3483 Eliminate contamination introduced through the air conditioning3484

supply system by utilizing properly installed and integrity tested3485ceiling mounted terminal HEPA filters.3486

Minimize infiltration of contamination from uncontrolled areas by3487the use of room pressure differentials and airlocks between air3488classes.3489

Continuous room pressure monitoring with alarms and recording3490devices that indicate out of spec conditions are recommended.3491





92

Consider automatic pressure controls to keep the spaces within3492specified pressure limits where process exhausts change, or where3493door and hatch are frequently opened or door seal integrity varies.3494

Dehumidification and post cooling coils should be considered for low3495humidity room control.3496

A dedicated air handling system is recommended, serving only the3497aseptic area and remaining operational for required pressure control3498when the main building systems are shut down during unoccupied3499periods.3500

HVAC systems for classified spaces should operate 24hours/day – 73501days/week.3502

Risk assessment should be performed to determine the need for fan3503redundancy (parallel fans or fan walls) Consider utilizing standby3504electric power generating systems to maintain fans and design3505pressure differentials in the event of local power failures.3506

The air handling system should be of the constant volume terminal3507reheat type utilizing industrial grade equipment.3508

Ductwork should be designed per SMACNA standards but in no case3509should it be constructed for less than 4" water gauge duct static3510pressure and seal Class "A".3511

Ductwork should be galvanized steel except where exposed (to a3512minimum extent) in production areas or subject to moisture, in which3513case it should be a minimum 304 stainless steel with cleanable3514finish. Cleaning materials used in the room should be considered.3515

Silencers are not recommended as they can harbor contaminants and3516viable organisms.3517

The supply fan should be equipped with dampers, vanes or speed3518controls which can be reset in order to maintain design airflow for3519the life of the air filters (whose pressure drop increases with3520time).3521

Air to an aseptic area should be supplied through ceiling mounted3522terminal HEPA filters. These terminal HEPA filters become part of3523the aseptic boundary and protect the room from outside3524contamination. The use of only remote bank mounted HEPA filters in3525the supply duct is not recommended. Access ports to introduce and3526monitor PAO (aerosol) challenge materials upstream on the non-3527aseptic side of the HEPA diffusers are suggested for filter3528integrity testing.3529

Air supplied through ceiling mounted terminal HEPA filters should be3530returned at floor level through multiple return duct drops. Return3531air to the recirculation unit should be filtered through 30% ASHRAE3532pleated and 85% or 95% ASHRAE bag filters to extend HEPA filter3533life. Recirculation HEPA/fan units mounted below the ceiling are not3534recommended as they require service within the aseptic area, do not3535

normally utilize low returns, and lack adequate pre-filtration.3536 The return air openings in the aseptic area should be located near3537

the floor, preferably on at least two (2) walls and along the long3538dimensions of the room to ensure maximum uniformity of airflow. More3539return openings are better than too few.3540

Differential air pressure should be employed to minimize3541infiltration of contaminants from outside the controlled area. The3542aseptic area should be designed for a positive pressure with all3543doors closed in relation to less clean adjacent areas outside the3544





93

controlled area (refer to latest issue of Federal Standard 209).3545Gowning areas should be supplied with air and maintained at a3546negative pressure relative to the controlled aseptic area and at a3547positive pressure relative to the outside and uncontrolled areas.3548Differential pressures are measured ACROSS airlocks (see the ISPE3549

Baseline Guides for Sterile and Biopharm Facilities.)3550 Each area should have an air supply and return with dampers to3551

permit proper balancing. The room layout of the aseptic suite will3552dictate the pressure relationships to be maintained. The room with3553exposed product is to be maintained most positive; while ante rooms3554leading to this room are to be maintained successively less positive3555down to the zero reference level of uncontrolled areas (the general3556building). Only high-pressure Grade 7airlocks that have HEPA3557filtered supply air may have pressures higher than the aseptic3558filling room. A control range should be established for each room3559pressure level such that the pressure can float within the range and3560still satisfy the specified differentials.3561

A remotely operated or automatic damper may be provided in the3562

return air duct from each room as a means of obtaining and setting3563 the established pressure differentials. Simple facilities may be3564successfully balanced using only manual dampers, especially if3565terminal HEPA filters do not load quickly.3566

If manual / remotely operated dampers are used, the remote damper3567controls should be tamper-proof or concealed in a lockable cabinet3568accessible to authorized personnel only. A differential pressure3569gauge should be provided for each room adjacent to the remote damper3570controls.3571

The manual/remote gauges and controls or automatic controls should3572be mounted in a common panel outside the controlled area. An audible3573alarm may be provided to indicate loss of area pressure control.3574This alarm may be manual reset type and equipped with a hard copy3575printout that indicates the out-of-range alarm.3576

Unidirectional airflow serves as a barrier between product and3577microbial and particulate contamination generated by the equipment3578and personnel within the aseptic area. Where possible, terminal HEPA3579filters should be located directly over the exposed product,3580components and equipment that are not protected by UFH.3581

When the central system air conditioning air quantity required to3582maintain room conditions is not sufficient to provide protection3583over the product, components, and equipment, a supplemental HEPA3584filtered air recirculating system may be employed. Because all of3585the cooler central system conditioned air is not supplied over the3586equipment, it may be distributed to the area in a checkerboard3587fashion or into the local recirculating fan inlet to maintain room3588temperature. The engineer should consider the heat generated from3589

the local recirculating system fan motor. This particular oversight3590is quite common and can lead to serious temperature stratification3591and overheating in the aseptic area.3592

Airflow patterns within the work space may be uniform with minimum3593turbulence. Ambient air may not aspirate into the work areas along3594the perimeter of the unidirectional airflow barrier. The heights and3595filter area should deliver Class 100 air at a velocity of 90 feet3596(27.5 meters) per minute, with uniformity within plus or minus 20%,3597measured at the filter face. Velocity at the work height should also3598





94

be measured. The optimal filter face velocity should be determined3599during qualification of the UFH using airflow visualization (―smoke3600testing‖). See the ISPE Sterile Baseline Guide. 3601

Room temperatures should be controlled by maintaining constant3602airflow and modulating a heating coil. Systems in which varying flow3603

is used as a means of controlling room temperatures are unacceptable3604because of their adverse effects on room pressures.3605

Where low relative humidity is required, special attention may be3606given to sealing the return duct systems to prevent inward air3607leakage from uncontrolled areas and resultant high humidity.3608

36094.9.3 Aseptic Potent Compounds:3610

3611

Processes should be contained in isolators, with dedicated HVAC for3612the containment enclosure.3613

Where the process leaks into the room, protect the HVAC system and3614other rooms on the system from hazardous compounds by utilizing non-3615recirculating primary air conditioning systems.3616

The exhaust or return air ducts must be fitted with HEPA filters3617protected from physical damage with a pre-filter or equivalent.3618These filters should be located within the room where they can be3619serviced by properly gowned and protected personnel.3620

If filters are located remote from the room where open processing3621occurs, they should be housed in a high containment bag-in/bag-out3622filter housing and identified as such. These filters contain the3623potentially hazardous compounds and minimize particulate "fall back"3624during fan failure.3625

Gowning areas shall be supplied with air and maintained at a3626negative pressure relative to the controlled aseptic area and at a3627positive pressure relative to the uncontrolled areas. The gowning3628area should be separated from the aseptic filling room by a high3629

pressure airlock.3630 The de-gowning area must be separated from the aseptic filling room3631

by a low pressure airlock. The de-gowning room shall be maintained3632negative relative to adjacent spaces on the uncontrolled side.3633

Material entering the aseptic filling room must be transferred via a3634HEPA filtered, high pressure tunnel, box or sterilizer. Material3635leaving the aseptic filling room must be transferred via a low3636pressure tunnel or box.3637

3638

4.10 PACKAGING/LABELING36393640






95

36433644


See the PACLAW Baseline Guide for product requirements.3647 Most products require a clean area for packaging, with HVAC meeting3648

CNC.3649




Return fan and mixing sections may not be required for areas with no3656pressure requirements, small local exhaust fans may be considered.3657

3658

4.11 LABS36593660






96

AMD

HOOD

AMD

Infiltration + Supply = Exhaust

Infiltration

ExhaustSupply

LAB

NOTE: An arbitrary value for INFILTRATION is chosen, then SUPPLY

is adjusted to track exhaust.

If supply is insufficient to satisfy room heat load, more exhaust

(EX2) may be needed.

AMD=Airflow Monitor

EX2

Hood

flow

control

36633664

Figure 4-12 Typical Lab HVAC schematic36653666


Further information on Labs for Quality Control is included in the3669ISPE Baseline Guide for Quality Labs.3670

Laboratories using volatile solvents or radioisotopes should be3671negative (commonly via airflow tracking) relative to corridors,3672offices and adjacent occupied space. Air from offices or technical3673spaces adjacent to laboratories should transfer into the laboratory.3674Classified clean lab spaces should be positive (via airflow3675tracking) relative to corridors, offices and adjacent occupied3676space. Provide a high pressure airlock where activities in3677positively pressurized spaces pose a threat to corridor air quality.3678

Where chemicals or other hazardous materials are handled, air3679

systems should be one hundred percent (100%) exhaust. Recirculation3680of this laboratory air is not acceptable.3681

Variable Volume Airflow Control Systems are recommended for3682increased safety through monitoring capabilities and decreased3683energy usage (using hood diversity and variable flow).3684

Where the minimum ventilation rate (for building or fire code) is3685greater than the total exhaust from hoods, VAV is NOT recommended.3686

Diffusers should be non-aspirating type selected and located to3687minimize velocity & turbulence near the hood face; design cross3688





97

drafts should not exceed 30 FPM within 24 inches of the hood3689opening.3690

100% outside air handling units are prone to stratification; use3691variable temperature constant internal flow volume pumped preheat3692coils or blenders to limit this effect. Provide propylene glycol3693

solution, IFB coils or a reliable, alarmed, pumped chilled water3694coil to prevent freeze-ups.3695

Silencers can help decrease noise from properly sized exhaust3696manifold valves. Use packless type for chemical exhaust applications3697located between the box and hood.3698

Do not oversize VAV boxes. Oversized boxes yield poor airflow3699control and have a limited range.3700

As a minimum exhaust fans should be AMCA Type B spark resistant3701construction.3702

Galvanized exhaust ducts, boxes and attenuators should be used3703except where process or research activity requires special corrosion3704resistance. Laboratory hood exhaust ducts and accessories which are3705inaccessible should be stainless steel (304). Laboratory hood3706

exhaust ducts which handle large quantities of acids should be high3707grade stainless steel, Hastelloy, FRP or other suitable material3708(stainless steel will corrode rapidly in the presence of high molar3709concentrations of Hydrochloric Acid).3710

The use of dilution air to maintain stack velocity is not3711recommended. The exhaust from most chemical laboratories is3712primarily composed of air. Maintain 10'-0" minimum stack height3713above building roof; although a stack height equal to 30% of the3714building height is preferred. If necessary, use variable geometry3715stacks (not Strobic fans) to maintain velocity at reduced airflows.3716Locate stacks to avoid re-entrainment of air into HVAC (considering3717the prevailing winds).3718

VAV systems should be sized with a diversity factor to allow for3719

savings in airflow and first cost of central heating and cooling3720 equipment. A factor of 70% of installed load is common; however, the3721diversity factor must take in to account the anticipated hood use.3722If 50% sash height is considered as full flow, do not use a further3723diversity factor.3724

Hard connect exhaust wherever possible. Provide positionable arms3725(such as Plymovent or Alsident) for point exhaust sources which do3726not support hard duct connections. These supplemental point exhausts3727should be served by an independent exhaust box (where possible) or3728connected directly to the main (with a volume damper or blast gate).3729

A general room exhaust should only be provided when the hood flows3730at minimum sash position provides an air change rate less than that3731required to meet heat loads or the specified minimum air change3732

rate.3733 Air change rate or exhaust quantity will usually dictate the supply3734

air quantity. Exhaust quantities should be reset upward when3735additional cooling is required.3736

Mount VAV lab controls in accessible panels either flush in alcove3737outside lab, or in dedicated room.3738

Manifolded exhaust systems are preferred except for perchloric acid3739hoods.3740

Use of energy conserving enclosures such as glove boxes is3741





98

encouraged.3742

Exhaust ductwork does not normally require insulation.3743

Approved exhausted chemical storage cabinets should be provided for3744solvents and hazardous materials.3745

Recover heat from laboratory utility equipment wherever possible.3746

Provide temperature alarms on refrigerators or freezers. Where3747critical, connect these to the BAS.3748

Where laboratory offices are on the exterior wall, heating at the3749perimeter wall is recommended.3750

The use of emergency power for exhaust systems should be considered3751on a case-by-case basis. In multi-fan manifolded systems the use of3752emergency power for at least one fan should be considered.3753

Where emergency power is not provided for exhaust fan(s) the hood3754alarms should be connected to emergency power or furnished with UPS3755to signal exhaust failure.3756

Supply Air Filtration - 30% ASHRAE and 85% ASHRAE (in series)3757

Exhaust Air Filtration - None (where energy recovery is employed 30%3758

ASHRAE filters are required). Scrubbers may be required for some3759 dedicated hoods.37603761

4.11.3 Vivarium:37623763

Vivarium facilities should consist of individual suites, each3764capable of maintaining its own "microenvironment", for the duration3765of the product study.3766

A system for control of room airflows and relative pressurization3767should be provided. Actual set points and directions of flow are3768dependent upon the operating plan of the space and must be3769determined on a case-by-case basis.3770

Ceiling-mounted non-aspirating diffusers, coupled with a minimum of3771

two (2) low returns on opposite walls with hinged stainless steel3772 grilles fitted with dust stop filters behind the grille, should be3773employed and should be arranged so as to minimize cross-3774contamination between subjects and between researchers and subjects.3775The axis of the non-aspirating diffuser radial fins should be3776parallel with the wall containing the low exhaust registers.3777

Slope exhaust air grille back box and provide weep holes so that3778wash down water that might be sprayed into the system will drain3779back to the room.3780

Humidity control should be provided for each room adjustable to a3781set point between fifty and sixty percent (50-60%), plus or minus3782ten percent (+/- 10%) RH of set point. Humidifiers utilizing clean3783steam should be provided centrally to maintain forty percent (40%)3784RH with ―trim‖ humidifiers capable of an additional thirty percent3785(30%) at each room. In colder climates, provide humidifiers in two3786locations within the AHU to allow the large amount of moisture to be3787added gradually, i.e., two thirds / one third.3788

Temperature regulation should be provided for each room adjustable3789to set point using terminal individual reheat.3790

Temperature, humidity and airflow transmitters should be located3791outside the room, in exhaust ductwork whenever possible. Edstrom and3792ATC sensors should be located adjacent to one another if possible.3793

HEPA filtration of room supply and exhaust air may be required,3794





100

38293830


Specific product requirements are in the appropriate Baseline Guide.3833 Once through air may be used for multi-product or solvent use.3834



Humidification should be considered for cold climates where static3839discharge control is a concern.3840

Risk assessment should be performed to determine the need for fan3841redundancy (parallel fans or fan walls)3842

Unidirectional flow modules (LUFH) that have recirculation should be3843supplied with a small percentage of fresh (or cooled) air to offset3844fan heat.3845

Return fan and AHU mixing sections may not be required for areas3846with no pressure requirements, small local exhaust fans may be3847considered.3848

3849

4.13 ADMINISTRATIVE AND GENERAL BUILDING38503851






101

38543855




Return fan and mixing sections may not be required for areas with no3862pressure, small local exhaust fans may be considered.3863

3864

4.14 WAREHOUSE38653866






102

38693870


See the PACLAW Baseline Guide for further information.3873 Many warehouse facilities do not have central air handling, using3874

only unit heaters. Be sure that air outlets do not overheat high3875stacked material.3876



Return fan and mixing sections may not be required for areas with no3881pressure, small local exhaust fans may be considered.3882

Mapping of temperature extremes in high bay warehouses is3883recommended.3884

3885

4.15 PROCESS EQUIPMENT CONSIDERATIONS38863887

In many cases there are specific requirements for equipment, or aspects3888to consider when looking at the HVAC design for the area containing3889equipment.3890

38914.15.1 Dust extract systems3892

3893Where there is a common dust extract system there are a number of3894





103

aspects to consider in the design:38953896

What happens if the unit fails?38973898

Does the unit have a damper that closes, preventing air leaving the3899

system – is the pressure difference between the rooms served by the3900system adequate to obtain flow – with a consequential risk of cross3901contamination?3902

3903

How does the unit clean?39043905

Some units are cleaned by a shaker mechanism, others use a pulse of3906compressed air – during this pulse, which is in the opposite3907direction to the normal airflow the extract air flow can halt , or3908even reverse for a short period, - is this acceptable?3909

3910

It should be noted that one of the advantages of a remote system (be3911it a common or dedicated system) is that the system heat gain is3912

outside the room, also the extract is often located near an area3913 where the equipment heat gain is high, so those gains are extracted3914from the room, reducing the load on the area HVAC system.3915

39164.15.2 Granulators/Coaters/Fluid Bed Dryers3917

3918These units typically have dedicated air handling systems that are3919independent of the area HVAC. The design should consider what happens3920during periods of non use – is there potential for moisture to migrate3921from the outside environment into the system, if the outside is high3922humidity.3923

3924What are the risks of corrosion during use – what ductwork materials3925should be used?3926

3927What areas of the duct are pressurized - what is the risk of drawing3928in untreated air – what is the risk of potentially contaminated (with3929product) air leaking out?3930

39314.15.3 Glassware depyrogenation tunnels3932

3933These units present a challenge to the HVAC system designer, as they3934are generally located between rooms with different area classifications3935(grades) and they operate intermittently, yet area pressure3936differentials are typically help at a consistent level – this usually3937means some type of active pressure control. (it should be noted that3938with the increasing use of risk analysis to determine areas of3939

patient/product risk, there may be opportunities to reduce the room3940 differential pressures during periods of no production).39413942

As the units are started up, and the temperatures /volumes stabilize3943there is a dynamic period in terms of changing airflow.3944

39454.15.4 Isolator systems3946

3947Barrier-isolator technology may be applied to certain processes where3948aseptic processing and/or containment of hazardous materials are3949





104

required.39503951

Using Isolator technology for aseptic processing and/or containment of3952hazardous material will reduce the exposure of operators and product to3953the operators to disinfection and fogging chemicals that would normally3954

be used in the aseptic processing suite of a conventional cleanroom.39553956Isolators should be automatically decontaminated by Vapor Phase3957Hydrogen Peroxide and then aerated to achieve concentrations of VHP3958that are less than one part per million. This operation should take3959place within the isolator so that there is no operator exposure to the3960VHP. The outside room should be monitored by VHP sensors as a further3961safety measure.3962

3963Monitoring for particulate and viable particles should be done within3964the isolator. The isolator air handling unit obtains supply air from3965the surrounding room and during different modes of operation returns to3966either the room or exhausts to the roof.3967

3968

For aseptic processing of non-potent products, intake air during3969production mode should be taken from the room and returned back to the3970room, while during aeration mode air should be taken from the room and3971exhausted through an independent exhaust air system. For potent3972compounding, intake air during production and aeration should be taken3973from the room and exhausted through an independent exhaust air system.3974

3975Air velocity during production is maintained to +/-20% of the average3976airflow, and is delivered from the HEPA air filter at a rate of 90 fpm3977(0.45 meters/sec) (measured at 12‖ or 300mm (nominal) below air filter3978face or air inlet diffuser (CG membrane or equivalent). Reduced air3979speed may be used during H2O2 bio-decontamination.3980

3981

Fresh air is provided to the inlet of the HEPA filter. Air is3982 recirculated from isolators chamber back to isolators plenum should be3983ducted by internal double glass windows or doors. A differential3984pressure device with display and alarming capabilities monitors the3985differential pressure between the internal zone (filter plenum) and the3986outside room pressure.3987

3988The air classification required for the background environment depends3989on the design of the isolator and the application. Room cooling loads3990for spaces in which isolators are located must take into account the3991heat generation by the isolator fan system(s). The most common agent3992for decontamination of isolators is vaporized hydrogen peroxide (VHP).3993Consideration should be given to treatment, e.g., catalytic converter,3994etc., of VHP gas prior to discharging to ambient at the end of the3995

sterilization cycle.39963997

Fresh air make-up from the surrounding room should pass through HEPA3998filters via the isolator. Exhaust air from VHP sterilization should3999have a scrubber or VHP neutralization. HEPA filters should be readily4000changeable from outside the Isolators.4001

4002Each zone will have access ports upstream the HEPA filtration to allow4003for introduction of DEHStest aerosol for filter integrity testing.4004





105

Filter faces shall be accessible with the fans operational forfilter4005integrity scanning.4006

4007The temperature control of all zones is provided by a cooling system of4008the intake air taken out of the room. A temperature measuring4009

transmitter with display and alarming capabilities will control and4010 monitor temperature.4011401240134014





106

5 DESIGN QUALIFICATION / DESIGN REVIEW (DQ/DR)4015

4016

5.1 DESIGN REVIEW/ DESIGN VERIFICATION/DESIGN QUALIFICATION40174018

There is one important thing to remember about design reviews– it is4019 far easier and cheaper to change a design before it is constructed,4020

than during or after construction.40214022

The process of reviewing a design (drawings and specifications) as it4023develops from concept to issue for construction status has a number of4024objectives:4025

4026

To ensure that the design follows the clients preferred custom and4027practice4028

To ensure that the design will perform to meet client expectations4029

To ensure that the concepts proposed are capable of performing to4030meet the requirements defined in the User Requirement Specification4031

(URS) in the clients opinion.4032 To ensure that the design minimizes risk to product quality /4033patient.4034

To ensure that the design is robust and will perform reliably4035

To ensure that the design proposed is cost effective.40364037

For systems able to affect product quality it is common practice to4038split these design reviews into two categories – (although this is not4039mandatory):4040

4041Engineering reviews4042

4043Quality (or GMP) focused reviews4044

4045Similarly it is common to perform a final specific ―quality‖ review to4046confirm that the system (and the specified related conditions for area4047it serves – Temperature, Humidity, Particle Classification,4048Differential Pressures etc.) comply with GMP regulations/company4049standards – this review may be called ―Design Qualification‘, or4050―Design Verification‖, allowing the statement to be formally made that4051–―the design is fit for its intended purpose‖, as well as confirming4052that the requirements defined in the URS are compliant.4053

4054It should be noted that there is not a mandatory requirement to perform4055this review – the process of approving the design to be released for4056construction or the overall review process may also be considered a4057verification or qualification of the design, because it confirms that4058

all client comments have been adequately addressed, and the client4059agrees with releasing the design for use.4060

4061An overview of a typical design /design review process is shown4062diagrammatically below:4063

4064





107

Yes – then write

system URS

Project Initiation /& Concept Design

Divide thescope intosystems

Ability toimpact product

Quality

No – then no

specific URS isgenerally required.

DesignDevelopment

Design Reviews

Issue forConstruction

Design

Changecontrol

ApproveDesign

40654066

Figure 5-1 Diagram of Design Review Process (Arrows missing)4067

4068 An effective design review is dependant on the people conducting it,4069although most companies are now trying to develop knowledge capture4070systems such as:4071

4072

Design review checklists (An example is included as an attachment)4073

Design guides – defining the preferred way of designing a given4074system4075

4076These approaches have a common objective of trying not to be too4077prescriptive, losing the ability to consider novel concepts, but4078ensuring that company experience is captured and considered.4079

4080In order to make the process as effective as possible it is important4081to pre-define the method to be used, and agree the review participants.4082

4083A preferred approach is to use a multi–disciplinary team to ensure all4084view points are considered, with Subject Matter Experts in HVAC,4085Controls and regulatory requirements.4086

4087For areas where high system reliability is required, e.g. Vivarium, a4088formal review may be conducted, such as a FMEA, to ensure that the4089design is adequately robust. A simplified version of this approach may4090be beneficial even for simple manufacturing facilities considering the4091impact of system failures on adjacent areas, to ensure that the design4092is robust.4093

4094

Notes taken from the review will be implemented through4095drawing/specification changes; if the revision cross references the4096notes it is not necessary to formally close out all actions in this GEP4097environment – the SME who will sign off the drawing is expected to4098check that all necessary changes have been incorporated.4099

4100In practice where there is a large project there will be multiple4101reviews at key stages – for example a review at the concept stage to4102ensure that the client team agrees with the proposals from the A&E4103design company – these may focus on individual systems, or on overall4104





108

areas of the design, e.g. HVAC controls..41054106

For smaller projects with perhaps only one system, there may be less4107reviews – the project team should agree the approach to be applied to a4108specific project.4109


4112As the design is developed it will evolve, with input from all4113interested parties.4114

4115Typically the process is formalized to make it more efficient.4116

4117An example of the approach is shown below:4118

4119

Client URS

Concept

design

developed by

A&E

consultant

Design

reviewed

Design revised to

suit review

comments

Design

concept

developed to

detail level

Detail design

reviewed

Design revised to

suit review

comments

Completed design

41204121

Figure 5-2 The Design Process41224123





109

The design review process is intended to ensure that:41244125

original ideas from the design team are captured and reviewed4126

company specific requirements / standards are incorporated in the4127design (after an evaluation of potential benefits/drawbacks to4128

ensure company requirements are ―best practices‖) 4129 the design will perform to meet the requirements defined in the URS4130

the design is robust and will perform reliably41314132

The review may be structured to cover all design aspects, or divided4133into two:4134

4135

A GEP review - to ensure that engineering best practices are4136incorporated4137

A cGMP review - to ensure that all compliance requirements are4138adequately addressed by the proposed design.4139

4140The cGMP review is typically straight forward and consistent - it is4141

expected that any resultant observations are tracked to ensure that4142they are addressed, with an audit trail created.4143

4144The GEP review may be more involved, (a lot of knowledge and experience4145within a company can be captured and used in the review process) also a4146formal audit trail is not usually required for GEP observations – 4147typically the reviewer ensures that comments have been addressed, hence4148there may be a benefit in keeping independent reviews.4149

4150This suggestion is developed into a series of categorized design4151challenges shown below:4152

4153Table 5-1 Design concept stage cGMP review4154

4155 Design Challenge Response ActionAre the units and associatedcontrollers located in acontrolled access space?Maintainability

(Consider accessibility to keycomponents of the system,filter maintenancerequirements, filter integritytesting (if required),regeneration requirements,emissions, etc.)

Review and evaluate the AHUservice distribution drawingand consider the following:How many AHU units (zones) areproposed, is the zoning basedon the process requirements?(.)





110

Are the airflow directions /differential pressures correctto control product exposure /cross contamination?Are the temperature and

humidity design and operatingconditions defined?

Are any area classificationsrequired / defined?

Are the systems once through orrecirculating?

(Are there provisions to handlesolvents, high potent compoundsor high particle generatingoperations, as required by theproduct/process operations?)Is the control scheme clearly

defined, including monitoringand alarm requirements?

41564157

Figure 5-2 Detail Design or IFC stage cGMP review41584159

Design Challenge Response ActionHave the peak external designconditions been established froma reliable source, whichconsiders local geographicalfeatures/ meteorological factors– lakes, prevailing wind

direction etc?Has the user definedavailability requirements forthe products to allow the designexternal conditions to bedefined? (i.e. the percentage oftime that the facility will beable to maintain themanufacturing conditions)Are the internal requirementsspecified:

Temperature / humidity / airflowdirection – area differentialpressures/classification.Review location of outside airintake and exhaust. Is theprevailing wind directiondefined for the site, with theHVAC inlet and outlet locationsdefined to demonstrate no riskof recirculation?Is the facility divided into





111

Design Challenge Response Actionmanufacturing zones (areas)?What rationale is used to dividethe facility into zones?Is the location of the

monitoring sensors specifiedsuch that they will giverepresentative readings of thespace conditions: are theyeasily accessible formaintenance and calibrationactivities?

(For large areas, such as awarehouse multi-point mappingand monitoring may be required,for smaller areas, 1 or 2 pointsis generally adequate, with thereading demonstrated asrepresentative of the areaswhere product is susceptible toconditions during qualificationusing sensors. Consider thesize of the room and thelocation of key processoperations (e.g. productexposure) in establishing thelocation and number of monitoredpoints.)If there area multiple airhandling units servicing themanufacturing area, how will

failure modes affect theintended operation? Willfailure of one unit increase therisk of cross contamination?Is there a site drawing/component numbering systemwhich has been used?Are airflow directions /differential pressures (fromclean to less clean) appropriateto provide the minimum risk ofproduct contamination / crosscontamination, considering

potential system failure modes?41604161

Design Challenge Response ActionAre there airlocks whichseparate areas of differentclassifications, with a targetdesign DP of 15 Pa across theairlock?





112

Design Challenge Response ActionThe design airlockclassification should be same asthe area served when measured atrest.

Are the airlocks specified withinterlocked doors?

(It is recommended that thedesign differential pressure isa minimum of 15 Pa to allow forconstruction issues.)Does the process requirecontainment; if so is exhaustair filtered using safe changehigh efficiency filters withsuitable re-filters (bag-in,bag-out)?Are there any provisions tohandle solvents, high potencydrugs, and/or high particlegenerating materials? If so,are the provisions in line withthe area GMP operationalrequirements?

(Airflow should be designed tocontain high potency compounds.

For biotech facilities designshall conform to the Center for

Disease Control biosafetycontrol levels.)Are the air handling systemsdesigned for re-circulationwhere appropriate, and withsuitable return air filtration?What assumptions have been madeto specify the position of thetemperature sensor to ensurethat it is representative ofroom conditions?What assumptions have been madeto specify the position of the

humidity sensor to ensure thatit is representative of roomconditions?Is there a qualified system formanufacturing areas to monitorand maintain records oftemperature, humidity, andairflow direction?

(Define what will be the system





113

Design Challenge Response Actionof record and what will be thesystem of control.)Is there a locally mounted alarmindicator for any out of limit

environmental condition -temperature, humidity, airflowdirection?

Have alarm limits been definedbased on product and processrequirementsHas the position of inlet/outletgrilles been specified wherenecessary?

(If the area is classified, itis common practice to designwith ceiling mounted supplygrilles and return air taken atlow level in the room?Is the area served a Laboratory,if so what considerations havebeen made for;

fume hoods

microenvironments, e.g. lowhumidity rooms

Sensitive scales?Does humidification use plant

steam, if so does it useapproved additives (21 CFR173.310) or chemical free steam?

(If so it should be injectedbefore the final HEPA filter -where one is used.)Is the ductwork specified usingan appropriate allowance forleakage – is it shown on thedesign?Are the AHUs mounted inside, ifnot what provision is there to

protect them and the staff fromthe weather during maintenance?Does the specification for theAHUs include access panels andtest ports to facilitatemaintenance, and HEPA filtertesting if required?Are AHUs designed for constantvolume, and low leakage ofconditioned air?





114

Design Challenge Response ActionHow does the specification ofthe AHU ensure that it will notdegrade or corrode during itsworking life, to affect its

performance?Are progressive pre-filtersspecified – what is the basisfor their selection?What final stage filters arespecified?

Are all classified areas servedvia 99.97 % efficient HEPAfilters? (Note terminalfiltration is preferred).

(H13 specified for in situleakage testing, or H 14)

.

Are lockable dampers specified,and is there a requirement torecord the as balanced settingin the commissioning records?Confirm that the specificationpermits no interior lining ofductwork, with any soundattenuators specified using nonshedding lining.What Security arrangements arethere for controls?What happens in the event ofpower failure?

Is the ductwork made ofGalvanized steel, or are therespecial requirements, for nonclassified areas does thespecification limit the use offlexible ductwork to 4 feetlong? Confirm that forclassified areas the use offlexible ductwork is notpermitted.

What are the leakage allowances– are they appropriate?

(The use of flexible hosing mustbe carefully evaluated.Maintenance requirements must bediscussed as part of the reviewprocess.)

41624163

Figure 5-3 Design concept stage GEP review41644165





115

Challenge Response ActionWhat considerations are made forreliability/robustness?Does the design proposeddemonstrate current best

practices?How are maintenance /calibration requirementsaddressed?How are failure modesconsidered?Are ceiling plenum returnsproposed – if so how would theceiling void be cleaned?

41664167

Figure 5-4 Detail Design or IFC stage GEP review41684169

CleanabilityChallenge Response ActionWhat arrangements are made tofacilitate cleaning the systeminternally?How does the design consider therisk of building sicknesssyndrome?OperabilityChallenge Response ActionAre airflow directions proposed for anycatering areas, to contain odor?Are there arrangements to extract fromcopier rooms?Is the AHU construction specified toavoid risk of external condensation?If not are the air handling systemsdesigned for re-circulation whereappropriate, and with suitable returnair filtration?What assumptions have been made tospecify the position of the temperaturesensor to ensure that it isrepresentative of room conditions ?What assumptions have been made tospecify the position of the humiditysensor to ensure that it is

representative of room conditions?How does the design allow for futurechanges in the room layout in terms ofsensor locations and zoning?MaintainabilityChallenge Response ResolutionAre the site specific requirementsdefined in terms of preferred suppliers?





116

Are AHUs located in an area suitable foreasy maintenance, suitably protectedfrom the external environment tofacilitate maintenance?Does the specification for the AHUs

include access panels and test ports tofacilitate maintenance?Is the system designed with progressivefiltration?

How have filter grades been decided – are they a site standard?Are lockable dampers specified, and isthere a requirement to record the asbalanced setting in the commissioningrecords?What Security arrangements are there forcontrols?What happens in the event of powerfailure?Is the fan drive external or a highefficiency/low loss design e.g. flatbelt?

What is the bearing design life at themaximum rated fan speed?ConstructabilityChallenge Response ResolutionIs the ductwork made of Galvanizedsteel, how is the internal finishspecified, to ensure that thegalvanizing is of good quality and

finish?Does the ductwork specification limitthe use of flexible ductwork to 4 feetlong?

41704171





117

6 EQUIPMENT FUNCTION, INSTALLATION, AND OPERATION4172

4173

6.1 EQUIPMENT FUNCTION AND MANUFACTURE41744175


The HVAC equipment section is geared around those items that deliver4178conditioned air to GMP spaces. The design and construction of the4179equipment is intended to meet safety, product and regulatory4180requirements while providing environmental comfort and protection to4181employees. They should have robust capabilities for achieving initial,4182continuous, and long-term operation, ease of maintenance, and low4183energy use.4184

4185HVAC equipment serving GMP areas are intended to work in conjunction4186with associated controls and sequences of operation systems to:4187

4188

Maintain room temperature and relative humidity4189

Maintain room pressurization and differential pressure cascades4190

Provide make up (fresh) air for ventilation and room pressurization4191

Minimize airborne contamination delivered to the conditioned space4192

Provide required air flow rates to maintain room cleanliness4193classification when required4194

41956.1.2 Air Handler Unit (AHU)4196

4197GMP air-handlers should be constructed to meet the more stringent4198performance, improved reliability, and maintenance requirements for4199critical areas being served. Air handler components such as coils,4200humidifiers, dehumidifiers, dampers, fans, motors, and filters should4201be designed and constructed so that the system can operate at 115% of4202anticipated design due to the potential for increased demand or future4203expansion.4204

42056.1.2.1 Cabinet Construction4206

4207In geographic regions of moderate to high humidity levels,4208consideration should be given to have no through metal (a thermal4209break) on all wall, floor, doorframe, ceiling sections and doors.4210Potential for exterior condensation is possible if thermal breaks are4211not properly designed and implemented. AHU designated to operate at4212locations with high temperature and humidity conditions should have a4213true thermal break construction.4214

4215

Total air leakage rate shall be no greater than ½% at 150% of the4216design positive/negative in total pressures or 50 cfm (1.42 m3/min),4217which ever is greater, or the requirements stated in the EN 18864218standard, for the most sever ―leakage class‖ operation. 4219

42206.1.2.2 Panel Insulating Materials4221

4222It is recommended that roof, floor and ceiling panels be insulated with4223foam (polyisocyanurate) that is FM approved and meets NFPA fire rating.4224





118

Foam should not be exposed to the air stream nor surrounding area.4225Where required by special conditions, panels may optionally be4226insulated with rock wool if the qualified vendor meets all minimum4227criteria herein. Panels should be constructed to be no less than 2‖4228(51mm) thick and that the equipment manufacturer should guarantee that4229

sweating will not occur anywhere on the AHU at the operating4230 environmental conditions, in which the cabinet will be exposed.42314232

6.1.2.3 Panel Lining4233

4234The interior wall and ceiling panel surfaces and joints should be4235ripple free, smooth, and continuous, constructed of a material such as4236aluminum or stainless steel, that can be wiped clean and will not4237easily rust or corrode. In compartments serving cooling coils or steam4238humidification injection, it is recommended to line this section with4239304L SS. It is unacceptable for exposed insulation or lining be4240exposed inside an air handling system serving a GMP area due to the4241potential of providing an area for mold propagation.4242

42436.1.2.4 Panel Joints4244

4245All interior joints should be sealed with RTV silicon sealant caulk,4246compliant with appropriate regulations for food grade applications,4247with all exterior joints sealed with caulking having at least a 25-year4248life with mold inhibitor.4249

42506.1.2.5 Duct Connections4251

4252Cabinet duct connections, which are of reduced size, can significantly4253reduce systems delivery capacity if selected to match ductwork mains.4254It is recommended that the return and supply duct connections be sized4255

large enough to ensure air velocity is no-greater-than 1,100 fpm.4256 Suitable transitions should then be connected to the main ductwork to4257ensure smooth and turbulent free transfer of air to duct mains.4258

42596.1.2.6 Removable Wall Panels4260

4261Removable panels provide a means to remove large components such as fan4262assemblies and coils that would not fit through the man door. The4263removable panel allows removal of panel using simple hand tools and4264avoid cutting or sawing through thermal breaks and cabinet constructed4265walls making removal and subsequent sealing possible.4266

42676.1.2.7 Flooring4268

4269 Flooring should be of a sufficient thickness to prevent oil caning or4270deformation when walked upon. Flooring should be of diamond faced4271aluminum plate with a minimum 3/16‖ (4.76mm) thickness. Floor seams4272should be fully welded and the perimeter edge should have a minimum 2‖4273(51 mm) lip turned up and sealed to the wall for a watertight floor4274system. Floor should be designed to have a capacity of 100-psf live4275load, to accommodate a service mechanic working inside unit.4276

4277





119

6.1.2.8 Condensate Pan4278

4279The cooling coil condensate drain pans (up and downstream) shall be of4280smooth 304L SS. The pan shall be double or triple sloping as to enhance4281total drainage. Its length shall extend beyond its downstream face, a4282

minimum of 12‖ (30 cm) or ½ the height of the coil, whichever is4283greater, and a minimum of 6‖ (15 cm) beyond its upstream face. (Refer4284to the ASHRAE – Systems & Equipment Handbook, Chapter 21.4.) Stacked4285cooling coils shall have their own drain pan, with drainage into the4286lower coil section(s). Its length shall extend beyond its downstream4287face, a minimum of 12‖ (30 cm) or ½ the height of the coil, whichever4288is greater, and a minimum of 4‖ (10 cm) beyond its upstream face. Drain4289pans shall slope a minimum 1:50 towards drain outlet. Connections4290shall be piped to exterior of unit casing.4291

4292Condensate drain traps shall be sufficiently designed and constructed4293so as to not cause puddles (which can lead to biological growth) and4294air movement into or out of the air handler during operating4295conditions.4296

42976.1.2.9 Wash Down Capability4298

4299In certain applications, the interior of the air handler is cleaned and4300washed down. In these applications, all AHU sections (excluding4301condensate pans) requiring drainage capability for wash down should4302have a 2‖ (51mm) minimum diameter opening fully welded around the4303perimeter. The opening shall be fitted with a secured/removable,4304flush-mounted, airtight 304 SS cover plate or plug.4305

43066.1.2.10 Roof4307

4308

Air handling units located outdoors should be provided with roof panels4309 sloped to a centerline peak or to one side as required while4310maintaining a flat ceiling inside. Entire panel shape should be fully4311insulated without gaps at the peak. Roof should have a minimum slope of43121:50 for drainage. All exterior AHUs should have perimeter roof gutter4313with appropriate down spouts and rain guards above all exterior access4314doors constructed of same materials as casings.4315

43166.1.2.11 Hardware4317

4318All hardware (i.e., screws, nuts, washers, etc.) should be 304 SS.4319Other materials, which oxidize or promote rust, should not be used in4320the construction of equipment.4321

43226.1.2.12 Doors4323

4324Access doors should be installed on all sections of the AHU (i.e.,4325coils, filters, fan, humidifier, etc.), wide enough (minimum width 24‖4326(610 mm)) to allow entry by an operator for cleaning and inspection.4327All coils should have an access door on each side (up/downstream).4328Access doors shall be arranged to open against the direction of higher4329relative pressure for safe use and positive air seal. Positive pressure4330sections of the air handler shall have doors labeled as such. Doors4331





120

should be of a double gasket compression design. All access doors4332should have an instrument test port to allow temperature and pressure4333readings to be collected without drilling into cabinet during air4334balancing commissioning.4335

4336

All doors should have impact, mar-resistant, clear view ports (double4337 pane wire, Mylar-backed glass or polycarbonate (Lexan)), minimum 12‖ x433812‖ (305 mm x 305 mm) or 12‖ (305 mm) diameter. 4339

4340All doors shall have handles located on the inside of the AHU for4341safety. Interior door handles will prevent someone from being trapped4342inside of the unit.4343

43446.1.2.13 Mixing Plenum4345

4346Mixing plenum is a chamber within an HVAC system where outdoor air is4347mixed with return air. The mixed air becomes the supply air for the4348space after passing thru filtration, heating or cooling steps within4349the air handler.4350

43516.1.2.14 Electrical4352

4353All lighting should consist of vapor tight fluorescent fixtures4354(typically 4 ft (1200 mm)) with two T8 lamps and electronic ballasts.4355All sections should have at least one fixture. There should be a4356minimum of two waterproof 6-hour maximum timer light switches per AHU,4357one per end.4358

4359Junction boxes should be weatherproof and all conduit penetrations4360should be sealed airtight.4361

4362All electrical components, wiring, and terminals shall be tagged. High4363

voltage terminals shall be labeled as such. Internal power cabling4364shall be shielded.4365

4366All materials and installation methods shall be in compliance with NFPA4367and NEC.4368

4369Sections with fans and moving parts shall have warning signs ―ISOLATE4370BEFORE ENTRY‖ affixed to doors. AHUs manufactured for Europe should4371have a CE mark (Conformite Europenne). A CSA (Canadian Standards4372Association) rating should be placed on all electrical devices.4373

43746.1.3 Fans4375

4376

Fan selection is critical for generating the proper quantity of air4377 (supply, return, exhaust/extract) and required pressure to overcome4378losses due to dampers, coils, filters, silencers, and ductwork. It is4379important to consider a number of items when selecting fans so they can4380operate smoothly over their intended life. This includes, materials of4381construction (rigidity, weight, corrosion, cleanability) determined for4382the type of operation (clean/contaminated air, humidity, temperature,4383severity), bearing, lubrication, direct vs. belt driven, static4384pressure flow sensing, and safety guards.4385

4386





121

Air handlers are configured as either a draw-thru or blow-thru4387operation, with the former most typically used. Draw-thru units have4388the fan located downstream of the pre-filters, coils, and humidifier.4389Their advantages include a shorter unit length, negative pressure on4390all access doors except the fan discharge section, and reheating of air4391

leaving the fan section, which will reduce reheat coil requirements.43924393Fan pressure performance and construction are identified as Class I,4394II, III, or IV by AMCA, based on certain minimum operating criteria. A4395Class I fan offered by any particular manufacturer has a lower4396allowable minimum operating range than its Class II counterpart. As a4397result, a Class I fan with less mechanical design strength and with4398less expense than a Class II fan. Typically, Class II & III fan4399performances are sufficient to handle pharmaceutical applications.4400

4401Fans typically used for air handlers on the supply side are either a4402direct driven plug/plenum fan or a belt driven centrifugal fan.4403Exhaust/extract operations typically use direct or belt driven vane4404axial or a belt driven centrifugal fan4405

4406Plenum fans are limited to approximately 12‖ static pressure and4407roughly 75,000 cfm of air, while centrifugal fans can produce 20‖ of4408static pressure and greater than 200,000 cfm of air. Vane axial fans4409can typically produce up to 10‖ static pressure and 100,000 cfm of air. 4410

4411Plenum fans should be designed for high efficiency, with non-4412overloading airfoil aluminum wheels. They should include inlet cones4413matched to the wheel intake rim to ensure efficient and quiet4414operation.4415

4416Vane Axial fans are designed where large volumes of air are required at4417moderate to high pressures. The tubular design, high efficiency rotor4418

and integral straightening vanes provide high performance using minimal4419 space. These fans are an excellent choice for HVAC systems using4420variable air volumes, clean rooms, and exhaust/extract. They are most4421efficient as return to air handlers and for exhaust/extract4422applications (fume hoods, bio-safety cabinets.) These units should be4423configured for direct drive though belt driven could be used.4424

4425Another variation of the direct drive fan configuration is an array of4426smaller plug fans (commonly called a fan wall) to replace a traditional4427single large fan. This arrangement reduces the overall footprint of the4428air handler, allows design flexibility, simplifies maintenance, reduces4429downtime, reduces low-frequency noise (rumble) within the air handler,4430and usually saves energy, The use of multiple direct-drive fans4431operating in parallel improves reliability by providing redundancy.4432

4433Direct driven fans eliminate belt replacement, guards, and belt4434shedding and alignment. In addition, there are no shaft bearings4435present, which eliminates lubrication.4436

4437All belt-driven fans should have their motor and fan belt/sheave4438assemblies completely enclosed (front and rear) in a rigid, 304 SS or4439painted steel guard that protects personnel from injury and have an4440access for measuring tachometer readings. These guards are to be4441





122

removable without the use of any tools but should include a warning4442label to notify the operator to secure the equipment prior to opening.4443Motor base shall automatically control belt tension and be of4444permanently aligned type to allow belt changes without realigning. For4445multiple belt systems, belts provided should be matched sets. Entire4446

fan assembly shall be centered in the air stream both vertically and4447 horizontally to assure proper airflow. All fan inlets and discharges4448should have 304 SS operator protective screens.4449

4450Belt driven fans should be laser aligned to decrease the chance of4451failure to bearing, shaft and belts and energy consumption. Fan belt4452tension is extremely important during their entire life. Special4453attention should be incorporated, especially when installing new V-4454belts. Once the new belt(s) have operated for a short time, they most4455likely will need to be readjusted due to belt wear-in. Improper under-4456tensioning will result in premature failure and increased energy usage.4457Over-tensioning can reduce bearing life. Synchronous belts reduce4458energy consumption since they don‘t slip during start-up and operation.4459

4460

All fan housings shall be continuously welded to provide strength and4461durability for extended service life. They should have a primer with at4462least one coat of industrial strength or epoxy paint finish to4463eliminate rusting. For centrifugal fans a drain connection should be4464included, located at the bottom of the fan housing for draining any4465fluids that may accumulate.4466

4467Fan wheels should be of aluminum construction where possible to reduce4468weight and rusting and be fully welded and non-overloading. All wheels4469are both statically and dynamically balanced. Fan shafts should be4470precision ground, polished and sized so that the first critical speed4471is at least 25% over the maximum operating speed. A shaft seal should4472be included to reduce leakage and protects the bearings from a4473

contaminated air stream.44744475Fan shaft bearings shall be selected for a minimum average life of ABMA4476L10 200,000 hours. Automatic bearing lubricators should be installed4477to increase bearing life and reduce maintenance. This will eliminate4478the possibility of over/under lubrication, resulting in premature4479bearing failure. Recommend lubricator installed directly to bearing4480housing. Lubricators should be sized to supply lubricant for a minimum4481of 6 months without refill or replacement. The vendor needs to work4482closely with the lubricator supplier to provide the proper lubricant4483and device for the intended operation of the air handler. Note: The4484lubricator should not be mounted or activated until the fan is put into4485full operation, to eliminate automatic, excessive lubrication and4486damage.4487

4488Include removable inlet and outlet fan guards to provide protection for4489personnel and equipment meeting OSHA standards.4490

4491Center the fan inlets in both the horizontal and vertical planes within4492the air handler.4493

4494For measuring fan airflow without impeding air movement in or near the4495fan inlet, which would increase system static pressure, it is4496





123

recommended to install, a combination piezometer ring and static4497pressure tap, integrated into the inlet cone. The inlet cone of the fan4498is used as the flow nozzle.4499

4500Vibration shall conform to ANSI/AMCA Standard 204, ―Balance Quality and4501

Vibration Levels for Fans‖ and have a maximum balance and vibration BV-4502 4 category. The vibration limits shall be 2.5 mm/s (0.10 ips) for4503rigid mounted (direct driven) fans and 3.8 mm/s (0.15 ips) for4504flexibility mounted (belt driven) fans. The balance quality grade for4505impellers shall be no greater than G2.5 mm/s (0.10 ips), ANSI S 2.194506(ISO 1940) ―Balance Quality for Rigid Bodies‖. Balance readings shall4507be taken by electronic type equipment in the axial, vertical, and4508horizontal directions on each of the bearings.4509

4510Fans and motors should be provided with vibration sensors with signal4511wiring brought out to a vibration interface enclosure mounted on the4512outside of the AHU to provide early warning and trending of bearing4513performance.4514

4515

6.1.3.1 Motors & Drives4516

4517All motors that are anticipated to operate at various loads should be4518inverter duty, rated NEMA premium efficiency and should comply with4519NEMA MG1, Part 31. A shaft grounding system or isolated bearings4520should be installed to prevent bearing failures caused by induced4521electrical current.4522

4523Motor bearings shall be selected for a minimum average life of ABMA L104524200,000 hours. Automatic bearing lubricators should be installed to4525increase bearing life and reduce maintenance. This will eliminate the4526possibility of over/under lubrication, resulting in premature bearing4527failure. Recommend lubricator installed directly to bearing housing.4528

Lubricators should be sized to supply lubricant for a minimum of 64529months without refill or replacement. The vendor needs to work closely4530with the lubricator supplier to provide the proper lubricant and device4531for the intended operation of the air handler. Note: The lubricator4532should not be mounted or activated until the fan is put into full4533operation, to eliminate automatic, excessive lubrication and damage.4534

4535It is recommended to include variable frequency drives (VFD) to control4536the volume of air delivered to the various spaces. The advantage of the4537VFD in lieu of variable inlet guide vanes include better volume4538control, energy usage, less maintenance, soft start of fan motor4539reducing the in-rush of electrical current and stress on the fan, and4540positive control feedback to the building automation. Invertors should4541

include line and load reactors to eliminate motor failure.45424543It is recommended fans with belt drives use a synchronous belt with4544matching sprocket in lieu of V-belts and sheave. The advantages include4545non-slip operation, longer life, less maintenance, little to no belt4546shedding, single sync. belt vs. multiple V-belts for same operation and4547reduced energy consumption. The one disadvantage is that it will4548possibly produce higher noise levels.4549

4550





124

6.1.4 Fume Exhaust/Extract Systems45514552

Laboratory and process fumes shall be directly exhausted to a safe4553location outside the building. To maximize the intent of exhausting4554unwanted contaminants, the inlets to the exhaust system should be as4555

close to the point of generation as possible. The exhaust plume height4556 shall be great enough to avoid re-entrainment of exhaust air into air4557inlets or onto roof and to disperse the exhaust. The effective stack4558height should be used when analyzing design issues.4559

4560Wherever an occupational or environmental risk may exist attributed to4561a HVAC or local exhaust ventilation (LEV) system installation, a4562building airflow wake simulation shall be performed. This simulation4563shall to verify the effective mitigation of aerosol contaminant re-4564entrainment to meet current ACGIH TLV® country-specific level, the4565company OEG for APIs, and/or biohazardous agent safety level. Factors4566impacting the wake flow requirements include: toxicity of the material,4567quantities and frequency of generation, inlet and exhaust placement,4568discharge filtration and velocities, prevailing wind directions and4569

velocities, existence of adjoining buildings or structures, and area4570topography.4571

4572Discharge velocities from exhaust stacks should be no less than 3,0004573fpm (15.24 m/s). Exhaust from the hoods, BSC, or process equipment can4574be accomplished by ducting each piece of equipment to a dedicated fan4575or by manifolding the ducts to a centralized fan system. The4576manifolded system is preferred due to its 100% redundancy and reduced4577energy and maintenance costs. However, when only a few hoods exist or4578hood locations are remote from one another or for specific4579applications, then individual dedicated fans will probably be more4580applicable.4581

4582

Fans should be located exterior to the building so as to establish a4583 negative pressure within the entire length of the exhaust ductwork.4584Where external location is not possible, the ductwork on the discharge4585of the fan, which will be under positive pressure, shall be welded pipe4586and pressure tested for zero leakage. Automatic dampers shall be4587strategically installed so as to not cause exhaust air to be drawn back4588down into the building or short cycled from an idled companion fan.4589

4590Care must be taken to address noise sensitive areas and aesthetics in4591the location of the fans and their operation. This may include4592acoustical silencer nozzles and roof sound barriers.4593

4594Two fan types are considered acceptable for this application. These4595include the preferred mixed-flow impeller (combines the benefits of4596

axial flow and centrifugal flow fans) or the centrifugal fan.4597Whichever fan application is chosen during project development, it4598should provide for safe, easy inspection and maintenance of the fan4599drive components. Fans shall meet AMCA type B or C spark-resistant4600construction. All metal surfaces shall be coated with an epoxy for4601protection against weather, UV, and chemical vapors. Fans and4602accessories shall have internal drain systems to prevent rainwater from4603entering building duct system.4604

4605





126

Air handler heating coil tubing should be of nominal 5/8‖ (15 mm) O.D.,46610.035‖ (0.89 mm) thick seamless cupro-nickel for better corrosion4662resistance, with aluminum fins of at least 0.0095‖ (0.24 mm) thickness.4663Coil casings and frames should be 304L SS with a center tube support4664for coils greater than 48‖ (1.2 m) in width. Preheat steam and hot4665

water coils should consist of no less than 2 rows to provide lower4666 downstream face temperature variation.46674668

Duct mounted coil tubing should be a minimum nominal 1/2‖ (13 mm) O.D.,46690.025‖ (0.64 mm) thick seamless copper, with aluminum fins of at least46700.008‖ (0.20 mm) thickness.4671

4672Coils should be fully drainable with vent and connections extending4673external to the AHU or ductwork. Include full port shut-off valves4674with hose connection with cap and chain. All steam coils should be4675fitted with vacuum breakers.4676

4677All coils, which are exposed to salt or corrosive conditions, should4678have corrosion resistant coating. All cooling coils should be coated4679

to enhance heat transfer and reduce biological growth.46804681

All coils shall be fitted onto 304L SS tracks for ease of removal.46824683

6.1.6 Humidifiers46844685

Humidifiers should be comprised of steam injection dispersion/sparge4686tubes and accessories to provide drip-free steam absorption without4687downstream condensate. When clean steam is required for4688humidification, sanitary tri-clamp connection control valves and4689thermostatic steam traps, along with other components made of 316L SS,4690should be used. Modulating steam control valves should be included to4691provide accurate control. A wye strainer should be installed upstream4692

of the control valve to provide it from dirt.46934694When located in the air-handling unit, the humidifier section should be4695located directly upstream of the cooling coil section to ensure4696efficient absorption of vapor into the air stream. The humidifier4697condensate drain pans (up and downstream) should be 12 gauge 304L SS,4698and at least 2‖ (5 cm) deep. Its length should extend beyond its4699downstream face to the upstream side cooling coil section and a minimum4700of 6‖ (15 cm) beyond its upstream face. Connections should be piped to4701exterior of unit casing.4702

4703When the humidifier is located within ductwork, the ductwork shall be4704constructed of fully welded 304L SS, 2 ft (0.6 m) upstream and 5 ft4705(1.5 m) downstream of the humidifier. Humidifier ductwork sections4706

shall be pitched downstream of the humidifier to a drain.47074708

6.1.7 Dehumidification47094710

When standard chilled/glycol systems are unable to sufficiently reduce4711relative humidity levels, several dehumidification systems are4712available to handle lower relative humidity limits.4713

4714These include:4715





127

4716

Run-around coil systems4717

Heat pipe systems4718

Dual-path systems4719

Desiccant systems47204721

Because they are capable of delivering air at much lower dew points4722than coils, desiccant systems have been the most widely used method for4723dehumidification in the pharmaceutical industry.4724

4725Proper layout of equipment should include filters upstream of the coils4726and fans downstream of coils (draw-through mode) to provide a small4727amount of reheat. Select low face velocity coils to reduce air pressure4728drop and improve dehumidification performance.4729

4730When dehumidification is integrated into a cooling system, pay special4731attention to these issues:4732

4733

Select and size HVAC equipment (coils, fan, pump, damper, etc.) for4734sensible and latent cooling at peak load conditions. These usually4735don‘t occur simultaneously. 4736

4737Design for energy efficiency at part-load conditions because peak load4738usually occurs for only about 2% of the operating time.4739

4740A run-around coil system is a simple piping loop with an upstream pre-4741cooling coil and a downstream reheating coil that sandwiches the main4742cooling coil. The circulating fluid is pumped to transfer heat from the4743warm mixed air to the off coil cold supply air. The run-around system4744reduces the cooling load on the main cooling coil; reheat is provided4745by the heat picked up by the circulating fluid in pre-cooling coil4746instead of by an external source of expensive energy.4747

4748The run-around loop requires a fractional horsepower pump and a three-4749way valve or a variable-speed drive (VSD) for the pump. For bigger4750systems, an expansion tank with air vent may be needed.4751

4752

4753

4754 Figure 6-1 Run-around cooling loop47554756

Heat pipes increase the effectiveness of air conditioning systems by4757helping to decrease the total cooling load of the air. The typical4758design consists of a refrigerant loop with two connected heat4759exchangers placed upstream (evaporator coil section) and downstream4760(condenser coil section) from the cooling coil. As the air passes4761through the first heat exchanger it vaporizes the refrigerant and is4762pre-cooled. This allows the coil to more effectively cool the air to a4763





128

point below the dew-point temperature and to extract more moisture. The4764air then passes through the second heat exchanger and is reheated,4765which liquefies the refrigerant, causing it to flow back to the first4766heat exchanger. The heat pipe system is hermetically sealed, uses a4767wicking action, and requires no pump. The increased dehumidification4768

capacity provided by heat pipes allows for a smaller cooling system.4769 However, the addition of heat pipes will increase the pressure drop,4770and fan power must be adjusted accordingly.4771

4772

47734774

Figure 6-2 Heat Pipe System47754776

A dual-path system uses two coils (either chilled water or DX) to4777separately cool the incoming outside air and return air. The hot and4778humid outdoor air is cooled by a primary coil to 42°F to 45°F for4779dehumidification. The secondary coil furnishes the sensible cooling of4780part of the relatively cool and dry return air. A portion of the return4781air may bypass the secondary coil and mix with the cooled return air4782stream. These two air streams are then mixed into supply air with4783appropriate temperature and humidity.4784

4785Dual-path systems offer competitive energy efficiency with run-around4786loop systems, and provide better control of the outside air ventilation4787rate. Dual-path systems decouple sensible cooling and latent cooling4788for easy control of the supply air temperature and humidity. Dual-path4789systems can be installed separately or integrated with additional4790HVAC/R equipment. The OA cooling coil should be sized for peak latent4791load, while the RA cooling coil should be sized for peak sensible load.4792The OA path controls the humidity of the supply air by modulating the4793chilled water flow, while the RA path controls the supply air4794temperature by adjusting the bypass damper position.4795

4796





129

47974798

Figure 6-3 Dual Path Cooling47994800

Desiccant Systems are applicable and the most prevalent when operations4801require large dehumidification and low space humidity levels that would4802be difficult to achieve with cooling-type dehumidification. They can be4803configured to condition part or all of the incoming air. The main4804factors, which influence this, include percentage of outside air,4805outside and space relative humidity levels, and the quantity of air4806flow for the conditioned spaces.4807

4808Desiccant materials possess the affinity for water vapor greater than4809that of air. They can either be solid or liquid as absorbents &4810adsorbents. Both solid and liquid desiccants are used in cooling4811systems, but solid desiccants are the most widely used for HVAC4812

operations.48134814

Absorbents are generally liquids or solids, which become liquid as they4815absorb moisture, i.e. they undergo a physical or a chemical change as4816they collect moisture. Typical absorbents include Lithium Chloride4817(LiCl) and Sodium Chloride (NaCl).4818

4819Adsorbents are mostly solids and do not under go any physical or4820chemical change when they come in contact with moisture. Water is4821adsorbed or held on the surface of the material and in the pores.4822Typical adsorbents include Silica Gel, Molecular Sieve and Activation4823Alumina, with Silica Gel being the most widely used.4824

4825The choice of desiccant material must be evaluated taking into account4826the amount of moisture to be removed, exposure to open product (some4827desiccants may not have regulatory (FDA and EU) approval when used in4828airstreams with direct contact with consumable items), and operating4829and maintenance costs.4830

4831The choice of a desiccant system affects the selection and sizing of4832the cooling coil, because the cooling coil only needs to handle the4833sensible load of the supply air, which allows for higher chilled water4834temperature and efficient operation. The sensible cooling load will be4835





130

higher because of the hot dry air leaving from the desiccant wheel (due4836to heat of adsorption). However, the addition of a desiccant wheel will4837increase the pressure drop, fan power and maintenance, and an4838additional motor is required to rotate the wheel. This extra energy4839usage must be counted accordingly. Desiccant systems should use low-4840

cost surplus heat, waste heat or solar heat for desiccant reactivation.4841 Dampers or VSD for fans should be installed to control airflow through4842the wheel. Side access for wheel and filter replacement and maintenance4843should be provided. Energy recovery and direct/indirect evaporative4844cooling are frequently incorporated in desiccant systems to reduce the4845cooling and heating energy.4846

4847Units should be capable of sustained operation without damage to the4848humidity transfer media. The dehumidifier should be a fully factory4849assembled package unit, complete with desiccant rotor, desiccant rotor4850drive assembly, reactivation heat source, filters, motors, fan(s),4851access panels, volume dampers, dust-tight electrical enclosure, and all4852component auxiliaries as recommended by the manufacturer for safe,4853unattended automatic operation. The unit should be fully automated and4854

equipped with differential pressure gauges and temperature4855transmitters, which measure and display the pressure drop across the4856desiccant wheel and the reactivation and pre-cooling air discharge4857temperatures.4858

4859The unit casing should be fabricated of strain-hardened aluminum for4860torsional rigidity and corrosion resistance. The casing should be4861welded, gasketed, and sealed to be air and vapor tight at design4862pressures and airflows. Air seals and internal partitions should4863separate the process and reactivation air streams at operating pressure4864differentials of up to 8‖ w.g. (1.993 kPa). The dehumidifier should4865have full-face seals on both the process air entering and the process4866air leaving sides of the wheel. These should seal the entire perimeter4867

of both air streams as they enter and leave the wheel. The seals4868 should have a minimum working life of 25,000 hours of normal operation.48694870

The desiccant wheel media shall be adsorbent, bacteriostatic, non-4871toxic, non-corrosive, and nonflammable, and fabricated entirely of4872inert, inorganic binders and glass fibers with the desiccant uniformly4873and permanently dispersed throughout the matrix structure to create a4874homogenous media. The desiccant wheel should have the capability of4875delivering nearly 100% of its drying capability for a minimum of 54876years.4877

4878Desiccant systems are more competitive when a low supply air dew-point4879temperature is required, latent load fraction is high, low- or no-cost4880reactivation heat from steam, hot water or waste heat is available, and4881

electricity costs are high when compared to gas costs.48824883

There are several circumstances that may favor desiccant systems rather4884than cooling-based dehumidification systems. These include:4885

4886

Economic benefit from low humidity4887

High moisture loads with low sensible load4888

Need for more fresh air4889

Exhaust air available for desiccant post cooling4890





131

Low thermal energy cost with high electrical demand4891

Economic benefit to dry duct work4892

Low-cost heat available for desiccant regeneration48934894

48954896

Figure 6-4 A package desiccant HVAC system (courtesy of ___________)48974898


Air filtration is one of the important HVAC components that affects the4901cleanliness of air delivered to the use point. The following is4902intended to be an overview of various filtration levels. It does not4903discuss in detail the construction of the filters themselves, since4904extensive detailed technical information is readily available from4905filter manufacturers.4906

4907Air filtration is performed at various locations within the HVAC system4908to attain the air cleanliness needed to protect the process (room4909airborne particles), occupants, and the air handling equipment and4910ductwork. Initial filtration/pre-filtration (Level I & II Filtration)4911is performed within the air-handling unit where outside and return air4912streams enter. The efficiency of the filters should be sufficient to4913keep the internal components (coils, fan) and the AHU itself relatively4914clean over an extended period of time, so they can perform as intended.4915Final filtration (Level III Filtration) occurs at the discharge section4916of the air handling unit after the air stream has been conditioned and4917is intended to protect the ductwork, terminal filtration (when4918

provided), personnel and the work space from airborne particles that4919may have been generated by the coils and supply fan. Terminal4920filtration, which is located at the room perimeter (ceilings and walls)4921is intended to provide both the cleanest air possible supplied into the4922room and when required, to capture air particulates generated by the4923processes served by the air handler and carried through the return4924ductwork.4925

4926The cleanliness of the filtered air will be influenced by several4927factors including the quantity and quality of the outside air4928





132

introduced into the system for ventilation/pressurization, the ratio of4929outside air to return air, and any introduction of particles within the4930air handler and ductwork.4931

4932All Pre- and Final-filtration grid systems should be of rigid4933

construction, usually aluminum or 304 SS. Consideration should be made4934 to make sure that all the air travels through the filters and does not4935bypass around the filters or the grid. Filters should be front-loaded4936to eliminate air bypass. Filter frames should have closed cell4937rubberized/neoprene-type gaskets only to prevent shedding. A separation4938of at least 2‖ (51 mm) should exist between the pre and post filters in4939the pre-filter section to reduce static pressure and increase the4940performance of the filters.4941

4942ASHRAE type filters should be designed at a maximum air velocity of 4504943fpm (2.3 m/s) when they are located in the air handler filter banks.4944Many designers choose to lower the design specification by 10 - 20% to4945provide future capacity.4946

4947

HEPA filter air velocities should be designed at a maximum of 100 fpm4948(0.51 m/s) when positioned as terminal supply air filters, and 450 fpm4949(2.3 m/s) when positioned as a terminal return, in an exhaust/extract4950air filter housing, or in the air handler.4951

4952Filters should be of standardized sizes so as to limit inventory and4953simplify ordering and replacements.4954

4955Filter classifications and ratings- (Editor‘s Note: We have yet to4956reconcile this table with additional detail to add to clarify the4957ASHRAE/MERV ratings, but I want to retain the existing details of the4958EN1822 and IEST ratings. I haven‘t yet been able to get all that on the4959same chart. attached below is this draft on 27June2008….Don Moore)4960

49614962





133

4963Table 6-1 ASHRAE vs. EU/EN filter ratings4964

4965

ASHRAEMERVSizeEfficiency,

Composite

% inSizeRange,

AverageParticlem

ASHRAE52.2

EU type(approx.)

EN 779(approx.)

(Note: These comparisons offilter rating systems are onlyapproximate as the test methodsare different. )

IEST Type (RP-CC001.4)

E1 -Range 10.30 -1.0

E2 -Range 21.0 -3.0

E3 -Range 33.0 -10.0

MERV

n/a n/a E3 < 20 1 EU 1 G 1

n/a n/a E3 < 20 2 EU 2 G 2

n/a n/a E3 < 20 3 EU 2 G 2

n/a n/a E3 < 20 4 EU 2 G 2

n/a n/a 20 ≤ E3

< 355 EU 3 G 3

n/a n/a 35 ≤ E3

< 50

6 EU 4 G 4

n/a n/a 50 ≤ E3

< 707 EU 4 G 4

n/a n/a 70 ≤ E3 8 EU 5 F 5

n/a E2 < 50 85 ≤ E3 9 EU 5 F 5

n/a 50 ≤ E2

< 6585 ≤ E3 10 EU 5 F 5

n/a 65 ≤ E2 85 ≤ E3 11 EU 6 F 6





134

< 80

n/a 80 ≤ E2 90 ≤ E3 12 EU 6 F 6

E1 < 75 90 ≤ E2 90 ≤ E3 13 EU 7 F 7

75 ≤ E1

< 8590 ≤ E2 90 ≤ E3 14 EU 8 F 8

85 ≤ E1

< 95

90 ≤ E2 90 ≤ E3 15 EU 9 F 9

95 ≤ E1 95 ≤ E2 95 ≤ E3 16 EU 9 F 9

EN 1822(approx.) *

EU 10 H10 HEPA 85% @MPPS

EU 11 H11 HEPA 95% @MPPS

EU 12 H12 HEPA 99.5% @MPPS

HEPA99.97% @0.3m**

A, B, E

EU 13 H13 HEPA 99.95% @MPPS99.99% @0.3 m**

C

EU 14 H14 HEPA 99.995%@MPPS99.999% @0.3 m**

D, K

U15 HEPA 99.9995% @MPPS99.999 @0.1-0.2 m**

F

U16 HEPA 99.99995% @MPPS99.9999 @0.1-0.2 m**

G

U17 ULPA 99.999995 @MPPS





135

* AllEN 1822testsat MPPS

** All tested with thermallygenerated DOP aerosol (0.3 mMMD; ie, CMD is near MPPS)F, G & K type filters aretested at either 0.1-0.2 or0.2-0.3 m. K type filters are99.995%.

Refer to IEST-RP-CC001.4 for ratingsperfilter type

4966

49674968





136

4969Filters are typically classified by either IEST Recommended Practice4970RP-CC001, ASHRAE Standard 52.2 or EN 779/1822 (European standards for,4971respectively, general ventilation filters/HEPA & ULPA filters). Since4972the different grading systems are based on different challenge4973

materials and sizes and use different measurement methods, comparisons4974 between the different grading systems are not exact. While the4975following table is an approximate comparison between filters classified4976by the different systems and is helpful in understanding relative4977performance of the various filter classes, the specific standard4978relevant to the requirements for your application must be quoted to4979avoid confusion.4980

49814982





137

Table 6-2 ASHRAE vs. IEST and CEN filter ratings49834984

Filter o tions and com arisonsASHRAE ASHRAE (M ERV)

IEST Type (RP-

CC001.4)

<65 <20 1 " EU 1 G 1

65+ <20 2 "

70+ <20 3 " EU 2 G 2>10 micron 75+ <20 4

80+ <20 5 " EU 3 G 3

85+ <20 6 " EU 4 G 4

90 25-30 7 "

3-10 micron 90+ 30-35 8 Pleated, throwaway, cartridge. Cotton

poly, synthetic1-3 micron 90+ 40-45 9 "

1-3 micron 95+ 50-55 10 " EU 5 F 5

1-3 micron 95+ 60-65 11 " EU 6 F 6

1-3 micron 95+ 70-75 12 "

0.3-1 micron 98+ 80-90 13 " EU 7 F 7

0.3-1 micron 98+ 90-95 14 Bag filters & rigid frame filters, fiberglass

or synthetic

EU 8 F 8

0.3-1 micron <100 95 15 EU 9 F 9

0.3-1 micron ~100 NA EN 182216 HEPA 95%+ @ 0.3 um** H10

HEPA 98% @ 0.3 um** EU 11 H 110 -0.3 micron ~100 NA 17 HEPA 99.97% @ 0.3um** A EU 12 H 12, H13

0 -0.3 micron ~100 NA 18 HEPA [email protected] um** C EU 14 H 14

0 -0.3 micron ~100 NA 19 HEPA [email protected] um** D U 150 -0.3 micron ~100 NA 20 ULPA 99.999 @0.12 um F U15

ULPA 99.9999 @ 0.12 um G U16

ULPA 99.999995 @ 0.12um U 17

** All tested with thermally generated

DOP aerosol (0.3 um MMD; ie, CMD is

near MPPS)

* All EN

1822 tests

at MPPS

(~0.12 um)

Disposable fiberglass, washable aluminum or foam rubber

Dust Spot

%

Arrestance

weight %

Particle Size ASHRAE

52.2

(Note: These comparisons of filter rating systems

are only approximate as the test methods are

different. )

EU type

(approx.)

EN 779

(approx.)

49854986





138

4987The following outlines Level I thru III and Terminal Filtration4988parameters.4989

49906.1.8.1 Level I Filtration (initial)4991

4992This is the lowest efficiency (and lowest cost) filtration level used4993for pre-filtration. Its intent to capture larger (3 microns and larger)4994particulates (insects, vegetation) typically introduced into an air4995handler from the outside air. It is also used as a pre-filtration to4996extend the life of Level II filtration. MERV 7 (EN G4) efficient4997filter is recommended.4998

49996.1.8.2 Level II Filtration (initial)5000

5001This more expensive filtration is typically located directly downstream5002of Level I filtration to capture smaller sized (0.3 microns and larger)5003particles to protect the coils and fan in air handling units, ductwork5004

and occupants. A MERV 14 (EN F7/8) efficient filter is recommended.500550066.1.8.3 Level III Filtration (Final)5007

5008This filtration is located at the discharge section of the air-handling5009unit downstream of Level I & II Filtration and fans/coils, and could5010use either ASHRAE or HEPA type filters.5011

5012ASHRAE Type - captures released mold and other growth which could be5013generated on the condensing (wet) cooling coils and then travel through5014the ductwork and to personnel. A MERV 14 (EN F7/8) efficient filter is5015recommended.5016

5017

HEPA Type - is used when the controlled space requires a clean room5018 classification (typically limited to Grade 8 if used without terminal5019filtration), when redundancy (with a terminal HEPA) is deemed5020necessary, or an as an additional layer of protection to extend the5021life of the downstream terminal HEPA filters. These filters should have5022a seamless sealing gasket (preferred) or a silicon gel seal on the5023downstream side of the filter to form a positive seal to eliminate air5024bypass around the filter perimeter. Permanent upstream and downstream5025media protective screens (media guards) should be included to prevent5026physical damage to the filter media. Individual HEPA filters should be5027able to be replaced without disruption of adjacent filters. H145028(99.995% @MPPS) efficient filter I recommended.5029

50306.1.8.4 Terminal Filtration5031

5032This level of filtration uses HEPA filters typically at the supply air5033terminal, and associated with cleanrooms classified as cleaner than ISO50348. A terminal filter may also be used on return/exhaust air when5035process room air is contaminated with environmentally sensitive5036particulates (hazardous airborne materials). These filters should have5037a silicone gel seal on the downstream side of the filter to form a5038positive seal to eliminate air bypass around the filter perimeter.5039Permanent upstream and downstream media protective screens (media5040





139

guards) should be included to prevent physical damage to the media.5041Individual HEPA filters in filter banks should be able to be replaced5042without disruption of adjacent filters. H14 (99.995% @MPPS) efficient5043filter is recommended.5044

5045

Terminal Air Filter Modules are constructed as either a single or5046multiple HEPA filter housing structure. They are positioned at the5047entry (ceiling) of the room and provide clean air into the space.5048

5049A terminal module is usually intended to house a single filter.5050The module should be complete with insulated housing (if ambient5051conditions surrounding the module would result in condensation),5052filter, test ports, grille, trim, and hardware. The body of the5053module is solidly constructed of cleanable rigid material (such as5054stainless steel or aluminum ) with the exposed trim being stainless5055steel. It should be designed for room side filter replacement.5056

5057A terminal plenum module or unidirectional air flow unit (UDF or5058UAF) is intended to house at least 2 filters to distribute5059unidirectional airflow over a specific area (typically an ISO 55060classification space). They are fabricated structural plenums that5061house the air inlet opening, filters, dampers, challenge dispersion5062manifold, test ports, optional sprinkler system, and an integral5063grid for support of gel seal filled framed filters, flush mounted5064lighting and perforated grill.5065

5066

Bag-in/Bag-out Housing is a side serviced filter housing designed to5067meet the air filtration needs of handling dangerous or toxic5068biological, radiological, cytotoxic or carcinogenic materials. It5069prevents hazardous airborne materials from escaping into the5070surrounding atmosphere. It is typically positioned at the perimeter5071(near floor) of the room where the material is generated.5072

5073The housing is constructed of stainless steel, should have zero5074leakage, and uses a control barrier to isolates personnel from5075hazardous materials when change-out of the HEPA filter is needed.5076The housing should have a silicon gel seal and be adequately5077reinforced to withstand a negative or positive pressure of 15" w.g.5078(3.75 kPa).5079

50806.1.8.5 Avoiding problems with HEPA filter performance:5081

5082There are some specific issues with HEPA filters that have been5083observed in recent years in pharmaceutical cleanrooms which require5084some attention to detail in order to avoid. Two of these are5085

5086 HEPA filter gel seal degradation, and5087

HEPA filter bleedthrough.50885089

HEPA filter gel seal degradation-50905091

Degradation of gel seals has been observed in cleanroom applications as5092silicone (siloxane) gel which appears to revert to a liquid state and5093begins dripping out of the gel track. This is sometimes accompanied by5094





141

5149HEPA filter bleedthrough5150

5151HEPA filter bleed-through is a phenomenon in which a filter fails a5152field integrity (leak) scan test using an aerosol challenge and a5153

photometer with an observed leakage across the entire face of the5154 filter media (not localized). This often occurs with filters that had5155previously passed a factory efficiency and scan test. It has been5156observed worldwide and is not limited to one filter or paper5157manufacturer. Further, it appears to be limited to HEPA (not ULPA)5158filters and to applications in which thermo-pneumatic (hot-block)5159aerosol generators were used for testing. Studies into the nature of5160this problem have resulted in determining that the following factors5161are crucial to understanding and avoiding the bleed-through problem:5162

5163- Particle size distribution of the challenge aerosol from the5164generator5165

5166- Impact of velocity on filter efficiency and bleed-through.5167

5168- Methods for specifying and testing HEPA filters5169

5170Particle size distribution of the challenge aerosol from the generator-5171

5172Aerosol particle sizes generated from Laskin-nozzle type generators are5173larger than those from hot-block generators (MMD size of 0.5 to 0.75174microns versus 0.2 to 0.3 microns). Although HEPA filters are often5175efficiency tested at 0.3 microns, the filters' actual Most Penetrating5176Particle Size (MPPS) is less than 0.3 microns, often in the 0.12 to51770.25 micron range. Thus, HEPA filters which may pass an integrity scan5178test in the factory with a Laskin nozzle generator (at 0.5 to 0.75179microns) may well fail a scan test in the field with a hot-block5180

generator due to bleed-through. It is important the filter supplier5181 know the field test challenge method to be used so the appropriate5182filter paper can be provided. Many issues can be avoided by simply5183stating the efficiency of the filter at the filter's MPPS.5184

5185Impact of velocity on filter efficiency and bleed-through-5186

5187Air velocity has a significant impact on filter performance. Increasing5188the velocity will decrease both the filter efficiency and the MPPS for5189that filter. Fr example, testing a specific filter for efficiency and5190integrity at 100 fpm face velocity and then field integrity testing at5191150 fpm will likely result in different results, Filter performance5192should be specified for the intended face velocity.5193

5194

Methods for specifying and testing HEPA filters-51955196

Bleed-through problems have been noted in filters that are integrity5197tested with hot-block generated aerosols up through commercially5198available filter classes Class C (Class J) and standard EN-1822 H145199filters.5200

5201In summary, bleed-through of HEPA filters occurs when they are5202subjected to field testing conditions which are more stringent than5203





142

their factory test conditions. This may occur when:52045205

- Actual field velocities are higher than factory tests52065207

- Actual field aerosol challenge particle sizes are smaller than5208

factory tests52095210- HEPA filter is not specified appropriately for actual field5211conditions5212

5213Recommended practices to avoid the bleed-through problem would be to:5214

5215- Specify the filter for the velocity it will see in the installation5216

5217- Factory test for efficiency and leakage at that velocity at the5218filter's MPPS5219

5220- If the filter will be field integrity tested with a hot-block5221generator, the filter should meet (as a minimum) the requirements for5222

an IEST Type K or an EN-1822 Type H14 with a local penetration limit of5223two times the global penetration (i.e. 0.01%) instead of the standard5224five times (0.025%) as called for in EN-1822.5225

52266.1.9 Ductwork5227

5228Ductwork construction and testing should be in accordance with Sheet5229Metal and Air Conditioning Contractors‘ National Association (SMACNA)5230and Heating and Ventilating Contractor‘s Association (HVCA) standards.5231Ductwork should be constructed of galvanized sheet metal. Stainless5232steel should be used when corrosion and continual cleaning occur. There5233shall be no interior insulation. Ductwork needs to be adequately5234supported so as to easily carry the weight of ductwork and insulation5235

along with in-line equipment and controls. If noise is a concern in-5236 line silencers should be installed. If vibration is an issue, flexible5237support and connections should be considered. When flexible ductwork is5238required to tie the branch into the terminal air device, its length5239should be keep to a minimum and should not exceed 10 feet (3 m).5240

5241Abrupt changes in the size and direction of the ductwork should be5242avoided otherwise increased noise, vibration, and pressure drop will5243result. Provide sufficiently sized duct access doors at appropriate5244locations to equipment (e.g. coils, humidifiers, control boxes,5245dampers). To preclude air leakage all ductwork shall be sealed with5246approved fire and smoke rated sealant in accordance with NFPA 255 or UL5247723 or equivalent. Ductwork leak testing percentages will vary from5248site-to-site, air system, and areas served. Recommendations include5249

the following performances for various applications. Ductwork should5250have 1% leakage with 0% leakage on positive pressure exhaust, 4‖ w.g5251(0.996 kPa) minimum static pressure class, and a maximum seal class A.5252

52536.1.10 Dampers and Louvers5254

5255Dampers are used to redirect, stop and vary the amount of air traveling5256within an HVAC System. Damper blade movement can be either parallel or5257opposed. Parallel blade dampers rotate in the same direction so that5258





144

zones, which can cause an increase in particulates levels, or excessive5314airflow, which can cause unwanted air turbulence.5315

5316Since these devices are located at the perimeter of the space (ceilings5317and walls), the choice of materials must be evaluated for compatibility5318

of the room‘s function. For clean room operation, stainless steel is5319 preferred to eliminate corrosion and rusting, which can occur to other5320materials and finishes that can occur during wash downs using5321aggressive cleaning agents.5322

5323Terminal filtration modules are used with room side HEPA filters to5324supply clean air operation and to retain contaminated air from leaving5325the room. Refer to the Filtration section for more detail.5326

53276.1.12 Ultraviolet (UV) Light5328

5329Ultraviolet light is an engineering control that may be used to5330supplement the existing filtration device(s) in a building‘s HVAC5331system. They can be mounted inside air ducts and placed adjacent to5332

cooling coils and condensate drip pans where biological growth can5333easily occur and lead to energy losses due to heat transfer reduction5334caused by fouling.5335

5336UV light has a wavelength of 100 – 400 nm, with the UVC (200 – 280 nm)5337wavelength considered the germicidal killing range, since it5338effectively inactivates bacteria and viruses. When microbes (bacteria,5339bacterial spores, viruses, yeast, mold and mold spores) are exposed to5340sufficient doses of UVC light, their DNA is destroyed, causing cell5341death or making replication (cell division) impossible. The optimal5342microorganism frequency killing occurs at the 253.7 nm wavelengths of5343UVC. To achieve the microbial inactivation the UV radiation exposure5344must be at least 400 J/m2. Many variables (air flow, humidity,5345

distance of microorganism to the UV light and time) take place in a5346 real world environment that will influence the dosage needed to cause5347microbial inactivation when exposed to the UV radiation. However, it is5348proven that UV light will kill any DNA-based organism given enough5349dosage and that UV light breaks down DNA over a cumulative basis.5350Therefore, as air circulates through the HVAC system containing a UV5351light, the UV light continuously cleanses the air. Extensive testing5352has been completed, which establishes the minimum UV exposure5353intensity/dosage needed to inactivate the microorganisms you are5354looking to control.5355

5356Ultraviolet germicidal irradiation (UVGI) systems are typically5357comprised of a series of lamps and ballasts. The recommended5358construction should include stainless steel lamp holding assembly and a5359

remote NEMA 12/13 control panel equipped with an electronic ballast,5360power supply, indicating lights, and a manual UV output control.5361Reflective polished aluminum paneling should be included to offer an5362economic means of boosting the average intensity field without5363additional power consumption. The system shall be safeguarded against5364accidental UV exposure. Air temperature is a consideration when5365specifying a cooling coil irradiation UV system, as the temperature5366inside the lamp is directly related to the UV output obtained.5367

5368





145

Since accumulation of dirt will decrease both the effect and life of5369the UV lamps, high efficiency upstream filtration is needed.5370

53716.1.13 Reliability and Maintenance Enhancements5372

5373

The reliability and maintenance of equipment is of utmost importance5374 within the pharmaceutical industry. Robust design and construction of5375HVAC equipment will increase their reliability and maintainability to5376perform properly from the start up of the operation and will continue5377beyond their normal anticipated life when they are properly maintained.5378Good maintenance procedures performed in a timely manner will over the5379life of the equipment, reduce costs and will have a positive impact on5380the outcome of the production process. Vivariums are extremely5381sensitive operations with long-term studies that require reliable and5382redundant systems, so as to achieve steady environmental conditions.5383

5384The following are some of the reliability and maintenance items that5385should be included:5386

5387

Redundant fans5388

Direct driven fans5389

Vibration monitoring of blower and motor bearings5390

Automated lubrication5391

Bearing life of ABMA L10 200,000 hours5392

Lower rotation speeds of motors and fan wheels5393

High efficiency filters53945395

6.1.14 Energy Reduction53965397

Designers are urged to find the simplest, effective solution for an5398HVAC system. Ideally the fan power should be reduced with load5399

(variable air flow). If this is not possible, then the systems should5400 be designed to reduce airflow during unoccupied periods for all or part5401of the system.5402

5403Designers are urged to fully investigate the required internal design5404criteria to avoid unnecessary energy use, to meet excessive high or low5405temperature or humidity requirements. This is also relevant for values5406of air change rates and pressure differentials. Similarly the external5407design conditions should also be investigated, to avoid over sizing of5408systems resulting in less than optimal performance and added project5409and operational costs.5410

5411Dedicated units for areas with specific requirements (i.e., longer5412hours of operation, lower or higher temperature and humidity, specific5413processing equipment, etc.) should be specified that would allow for5414the shut down or set back of central systems.5415

5416The control and use of outside air should be carefully evaluated to5417avoid additional air quality conditioning, resulting in a substantial5418energy penalty. The guidelines established in ASHRAE 62.1, Ventilation5419for Acceptable Indoor Air Quality, should be followed to ensure a5420healthy indoor environment.5421

5422





146

Designers are urged to increase air handling coil area, distribution5423duct and piping sizes as much as practical to reduce friction losses5424affecting fan and pump sizes. As previously indicated, reduced energy5425costs should be significantly greater than that, which would occur from5426the increased capital costs over the life of the building.5427

5428 Avoid over sizing equipment for future needs unless it is deemed a5429likely probability to occur, as this could mean that a fan or pump will5430be operating at an inefficient part load condition. If this is5431unavoidable, use VFD control of the fan or pump.5432

54336.1.14.1 Air Filtration Systems5434

5435Use filters with good filtration efficiency with a comparatively low5436average pressure drop. The low average pressure drop translates into5437reduced fan power and then into energy savings. Also good filtration5438results in cleaner coils and equipment to optimize heat transfer and5439reduced frequency of equipment wash down.5440

54416.1.14.2 Drive Belts5442

5443Up to 7% efficiency can be lost with traditional v-belt drives due to5444belt slippage from worn and improper tensioning. This can be reduced5445dramatically by using direct driven fans when possible. Cogged or5446synchronous belt drives should be considered which could improve the5447drive efficiency by 2% In addition to saving energy, synchronous belts5448run cooler and tend to last longer then v-belts5449

54506.1.14.3 Economizer5451

5452The outside air economizer saves on cooling energy when outside ambient5453

conditions (sensible & latent heat) are favorable (typically in the5454 shoulder months of the year) rather than using warmer return air to5455reduce the load on the cooling section. When the outside ambient5456temperature conditions are lower than the inside space temperature,5457increased draw of the cooler and less humid outside air will reduce5458cooling energy that would otherwise come from mechanical cooling. An5459outside air economizer is a collection of air dampers and controls that5460allows the outside air to be drawn into the air handler. Typically,5461this is setup as an all or no situation, meaning that when comparing5462the inside to outside conditions, the condition that is most favorable5463to cause the lower energy usage would apply.5464

5465Since the supply, return, outside and exhaust air quantities can change5466during the function of the economizer cycle; this can lead to changes5467

in the facility room pressurization. If another air handler is serving5468an adjacent area, it is possible for room pressure excursions to occur5469due to the changing air quantities as a result of varying positions of5470dampers in the HVAC system. The use of the economizer in areas that5471require pressurization control must be carefully evaluated to adopt.5472This operation is typically limited to non-classified operations.5473Additionally, the use of additional outside air can shorten filter life5474due to filtering of less cleaner outside air. The control and use of5475outside air should be carefully evaluated to avoid additional air5476quality conditioning, resulting in a substantial energy penalty. The5477





149

properly aligned and air handler cabinet is not leaking in excess of5587the specified value.5588

5589Condensate drain pans shall be filled with water to confirm that proper5590drainage occurs while the unit is operating.5591

5592 6.2.3 Fans55935594

Proper fan installation and startup are critical for producing5595sufficient airflow in a safe manner since a tremendous amount of5596kinetic energy is produced and without this, catastrophic results can5597result.5598

5599Laser alignment must be performed on the fan and motor shafts shall be5600completed when the fan has been installed at the site because shipping5601and installation can alter the factory alignment.5602

5603Drive belts shall be adjusted to their proper tension prior to start5604up. Following a short period of operation, the belts will need to be5605

re-tensioned.56065607

Bearings must be checked for proper lubrication. If automatic5608lubrication units have been installed, they should be activated only at5609the time of startup.5610

5611Fan wheel should be turned over by hand to see that it runs free and5612does not strike fan housing. Check location of wheel in relation to5613fan inlets and be sure fan housing is not distorted. Electrically jog5614the fan to check for proper rotation.5615

5616Vibration testing shall be performed following installation and start5617up to promote longevity and reliable operation of the equipment.5618

5619 6.2.4 Exhaust / Extraction Systems56205621

These systems are intended to remove unwanted air from within the5622building. When installing exhaust / extraction systems, the following5623items should be followed:5624

5625It is recommended to have the exhaust fans placed on the exterior of5626the building so as to produce a negative pressure on all ductwork5627within the building to eliminate the possibly of contaminated air not5628being totally exhausted from the building. Ductwork shall have the5629installation quality of achieving zero leakage.5630

5631The mounting of stacks should be carefully evaluated. Their location5632

can cause undue air contaminants to reenter the building through air5633intakes along with producing noise that could be an annoyance to5634surrounding businesses and residential communities.5635

5636Ductwork or stacks should be independently supported since the5637additional weight may stress the fan housing and result in vibration,5638which can transmit to building structure. Guide wires (supports) will5639need to be evaluated for inclusion onto stacks to ensure adequate5640support.5641





150

5642When condensation may occur, the duct system should be watertight and5643provisions should be made for proper sloping and drainage.5644

5645Install fire dampers and explosion vents in accordance with the5646

National Fire Protection Association Codes and other applicable codes5647 and standards.56485649

Locate fans and filtration equipment such that maintenance access is5650serviceable.5651

56526.2.5 Heating & Cooling Coils5653

5654Coils should be inspected for concealed or visible damage prior to5655acceptance of delivery. The coil fins should be combed after5656installation to foster good air distribution and heat exchange.5657

5658Piping to the coil must be independently supported to avoid deforming5659the coil nozzle, headers or tubes, and stressing the brazed joints. It5660

is recommended that piping have shut off valves and union fittings to5661facilitate coil removal, should repairs be necessary.5662

5663Insulation with protective jackets should be included on all piping to5664eliminate burning, condensation and reduce heat loss/gain.5665

5666For better control of the fluid flow through the coil, the control5667valve should be put on the return piping.5668

5669Supply and return line shut-off valves should be provided to facilitate5670service and maintenance.5671

5672Coils must be vented of air on initial start-up and should include a5673

manual or an automatic air vent.56745675For cooling coils, the term ―moisture carry-over‖ describes the action5676of condensate being blown off the coil‘s surface with cooled air.5677Following startup when dehumidification occurs, observe if moisture5678carry over does not occur. If it does occur, check the coil face5679velocity to make sure it doesn‘t exceed the design parameters. If5680carryover occurs, then the following resolutions are available:5681

5682Reduce the coil face velocity (may not be possible if rooms need more5683airflow)5684

5685Install a perforated screening so as to more evenly distribute the air5686across the coil thus producing a more even face velocity5687

5688Install a mist eliminator after the coil5689


5692The steam distribution manifold should be placed where the air5693temperature is capable of absorbing steam being discharged without5694causing condensation at or after the unit. This will normally be5695downstream of the heating coil and upstream of the cooling coil to act5696





151

as a mist eliminator when located within an AHU.56975698

When located within ductwork, approximately 1foot (30cm) upstream and 65699ft (1.8 M) downstream of the humidifier, the ductwork should be5700constructed of stainless steel to eliminate the possibility of rusting5701

if the ductwork becomes wet. Access panels should be located up and5702 downstream of the humidifier for servicing.57035704

A drain pan and condensate piping should be included to catch and carry5705away water, which typically can occur from humidification spitting5706during startup. Do not place the steam distribution manifold where5707visible discharge mist will impinge directly on a metal surface.5708

5709Do not place the steam distribution manifold too near to the face of5710filters, otherwise the possibility of saturating the filters will5711greatly shorten their life.5712

5713Humidifier steam supply should be taken off the top of the steam main5714rather than off the bottom to ensure, the driest steam is provided to5715

the distribution manifold.57165717

To assure that absorption of the steam will take place into the air5718stream, air duct design needs to permit uniform airflow over the cross5719section of the steam distribution manifold.5720

5721A high limit humidity sensor shall be installed within a relatively5722short distance of the humidifier after absorption of the steam has5723occurred to shut the humidifier control valve if the air stream5724relative humidity typically exceeds 85% to preclude the accumulation of5725moisture onto surfaces.5726

5727A device to prove airflow is recommended to prevent steam valve from5728

opening unless air is moving in duct.572957306.2.7 Dehumidifiers5731

5732This section focuses only on desiccant dehumidification systems since5733they are the most common means of removing moisture for the5734pharmaceutical industry.5735

5736Desiccant units shall have provisions for clear and unobstructed5737space/clearance to allow removal and replacement of the desiccant5738wheels, fans filters, etc.5739

5740The air from the reactive portion of the wheel should be ducted (sloped5741to the outside) to the exterior of the building due to its high5742

moisture and heat content. Do not locate the intake and outlet for the5743process and reactivation air streams too close together to avoid short5744cycling, which will lesson the overall dehumidification capacity.5745

574657475748

Wheels using lithium chloride should be kept hot and rotating, even5749when dehumidification is not required, to avoid damage to the desiccant5750due to over-absorption.5751





152


5754Filters should be installed prior to construction to keep the AHU,5755components and ductwork clean from contaminants when the system is5756

energized to preliminarily conditioned spaces. Once construction of the5757 building and spaces has been completed, these filters shall be removed5758and replaced with clean filters.5759

5760Filters should be installed with appropriate clamping mechanisms to5761assure that all air travels through the filters and does not bypass5762around them or their supporting grid.5763

5764Each filter section should have a Magnehelic® (local display only) or5765Photohelic® (local and BMS contacts) gauge, or equivalent, mounted with57663-way valves for ease of calibration and without the need for shutdown.5767The gauge piping allows for differential pressure readings for each or5768combination of filters.5769

5770

HEPA/ULPA filters are sensitive components and should be handled with5771special care and consideration needs to be taken in the selection of5772the carrier used for transport of filter shipment. The filters shall be5773stored in such a manner as to prevent damage or intrusion of foreign5774matter. The recommended controlled storage environmental for the5775filters should be within 40–100 ºF (4–38 ºC) and 25–75% RH. Storage5776should be indoors, under roof and be thoroughly protected from5777moisture.5778

5779Carefully check each pallet of filters before accepting shipment from5780the carrier. Pallets of filters that have been damaged or broken down5781should not be accepted without a thorough inspection and appropriate5782comments noted on the shipping documentation.5783

5784 Competent personnel and proven techniques and procedures should be5785established for the installation of the filters. Prior to installation5786of HEPA/ULPA filters, inspect duct and filter housing for cleanliness5787and any obstructions that might impair filter operation. Unpack the5788filter and thoroughly inspect for damage. Exercise extreme caution to5789avoid damaging the filter media. If the media is damaged and has any5790visible holes, do not install filter.5791

57926.2.9 Ductwork5793

5794Ductwork is typically located in difficult to access locations.5795Sufficient access to service components such as volume control devices5796and reheat coils should be provided. Protection of the ductwork during5797

construction and access to and around it must be adequately provided;5798otherwise, damage to the ductwork will result in loss of airflow5799transmission and increased air pressure and velocity. In addition,5800insulated ductwork that has been compromised will result in5801condensation and rusting and loss or gain in heat.5802

5803The use of flexible ducting should be limited to minimum lengths,5804properly supported and securely fastened at each end. Avoid sharp5805bends and turns, which will reduce the cross-sectional area of the5806





153

flexible duct, that can result in reduced air volume delivery.58075808

Ductwork shall be thoroughly wiped and cleaned of oil, dirt, and metal5809shavings after fabrication at the sheet metal shop and prior to field5810installation. Use a solution of 70% IPA and lint free wipes to remove5811

any oils or grease, which has accumulated during the fabrication and5812 installation of the ductwork.58135814

After ductwork is cleaned, openings should be covered with plastic5815sheeting and tape to preserve their state.5816

5817It is recommended to avoid use of self drilling sheet metal (Tek)5818screws as they generate small metal chips as a result of drilling into5819the ductwork, depositing these contaminants inside the cleaned5820ductwork. Self piercing (zip) screws are preferred when there is5821concern for loose contamination fragments inside the ductwork.5822

5823Other trades who later install pressure test ports, smoke detectors,5824temperature sensors and duct traverse testing ports can contaminate5825

interior of ductwork with metal chips as a result of their field5826penetrations into duct. Ductwork penetrations of the duct wall should5827be performed in a manner to maintain ductwork interior cleanliness.5828Where metal shavings or debris are produced, clean interior of duct,5829providing access as required and sealing the access opening. Failure5830to follow these practices can result in sharp metal fragments being5831blown into the delicate HEPA filter media causing nuisance filter5832integrity failures.5833

5834Prior to insulating and pressure testing new ductwork, the Owner or5835Owner‘s representative should perform a field inspection to ensure5836installation is in compliance with design specifications. A simple5837check list can be developed.5838

5839 It is recommended to apply tight air leakage tolerances and perform5840pressure testing of ductwork systems serving a cGMP system to avoid:5841

5842Increase use of outside air to overcome supply losses5843

5844Increase in energy costs to operate system5845

5846Operating equipment at their maximum capacity resulting in no reserve5847capacity5848

5849Unwanted air into surrounding spaces from positive pressurized ductwork5850and into negatively pressurized ductwork5851

5852It is recommended to use the ―Total Percentage Method‖ - A percentage5853of total air delivery of duct section under test at a specific static5854pressure for performing duct leakage. The following are recommended5855leakage percentage for various operations:5856

5857Increase use of outside air to overcome supply losses5858

5859Zero percent leakage for positive pressure exhaust duct on hazardous5860operations5861





154

5862No more than One (1) percent for cGMP areas5863

5864No more than Two (2) percent for laboratory systems5865

5866

No more than Three (3) percent for support and administrative areas58675868Classified and Rooms requiring pressuredifferential

Test 100% Supply and Return

Laboratories Test 100% Supply and Return/Exhaust

BSC and Hoods Test 100%

Support and Admin areas Test 50% Supply & return

5869Table 6-3 Ductwork Testing Requirements5870

5871The duct leakage testing must be performed with traceable calibrated5872

test instruments and documented with signed approvals from the owner or5873owner‘s representative. 5874

5875Leakage from non-duct components (fire dampers, smoke dampers, air flow5876monitors, duct heating coils, manual volume damper quadrants and access5877doors) is an integral part of the overall system leakage, and these5878components shall be involved in the duct leakage tests.5879

5880It is recommended the Owner or Owner‘s representative be present to5881witness and sign off on duct cleanliness and duct leakage testing.5882

5883Once construction is completed, the system should be blown down for a5884period of 1 hour to purge the ductwork of any loose and light debris5885

that may have accumulated. Blow down will not flush the system of5886 metal fragments as a result of poor ductwork cleanliness quality5887control.5888

58896.2.10 Dampers & Louvers5890

5891Actuators must be accessible for service and maintenance. Inspect5892drive linkages so they are secure and will operate without binding over5893their full range of travel.5894

5895To reduce bypass around damper perimeter, assemblies should be sealed5896to the framing of the opening.5897

58986.2.11 Diffusers and Registers5899

5900Diffusers and registers should be installed in such a way to prevent5901poor distribution of air, minimize drafts, and short-circuiting of5902supply air.5903

59046.2.12 Ultraviolet (UV) Lights5905

5906UV lighting wavelength degrades many plastics (including synthetic air5907filters media and frames, plastic coated wires, gaskets, grommets, and5908





155

duct insulation). Avoid direct UV exposure where possible and keep the5909material at least 3 feet (~1 m) from the light source.5910

5911UV power supply circuit should be interrupted upon the loss of airflow5912over the lighting elements.5913

5914 The UV power supply should be de-energized when the lamp access door is5915opened or when the door of the air handler is opened. This is to5916protect personnel from UV exposure. UV installations should minimize5917escape of the light through direct or indirect transmission. In5918addition, warning signs should be placed in the area to advise5919personnel.5920

5921When installing lamp fixtures, consideration should be given to the5922heat dissipation of the ballast and the additional heat load produced5923in the conditioned air stream. If the ballast is installed externally5924to the duct then heating is usually not an issue.5925

5926Do not touch emitter glass without gloves. Oil from fingerprints will5927

permanently etch glass of emitter and weaken structure. If necessary5928clean emitter using isopropyl alcohol and lint free wipe.5929

59306.2.13 Building5931

5932Construction activities typically occur at a tightly coordinated and5933accelerated pace to meet schedule commitments. The Owner needs to5934review the site on a regular schedule to verify design intent,5935construction quality and integration of systems occur as planned.5936Ongoing site visits should be conducted during all phases of the5937building construction and the installation of equipment and services.5938One of the main reasons for auditing is to identify deficiencies that5939if not corrected will result in unacceptable conditions, which can5940

affect the performance of the HVAC system. The following identify just5941 some of the construction issues.59425943

Air migration through the building caused by poorly and unsealed5944penetrations and finishes can lead to unacceptable control of space5945differential pressures, fumes and dirt which will compromise room5946classification. The following items should be checked, noted and5947resolved during walk throughs.5948

5949

piping5950

ductwork5951

electrical conduit and receptacles5952

doors5953

diffusers and registers5954 architectural wall and ceiling joints5955

lighting fixtures59565957

The gap between the finished floor and the bottom of door should be5958uniform at approximately 3/16 inch (4 mm) when closed. Door floor5959sweeps are not recommended for swinging doors due to their accumulation5960of dirt, scratching of floor, and maintenance.5961

5962





156

Hard-ceiling construction is preferred for pressure-controlled spaces.5963In addition, air migration above the ceiling should be minimized5964between controlled and uncontrolled space.5965

5966Where possible, service distribution and pipe work should be located5967

outside the cleanroom, in an adjacent utility space to promote better5968 airflow patterns and produce fewer pockets for dirt to accumulate. In5969addition, this action will increase maintainability of the equipment.5970

5971During construction, cleaning procedures should be enforced to minimize5972the accumulation of construction debris and dirt. If this is not5973controlled, extensive time and repetitive cleanup steps will be5974required, which will affect the commissioning and qualification of the5975building and HVAC systems.5976

5977Procedures should be in place for all personnel to wear appropriate5978gowning (i.e. – booties, smocks) so as to keep out dirt from areas5979which have been designated and substantially complete and cleaned, in5980addition to providing tacky floor mats and shoes cleaners. At this time5981

equipment, walls, floors should have been wiped down, floors swept and5982vacuumed.5983

5984

6.3 EQUIPMENT OPERATION AND MAINTENANCE59855986


The maintenance of systems is vital to achieving proper operation,5989appearance, longevity and safety. Inadequate maintenance will5990eventually lead to unexpected and extended shutdowns. It will also lead5991to underperformance for maintaining the various environmental5992(temperature, humidity, air quality, air flow and pressurization)5993aspects required for good cGMP facilities.5994

5995Predictive Maintenance describes a range of technologies used to detect5996developing machinery degradations at an early stage, before they can5997become a problem. This allows maintenance personal to order parts,5998schedule manpower, and plan multiple repairs during a scheduled5999shutdown. The goal of PdM is to proactively correct machinery6000degradation before significant deterioration occurs to a critical6001component or equipment item.6002

6003Traditional Preventative Maintenance (PM) practices cannot identify6004mechanical equipment failures that are preceded by detectable changes6005in operating temperature, vibration signatures, and bearing wear6006indictors. Equipment is susceptible to unplanned catastrophic failure6007

that interrupts production operations, causes risk to product, and6008 results in reactive repairs that are more expensive than planned6009repairs.6010

6011Physical appearance of equipment and the surroundings can convey a6012perception of the quality of the maintenance performed upon the6013equipment. Spent materials, extra parts and trash could give a6014regulatory inspector the impression of sloppy maintenance practices.6015Maintaining clean heating, ventilation and air-conditioning (HVAC)6016systems is an important part of sustaining acceptable indoor air6017





157

quality (IAQ). Contaminants in HVAC systems can take many forms. Common6018contaminants include dust particles (viable and non-viable), active6019bacterial or fungal growth, debris from HVAC components (rust, belt6020shedding, grease), insulation, mold spores, and other items. For these6021reasons good housekeeping practices need to be followed.6022

6023 Periodic walk downs of mechanical areas to evaluate state of6024housekeeping to ensure compliance is maintained at an acceptable level6025of quality.6026

60276.3.2 Air Handling Units (AHU)6028

6029The unit, which is really a box filled with components to condition and6030transfer air should be periodically inspected to identify air leakage,6031rusting, condensate drainage, dirt accumulation and for the proper6032operation of doors, dampers & actuators, lighting and switches.6033

6034Periodic cleaning of the unit‘s interior will be needed especially for6035units serving classified spaces and in particular aseptic operation. A6036

cleanliness inspection should consider all components within the unit6037such as filters, heating and cooling coils, condensate pans, condensate6038drain lines, humidification systems, acoustic insulation, fans, fan6039compartments, dampers, door gaskets and general unit integrity. Though6040prefilters are installed, they are not intended to remove all air6041particulates. Dirt accumulation can lead to microbial growth. Typically6042the units are washed down with a solution that will kill6043microorganisms, while at the same time eliminating grease and oil,6044which may have been dispersed from bearing and other lubricated joints.6045

6046It is recommended to remove visible rust and repaint surfaces to return6047their appearance to new.6048

6049

Pools of standing water in the condensate drain pans can lead to6050 microbial growth and rusting. Check for proper drainage during hot and6051humid periods when condensate generation is high.6052

6053Lighting fixtures where the fluorescent tubes or ballasts have failed6054will result in poor lighting levels, which can negatively impact6055maintenance on the AHU components and for personnel safety.6056

6057Electrical switches and receptacles can lead to electrical hazards,6058poor or no operation of the components they are serving and increased6059maintenance.6060

6061Door maintenance is very important to the air tightness of the unit.6062From the constant use of the doors, the gaskets, frame, hinges and6063

latching handles tend to loosen and get worn out. This can lead to6064lower air delivery by the unit, sweating and infiltration of dirt.6065

6066All the other components, which are needed to fulfill the role of the6067air-handling unit, are discussed below.6068

60696.3.3 Fans6070

6071They generate airflow, whether for supply, return, or exhaust.6072





158

Maintaining the desired airflow is critical to providing the6073conditioned supply air through the ductwork system and into the space.6074They also exhaust/extract air from spaces, fume hoods and bio-safety6075cabinets to expel unwanted air outside of the building. Additionally,6076return fans provide semi-conditioned air back to air handling units6077

6078 Fans have several components, which if not properly maintained will6079lead to diminished airflow capacity and eventual failure. They include6080the fan housing, wheel, bearings, belts, guards and motor.6081

6082The wheel, which generates the airflow, needs to be checked6083periodically for accumulation of dirt, mechanical fatigue and6084imbalance. These will eventually result in increased vibration and6085noise and possible catastrophic failure and a life threatening6086condition. If present and not removed, the desired airflow volume may6087not be achieved. In addition, dirt accumulation on the fan impeller6088will become unbalanced, causing vibration and overloading of the shaft6089and motor bearings resulting in catastrophic failure (i.e. broken6090blades and housings).6091

6092Bearing failure is common due to over or under lubrication and the use6093of lubricants, which are not intended for the environment they6094encounter. Personnel need to have proper training and services provided6095from bearing manufacturers and lubrication vendors are recommended.6096Vibration and temperature monitoring can assist in trending analysis to6097identify impending bearing failure.6098

6099Belt drives need proper care especially as it relates to maintenance.6100There are extensive procedures for removing, installing and starting-up6101of equipment with belt drives. One item in particular, belt tension, is6102one of the most common root causes for premature failure. The following6103provides several important steps to follow:6104

6105 Check belt tension, using a tension gauge or Sonic Tension Meter.6106Adjust the belt drive‘s center distance until the correct tension is6107measured.6108

6109Rotate the belt drive by hand for a few revolutions. Re-check the belt6110tension and adjust as necessary.6111

6112Start the drive, looking and listening for any unusual noise or6113vibration. If the motor or bearings are hot, the belt tension may be6114too high.6115

6116V-belt Run-In Procedure - A run-in procedure is recommended for all V-6117belt drives so that the optimum belt life can be achieved. A run-in6118

consists of starting the drive and letting it run under full load for6119up to 24 hours. After the belts have run-in, stop the belt drive and6120check the belt tension. Running the belts under full load for an6121extended period of time will seat the V-belts into the sheave grooves.6122V-belt tension will drop after the initial run-in and seating process.6123This is normal. Adjust the belt tension as necessary. Since tension in6124V-belts will drop after the initial run-in and seating process, failure6125to check and re-tension the belt will result in low belt tension, belt6126slippage and reduction of airflow. This slippage will result in6127





159

premature belt failure.61286129

Motors should be capable of operating for more than 10 years without6130major problems. Properly maintained. Since motors are expensive to6131purchase and their operating costs are high (e.g. 25hp motor x 87606132

hrs/yr. x $0.075/kwh = $12,250/yr.) maintenance is vital to keep these6133 costs at a minimum and the following few steps should be followed:61346135

External cleaning should be done periodically to remove any contaminant6136that would affect heat dissipation from the motor. Wipe, brush, vacuum6137or blow accumulated dirt from the frame and air passages of the motor.6138Dirty motors run hot when thick dirt insulates the frame and clogged6139passages reduce cooling airflow. Heat reduces insulation life and6140eventually causes motor failure.6141

6142Check for signs of corrosion. Serious corrosion may indicate internal6143deterioration and/or a need for external repainting.6144

6145Lubricate the bearings only when scheduled or if they are noisy or6146

running hot. Do NOT over-lubricate. Excessive grease and oil creates6147dirt and can damage bearings.6148

6149Feel the motor frame and bearings for excessive heat or vibration.6150Listen for abnormal noise. All indicate a possible system failure.6151Promptly identify and eliminate the source of the heat, noise or6152vibration.6153

6154Belt and motor drive guards should be securely fastened so as not to6155cause vibration and noise and possible damage to equipment and person.6156

61576.3.4 Fume Exhaust / Extraction Systems6158

6159

Exhaust systems serving pharmaceutical operations need to have a high6160 level of reliability due to the impact on the process should they fail.6161Maintenance must be performed more diligently to ensure equipment up6162time.6163

6164Inspect the system to ensure it is free of debris and dirt. If present6165and not removed, the desired airflow volume may not be achieved.6166

6167Control dampers shall operate freely6168

6169Check the flexible duct connections to make sure they are not leaking6170air due to deterioration or wear.6171

6172Fans are the primary component to the operation of fume exhaust /6173

extraction systems, refer to the Fan section for details.61746175

6.3.5 Heating & Cooling Coils61766177

Coils, whether for heating, cooling or dehumidifying all have one thing6178in common as it relates to their maintenance. They must be clean both6179internally and externally and the fins for heat transfer must be intact6180and undamaged. Since cooling coils typically have a dual function of6181reducing both the sensible (cooling) and latent (de-humidify) heat of6182





160

the air, they are more sensitive to reduction in heat transfer than6183that of heating coils. Cooling coils have a greater affinity for the6184accumulation of dirt since they are typically wet. Typically coils,6185especially cooling coils are externally cleaned once a year since this6186is the side of the coil, which encounters the most accumulation of6187

dirt. Internal cleaning is typically reserved when differential6188 pressures (inlet vs. outlet) increase beyond what the manufacturer6189would recommend as acceptable for the particular operation. By6190maintaining good water treatment, the tubes of the coils should remain6191clean and the heat transfer capability should remain high for a number6192of years. When face and bypass heat coils are used, the mechanisms6193which control the divergence of air should be inspected annually to6194make sure they properly operate smoothly over their entire range of6195motion.6196

6197All coils use control valves to modulate the amount of heat transfer6198fluid, which ultimately controls the discharge air temperature. These6199valves wear out over time due to the constant modulation to control the6200supply quantity of fluid to provide the required discharge6201

temperatures. These valves should be included in a regularly scheduled6202maintenance program.6203


6206Humidifiers are necessary to increase air moisture contact in low6207humidity climates. Steam humidification using plant steam is the most6208common means of achieving proper levels to spaces. Though there are6209approximately 9 components that make up the humidifier system the6210following are those items that really need to be inspected and6211maintained.6212

6213Inspect the strainer screen at least twice per year. If fouled, steam6214

capacity for humidification will be reduced.62156216Inspect the control valve annually to ensure that: (1) the valve closes6217off steam tight, (2) the stem packing is not leaking steam, and (3) the6218diaphragm in the actuator is not leaking air.6219

6220Inspect the sealing and O-rings, if they leak steam, otherwise they6221will disperse steam into the surrounding area with the possibility of6222personnel injury.6223

6224Inspect the dispersion nozzles for proper dispersion of steam into the6225airstream. If steam is not dispersing properly, capacity can be6226reduced.6227

6228

Inspect the silencer at least annually for cleanliness.62296230

6.3.7 Dehumidifiers62316232

Dehumidification of the air supplied to spaces requiring lower humidity6233levels is achieved by either chilled water or by desiccants. The6234maintenance of chilled water coils is discussed in the ―Heating and6235Cooling Coils‖ section. The maintenance of desiccant units includes a6236number of components and includes filters, wheel drive assembly, the6237





161

wheel support bearing, fan, fan belts and controls. Maintenance of fans6238and belts are discussed in the ―Fans‖ section. 6239

6240Like any other mechanical equipment, desiccant components must be6241maintained according to a recommended schedule.6242

6243 Since a desiccant system has incoming air on the supply side and a6244second air stream for reactivation, both sets of inlet filters need6245replacement. If filters are not changed, airflow will be reduced.6246Clogged filters on the supply or process air will cause thermal6247discomfort due to reduced airflows. Clogged filters on the reactivation6248side cause two problems. First, there is not enough air to remove the6249moisture from the desiccant wheel, so system performance is reduced.6250Then as filters load still further, there is not enough air to absorb6251the heat from the burners, so the unit shuts down because the6252temperature in reactivation is too high as the air enters the wheel.6253About 90% of reported problems related to desiccant systems can be6254traced to clogged filters.6255

6256

The drive belt around the desiccant wheel must be tight enough to turn6257the wheel, but not so tight as to put an excessive load on the drive6258motor shaft bearings. Desiccant units are equipped with automatic6259tensioning devices, but belt tension should be checked at least twice a6260year, or when the filters are changed, to be certain the belt is6261neither too slack nor too tight.6262

6263In addition to bearings on the fan section of the unit the desiccant6264wheel also has bearings. They should be inspected at the same time that6265the fan bearings occur and should be greased based on the operation and6266the manufacturers recommendation. Typically greasing is only needed6267once a year due to their slow rotational speed.6268

6269

Controls must have regular recalibration to make sure the system6270 maintains a steady state of operation.62716272


As filters load with particles, resistance to airflow increases (i.e.6275differential pressure (DP)) to a point where if they are not replaced6276with new ones, airflow could be reduced and the filters might collapse.6277On the other hand, as filters load with material, their efficiency6278increases somewhat. Ideally, filters should be replaced based on a6279predetermined differential pressure and the cost of the filters. This6280optimizes on the total cost of ownership (TCO) for the replacement and6281energy costs of the filters. Higher energy costs typically require6282lower differential pressure set points for change outs. Filters should6283

be properly installed, so as not to cause air bypassing which can lead6284to downstream dirt in the air stream, negating the main purpose of the6285filters. Filter manufacturers can provide the optimal scenario for6286achieve lowest total cost of ownership based on the operating6287conditions at the site.6288

62896.3.8.1 ASHRAE type filters should be replaced within two years of6290service, even if pressure differential criteria limits have not yet6291been reached. This eliminates potential microbial growth and filter6292





162

degradation. Filters should be inspected at a minimum of two times per6293year for integrity.6294

6295ASHRAE type filters (non-HEPA) are not to be repaired nor require leak6296testing.6297

6298 6.3.8.2 HEPA filters are critical to various pharmaceutical operations.6299They are intended to almost totally remove all particles from air6300passing through them. They may be field tested for integrity against6301leaks. Leaks greater than or equal to 0.01% of the upstream aerosol6302concentration require that the filters be replaced or patched. Testing6303is normally performed once a year for most GMP operations, but aseptic6304manufacturing requires testing every six months for some areas (See the6305appropriate Baseline Guide)..6306

6307Detection of HEPA filter leaks occurs in several ways. The filter6308media may be easily damaged by rough handling or touching with6309instruments or hands. Leaks may also occur along the boundary where the6310media is attached to the frame by a sealant. The adhesive material can6311

sometime crack or separate its bonding from the frame. This usually6312occurs due to poor quality control manufacturing processes and using6313adhesives that are incompatible with materials in the air stream and6314application. Another other major leak source is at silicon gel seals6315where the filter housing meets the knife-edge of the filter grid6316system. Over time, the gel can deteriorate due to exposure to aerosols6317used in the testing of filters. (See 6.1.8).6318

6319When leaks are detected, the filter may be replaced or repaired. IEST6320has specific procedures that should be followed . Of utmost concern is6321the size and area of the patch over the leak. HEPA filters should be6322replaced when the patchable HEPA filter area is more than an 3% of the6323net face area of the filter as furnished from the factory, or when a6324

single patch has a lesser linear dimension exceeding 1.5 inches6325 (3.8 cm) (IEST-RP-CC034.2). Patching material should be RTV silicon6326sealant caulk, which meets the FDA 21CFR 177.2600 and USDA for food6327grade applications. (It is not recommended to attempt to use caulk to6328repair a leak between silicone gel and the filter frame knife-edge.)6329

6330Care must be provided when storing, handling installing and testing6331HEPA filters. They should be stored in an environmental controlled6332location within 40–100 ºF (4–38 ºC) and 25–75% relative humidity.6333Filters shall be stored in such a manner as to prevent damage or6334intrusion of foreign matter.6335

6336In handling operations, care should be taken to follow manufacturer‘s6337recommendations and prevent damage from:6338

6339 Dropping of cartons6340

Vibration6341

Excessive movement6342

Rough handling6343

Improper storage or stack height63446345

Prior to installation it is recommended that information on individual6346filters and filter housings be recorded (model number, serial number,6347





163

performance, factory test data, etc.). This can resolve future6348questions as to filter efficiency, replacement filters or issues6349arising from a product recall.6350

63516.3.9 Ductwork6352

6353 Periodic inspections of HVAC ductwork can identify potential problems6354(dirt, debris, leaks and corrosion) which can be corrected before6355unexpected shut downs and extensive repairs are needed. Ductwork can6356loss its seal over time and can be a source of excessive leakage or6357entrainment that can affect room pressurization. Ductwork that has6358been crushed will lead to insufficient airflow, increased noise and6359poor control. Ductwork that has lost its insulation should be quickly6360replaced so as to not cause sweating, with the potential of6361condensation getting into work areas, rusting and mold growth.6362

63636.3.10 Dampers & Louvers6364

6365These need to be checked for dirt accumulation and free movement6366

without binding of the linkages over the full range of operation (full6367open to close). Linkages should not be loose. Dampers for low leakage6368applications, which typically have gaskets, will need to be replaced if6369they have become hardened or do not provide a good seal. If these units6370are allowed to accumulate dirt or don‘t operate properly will result in6371insufficient air distribution.6372

63736.3.11 Diffusers And Registers6374

6375These need to be checked for dirt accumulation and free movement6376without binding of the linkages over the full range of operation (full6377open to close). Linkages should not be loose. If these units are6378allowed to accumulate dirt or don‘t operate properly will result in6379

insufficient air distribution.638063816.3.12 Ultraviolet (UV) Lights6382

6383The only significant maintenance required for ultra-violet lighting6384used as a germicide is the replacement of the UV lamp or bulb. The6385bulbs typically last about 8,000 hours. Their life will be shortened6386when dirt has accumulated on them. Dirt acts as a barrier for the lamp6387to emit sufficient intensity to effectively destroy microbes. UV6388lighting using ballasts will have a long life of typically more than 56389years.6390

63916.3.13 Building6392

6393

As buildings age, the architectural (ceiling, walls, doors, ceiling6394fixtures), mechanical and electrical (piping, ductwork, conduit,6395receptacles) components, which penetrate the conditioned perimeter,6396tend to lose their airtight seals. This can lead to nuisance problems6397of identifying the sources. This can result in not achieving room6398pressurization and undesirable air flows into or out of spaces. When6399this occurs, room pressurization cascades are affected and can drift,6400requiring adjustments to maintain compliance.6401

6402





164

6.3.14 Air Balancing64036404

Testing, Adjusting and Balancing (TAB) for HVAC systems should be6405performed within a specific frequency to ensure sufficient current6406documentation is available for regulatory agencies to demonstrate6407

system compliance as well as verify general operation of other less6408 critical systems are operating as energy efficient as possible. When6409changes to the space or HVAC equipment occurs, TAB shall occur at that6410time. At a minimum recalibration of instruments, air changes per hour6411(ACPH) and differential pressure (DP) shall occur at least annually for6412GMP spaces and full rebalancing should be evaluated to be performed at6413least every 5 years and 7 years for non-GMP spaces. A total rebalancing6414can uncover unsuspected increases in energy consumption and potential6415equipment failures.6416

6417

Room Type Frequency

Aseptic Operation (Grades 5-7) - Re-calibration of

Instruments, ACPH & differential pressure; testHEPA filters 6 month

GMP Classified Operation (Grade 8) - Re-calibrationof Instruments, ACPH & differential pressure, testHEPA filters

1 year

All GMP Spaces, Pilot Plants, Animal Facilities,Laboratory Space, R&D Space - full rebalancing

5 years

Non-GMP Spaces including electrical & mechanicalrooms, auditoriums, utility spaces, central plantventilation, kitchens and offices - fullrebalancing

7 years

6418

Table 6-4 Suggested maintenance frequency64196420





165

7 VERIFICATION AND TESTING6421

6422


A new alternative methodology will be proposed for preparing regulated6425 facilities for their intended use in the ISPE Baseline Guide for6426Installation and Verification, in draft form as of this writing This6427guide covers a parallel scope to the Commissioning & Qualification6428Baseline guide and introduces new terms, concepts, and process6429improvements. It is designed to increase the value of critical6430activities and remove wasteful activities that do not contribute to6431ensuring product quality or patient safety. This Baseline Guide follows6432the principles of ASTM Standard E2500-2007.6433

6434Although the premise of this HVAC guide is to provide the "how" of6435implementing those HVAC requirements and concepts found in the baseline6436guides, this chapter is groundbreaking in that this proposed6437methodology has not yet been put into practice by the industry at6438

large. The challenge in providing guidance on how to implement the6439recommendations of the proposed Baseline guide is that there are6440limited practical applications or experience to draw from. But since6441the timing of this guide should coincide with the release of the new6442Baseline guide, the authoring team felt it would benefit the industry6443to try to define the "how", using HVAC systems to as examples to6444deliver clear and consistent guidance. As with any first attempt,6445there is always room for improvement, but the interpretations provided6446in this guide may be used as a template for other systems and6447equipment.6448

6449Key concepts and terminology proposed for the Installation and6450Verification Guide are used extensively in this guide. The Baseline6451

Guide will provide more depth regarding these concepts and terms.64526453

7.2 PHILOSOPHY64546455

The commissioning and qualification philosophy used to date6456incorporates Good Engineering Practices (GEP) and Impact Assessment.6457Systems and components that were designated as Direct Impact were6458subject to qualification, in addition to commissioning. The difficulty6459encountered in this process is that some companies found it difficult6460to leverage commissioning activities and documentation into6461qualification, so they re-commissioned a system to gather qualification6462documents. Some of the compliance-related activities included general6463engineering-focused activities that added little or no compliance value6464(such as qualifying fan speeds or prefilters).6465

6466The new methodology is based on:6467

6468

Thorough understanding of the product and process and the role of6469science6470

Use of risk assessments (instead of impact assessments) to determine6471the scope and extent of required verification in the overall Risk6472Management Process, which is related to patient safety6473

Notion of Design Space6474





166

Focusing on practices that lead to achieving fitness for purpose.64756476

7.3 PRINCIPLES64776478

Key principles that provide the basis for developing engineering6479

requirements are:64806481

The assessment and designation of criticality should be primarily6482based on impact on the safety and efficacy of the drug product to6483the patient6484

6485

Critical Quality Attributes (CQAs) should drive the focus of the6486risk assessment along with Critical Process Parameters (CPPs)6487

6488

Risk assessment shall be performed in the "design space", the6489intersection of CQAs and CPPs, and is subject to regulatory6490assessment and approval.6491

6492

The Installation and Verification process shall have value added6493activities and shall remove those activities that are wasteful and6494non-value adding.6495

6496

Verification practices performed solely for regulatory compliance6497should be avoided. 26498

64997.3.1 Good Engineering Practice6500

6501Good Engineering Practice (GEP) is the practice under which all6502engineering activities and documentation are created. It applies to all6503facilities, not just pharmaceutical facilities. GEP encompasses the6504following:6505

6506 Design and installation that takes full account of cGMP, safety,6507

health, environmental, ergonomic, operational, maintenance,6508recognized industry guidance, and statutory requirements.6509

6510

Professional and competent project management, engineering design,6511procurement, construction, installation and commissioning6512demonstrating functionality per design specifications.6513

6514

Appropriate documentation, including design concepts, design6515schematic drawings, as-installed drawings, test records, maintenance6516and operations manuals, statutory inspection certificates, etc.6517

6518

Well planned commissioning activities and documentation following sound6519Engineering Principles and Good Engineering Practices make a6520significant contribution in preparing for and achieving first time6521success to meet installation and verification requirements.6522

6523

2 If a practice adds to the assurance that the equipment or system will work asintended then that practice should be performed whether or not the system ispart of GMP manufacturing operations. If it does not, then that practiceshould not be performed unless specifically required for compliance.





167

7.3.2 GMP65246525

Sustainability and Commissioning/Verification65266527

TEXT NEEDED6528

65297.4 REGULATORY EXPECTATIONS6530

6531TEXT NEEDED6532

6533US – This approach is recognized by the FDA as ONE method of verifying6534fitness of the HVAC system for production. Activities in this approach6535follow the principles in ASTM E2500.6536

6537EU – unknown at this time whether EU regulators will accept less6538voluminous Qualification packages.6539

6540Other - ?6541

6542 Regulatory expectations are covered by the appropriate ISPE Facility6543Baseline Guide. As these expectations sometimes change, this guide6544defers to the Baseline Guides.6545

6546

7.5 KEY CONCEPTS OF VERIFICATION65476548

The verification process for HVAC Systems is a subset of the6549verification process for the manufacturing system. These key concepts6550have been driven by the FDA Initiative Pharmaceutical cGMP‘s for the655121s Century – A Risk Based Approach, and by ICH Q9 Quality Risk6552Management. The overall direction is a shift toward the safety of the6553patient using a risk and science-based approach to the specification,6554design and verification of the manufacturing system. This Section6555addresses the application of the key concepts described in ASTM E2500-655607 to the installation and verification of HVAC Systems.6557

6558The goal of this approach is to improve patient safety while6559controlling costs and reducing non-value adding effort.6560

6561It should be noted that these Key Concepts focus on patient safety and6562product quality (GMP). The verification of the specification and6563design as it impact worker safety, health, environmental and other non-6564GMP concerns should also be considered.6565

65667.5.1 Risk-based and Science-based Approach6567

6568

The level of risk to product quality should be based on scientific6569knowledge that leads to protection of the patient. The level of effort6570expended in the quality risk management process should reflect the6571level of risk. Product and process information related to product6572quality and patient safety should be the basis of the science- and6573risk-based decision to insure that manufacturing systems are designed6574and verified to be fit for their intended use.6575

6576Considerations include Critical Quality Attributes (CQAs), Critical6577Process Parameters (CPPs), process control strategy and prior6578





168

production experience.65796580

For HVAC Systems, the risks of system failures and interruptions need6581to be addressed during the specification and design part of the6582process.6583

6584 7.5.2 Critical Aspects of Manufacturing Systems65856586

Critical Aspects of Manufacturing Systems are typically functions,6587features, abilities, and performance characteristics necessary for the6588manufacturing process and systems to ensure consistent product quality6589and patient safety.‖ HVAC systems may affect the manufacturing system6590and the critical aspects. Verification activities should focus on the6591critical aspects of the Manufacturing system and HVAC subsystem‘s6592effect.6593

65947.5.3 Quality by Design6595

6596Quality by design concepts should be applied to the manufacturing6597

system through the life cycle. Quality should not be a verification6598only phase activity.6599

66007.5.4 Good Engineering Practice6601

6602Good Engineering Practice a set of established engineering methods and6603standards that are applied throughout the life cycle to deliver6604appropriate and effective solutions. For HVAC systems GMP6605requirements, code requirements including sustainability requirements6606and energy efficiency, safety, health environmental, ergonomic6607operational, and maintenance must be address. Preceding chapters6608discuss how to implement Good Engineering Practice for HVAC systems.6609

6610

7.5.5 Subject Matter Experts66116612Subject Matter Experts have specific expertise and responsibility in a6613particular area or field . For HVAC Systems this could include the6614HVAC Engineer, quality unit, automation, or operations.6615

66167.5.6 Use of Vendor Documentation6617

6618Vendor documentation may be used in the verification process if it is6619produced by a vendor with an acceptable quality system. A risk and6620science based approach can be used to determine if the vendor‘s6621practices are aligned with the risks possible with the selected6622equipment or system.6623

6624

7.5.7 Continuous Improvement66256626

Continuous improvement can happen as information is gained from6627operations. Improvements can be based on periodic reviews and6628evaluation, operational data and root-cause analysis of failures. For6629HVAC systems energy optimization is typically reviewed. Such6630improvement should be encouraged, although current Change Management6631programs often discourage change for any reason.6632

6633





170

maintain or improve our overall product quality?66896690

The interdisciplinary expert team forms the foundation for developing a6691risk management plan. Team members decide on methodologies to6692determine acceptable levels of risk and appropriate tools to evaluate6693

risk (e.g. FMEA) after identifying the User Requirements. User6694 Requirements should identify the Critical Process Parameters (CPP),6695Critical Quality Attributes (CQA) and other critical aspects related to6696product quality and patient safety.6697

6698Once the critical aspects (CPP, CQA, etc.) have been identified by the6699interdisciplinary team and documented, the quality unit then approves6700this document as the basis for the Verification Plan that will be6701developed. Furthermore, engineers need to know what type of tests the6702quality unit will expect to be performed after the verification process6703is complete in order to prepare systems to pass these tests.6704

6705Verification, similar to ―commissioning and qualification (for direct6706impact systems)‖, is one process that covers the activities, testing,6707

and documentation required to evaluate systems, equipment, and6708environments and confirm they are fit for their intended use. It is6709based on good engineering practices coupled with the risk management6710plan developed in the risk assessment phase. The types of checks and6711tests to be performed are developed by the Subject Matter Expert (SME).6712For example, the HVAC SME would design a verification plan that would6713verify the acceptance criteria that meets the critical aspects (CQA,6714CPP …) within the framework of the risk management plan.6715

6716For an overview of the verification process, refer to figure 7.1:6717

67187.6.4 Commissioning & Qualification process – SEE APPENDIX6719

6720

7.6.5 Acceptance and Release67216722The acceptance and release phase confirms that the manufacturing system6723and support HVAC system are fit for their intended use. This is the6724last check before initial operation.6725

6726

7.7 SUPPORTING PROCESSES67276728

The activities described here can be part of the Specification, Design6729and Verification (SDV) Process. They occur throughout the SDV process.6730

67317.7.1 Quality Risk Management (QRM)6732

6733

Quality Risk Management is the high level concept that is applied to6734 all systems including HVAC. QRM will define the risk assessment6735process for the manufacturer. The Risk Assessment for the HVAC system6736should be addressed in the overall Risk Assessment activity..6737

67387.7.2 Design Review6739

6740Design reviews are planned systematic reviews of specifications,6741design, design development and continuous improvement changes performed6742throughout the life cycle of the manufacturing system. For HVAC6743





171

systems in the design phase, reviews typically occur at the basis of6744design (BOD), schematic design, design development and construction6745document phases. HVAC equipment specifications are often not available6746until the construction document phase and their review is critical to6747system quality.6748

6749 7.7.3 Change Management67506751

Change Management should be implemented on changes that affect critical6752aspects of the manufacturing system, both before and after acceptance.6753After acceptance, changes that affect GMP critical parameters need to6754be approved by the Quality unit prior to implementation. With6755continuous improvement as a goal of the FDA initiative, it is expected6756that systems that have been verified and accepted for intended use will6757be modified to achieve improved patient safety or reduce operating6758costs as opportunities arise during the manufacturing system‘s life6759cycle.6760

67616762





172

8 DOCUMENTATION REQUIREMENTS6763

6764


Oncean HVAC system has been qualified, one must ask ―what is the

6767 proper disposition of the HVAC system documentation?‖ Many will go to6768maintenance and operations, but others may be required for CMC filings6769and will become ―Critical Master Documents‖ - engineering documents6770maintained as GMP records.6771

6772This section discusses documents typically required for these purposes6773and gives some warnings regarding improper classification and use of6774documents.6775

6776

8.2 ENGINEERING DOCUMENT LIFECYCLE67776778

8.2.1 Planning Lifecycle67796780

It is wise to define the lifecycle of all documents to be created on a6781project early in conceptual design, but no later than during BOD6782(Basis of Design) development. This advance planning eliminates6783ambiguity and prevents loss of data.6784

6785The planning document should define which documents are required only6786for construction, which will be part of an Engineering Turnover Package6787(ETOP) for maintenance / operations, which will be leveraged into6788verifications (or qualifications) and which will be maintained as6789record documents for Maintenance and GMP use.6790

6791Defining the contents of the ETOP early in a project also allows the6792easy capture of design calculations and risk assessments as they are6793

generated. The best practice for capture of design and construction6794information into an ETOP is to utilize Document Management /6795Collaboration software which will apply the appropriate lifecycle to6796documents as they are generated and approved.6797

6798A good method for the planning and updating of document lifecycle is6799the ―Traceability Matrix‖ (a documentation of the plan and progress of6800documentation and concepts through the design, construction,6801verification and process validation sequence). The traceability matrix6802not only shows this progress, it also serves to maintain the chain of6803design intent, linking final documents all the way back to conceptual6804design documents.6805

68068.2.2 Typical Steps in the Document Lifecycle6807

6808HVAC documents typically start their lifecycle as conceptual Airflow6809and Instrument Diagrams (AF&ID), room/zoning layouts, room condition6810tables (T, RH, area class, DP, etc), load calculations and design6811basis/assumption tables. These documents progress through the6812Engineering Process to Plan Drawings, Detail Drawings, Specifications,6813Calculations and Tables.6814

6815Plans, details and diagrams should be updated throughout (or after) the6816





174

Area Classification Diagrams6869

Pressure or Airflow Direction ―Maps‖ 6870

AHU Zoning Diagrams6871

Control Diagrams68726873

8.5 GMP HVAC DOCUMENTS68746875

It is important to align with the risk assessment performed in the6876design process to determine the HVAC documents which will be leveraged6877into Verification or that will need to become Critical Master6878Documents. Since the risk assessment will vary by project the following6879lists of typical documents must be reviewed against project/product6880needs.6881

68828.5.1 Verification Documents6883

6884Documents that are typically leveraged into Verification are:6885

6886

As-built Airflow and Instrument Diagrams6887 Room Environmental Conditions Tables6888




Control Diagrams and/or FRS for Direct Impact Systems6892

Critical Instrument Specifications6893

Commissioning Documents:68946895

Filter Integrity Testing6896

Air Balance6897

Face Velocity Testing6898

Pressure Relationships6899

Critical Alarm Testing6900

Test Protocols and Supporting Information69016902

Documents that are typically produced during Verification (or Process6903Validation) are:6904

6905

Airflow Visualization for Grade 5 or Local Protection areas6906

Total Airborne Particulate Testing6907

Viable Airborne Particulate Testing6908

Test Protocols and Supporting Information69096910

8.5.2 Critical Master Documents69116912

Critical Master Documents are HVAC documentation that is used to6913provide information for the CMC section of a drug filing and is subject6914to regulatory review6915

6916Documents that are typically maintained as critical master documents6917are:6918

6919

As-built Airflow and Instrument Diagram6920





175

Risk Assessments and Traceability Matrix6921

Room Environmental Conditions Tables6922




Verification and Validation Documents69266927

Filter Integrity Testing6928

Air Balance6929

Face Velocity Testing6930

Pressure Relationships6931

Critical Alarm Testing6932

Airflow Visualization for Grade 5 or Local Protection areas6933

Total Airborne Particulate Testing6934

Viable Airborne Particulate Testing69356936693769386939





176

APPENDICES6940

6941

9 PSYCHROMETRICS6942

6943Note to reviewer: This chapter is a mess. The graphics must be redrawn6944(if you have better ones, we‘ll take them). Do the best you can but6945please don‘t comment on the graphics… we know they suck. 6946

6947

9.1 DRY-BULB TEMPERATURE69486949

Symbol: tDB69506951

Units: °F (°C)69526953

Example: 70°F DB (21C)69546955

Dry bulb temperature can be read with an ordinary thermometer, RTD or6956temperature sensor that has no water on its surface. The process of6957changing just the dry bulb temperature is referred to as ―sensible6958heating‖ or ―sensible cooling‖.6959

6960The dry bulb temperature of the air is represented as vertical lines,6961increasing in temperature from left to right on the psychrometric6962chart.6963

6964

696569666967

9.2 WET-BULB TEMPERATURE69686969

Symbol: tWB6970





177

6971Units: °F (°C)6972

6973Example: 65°F WB (18 C)6974

6975

Wet bulb temperature is indicated by an ordinary thermometer having its6976 sensing section (bulb) covered with a sleeve wetted with (distilled)6977water in rapidly moving air, measuring the reading as the water6978evaporates. Heat is removed from the thermometer bulb, required for6979evaporation, cooling the thermometer in proportion to the amount of6980evaporation. This in cooling lowers the temperature of the ―wet bulb‖6981thermometer. How much the wetted sleeve cools depends on the rate at6982which the water on the wick evaporates, which depends on the dry bulb6983temperature of the air and the moisture content of the air. If the air6984is very dry, the water on the wet bulb wick will evaporate very quickly6985and the temperature will drop sharply, however, if the air already6986contains a lot of moisture, very little moisture will be able to6987evaporate from the wick and the temperature will change very little.6988When the air is saturated with moisture (100% relative humidity), no6989

water will evaporate to cool the thermometer bulb and the wet bulb6990temperature will be the same as the dry bulb temperature. The lowest6991temperature attained by passing air over the wetted sleeve results from6992evaporating the moisture in the wetted sleeve.6993

6994The wet bulb temperature of air is represented as downward slanting6995lines from top-left to bottom-right on the psychrometric chart.6996

6997

90

85º

80º

75º

70º

65º

60º

55º

50º

45º35º 40º

Wet Bulb Temperature (Degrees F) 6998

6999

9.3 DEW-POINT TEMPERATURE70007001

Symbol: tDP70027003





178

Units: °F (°C)70047005

Example: 62°F DP (16ºC)70067007

The temperature at which water vapor leaves the air and collects on7008

objects in the form of fine water droplets, or bands together and7009 becomes fog, is called the saturation or dew point (DP) temperature.7010The higher the amount of moisture in the air, the higher the dew point7011temperature.7012

7013Dew point temperature is represented by horizontal lines extending7014across the chart, intersecting with the saturation line, the left7015boundary of the psychrometric chart.7016

7017

85

80

75

7070187019

Relative humidity (Percent of saturation)70207021

Symbol: RH70227023

Units: %70247025

Example: 77% RH @ 72° F DB70267027

Relative humidity is the ratio of the amount of water vapor in the air7028to the maximum amount of water vapor the air can hold at the same7029temperature and pressure, expressed as a percentage. The air‘s ability7030to hold moisture increases as the temperature of the air increases. It7031is important to define the dry bulb temperature of the air when using7032relative humidity since it is relative to a specific dry bulb7033temperature.7034

7035





181

7107

15.0

14.5

14.0

13.5

12.5 13.0

710871092.4.3.8 Humidity ratio or Specific Humidity7110

7111Symbol: W7112

7113Units: lbs of water vapor / lbs of dry air or grains/lb7114(kgWV/kgDA)7115

7116Example: 85 grains/lb7117

7118Humidity ratio is a measurement of the actual amount of water in the7119air and is independent of the air‘s temperature, in either lbs / lbs or7120in grains/lb dry air. The weight of the moisture in the air is7121

compared to the weight of the air.71227123Humidity ratio can be read by tracing a horizontal line from an7124established condition on the chart, to the charts right edge, where the7125scale indicates the weight of the moisture in grains per pound. If the7126scale is expressed in grains of moisture per pound (gr/lb) of air and7127there is a need to convert the scale to pounds of moisture per pound of7128air, divide the number of grains by 7,000. If the scale is expressed7129in pounds of moisture per pound of air and there is a need to convert7130the scale to grains of moisture per pound of air, multiply the number7131of pounds by 7,000.7132

7133





182

Humidity Ratio (Grains of water per lb of air)

290270250230

210190170150130110907050

71347135

7136 Vapor Pressure71377138

Symbol: pWV71397140

Units: ―hg (Pa) 71417142

Example: 0.5691‖hg 71437144

Water vapor pressure is the pressure exerted by the water vapor7145molecules.7146

7147The vapor pressure scale is found on the right side of the chart,7148increasing linearly from the bottom of chart to the top of chart.7149

7150

1.8

1.6

1.4

1.2

1.0

.8

.6

.4

.1

Water Vapor Pressure

71517152





183

7153

9.7 EIGHT FUNDAMENTAL VECTORS71547155

There are a total of eight (8) fundamental vectors or processes that7156occur on a psychrometric chart.7157

71581. Humidification71592. Heating and humidification71603. Sensible heating71614. Chemical dehumidification71625. Dehumidification71636. Cooling and dehumidification71647. Sensible cooling71658. Evaporative Cooling7166

7167

Humidification

Evaporative Cooling Heating & Humidification

Sensible CoolingSensible heating

Cooling & DehumidificationChemical Dehumidification

Dehumidification

716871697170





184

Four Basic Processes

Humidification

C (latent heating)

OnlySensible Heating

Only

B A

Sensible Dehumidification

Cooling Only (latent cooling)

D Only

7171717271737174

System Mapping71757176

OA

Cooling & MA

Dehumidification Mixing

Process RM Process

Room Effect Process

Fan Heat Process

A Four-process Air-conditioning Cycle

7177717871797180





185

10 COMMISSIONING AND QIUALIFICATION PROCESS7181

7182

10.1 COMMISSIONING AND QUALIFICATION71837184

Traditional approach to verifying that the HVAC system is fit for7185 purpose has been to compare field generated documentation (IQ, OQ, and7186PQ) to ―front end‖ requirements for the system (URS, FS, detail7187design). The relationship is defined as below, using a variation of the7188―V-Diagram‖ from GaMP: 7189

719071917192

Figure 10-1 Traditional HVAC Qualification719371947195719671977198

7199720072017202720372047205720672077208720972107211

72127213721472157216721772187219

Although the method shown above is covered in more detail in the ISPE7220Baseline Guide for Commissioning and Qualification. It has considerably7221reduced the amount of paperwork for GMP compliance, individuals and7222their companies continue to generate large volumes of qualification7223documentation that add no value. The method described earlier (see7224Chapter 8) requires even less paperwork to be generated for compliance,7225

focusing on risk assessment to identify the HVAC areas and items7226needing attention.7227

72287229

User Requirement

(What HVAC Mustdo… Acceptance

Functional Design

("How it works" as

Detail Design( How to make or

install)

OperationalQualification

(Do the systems

PerformanceQualification

(Can we make

PQ Test Plan

OQ Test Plan

IQ Test Plan

Implementation

(incl. FAT)

Impact Assessment

DesignDevelopment

Installation Qualification

From ISPE BaselineGuide

for Commissioning &

Enhanced Design Review occurs all through design

PQ Docs

SOPs

Training

IQ Docs

Verify installation

Install critical components and

Direct Impact Systems

OQ Docs

HEPA Tests

Alarm tests





186

72307231

10.2 IMPACT RELATIONSHIPS72327233

The following chart addresses the inter-relationships between critical7234

parameters for Aseptic Process (a classified space) and the HVAC7235components. Items in shaded boxes are more critical (i.e. Direct7236impact) as determined by the C&Q Baseline Guide‘s methods. 7237

723872397240724172427243





187

7244724572467247

10.3 RISK ASSESSMENT MATRIX7248

7249From GAMP® 5, 2008.7250

72517252725372547255725672577258725972607261

7262





188

72637264

11 MISCELLANEOUS HVAC INFORMATION7265

7266

11.1 GLOSSARY OF TERMS

72677268

11.2 EQUATIONS USED IN HVAC AND THEIR DERIVATION72697270

This document resides on the ISPE HVAC COP website.72717272


Many engineering students are exposed to the basic laws of fluids and7275thermodynamics in college. Then sometime after graduation and taking a7276job in the pharma industry, the laws of physics are repealed and often7277contradicted by ‖GMP drivers‖ and business practices. The engineer7278often does not ask if physical requirements dictated by management or7279the Quality Group make sense from an engineering standpoint. The7280successful pharmaceutical HVAC engineer applies the laws of physics to7281satisfy GMP as well as business drivers and does not turn his back on7282those basic laws.7283

7284These laws go back hundreds of years, based on Newton‘s theories. The7285experienced HVAC designer will remember these laws; neophytes should7286read and use this article with extreme caution. In fact, if possible,7287hire a professional engineer to do the calculations. But there‘s7288nothing wrong with folks who are not HVAC geeks trying to understand7289the basics. The laws governing HVAC are not rocket science. I took7290rocket science in college, so I should know.7291

7292Note that this article is written in English (i.e. AMERICAN) units. I7293

leave it to the calculator experts to convert to metric.72947295

11.2.2 Room Differential Pressure72967297

Air, like any gas, expands as it is heated and contracts (become more7298dense) as it is cooled. For every 5 degrees F that air is heated, it7299expands (becomes less dense) about 1 percent.7300

7301The ideal gas law states that the pressure P and the volume V of a gas7302are proportional to its temperature. If you heat a gas (in HVAC, the7303gas is air) it wants to expand to a larger volume, but if it‘s7304constrained in a fixed volume container, its pressure will increase and7305it becomes more dense.7306

7307PV = NRT7308

7309Where R is the universal gas constant and N the mass of the gas in7310question. Since R is constant, and N is usually always fixed for a7311particular situation, the equation boils down to7312

7313PV is proportional to T7314

7315Bernoulli‘s Equation for fluid dynamics also plays a role in HVAC.7316





190

little.73727373

This method ignores ―duct‖ entry loss and the pressure recovery that7374offsets it, such that the resultant calculated air velocity will be7375more than is required to create a pressure differential between two7376

rooms. Since rooms are rarely as tight or well constructed as we would7377 like, this method gives us a little extra calculated airflow quantity7378to play with during commissioning. In this case, we can replace VP7379with DP (the differential pressure between the two spaces, inches w.g.)7380

7381V = 4005 x square root of DP7382

7383For example, the VP of air flowing at 890 feet per minute is 0.057384inches w.g. or 12.5 Pa. The above equation implies that the air flowing7385through the cracks between two rooms at 0.05‖ DP has a velocity of 8907386feet per minute. In reality, because of geometry where the air enters7387the crack, and the length of the path of travel, velocity may be much7388less (and therefore the air volume leaking through is less) and we7389would still measure a DP of 0.05‖. However, where the area of the crack7390

is large, as for an open door, and the differential pressure required7391is significant (as for a classified room needing 0.05‖ or more)7392outrageous quantities of airflow will be needed. Using the equation7393

7394Q = V x A7395

7396where Q is cubic volume per time, usually cubic feet/minute (CFM), V is7397velocity in feet/minute, and A is area in square feet, an open 207398square foot door with air flowing through it at 890 ft/min (to maintain73990.05‖ DP) requires an airflow of 17,800 CFM !!! This may be more than7400the capacity of the entire HVAC system and is a strong justification7401for airlocks, as stated in the del Valle article. A closed7402―pharmaceutical grade‖ door typically has a crack area of 0.3 square7403

feet or less, needing less than 300 CFM to maintain 0.05‖ w.g. across7404 the closed door. It is not wise for an HVAC designer to assume a7405certain leakage rate without knowing about the type of door to be used7406- is it a tight sterile room door with seals (leaking as little as 507407CFM at 10 Pascals) or a warehouse sliding door leaking over 1000 CFM7408closed? Details as small as door seals can have a big impact on air7409balance.7410

741111.2.3 FANS:7412

7413A useful equation for fan power is:7414

7415

HP is proportional to x P x Q74167417

Where HP is horsepower, is fan efficiency at the operating point, P7418is fan pressure and Q is fan airflow in cubic volume per time (such as7419CFM). From the pressure equations above, if airflow in an existing duct7420system must be doubled, we must QUADRUPLE the fan‘s delivery pressure7421as well as double its airflow, thus needing EIGHT times the horsepower.7422It is better to slightly oversize an HVAC system‘s fan and ductwork and7423not need all the horsepower installed than to run out of horsepower7424when the system can‘t supply enough air to meet required room7425particulate levels. When this happens, additional filtered airflow must7426





191

be provided from the HVAC system at considerable cost and construction7427time, or by adding local filtered air supply units serving only the7428areas needing more air.7429

743011.2.3 Room Air Balance:7431

7432 The most basic AIR BALANCE equation is:74337434

Air Volume in = Air volume out, or Q in = Q out or74357436

SUPPLY + INFILTRATION = RETURN + EXHAUST + EXFILTRATION74377438

For a fixed volume (i.e. not a balloon), any air that enters the room7439has to leave the room. In a cleanroom, exfiltration is difficult to7440measure (it‘s the air flowing under the door and out the cracks in the7441wall), but it can be calculated. It‘s surprising how many HVAC7442designers forget to do an air balance check on EACH fixed volume.7443Beside rooms, air handlers are also fixed volumes.7444

7445

Note that air handled only INSIDE a room, such as with a ceiling7446mounted fan-filter unit (FFU) or local class 100 hood, does not really7447leave the room nor enter it, and does not affect the room's air balance7448relative to the building. However, the FFU unit DOES add its air7449changes as well as filtered air supply volume to the room HVAC supply,7450and it will contribute to faster room recovery time and help reduce7451room airborne particle levels. (See the next section)7452

745311.2.4 Airborne Particle Levels7454

7455Another simplified equation deals with air particles per unit volume7456(C):7457

7458

C avg = C s + PGR/Q74597460Where C avg is average particles per cubic foot in the pressurized7461room, C s is the particle concentration in the air supply (often7462negligible), PGR is the STEADY STATE internal particle generation rate7463in particles per minute, and Q is the supply airflow in cubic7464feet/minute including contributions from in-room fan-HEPA units (FFU).7465With little air mixing (turbulence) in the room, localized values of C7466may be orders of magnitude more or less than Cavg. When a room is at7467rest, and PGR approaches zero (assuming that there are no particles7468leaking into the room), the equation above indicates that room counts7469will eventually approach the particle counts in the supply air.7470

7471Note that the equation above ignores air changes and room volume. The7472

value of C avg will be the same regardless of room volume as long as7473the airflow (Q) and particle generation (PGR) are constant. Therefore,7474the particle counts in a big room running a certain process will be the7475same as the particle counts in a small room running that identical7476process, as long as the Q and particle counts of the supply airflow are7477the same.7478

747911.2.5 Recovery7480

7481





193

A HEPA filter passes a certain percentage of upstream particles of the7537most penetrating particle size (MPPS), in the traditional case,7538particles at 0.3 microns. In reality, the MPPS of a modern HEPA is more7539like 0.15 to 0.25 micron. In another filter (ULPA for example) the MPPS7540is in the range of 0.10 to 0.15 microns. For a given particle size, the7541

overall leakage of a series of HEPA filters in a supply air path is the7542 product of the leakages for each of the filters. If L is the leakage as7543a percent of upstream concentration, two HEPA filters in series will7544have a leakage Ltot of:7545

7546Ltot = L1 x L27547

7548Where Ltot is the resultant leakage, L1 is the leakage of the first7549HEPA, and L2 is the leakage of the second HEPA. For a pair of standard755099.97% HEPA filters (assuming 0.03% leakage at MPPS),7551

7552Ltot = 0.03 x 0.03 = 0.0009 % leakage at MPPS7553

7554Thus, placing two 99.97% HEPA filters in series with no particle7555

sources between them creates a virtual 99.9991% HEPA filter at the7556MPPS. If the filter‘s WORST penetration – such as at a pinhole – is75570.03%, then combined results will be even better. Beside the obvious7558advantages in particle removal, there is an engineering advantage if7559the primary HEPA is at the air handler and the second HEPA filter is at7560the room (a terminal HEPA). The terminal filter sees very little7561challenge, and therefore its pressure drop increases so slowly that its7562flow is not reduced significantly (if at all) over months or perhaps7563years of service. Air balance of the system is easier, requiring less7564in-duct hardware such as constant volume devices, and room pressure7565deviations due to decay of supply airflow are less likely. Since this7566is an article on equations and not economics, the reader is free to7567pursue the discussion on cascaded HEPA filters in the appendix of the7568

Sterile Baseline Guide.75697570Note also that (according to EN1822) HEPA filters may be rated at MOST7571PENETRATING PARTICLE SIZE. A HEPA rated 99.97% at 0.3 micron has LESS7572leakage for larger particles. But it should also have less leakage for7573SMALLER particles*. Since bacteria and spores are usually much larger7574than 0.3 micron, and viruses are smaller than 0.3 micron, a 99.97%7575filter with MPPS at 0.3 microns is a good filter for pharmaceutical7576applications. Other filters, such as 99.99% HEPA, ULPA, or Teflon,7577would perform even better but would cost more at higher cost.7578

7579* In reality, many present-day HEPA filters have been tested to reveal7580that, although they do capture 99.97% or better of particles at 0.37581microns, their true MPPS is somewhat smaller with less capture than7582

99.97%. A HEPA filter rated at 99.97% at 0.3 microns may actually be as7583low as 99.9% at 0.1 to 0.2 micron MPPS. If viruses are a concern, the7584HEPA may be scanned to 99.99% or better using a smaller aerosol (such7585as thermally generated PAO), or ULPA filters may be advisable.7586

758711.2.7 Summary7588

7589These equations are meant to be a starting point for the HVAC designer7590and commissioning person. They do not address all the nuances that7591





194

affect the HVAC in a pharmaceutical facility. But HVAC personnel who7592ignore the basics of physics are doomed to long drawn-out start-ups and7593less than desirable system performance. Those who over-design because7594they don‘t understand the facility are wasting the Owner‘s money. 7595

7596

Readers desiring more information, perhaps to the point of nausea, are7597 welcome to attend the three-day ISPE Pharmaceutical HVAC course where7598these principles, and the overzealous aspirations of erstwhile7599designers, are explored.7600





195

12 REFERENCES7601

7602Airlocks for Biopharmaceutical Plants, del Valle, Pharmaceutical7603Engineering , Volume 21, Number 2, March/April 20017604

7605

ISPE Baseline® Guide for Sterile Manufacturing, Volume 3 first edition,7606January 19997607

7608ISPE Baseline® Guide for Biopharmaceuticals, Volume 6 first edition,760920037610

7611

12.1 SUMMARY OF USEFUL CLEANROOM EQUATIONS76127613

See text for symbols76147615

Ideal Gas Law PV = NRT76167617

Flow due to differential pressure VP ~ P2 – P17618

7619Airflow through an opening Q = V x A7620

7621

Fan horsepower HP = x P x Q76227623

Air balance SUPPLY + INFILTRATION = RETURN + EXHAUST +7624EXFILTRATION7625

7626Average airborne particle level C avg = C s +7627PGR/Q7628

7629Air changes AC/hr = 60 x Q/Volume7630

7631

Room recovery C (at rest) = (Cop – 7632 Cs) (-Nt) + Cs76337634

Cascaded HEPA filters Ltot = L1 x L2763576367637





196

7638

12.2 PRESSURE CONTROL WHEN AIRLOCKS ARE NOT POSSIBLE7639764076417642

7643

764412.3 HEPA FILTERS FOR HOT ZONES (DEPYROGENATION)7645

76467647

12.4 USEFUL REFERENCE MATERIALS764876497650

12.5 HVAC EXAMPLES AND WORKBOOK (???)765176527653

12.6 EXAMPLE DOCUMENTS76547655

RISK MITIGATION IN STERILE HVAC7656

7657RISK DESCRIPTION7658

7659RISK PROBABILITY7660

7661RISK IMPACT ON PRODUCT/PATIENT7662

7663ABILITY TO DETECT7664

DOOROpen

Closed

(and leaking)

BYPASS DAMPERLow airflow

High airflow

To get observable airflow pattern from the clean room to the ―dirtier‖ room

with the door open,

we need a transport velocity of at least100 ft/min (0.5 m/sec). For a 2 sqmeter (20 sq ft) door, the leakage has tobe about 2000 CFM (3200 Cum/hr). Whenthe door closes we need about 300 CFM (500 cu.m/hr) to create 12 Pa DP. The

remaining air passes through the ―bypass‖ opening (damper).

An automated bypass damper can do the job, but a fixed orifice damper or a―gravity‖ damper will, too.

A fixed orifice damper will require a little more airflow

Total airflow with door closed = Total airflow with door open

DP = 12 PaDP = zero

―Cleaner‖

room





198

to adjust fan delivery (RPM or inlet vane) to compensate for airflow7720changes in the system. Alarm this airflow monitor.7721

7722Risk – Failure or absence of a prefilter (HEPA or lower grade)7723

7724

Risk Probability – medium. Prefilters can fail if not periodically7725 monitored.77267727

Risk to Patient – Low to none. The final HEPA filter is the GMP filter77287729

Ability to detect – Filter load and visible leaks can be detected by7730visual inspection and pressure drop monitoring. However, undetectable7731leaks will lead to premature loading of HEPA filters.7732

7733Risk Reduction – Prefilters are a good business practice to extend the7734life of HEPA (GMP) filters. Install DP indicators and visually inspect7735at least weekly.7736

7737Risk – upset of room air balance due to action of CV boxes on air7738

supply.77397740

Risk probability – medium. It DOES happen77417742

Risk Impact – medium. Changes in air balance will change room7743pressures. Adverse pressure relationships may follow, but usually7744pressure relationships do not reverse.7745

7746Ability to detect – high. DP alarms will detect7747

7748Risk reduction – avoid the use of CV boxes. If air supply is held7749constant (see above) and double HEPA filters are used (primary in AHU7750and terminal filters) then CV boxes should not be needed.7751

7752 Risk – Pressure reversals due to action of room pressure control7753dampers.7754

7755Risk probability – medium. Usually a small system can be tuned such7756that active pressure control will not adversely affect pressure7757relationships, but large systems may be more difficult to keep in7758control. Also, controls may ―wind up‖ due to doors being open too long,7759then when doors close pressure relationships reverse.7760

7761Risk Impact – high. Pressure reversal may upset air balance in7762Depyrogenation equipment or introduce large quantities of contamination7763from room to room.7764

7765

Ability to detect – high. Pressure alarm.77667767

Risk reduction – use airlocks between air classes. Ignore momentary DP7768changes due to doors opening and closing. Choose which dampers should7769be ―fast‖ and which‖ slow‖. Consider eliminating automated pressure7770control by simplifying the air balance (no variable exhausts, etc).7771

7772Risk – Failure of Unidirectional Flow Hood over Grade 5 (EU Grade A)7773area7774

ISPE- HVAC.pdf

Documents

Transcript of ISPE- HVAC.pdf