good manufacturing practices for heating ... - who.int · 82 this document represents part 2 of the...

Working document QAS/18.759

February 2018

Draft document for comment

1

2

GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION 3

AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE 4

PHARMACEUTICAL DOSAGE FORMS: PART 2 5

6

INTERPRETATION OF PART 1 – GMP FOR HVAC SYSTEMS 7

8

(February 2018) 9

DRAFT FOR COMMENT 10

11

12

13

14

15

© World Health Organization 2018 16

All rights reserved. 17

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 18 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 19 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 20 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 21 website. 22

Please send any request for permission to: 23

Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Department of Essential 24 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; 25 email: [email protected] 26 27 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 28 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 29 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 30 border lines for which there may not yet be full agreement. 31

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 32 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 33 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 34

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 35 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 36 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 37 Organization be liable for damages arising from its use. 38

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 39 40

Should you have any comments on the attached text, please send these to Dr S. Kopp,

Group Lead, Medicines Quality Assurance, Technologies Standards and Norms

([email protected]) with a copy to Mrs Xenia Finnerty ([email protected])

by 26 April 2018.

Medicines Quality Assurance working documents will be sent out electronically only and

will also be placed on the Medicines website for comment under “Current projects”. If you

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Working document QAS/18.759 page 2

41

SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/18.757: 42

GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-43

CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE 44

FORMS: PART 2 45

46

INTERPRETATION OF PART 1 – GMP FOR HVAC SYSTEMS 47

48

49

Preparation of document by Dr A. J. van Zyl,

consultant

January–

February

2018

Circulation of working document for public

consultation

February 2018

Consolidation of comments received and review of

feedback

May 2018

Discussion during the informal consultation on

GXPs for medicines and inspection tools

July 2018

Circulation of working document for public

consultation

August 2018

Consolidation of comments received and review of

feedback

September 2018

Presentation to the 53rd meeting of the WHO Expert

Committee on Specifications for Pharmaceutical

Preparations

22–26 October

2018

Any further action …


BACKGROUND 50

The World Health Organization (WHO) published the first edition of the WHO Guidelines on 51

good manufacturing practices for heating, ventilation and air-conditioning systems for non-52

sterile pharmaceutical dosage forms in WHO Technical Report Series, No. 937, in 2006. 53

Having considered various comments and the recommendations through public consultation 54

over several years, the WHO Expert Committee on Specifications for Pharmaceutical 55

Preparations (ECSPP) agreed during its 51st meeting held in October 2017, that the Good 56

manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile 57

pharmaceutical dosage forms guidelines, as amended, be adopted as Part 1. 58

It was agreed that Part 1 consists of guidelines that contain good manufacturing practices 59

(GMP) recommendations for heating, ventilation and air-conditioning (HVAC) systems for 60

non-sterile products, and further agreed that Part 1 be supported by an additional document 61

that reflects the interpretation of the recommendations in Part 1. 62

This document is Part 2 and will be considered for adoption as such after consultation. 63

64


Contents 65

page 66

Section 1 and 2. Introduction and Scope 67

3. Glossary 68

4. Premises 69

5. Design of HVAC systems and components 70

6. Full fresh air and recirculation systems 71

7. Air filtration, airflow direction and pressure differentials 72

8. Temperature and relative humidity 73

9. Dust, vapour and fume control 74

10. Protection of the environment 75

11. Commissioning 76

12. Qualification 77

13. Maintenance 78

79


Section 1 and 2 : Introduction and Scope 80

81

This document represents Part 2 of the HVAC systems guidelines. It contains non-binding 82

examples, drawings, technical representations and interpretation in support of Part 1 of the 83

HVAC systems guidelines. 84

85

It is intended to be a basic and explanatory guide for use by pharmaceutical manufacturers 86

and GMP inspectors. It is not intended to be prescriptive in specifying requirements and design 87

parameters but it attempts to facilitate a harmonized understanding of expectations for HVAC 88

systems for manufacturers of non-sterile products. 89

90

Part 1 and Part 2 focus on good practices for HVAC systems for non-sterile products. Where 91

applicable, some of the principles referred to may be considered in the HVAC design and 92

approach for other dosage forms. These two documents are, however, not intended to be used 93

as enforceable criteria for the design or review of HVAC systems for, e.g. APIs or sterile 94

products. 95

96

Other relevant national and international standards, as applicable, should be considered when 97

Part 1 and Part 2 are used. These include, but are not limited to, the current publications such 98

as ISO 14644 and ASHRAE standards. 99

100

In general, HVAC systems can play an important role in facilitating a suitable environment 101

for the manufacture of quality pharmaceutical products. Therefore careful consideration should 102

be given to the design of the HVAC system. When designing an HVAC system, careful 103

consideration should also be given to the building design and layout of areas as these may 104

influence the decision and design relating to, for example, the number of air handling units 105

(AHUs), components in AHUs, room pressure, pressure differentials, pressure cascades, 106

levels of filtration, humidification, dehumidification, heating and cooling of air. These may in 107

turn have an impact on the quality of materials and products as well as the functioning of 108

equipment and instruments. 109

110

The conditions of areas should be defined and should be appropriate for the storage, 111

manufacturing and use, as appropriate, for equipment, instruments, materials and products. It 112

should further ensure that comfortable conditions are maintained for operators. 113

114

Risk assessment 115

116

In line with the current approach in GMP, risk identification should be done for utilities such 117

as HVAC systems. A science-based, comprehensive exercise of risk assessment should be 118

used to determine risks related to possible failure of the HVAC system and AHUs (including 119

their components and subcomponents). An appropriate risk assessment tool such as failure 120

modes and effects analysis (FMEA) or fault tree analysis (FTA) should be selected. Controls 121

should be identified to eliminate the risks, or minimize the risk to an acceptable level. For 122

example, the effect of the failure of one or more AHUs in the HVAC system; the failure of 123


dust extraction systems; the failure of AHU components such as filters, heating coils, cooling 124

coils and fans should be assessed and appropriate controls should be identified and 125

implemented. 126

127

For more information on risk assessment, refer the current WHO guidelines on Quality risk 128

management. 129

130

Design parameters 131

132

Manufacturers should define the design parameters of the HVAC system to ensure 133

appropriate operation and functioning of the system that is needed for all the areas. Special 134

consideration should be given to the required conditions for storage and handling of materials 135

and products, equipment and instrument functioning, personnel requirements and 136

contamination control. 137

138

Section 3. Glossary 139

140

For definitions and abbreviations, see Part 1. 141

142

143


Section 4. Premises 144

145

Premises design 146

147

Both the architectural design of the building and that of the HVAC system should be 148

carefully considered when attempting to achieve the general objectives of preventing 149

contamination, cross-contamination and ensuring an appropriate environment for the 150

production and control of pharmaceutical products. The layout of the premises should 151

facilitate unidirectional flow of material and personnel; building finishes should not result in 152

contamination (e.g. through shedding of particles) and should ensure that the required 153

environmental conditions, cleanliness and containment are achieved and maintained. 154

155

Air infiltration of unfiltered air into production areas should be prevented. Manufacturing 156

facilities should normally be maintained at a positive pressure relative to the outside, to limit 157

the ingress of contaminants. Where facilities are to be maintained at negative pressures 158

relative to the ambient pressure, special precautions should be taken. 159

160

Where necessary, air locks, change rooms and pass-through hatches may be considered and 161

provided with effective ventilation and filtered air. Special attention should be given to door 162

design as gaps between doors and floors, doors opening into low pressure areas and sliding 163

doors can result in changes in pressure differential between areas. An interlocking system and 164

a visual and/or audible warning system may be used to prevent the opening of more than one 165

door at a time where required. 166

167

In addition to the design of the premises, general controls should be in place to ensure 168

protection of materials, products and personnel. The HVAC system can play a role in 169

achieving this objective. Where identified, areas should be maintained within defined limits 170

for temperature, relative humidity, viable and non-viable particles. In such cases, the areas 171

are considered to be “clean areas” (also referred to as “zones, rooms”, etc.). To ensure that 172

the clean area is maintained at the defined limits, areas are normally classified. When 173

classifying the area, the manufacturer should state whether the classification is for the “as 174

built”, “at rest” or “in operation” condition. For details including definitions, see ISO 14644. 175

The following describes approaches (and illustrations by means of diagrams) of different 176

room arrangements and room pressures. 177

Weighing/dispensing and sampling areas 178

A room for weighing (e.g. dispensing of materials), should be of appropriate design. It is 179

often advantageous to have several rooms associated with the weighing activity. These may 180

include a pre-weighing staging area, personnel airlock, material airlock, weighing area with a 181

containment booth, post-weighing staging area, washing area and provision for waste 182

removal. The HVAC system for such areas should ensure that the areas have at least the same 183

area classification as other production areas where materials and products are exposed to the 184

environment, logical flow of material and personnel, appropriate number of AHUs, pressure 185


differentials, containment, dust control, and air exchange rate. 186

187

The objective of having a booth in a weighing room is to provide dust containment and 188

operator protection. For example, the dust generated at the weighing location should be 189

extracted through a perforated worktop, thus protecting the operator from dust inhalation, but 190

at the same time protecting the product from contamination by the operator by means of the 191

vertical airflow stream. The airflow velocity should be such that it does not disrupt the 192

sensitivity of balances. The operator should neither obstruct the airflow nor become a source 193

of contamination of the materials or products. 194

195

196


Figure 1. Example of a weighing area 197

198

SOB

Dispensary Pre-Staging Room

Change

Room

Weigh Booth

Wash Bay

Re

turn

Air S

ha

ft

Perforated Worktop

Airflow Protection

Plenum

Floor

Scale

BIN

BIN

Dispensary Post-Staging

Room

Pallet

Ma

teria

l F

low

Ma

teria

l F

low

BIN

BIN BIN

BINBIN

25 Pa

35 Pa

35 Pa

35 Pa

15 Pa

Table Scale

199

Figure 2. Example of a weighing area 200

201

Dispensary Pre-Staging Room

Weigh

Booth 1

Re

turn

Air S

ha

ft

Airflow

Protection

Plenum

Dispensary

Post-Staging

Room

Wash

BayMAL

MALChange

Room

Weigh

Booth 2

Re

turn

Air S

ha

ft

Airflow

Protection

Plenum

Wash

BayMAL

MALChange

Room

Production Passage

Wa

reh

ou

se

Are

a

Brocken

Bulk

Store

MAL

MALMaterial Flow

202

Similar aspects may be considered when designing a sampling area, as materials and primary 203

components may be exposed to the environment during sampling. 204

205

Sampling of materials such as starting materials, primary packaging materials and products, 206

should be carried out in the same environmental conditions that are required for the further 207

processing of the product 208


Figure 3. Example of a sampling area 209

SO

B

Change

Room

Sampling

Booth

Wash Bay

Re

turn

Air S

ha

ft

Airflow Protection

Booth Plenum

PTH

Warehouse

Area30 Pa

15 Pa

25 Pa

5 Pa

Material Flow

Material Flow

Perforated

Worktop

210

211

Figure 4. Example of a sampling area 212

SO

B

Entry MAL

Change

Room

Sampling Booth

Wash Bay

Write-up Worktop

APB (Airflow

Protection Booth)

Exit MAL

Return Air Plenum

Material Flow

25 Pa

15 Pa

30 Pa

25 Pa 25 Pa

Material Flow

Wa

reh

ou

se

Are

a5

Pa

213

214

A clean corridor concept is usually recommended for non-sterile oral solid dosage form 215

production areas where there is then a higher pressure in the corridor compared to airlocks or 216

production rooms. This is to facilitate containment of dust and contaminants that may have 217

been generated in production rooms (see also the principles mentioned in the section on 218

sampling and dispensing). 219

220

To further support containment, consideration may also be given to have material airlocks 221

(MAL) and personnel airlocks (PAL), where needed, for entry and exiting processing areas. 222

Appropriately designed airlocks can assist in ensuring containment. Additional controls such 223

as pressure differentials between areas, an appropriate number of air changes in an area and 224

sufficient filtration of air should be in place. 225

226

227


Figure 5. Example of a change room and some production areas 228

SOB

Male

Change

Room

SOB

Female

Change

Room

Lobby

Female

Ablution

Male

Ablution

Production

Passage

0 Pa

15 Pa

15 Pa-10 Pa

-10 Pa

30 Pa

Un-classified Zone

229

Figure 6. Example of a compression cubicle with MAL and PAL (also used as an area to 230

change garments) 231

Compression

Cubicle

Change

Room

MAL

Pa

ssa

ge

Low Level

Return A

ir

Low L

evel

Ret

urn

Air

SO

B

25 Pa

35 Pa

25 Pa

15 Pa

Supply

Air

Grille

232

233


Washing areas should be designed and used in such a manner that equipment and components 234

will not be re-contaminated after cleaning. The system supplying and extracting air from the 235

area(s) should be suitably designed to ensure that this objective is achieved. Principles that 236

may be considered include (but are not limited to) filtration of air, pressure differentials 237

between areas and airflow directions. 238

Figure 7. Example of a washing area 239

Dirty

Equipment

Store

Wash Bay

Pa

ssa

ge

15 Pa30 Pa

45 Pa

35 Pa

Clean Equipment

Store

Equipment

Drying

Material Flow Material Flow

25 Pa

Ma

teria

l F

low

Material Flow Material Flow

240

241

Section 5. Design of HVAC systems and components 242

243

The HVAC system should be appropriately designed, taking into consideration the design of 244

the facility with various rooms or areas for the storage of materials and in-process materials 245

or products, processing, movement of materials, products and personnel. The required 246

cleanliness classification should be achieved, as well as other parameters such as airflow 247

direction, air filtration, air exchange rate, airflow velocity, air volumes, pressure differentials, 248

temperature and relative humidity, viable and non-viable particle counts and containment. 249

Conditions and limits should be specified based on need. Manufacturers should determine 250

and define limits for these. These should be realistic, appropriate and scientifically justifiable. 251

In determining these, relevant factors and risks should be considered including but not limited 252

to possible failures of AHUs, seasonal variations, properties and types of materials and 253

products, number of personnel and risks of cross-contamination. 254

255

Other aspects such as the number of AHUs, dust collecting or dust extraction systems, the 256

need for recirculation of air, percentage of fresh air (in the case of recirculated air) and the 257

level of filtration of air should be defined by the manufacturer when considering the design of 258

the facility and activities in different areas and rooms. 259

260

Manufacturers should maintain schematic drawings of the HVAC system, AHUs and 261

components. These should reflect the initial design and installation, as well as the current 262

situation. Changes made during the life cycle of the system should be reflected in change 263


control records and qualification protocols and reports as appropriate. 264

265

The components selected in an HVAC system should be of sufficient capacity to ensure that 266

the design objectives are met (e.g. for heating, cooling, humidification, dehumidification, air 267

flow volumes), taking impacting factors into consideration such as loss of air due to leakage 268

and seasonal variations. Materials of construction for components and their placement should 269

be such that these do not become the source of contamination. For example, components 270

should not shed particles and the sequence of components should be logical, e.g. filters 271

should be placed in such a manner that any possible contaminants generated in the system 272

can be retained by filters and not be introduced into the production area. 273

274

To prevent contamination of areas, access to components such as ventilation dampers, filters 275

and other services should be accessible from outside the manufacturing areas (such as service 276

corridors). 277

278

The overall design should be such that there is no possibility of undesired, unfiltered air or 279

contaminants entering into manufacturing areas. 280

Containment 281

282

Manufacturers should ensure that appropriate measures are taken to contain product dust in a 283

manufacturing area, thus preventing or minimizing the risk of contamination of other areas 284

and possible cross-contamination. In some cases, it may be advisable to have airlocks or pass 285

through hatches between rooms or areas. In addition, sufficient dilution, pressure differentials 286

(recommended minimum values of 5 to 15 Pa) and airflow directions can further support 287

containment in an area. 288

289

Cleanliness 290

291

Areas should be maintained at the defined levels of cleanliness and classifications. The 292

HVAC system can support this through, e.g. appropriate levels of filtration of air, airflow 293

directions, dilution, dust removal and air exchange rate. Equipment, containers, personnel and 294

other related components should be appropriately located or placed in areas so as not to 295

obstruct airflow and effectiveness of the HVAC system. 296

297

Recontamination should be prevented by ensuring that material and personnel movement is 298

within the same area classification and not back and forth between areas of different 299

classification. Where such back-and-forth movement is unavoidable, appropriate controls 300

should be identified and implemented to ensure that moving from a higher class to a lower 301

classified area and back to a higher classified area will not result in contaminants being 302

brought into the cleaner classified area. 303

304

Automated monitoring systems 305

306


The performance of the HVAC system achieving and maintaining the desired results for 307

parameters such as temperature, relative humidity, airflow and pressure differential should be 308

carefully controlled and monitored. This is to ensure that there is no departure from these 309

limits during manufacturing. Monitoring systems should be in place to ensure that the system 310

operates within its design limits. Manual or automated (computerized) systems may be used. 311

312

Manual systems of monitoring may not always provide sufficient proof that the system is able 313

to maintain all conditions throughout the manufacturing period. 314

315

Automated monitoring systems may provide ongoing monitoring possibilities with better 316

assurance of compliance with the defined limits. Where these automated systems are 317

considered to be GXP systems, these should be appropriately validated. The scope and extent 318

of validation of the computerized system should be determined, be justifiable and 319

appropriately executed. This includes, but is not limited to, access and privileges to the 320

software, setting of limits, monitoring and acknowledging alarms, audit trails, controls, 321

monitoring and reporting. 322

323

Switching off of AHUs 324

325

It is recommended that the HVAC system be operational on an ongoing basis. Where a 326

manufacturer decides to use energy saving modes or switch some selected AHUs off at 327

specified intervals such as overnight, weekends or extended periods of time, care should be 328

taken to ensure that materials and products are not affected. In such cases, the decision, 329

procedures and records should be sufficiently documented and should include risk 330

assessment, standard operating procedures (SOPs), records and validation. This includes 331

procedures and records for the start-up and shut-down sequence of air handling units. 332

333

Section 6. Full fresh air and recirculation systems 334

335

Manufacturers may select to have full fresh air systems or recirculate treated air supplied to 336

production areas (In a full fresh air system, no air is recirculated. In recirculation systems, a 337

defined percentage of the air is recirculated.). In both cases, the air supplied to the production 338

areas should be appropriately treated to ensure that the environmental conditions specified are 339

met and that the risks for contamination and cross-contamination are controlled. 340

341

Manufacturers using recirculation systems should determine the percentage of fresh air to be 342

supplied to the relevant manufacturing areas, as required by national and international 343

standards. This volume of air should be verified during qualification. 344

345

In both scenarios, appropriate levels of filtration should be applied to prevent contamination 346

and cross-contamination. Manufacturers should ensure that when HEPA filters are used that 347

these are appropriately installed, not damaged and thus suitable for the intended use (see tests 348

described below under the section of qualification). 349

350


Figure 8. Example of a full fresh-air system 351

352

PRODUCTION

FACILITY

Prim

ary

Filt

er

Exh

au

st A

ir

Fa

n

Se

co

nd

ary

Filt

er

HE

PA

F

ilte

r

EXHAUST AIR HANDLING UNIT

Fresh Air

Exhaust Air

Degree of filtration required

depends on exhaust air contaminants

Prim

ary

Filt

er

Su

pp

ly A

ir

Fa

n

Se

co

nd

ary

Filt

er

HE

PA

F

ilte

r

AIR HANDLING UNIT

Co

olin

g C

oil

-

S

S

R

F

= Supply Air

= Return Air

= Fresh Air

F

S

E = Exhaust Air

E E

E

+

353

354

Section 7. Air filtration, airflow direction and pressure differentials 355

356

Effective ventilation and appropriate levels of filtration are recommended in basic GMP 357

guidelines. Manufacturers should determine which classes of filters should be used in 358

ensuring that contaminants from outside are not introduced into manufacturing areas and that 359

where recirculation systems are used, filtration of recirculated air should be effectively 360

treated to ensure that there is no risk of cross-contamination. Where different products are 361

manufactured in different rooms in the same facility at the same time, appropriate controls 362

should be in place to ensure containment and the prevention of contamination and cross-363

contamination. 364

365

Filters selected for air filtration, air changes and airflow direction should be determined and 366

specified. When a manufacturer chooses to install high efficiency particulate air (HEPA) filters 367

to achieve the desired degree of filtration of air, these filters may be placed in the AHU or 368

may be installed terminally near the supply grille. 369

370

The number of air changes or air exchange rates should be sufficient. A guidance value is 371

between 6 and 20 air changes per hour. Manufacturers should also establish how much time it 372

takes for a room, which is out of its classification, to return within the specified class. This is 373

often referred to as clean-up or recovery time. A guidance time period for clean-up or 374

recovery is about 15 to 20 minutes 375

376

Airflow directions should be specified and proven to promote containment and not be 377

adversely affected or obstructed by equipment, utilities, containers or personnel. The location 378

of supply and return or exhaust air grilles should facilitate appropriate airflow directions in an 379

area. 380

381

Figure 9 is a schematic diagram of air-handling system serving rooms with horizontal 382

directional flow, vertical directional flow and turbulent flow, for rooms 3, 4 and 5, 383

respectively. In these room, the HEPA filters are indicate to have been placed terminally 384


mounted at the rooms and not in the AHU. Terminally-mounted HEPA filters can assist with 385

preventing cross-contamination from room to room in the event of a fan failure condition. 386

387

Figure 9. Example of horizontal airflow, vertical flow and turbulent flow 388

389

Prim

ary

Filt

er

Su

pp

ly A

ir

Fa

n

Se

co

nd

ary

Filt

er

AIR HANDLING UNIT

Room with

Vertical UDAFRoom with

Horizontal UDAF

ROOM 4ROOM 3

= Supply Air

= Return Air

= Fresh Air

R S

HE

PA

F

ilte

rs

Room with low

level return air

ROOM 5

HEPA Filters

Co

olin

g C

oil

-

S

S

SS

S

F

F

R

R

R

R

R

S

S

S

R

R

+

+ +

390

391

The pressure differential should be of sufficient magnitude to ensure containment and 392

prevention of flow reversal, but should not be so high as to create turbulence problems. It is 393

suggested that pressure differentials of between 5 Pa and 20 Pa be considered. Where the 394

design pressure differential is too low and tolerances are at opposite extremities a flow 395

reversal can take place. There should be no risk of overlap in the acceptable operating range, 396

e.g. 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in the failure 397

of the pressure cascade. The upper and lower limits for pressure differentials between areas in 398

a facility should be defined by the manufacturer. Where there are interleading rooms the 399

limits should be appropriate to ensure that there is no overlap in actual values as this may 400

result in loss in pressure differential between areas and even reversal of air flow. 401

402

The pressure control and monitoring devices used should be calibrated and where possible, be 403

linked to an alarm system set according to the determined levels. 404

405

Figure 10: Examples of pressure cascades 406

407


Encapsulation

Airlock

Tablet

Compression

Production Corridor

Design Condition (15 Pa Pressure Differential)

30 Pa ± 3 Pa

15 Pa ± 3 Pa

Tablet

Compression

15 Pa ± 3 Pa15 Pa ± 3 Pa

15 Pa ± 3 Pa

Air Leakage Air Leakage

Air L

ea

ka

ge

Air L

ea

ka

ge

Air L

ea

ka

ge

Encapsulation

Airlock

Tablet

Compression

Production Corridor

33 Pa

Tablet

Compression

12 Pa


Air L

ea

ka

ge

Air L

ea

ka

ge

Air L

ea

ka

ge

Encapsulation

Airlock

Tablet

Compression

Production Corridor

27 Pa

18 Pa

Tablet

Compression


Air L

ea

ka

ge

Air L

ea

ka

ge

Air L

ea

ka

ge

Image of room pressure gauge

indicating colour coded normal,

alert & action parameters

Maximum Differential (21 Pa Pressure Differential)

12 Pa 12 Pa

12 Pa

Minimum Differential (9 Pa Pressure Differential)

18 Pa

18 Pa18 Pa

408

409

Airlocks 410

411

Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock and 412

bubble airlock: 413

414

cascade airlock: higher pressure on one side of the airlock and lower pressure on 415

the other; 416

sink airlock: lower pressure inside the airlock and higher pressure on both outer sides; 417

bubble airlock: higher pressure inside the airlock and lower pressure on both outer 418

sides. 419

420

Figure 11: Example of cascade airlock 421

(In most cases the internal pressure of the airlock is not critical. The pressure differential 422

between the two outer sides is the important criteria.) 423

424

Material Airlock

Cascade Airlock


22.5 Pa15 Pa 30 Pa

425

426

427


Figure 12: Example of sink airlock 428

429

Material Airlock

Sink Airlock


15 Pa

30 Pa30 Pa

430

431

432

Figure 13: Example of bubble airlock 433

434

Material Airlock

Bubble Airlock


30 Pa15 Pa15 Pa

435

436

Note: The diagrams above and the differential pressures shown here are for illustration 437

purposes only. Pressures indicated in these examples are absolute pressures, whereas the 438

local pressure indication would most likely be pressure differential from room to room. 439

440

Additional controls should be identified through risk identification and risk assessment. For 441

example, where possible, personnel should not move between different areas during 442

production (such as compression rooms and in process control laboratories) unless there is no 443

risk of contamination of other areas. Personnel often become sources of contamination as 444

they may carry dust from one area to another. Controls may include airlocks or gowning 445

procedures. 446

447

Section 8: Temperature and relative humidity 448

449

Manufacturers should set appropriate upper and lower limits for temperature and relative 450

humidity for different areas. The required storage conditions specified for the materials and 451

products should be considered when the limits are defined. The HVAC system should be 452

designed in such a manner that these limits can be achieved and be maintained through all 453

seasons. 454

455


Systems for dehumidification or humidification require special considerations due to their 456

contamination risk (e.g. condensate formation, bacterial and fungal contamination, 457

contaminated steam and risks when using mobile systems between different areas). 458

Chemicals such as corrosion inhibitors or chelating agents, which could have a 459

detrimental effect on the product, should not be added to the boiler system. Humidification 460

systems should be well drained. No condensate should accumulate in air-handling systems. 461

Other humidification appliances such as evaporative systems, atomizers and water mist sprays, 462

should not be used because of the potential risk of microbial contamination. Air filters should 463

not be installed immediately downstream of humidifiers as moisture on the filters could lead 464

to bacterial growth. Cold surfaces should be insulated to prevent condensation within the 465

clean area or on air-handling components. Chemical driers using silica gel or lithium chloride 466

are acceptable provided that they do not become sources of contamination. 467

468

Section 9. Dust, vapour and fume control 469

470

Manufacturers should ensure that dust-generated vapours and fumes are effectively removed 471

from the manufacturing areas. Extraction or collecting systems should be designed and 472

qualified to demonstrate this. Sufficient air velocity should be maintained in such systems to 473

effectively remove dust and vapours. 474

475

A dust extractor should normally not serve different rooms where different products can be 476

processed at the same time due to the risks such as backflow or flow from room to room 477

resulting in possible contamination and cross-contamination. 478

479

Wherever possible, dust or vapour contamination should be removed at source, i.e. as close as 480

possible to the point where the dust is generated. Dust extraction ducting should be designed 481

with sufficient transfer velocity (determined by the manufacturer depending on materials and products 482

processed) to ensure that dust is carried away, and does not settle in the ducting (a guidance value 483

is 15–20 m/s). As vapours can be problematic, extraction may be supported by directional 484

airflow to assist in the removal. The density of the vapour should be taken into consideration 485

with extract grilles at a high level or possibly at both high and low levels. 486

487

Section 10. Protection of the environment 488

489

Manufacturers should have controls in place to ensure that air from production areas, 490

including contaminated air from equipment such as fluid bed driers, is passed through 491

appropriate levels of filtration to ensure that the environment is not polluted. Manufacturers 492

should consult national and international environmental legislation. 493

494

Section 11. Commissioning 495

496

Where manufacturers perform commissioning, this should be clearly documented. 497

498

Section 12. Qualification 499


500

Manufacturers should consider all stages of qualification for their HVAC systems. This 501

includes, where appropriate, user requirement specification, design qualification, factory 502

acceptance test, site acceptance test, installation qualification, operational qualification and 503

performance qualification. Qualification to be done over the life cycle of the HVAC system 504

should be described and executed including, e.g. when changes are made to the system. 505

506

Validation master plan(s), protocols, reports and source data for tests should be available. The 507

scope and extent of qualification should be determined based on risk assessment. Parameters 508

with limits included in qualification (such as temperature test, airflow direction, viable and 509

non-viable particle counts) should be justified by manufacturers. The procedures followed for 510

the performance of the tests should generally be in line with the standard as described in ISO 511

14644 512

513

Some of the typical HVAC system parameters that should be included in the tests during 514

qualification are listed below. It is recommended that the tests be done at defined intervals. 515

The tests typically cover: 516

517

— temperature; 518

— relative humidity; 519

— supply air quantities; 520

— return air or exhaust air quantities; 521

— room air-change rates; 522

— pressure differentials; 523

— airflow direction test; 524

— installed filter leakage tests; 525

— particle counts; 526

— clean-up or recovery rates; 527

— microbiological counts; 528

— warning/alarm systems. 529

530

Table 1. Considerations in testing 531

532

Test parameter

Test procedure Note

Temperature ISO 14644 and WHO

Technical Report

Series, No. 961

Consider the

temperature mapping

test as described in

WHO Technical

Report Series

Relative humidity ISO 14644 and WHO

Technical Report

Series, No. 961

See Temperature

mapping test for

principles


Pressure differential ISO 14644

Airflow volumes ISO 14644

Installed filter leakage ISO 14644

Particle counts ISO 14644

Airflow direction ISO 14644 or

company procedure

(smoke test)

Where a smoke test is

performed, ensure a

continuous capture of

the process, e.g.

video, with correct

angles to demonstrate

flow direction and

identification of date,

time and area filmed

and recorded in a

traceable manner

Air flow velocity ISO 14644

Recovery

533

Section 13. Maintenance 534

535

Manufacturers should maintain current documentation for HVAC systems which include 536

operation and maintenance manuals, schematic drawings, procedures and records. 537

538

Repairs, maintenance and preventive maintenance (including cleaning, replacement of 539

components, changes, qualification) should be executed in accordance with procedures. 540

Records for these should be maintained for an appropriate time. 541

542

*** 543

544

545

546

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