GMP guidelines for HVAC

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Working document QAS/15.639 August 2015 Draft document for comment

SUPPLEMENTARY GUIDELINES ON

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GOOD MANUFACTURING PRACTICES FOR HEATING,

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VENTILATION AND AIR-CONDITIONING SYSTEMS FOR

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NON-STERILE PHARMACEUTICAL DOSAGE FORMS

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(August 2015) 5

DRAFT FOR COMMENT

6 7 8 9 10 11

© World Health Organization 2015

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This draft is intended for a restricted audience only, i.e. the individuals and organizations having

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received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted,

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distributed, translated or adapted, in part or in whole, in any form or by any means outside these

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individuals and organizations (including the organizations' concerned staff and member

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organizations) without the permission of the World Health Organization. The draft should not be

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displayed on any website.

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Please send any request for permission to:

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Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms,

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Department of Essential Medicines and Health Products, World Health Organization, CH-1211

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Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: [email protected]

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The designations employed and the presentation of the material in this draft do not imply the

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expression of any opinion whatsoever on the part of the World Health Organization concerning the

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legal status of any country, territory, city or area or of its authorities, or concerning the delimitation

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of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which

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there may not yet be full agreement.

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The mention of specific companies or of certain manufacturers’ products does not imply that they

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are endorsed or recommended by the World Health Organization in preference to others of a similar

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nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are

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distinguished by initial capital letters.

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All reasonable precautions have been taken by the World Health Organization to verify the

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information contained in this draft. However, the printed material is being distributed without

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warranty of any kind, either expressed or implied. The responsibility for the interpretation and use

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of the material lies with the reader. In no event shall the World Health Organization be liable for

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damages arising from its use.

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This draft does not necessarily represent the decisions or the stated policy of the World Health

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Organization.

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Should you have any comments on the attached text, please send these to Dr S. Kopp, Dr S. Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms

([email protected]) with a copy to Ms Marie Gaspard ([email protected]) by 10 October 2015.

Medicines Quality Assurance working documents will be sent out electronically only and will also be placed on the Medicines website for comment under “Current projects”. If you do not already receive our draft working documents please let us have your email address (to [email protected]) and we will add it to our electronic mailing list.

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Working document QAS/15.639 page 2

SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF 41

DOCUMENT QAS/15.639 42

SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING 43

PRACTICES FOR HEATING, VENTILATION AND AIR- 44

CONDITIONING SYSTEMS FOR NON-STERILE 45

PHARMACEUTICAL DOSAGE FORMS. 46

PROPOSAL FOR REVISION 47

48 49 50 51

Discussion of proposed need for revision in view of the current trends in engineering and experience gained during the implementation of this guidance in inspection during informal consultation on data management,

bioequivalence, GMP and medicines’ inspection

29 June– 1 July 2015

Preparation of draft proposal for revision by D. Smith, consultant to the Medicines Quality Assurance group and Prequalification Team (PQT)-Inspections, based on the feedback received during the meeting and from PQT-Inspections

July-August 2015

Circulation of revised working document for public consultation

September 2015

Consolidation of comments received and review of feedback

10 October 2015

Presentation to fiftieth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations

12–16 October 2015

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Working document QAS/15.639 page 3 BACKGROUND

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During the consultation on data management, bioequivalence, GMP and 53

medicines’ inspection held in 2015 the possible revision of the guidance 54

for (WHO Technical Report Series, No. 961, Annex 5, 2011) was 55

discussed with the inspectors. It was suggested that in light of the new 56

developments a draft for revision be prepared. This new proposal for 57

revision was drafted based on the feedback received, the new, current 58

trends in engineering and the experience gained during the implementation 59

of this guidance in inspection. 60

At the same time, the opportunity was used to improve the graphic images 61

and make them more readable in e-version as well as in print. 62

Summary of main changes

63

Below is a list of the main changes that have been made to the WHO Technical 64

Report Series, No. 961, 2011, Annex 5: Supplementary guidelines on good 65

manufacturing practices for heating, ventilation and air-conditioning systems for

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non-sterile pharmaceutical dosage forms.

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1. The Premises section has been moved towards the beginning of the document 69

due to its important impact on HVAC designs. In addition the text has been 70

expanded and a number of sample layouts have been included. 71

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2. The HVAC sections have been re-arranged into a more logical sequence. 73

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3. The Commissioning, Qualification and Validation (C, Q & V) section has 75

been aligned with the proposed revisions to the Supplementary GMP 76

Validation TRS937 Annex4 guideline. 77

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4. Significant notes were added under the new Supplementary notes on test 79

procedures section.

80 81

5. The Maintenance section has been separated out of the C, Q & V section. 82

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6. All the diagrams have been revised (mainly to achieve better clarity). 84

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7. Throughout the document additional notes have been added and text revised 86

to provide better understanding and avoid ambiguity. 87

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8. A list of abbreviations has been added. 89

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Working document QAS/15.639 page 4 Contents 91 page 92 1. Introduction 93 2. Scope of document 94 3. Glossary 95 4. Premises 96

5. Design of HVAC systems and components 97 5.1 General 98 5.2 Air distribution 99 5.3 Recirculation system 100

5.4 Full fresh-air systems 101

5.5 Additional system components 102

6. Protection 103

6.1 Products and personnel 104 6.2 Air filtration 105 6.3 Unidirectional airflow 106 6.4 Infiltration 107 6.5 Cross-contamination 108

6.6 Displacement concept (low pressure differential, 109

high airflow) 110

6.7 Pressure differential concept (high pressure differential, 111

low airflow) 112

6.8 Physical barrier concept 113

6.9 Temperature and relative humidity 114

7. Dust control 115

8. Protection of the environment 116

8.1 General 117

8.2 Dust in exhaust air 118

8.3 Vapour and fume removal 119

9. Commissioning, qualification and validation 120 9.1 General 121 9.2 Commissioning 122 9.3 Qualification 123

9.4 Supplementary notes on test procedures 124 10. Maintenance 125 11. Abbreviations 126 References 127 Further reading 128 129

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Working document QAS/15.639 page 5 1. Introduction

130 131

Heating, ventilation and air-conditioning (HVAC) play an important role in 132

ensuring the manufacture of quality pharmaceutical products. A well designed 133

HVAC system will also provide comfortable conditions for operators. 134

135

These guidelines mainly focus on recommendations for systems for 136

manufacturers of solid dosage forms. The guidelines also refer to other 137

systems or components which are not relevant to solid dosage form 138

manufacturing plants, but which may assist in providing a comparison 139

between the requirements for solid dosage-form plants and other systems. 140

141

HVAC system design influences architectural layouts with regard to items 142

such as airlock positions, doorways and lobbies. The architectural components 143

have an effect on room pressure, differential cascades and cross-144

contamination control. The prevention of contamination and cross-145

contamination is an essential design consideration of the HVAC system. In 146

view of these critical aspects, the design of the HVAC system should be 147

considered at the concept design stage of a pharmaceutical manufacturing 148

plant. 149

150

Temperature, relative humidity and ventilation should be appropriate and 151

should not adversely affect the quality of pharmaceutical products during 152

their manufacture and storage, or the accurate functioning of equipment. 153

154

This document aims to give guidance to pharmaceutical manufacturers 155

and inspectors of pharmaceutical manufacturing facilities on the design, 156

installation, qualification and maintenance of the HVAC systems. 157

These guidelines are intended to complement those provided in Good 158

manufacturing practices for pharmaceutical products (1) and should be read 159

in conjunction with the parent guide. The additional standards addressed by 160

the present guidelines should, therefore, be considered supplementary to 161

the general requirements set out in the parent guide. 162

163

2. Scope of document 164

165

These guidelines focus primarily on the design and good manufacturing 166

practices (GMP) requirements for HVAC systems for facilities for the 167

manufacture of solid dosage forms. Most of the system design principles 168

for facilities manufacturing solid dosage forms also apply to facilities 169

manufacturing other dosage forms and other classes of products including 170

biological products, herbal medicines, complimentary medicines and 171

finishing process steps for APIs . Additional specific requirements apply 172

for handling of sterile products and hazardous products. Guidelines for 173

hazardous, sterile and biological product facilities are covered in separate 174

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WHO guidelines (WHO Technical Report Series, No. 957, Annex 3, 175

Technical Report Series, No. 961 Annex 6 and working document 176

WHO/BS/2015.2253, intended to replace Technical Report Series, No. 177

822, Annex 1, 1992, respectively). 178

179

These guidelines are intended as a basic guide for use by pharmaceutical 180

manufacturers and GMP inspectors. 181

They are not intended to be prescriptive in specifying requirements and design 182

parameters. There are many parameters affecting a clean area condition and it 183

is, therefore, difficult to lay down the specific requirements for one particular 184

parameter in isolation. 185

186

Many pharmaceutical manufacturers have their own engineering design and 187

qualification standards, and requirements may vary from one manufacturer 188

to the next. Design parameters and user requirements should, therefore, be 189

set realistically for each project, with a view to creating a cost-effective 190

design, yet still complying with all regulatory standards and ensuring that 191

product quality and safety are not compromised. The three primary aspects 192

addressed in this manual are the roles that the HVAC system plays in product 193

protection, personnel protection and environmental protection (Figure 2). 194

195

Cognizance should be taken of the products to be manufactured when 196

establishing system design parameters. A facility manufacturing multiple 197

different products may have more stringent design parameters with respect 198

to cross-contamination control, compared with a single product facility. 199

200

Risk assessment studies should be an integral part of the facility design and 201

implementation, from the URS stage right through to validation, as 202

indicated in the diagram below (Figure 1). Validation protocols and criteria 203

should be justified by links to a written risk assessment. 204

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Working document QAS/15.639 page 7 Figure 1

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GMP compliance sequence diagram 207 RISK ASSESSMENT STUDIES USER REQUIREMENT SPECIFICATION FACILITY LAYOUTS QUALIFICATION & VALIDATION HVAC & SERVICES DESIGNS PROJECT INCEPTION RISK ASSESSMENT STUDIES ENERGY EFFICIENCY STUDIES

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C

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Installations 208 209 210

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Figure 2 211

The guidelines address the various system criteria according to the 212

sequence set out in this diagram 213

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Working document QAS/15.639 page 9 3. Glossary

216 217

The definitions given below apply to terms used in these guidelines. They 218

may have different meanings in other contexts. 219

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acceptance criteria

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Measurable terms under which a test result will be considered acceptable. 222

223

action limit

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The action limit is reached when the acceptance criteria of a critical 225

parameter have been exceeded. Results outside these limits will require 226

specified action and investigation. 227

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air changes per hour

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The volume of air supplied to a room, in m3/hr, divided by the room volume, in m3. 230

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air-handling unit

232

The air-handling unit serves to condition the air and provide the required air 233

movement within a facility. 234

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airflow protection booth

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A booth or chamber, typically for purposes of carrying out Sampling or 237

Weighing, in order to provide product containment and operator protection. 238

Similar to UDAF protection but not necessarily a Grade A condition. 239

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airlock

241

An enclosed space with two or more doors, which is interposed between 242

two or more rooms, e.g. of differing classes of cleanliness, for the purpose 243

of controlling the airflow between those rooms when they need to be 244

entered. An airlock is designed for and used by either people or goods 245

(PAL, personnel airlock; MAL, material airlock). 246

247

alert limit

248

The alert limit is reached when the normal operating range of a critical 249

parameter has been exceeded, indicating that corrective measures may need 250

to be taken to prevent the action limit being reached. 251

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as-built

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Condition where the installation is complete with all services connected and 254

functioning but with no production equipment, materials or personnel present. 255

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at-rest

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Condition where the installation is complete with equipment installed and 258

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operating in a manner agreed upon by the customer and supplier, but with 259

no personnel present. 260

261

central air-conditioning unit (see air-handling unit) 262

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change control

264

A formal system by which qualified representatives of appropriate 265

disciplines review proposed or actual changes that might affect a validated 266

status. The intent is to determine the need for action that would ensure that 267

the system is maintained in a validated state. 268

269

clean area (cleanroom)11

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An area (or room or zone) with defined environmental control of particulate 271

and microbial contamination, constructed and used in such a way as to reduce 272

the introduction, generation and retention of contaminants within the area. 273

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closed system

275

A system where the product or material is not exposed to the manufacturing 276 environment. 277 278 commissioning 279

Commissioning is the documented process of verifying that the equipment 280

and systems are installed according to specifications, placing the equipment 281

into active service and verifying its proper action. Commissioning takes 282

place at the conclusion of project construction but prior to validation. 283

284

containment

285

A process or device to contain product, dust or contaminants in one zone, 286

preventing it from escaping to another zone. 287

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contamination

289

The undesired introduction of impurities of a chemical or microbial nature, 290

or of foreign matter, into or on to a starting material or intermediate, during 291

production, sampling, packaging or repackaging, storage or transport. 292

293

controlled area

294

An area within the facility in which specific environmental facility 295

conditions and procedures are defined, controlled, and monitored to prevent 296

degradation or cross-contamination of the product. 297

1_{Note: Clean area standards, such as ISO 14644-1, provide details on how to classify air cleanliness by}

means of particle concentrations, whereas the GMP standards provide a grading for air cleanliness in terms of the condition (at-rest or operational), the permissible microbial concentrations, as well as other factors such as gowning requirements. GMP and clean area standards should be used in conjunction with each other to define and classify the different manufacturing environments.

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Working document QAS/15.639 page 11 298

controlled-not classified

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An area where some environmental conditions are controlled (such as 300

temperature), but the area has no cleanroom classification 301

302

critical parameter or component

303

A processing parameter (such as temperature or relative humidity) that 304

affects the quality of a product, or a component that may have a direct 305

impact on the quality of the product. 306

307

critical quality attribute

308

A physical, chemical, biological or microbiological property or characteristic 309

that should be within an appropriate limit, range or distribution to ensure 310

the desired product quality. 311

312

cross-contamination

313

Contamination of a starting material, intermediate product or finished 314

product with another starting material or product during production. 315

316

design condition

317

Design condition relates to the specified range or accuracy of a controlled 318

variable used by the designer as a basis for determining the performance 319

requirements of an engineered system. 320

321

design qualification

322

Design qualification is the documented check of planning documents and 323

technical specifications for conformity of the design with the process, 324

manufacturing, GMP and regulatory requirements. 325

326

direct impact system

327

A system that is expected to have a direct impact on product quality. These 328

systems are designed and commissioned in line with good engineering 329

practice and, in addition, are subject to qualification practices. 330

331

exfiltration

332

Exfiltration is the egress of air from a controlled area to an external zone. 333

334

facility

335

The built environment within which the clean area installation and associated 336

controlled environments operate together with their supporting infrastructure. 337

338

good engineering practice

339

Established engineering methods and standards that are applied throughout 340

the project life-cycle to deliver appropriate, cost-effective solutions. 341

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342

hazardous substance or product

343

A product or substance that may present a substantial risk of injury to health 344 or to the environment 345 346 HVAC 347

Heating, ventilation and air-conditioning. Also referred to as Environmental 348

control systems 349

350

indirect impact system

351

This is a system that is not expected to have a direct impact on product 352

quality, but typically will support a direct impact system. These systems are 353

designed and commissioned according to good engineering practice only. 354

355

infiltration

356

Infiltration is the ingress of air from an external zone into a controlled area. 357

358

installation qualification

359

Installation qualification is documented verification that the premises, 360

HVAC system, supporting utilities and equipment have been built and 361

installed in compliance with their approved design specification. 362

363

Most penetrating particle size (MPPS)

364

MPPS is a means of determining HEPA & ULPA filter efficiencies. The 365

MPPS is the particle size with the highest penetration for a defined filter 366

medium. (MPPS Integral overall efficiency is the efficiency, averaged over 367

the whole superficial face area of a filter element under a given operating 368

conditions of the filter. MPPS local efficiency is the efficiency, at a specific 369

point of the filter element under given operating conditions of the filter) 370

371

NLT

372

Not less than 373

374

NMT

375

Not more than 376

377

no-impact system

378

This is a system that will not have any impact, either directly or indirectly, on 379

product quality. These systems are designed and commissioned according 380

to good engineering practice only. 381

382

non-critical parameter or component

383

A processing parameter or component within a system where the operation, 384

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Working document QAS/15.639 page 13 contact, data control, alarm or failure will have an indirect impact or no 385

impact on the quality of the product. 386

387

normal operating range

388

The range that the manufacturer selects as the acceptable values for a parameter 389

during normal operations. This range must be within the operating range. 390 391 OOS 392 Out of specification 393 394 operating limits 395

The minimum and/or maximum values that will ensure that product and 396

safety requirements are met. 397

398

operating range

399

Operating range is the range of validated critical parameters within which 400

acceptable products can be manufactured. 401

402

operational condition

403

This condition relates to carrying out room classification tests with the 404

normal production process with equipment in operation, and the normal 405

staff present in the specific room. 406

407

operational qualification (OQ)

408

Operational qualification is the documentary evidence to verify that the equipment 409

operates in accordance with its design specifications in its normal operating range 410

and performs as intended throughout all anticipated operating ranges. 411

412

oral solid dosage (OSD)

413

Usually refers to an OSD plant that manufactures medicinal products such 414

as tablets, capsules and powders to be taken orally. 415

416

pass-through-hatch (PTH) or pass box (PB)

417

A cabinet with two or more doors for passing equipment or product, whilst 418

maintaining the pressure cascade and segregation between two controlled 419

zones. A passive PTH has no air supply or extract. A dynamic PTH has an 420

air supply into the chamber. 421

422

performance qualification (PQ)

423

Performance qualification is the documented verification that the process and/ 424

or the total process related to the system performs as intended throughout all 425

anticipated operating ranges. 426

427 428

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point extraction

429

Air extraction to remove dust with the extraction point located as close as 430

possible to the source of the dust. 431

432

pressure cascade

433

A process whereby air flows from one area, which is maintained at a higher 434

pressure, to another area at a lower pressure. 435

436

qualification

437

Qualification is the planning, carrying out and recording of tests on 438

equipment and a system, which forms part of the validated process, to 439

demonstrate that it will perform as intended. 440

441

quality critical process parameter (QCPP)

442

A process parameter which could have an impact on the critical quality 443 attribute. 444 445 relative humidity 446

The ratio of the actual water vapour pressure of the air to the saturated 447

water vapour pressure of the air at the same temperature expressed as a 448

percentage. More simply put, it is the ratio of the mass of moisture in 449

the air, relative to the mass at 100% moisture saturation, at a given 450

temperature. 451

452

standard operating procedure (SOP)

453

An authorized written procedure, giving instructions for performing 454

operations, not necessarily specific to a given product or material, but of a 455

more general nature (e.g. operation of equipment, maintenance and cleaning, 456

validation, cleaning of premises and environmental control, sampling and 457

inspection). Certain SOPs may be used to supplement product-specific 458

master and batch production documentation. 459

460

turbulent flow

461

Turbulent flow, or non-unidirectional airflow, is air distribution that is 462

introduced into the controlled space and then mixes with room air by means 463

of induction. 464

465

unidirectional airflow (UDAF)

466

Unidirectional airflow is a rectified airflow over the entire cross-sectional 467

area of a clean zone with a steady velocity and approximately parallel 468

streamlines (see also turbulent flow). 469

470

validation

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Working document QAS/15.639 page 15 The documented act of proving that any procedure, process, equipment, 472

material, activity or system actually leads to the expected results. 473

474

validation master plan (VMP)

475

Validation master plan is a high-level document which establishes an 476

umbrella validation plan for the entire project, and is used as guidance by 477

the project team for resource and technical planning (also referred to as 478

master qualification plan). 479

480

4. Premises 481

482

4.1. There is a close relationship between architectural design and HVAC 483

design, as they both have an impact on the functionality of the other. 484

HVAC system design influences architectural layouts with regard to items 485

such as airlock positions, doorways and lobbies. The architectural layouts 486

and building components have an effect on room pressure differential 487

cascades and cross-contamination control. The prevention of contamination 488

and cross-contamination is an essential design consideration of the HVAC 489

system. In view of these critical aspects, the design of the HVAC system 490

should be considered at the concept design stage of a pharmaceutical 491

manufacturing plant, and the design should be closely co-ordinated with the 492

architectural designers. In addition the architectural layout must ensure that 493

the material flow is in a logical sequence, excluding material flow reversals 494

where possible. 495

496

4.2. As the efficient operation of the air-handling system and cleanliness levels 497

attained are reliant on the correct building layout and building finishes, the 498

following items should be considered. 499

500

4.2.1. Adequate airlocks, such as personnel airlocks (PAL) and/or material 501

airlocks (MAL), change rooms and passages should be provided to protect 502

passage between different cleanliness conditions. These should have supply 503

and extract air systems as appropriate. 504

505

4.2.2. Areas such as airlocks, change rooms and passages, should be 506

designed so that the required pressure cascades can be achieved. 507

508

4.2.3. Detailed diagrams depicting pressure cascades, air flow directions 509

and flow routes for personnel and materials should be prepared and 510

maintained. 511

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4.2.4. Where possible, personnel and materials should not move from a 513

higher cleanliness zone to a lower cleanliness zone and back to a higher 514

cleanliness zone (if moving from a lower cleanliness zone to a higher 515

cleanliness zone, changing /decontamination procedures should be 516

followed). 517

518

4.2.5. The final stage of the changing room should be the same GMP 519

classification grade as the area into which it leads. Changing rooms should 520

be of a sufficient size to allow for ease of changing. Changing rooms should 521

be equipped with mirrors so that personnel can confirm the correct fit of 522

garments before leaving the changing room. Appropriate hand wash and 523

sanitizing facilities should be provided. Hand-wash basins should be 524

provided with elbow taps or sensor operated taps. 525

526

4.2.6. Door gaps around the door perimeter have a marked impact on the 527

pressure differential across the doorway. The fit of the doors should be 528

agreed upon between the architect and the HVAC designer to ensure that 529

the correct leakages are allowed for. Likewise the maintenance of doors is 530

a critical factor in room pressure control (a poorly fitting door can severely 531

compromise a room pressure differential). 532

533

4.2.7. Where the opening and closing of airlock doors could lead to cross-534

contamination, these airlock doors should not be opened simultaneously. 535

An interlocking system and a visual and/or audible warning system should 536

be operated to prevent the opening of more than one door at a time. 537

538

4.2.8. Doors should be carefully designed to avoid un-cleanable recesses; 539

sliding doors may be undesirable for this reason. Swing doors should open 540

to the high-pressure side and be provided with self-closers. Exceptions are 541

permitted based on egress and site environmental, fire, health and safety 542

containment requirements. 543

544

4.2.9. The choice of building finishes and materials also has an impact on 545

air conditioning performance and air cleanliness. Materials should be 546

selected that will provide a well-sealed building to facilitate room pressure 547

control. Materials and paint finishes should also be non-dust and particle 548

liberating as this impacts on room cleanliness. Finishes should be easy to 549

clean and non-absorbent. To reduce the accumulation of dust and to 550

facilitate cleaning, there should be no un-cleanable recesses and a minimum 551

of projecting ledges, shelves, cupboards and equipment. 552

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Working document QAS/15.639 page 17 4.3.554 The following diagrams illustrate some typical room and suite layouts with

their associated room pressures. These are purely examples and other 555

factors may dictate different room arrangements and room pressures. 556

557

Figure 3 558

Typical weigh booth layout 559

560

SOB

Dispensary Pre-Staging Room Change Room Weigh Booth Wash Bay R e tu rn A ir S h a ft Perforated Worktop Airflow Protection Plenum Floor Scale BIN BIN Dispensary Post-Staging Room Pallet M a te ri a l F lo w M a te ri a l F lo w BIN BIN BIN BIN BIN 25 Pa 35 Pa 35 Pa 35 Pa 15 Pa Table Scale 561 562 563 564 565

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Figure 4 566

Typical dispensary suite 567

568

Dispensary Pre-Staging Room Weigh Booth 1 R e tu rn A ir S h a ft Airflow Protection Plenum Dispensary Post-Staging Room Wash Bay MAL

MAL Change_Room

Weigh Booth 2 R e tu rn A ir S h a ft Airflow Protection Plenum Wash Bay MAL

MAL Change_Room Production Passage W a re h o u s e A re a Brocken Bulk Store MAL MAL Material Flow 569 570 571

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Working document QAS/15.639 page 19 Figure 5

572

Sampling booth for small volumes 573 574 S O B R e tu rn A ir S h a ft 575 576 577 Figure 6 578

Sampling Booth for larger volumes 579

580 581 582

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Figure 7 583

Change rooms and ablution layouts 584

585

Figure 8 586

Compression cubicle with change room and MAL 587 P a s s a g e Lo_w L ev_el R etu_rn A ir Low Lev el Ret urn Air S O B 588

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589

Compression cubicle without change room and MAL 590

(inclusion of airlocks dependant on risk assessment) 591 Compression Cubicle Pa ssa g e Lo_w L ev el R etu_rn A ir Low Lev el Ret urn Air 30 Pa 15 Pa Supply Air Grille 592 593

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Working document QAS/15.639 page 22 Figure 10 594 Wash-bay suite 595 P a ss a g e M a te ri a l F lo w 596 597

5. Design of HVAC systems and components 598

599

5.1.600 General 601

5.1.1. The required degree of air cleanliness in most OSD manufacturing 602

facilities can normally be achieved without the use of high-efficiency 603

particulate air (HEPA) filters, provided the air is not recirculated or in the 604

case of a single-product facility. Many open product zones of OSD form 605

facilities are capable of meeting ISO 14644-1 Class 8 or Grade D, “at-rest” 606

condition, measured against particle sizes of 0.5 µm and 5 µm, but 607

cleanliness may not necessarily be classified as such by manufacturers. 608

609

5.1.2. A risk assessment should be carried out to determine the cleanroom 610

conditions required and the extent of validation required. 611

612

5.1.3. There are two basic concepts of air delivery to pharmaceutical 613

production facilities: a recirculation system, and a full fresh air system 614

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Working document QAS/15.639 page 23 (100% outside air supply). For recirculation systems the amount of fresh air 615

should not be determined arbitrarily on a percentage basis, but, for example, 616

by the following criteria: 617

618

• sufficient fresh air to compensate for leakage from the facility and 619

loss through exhaust air systems; 620

• sufficient fresh air to comply with national building regulations 621

(depending on occupant density, between 1 and 2.5 ACPH will often

622

satisfy occupancy requirements); 623

• sufficient fresh air for odour control; 624

• sufficient fresh air to provide the required building pressurization 625

626

5.1.4. Where automated monitoring systems are used, these should be 627

capable of indicating any out-of-specification (OOS) condition without 628

delay by means of an alarm or similar system. Sophisticated computer-629

based data monitoring systems may be installed, which can aide with 630

planning of preventive maintenance and can also provide trend logging. 631

632

(This type of system is commonly referred to as a building management 633

system (BMS), building automation system (BAS) or system control and 634

data acquisition (SCADA) system. If these systems are used for critical 635

decision-making, they should be validated. If the BMS is not validated in 636

full (or in part for these critical parameters), an independent validated 637

environmental monitoring system (EMS) should be provided, specifically 638

for recording and alarming critical parameters. Critical parameters could 639

include for example, room temperature in production areas, humidity, 640

differential pressures, fan failure alarms, etc.) 641

, 642

5.1.5. Failure of a supply air fan, return air fan, exhaust air fan or dust 643

extract system fan can cause a system imbalance, resulting in a pressure 644

cascade malfunction with a resultant airflow reversal. 645

646

5.1.6. A fan interlock failure matrix should be set up, such that if a fan 647

serving a high pressure zone fails, then any fans serving surrounding lower 648

pressure areas should automatically stop, to prevent an airflow reversal and 649

possible cross-contamination. This fan stop-start matrix should apply to the 650

switching on and switching off of systems to ensure that there is no flow 651

reversal causing cross-contamination. 652

653

5.1.7. Appropriate alarm systems should be in place to alert personnel if a 654

critical fan fails All critical alarms should be easily identifiable and visible 655

and/or audible to relevant personnel. 656

657 658

(24)

5.2.659 Air distribution 660

5.2.1. The positioning of supply and extract grilles should be such as to 661

provide effective room flushing. Low-level return or exhaust air grilles are 662

usually preferred. However, where this is not possible, a higher air change 663

rate may be needed to achieve a specified clean area condition, e.g. where 664

ceiling return air grilles are used. 665

666

5.2.2. There may be alternative locations for return air. For example, 667

referring to Figure 11, Room 1 (low-level return air) and Room 2 (ceiling 668 return air).. 669 670 671 Figure 11 672

Air-handling system with high-efficiency particulate air filters in air-673 handling unit 674 675 P ri m a ry F ilt e r S u p p ly A ir F a n S e co n d a ry F ilt e r H E P A F ilt e r C o o lin g C o il 676 677

The airflow schematics of the two systems (Figures 1 1 and 1 2) indicate 678

air-handling units with return air or recirculated air, having a percentage 679

of fresh air added. Depending on product characteristics and dust loading 680

it is sometimes preferable to fit filters on return air outlets or in return air 681

ducting. 682

(25)

Working document QAS/15.639 page 25 Figure 12 is a schematic diagram of an air-handling system serving 684

rooms with horizontal unidirectional flow, vertical unidirectional flow and 685

turbulent flow, for rooms 3, 4 and 5, respectively. In this case the HEPA 686

filters are terminally mounted at the rooms, and not in the AHU. 687

Terminally mounted HEPA filters can assist with preventing cross-688

contamination from room to room in the event of a fan failure condition. 689

The decision whether to install terminal HEPA filters should be based on a 690 risk-assessment study. 691 692 693 694 Figure 12 695

Horizontal unidirectional flow, vertical unidirectional flow and 696 turbulent flow 697 698 P ri m a ry F ilt e r S u p p ly A ir F a n S e c o n d a ry F ilt e r H E P A F il te rs C o o lin g C o il 699 700 5.3.701 Recirculation system 702

5.3.1. There should be no risk of contamination or cross-contamination 703

(including by fumes and volatiles) due to recirculation of air. 704

705

5.3.2. Depending on the airborne contaminants in the return-air system 706

it may be acceptable to use recirculated air, provided that HEPA filters 707

are installed in the supply air stream (or return air stream) to remove 708

contaminants and thus prevent cross-contamination. The HEPA filters for 709

this application should have an EN 1822 classification of H13. 710

711

5.3.3. HEPA filters may not be required where the air-handling system 712

is serving a single product facility and there is evidence that cross- 713

contamination would not be possible. 714

(26)

5.3.4. Recirculation of air from areas where pharmaceutical dust is not 716

generated such as secondary packing, may not require HEPA filters in the 717

system. 718

719

5.3.5. HEPA filters may be located in the air-handling unit or placed 720

terminally. Where H E P A fi l t e r s a r e t e r m i n a l l y m o u n t e d t h e y 721

s h o u l d preferably not be connected to the ducting by means of flexible 722

ducting. Due to the high air pressure required for the terminal filter, this 723

connection should preferably be a rigid duct connection. Where flexible 724

ducting is used, it should be as short as possible and properly fixed to 725

withstand duct pressure. When HEPA filters are terminally mounted, it 726

should be possible to carry out filter integrity tests from within the room. 727

The filter housings will therefore require ports for measuring appropriate 728

upstream concentration (refer to ISO 14644.3) and penetration 729

concentration from within the room. In addition it should be possible to 730

monitor the filter pressure drop in individual HEPA filters. 731

732

5.3.6. Air containing dust from highly toxic processes and/or solvents or 733

flammable vapours should never be recirculated to the HVAC system. 734

735 736 737

5.4.738 Full fresh-air systems 739

740

5.4.1. The required degree of filtration of the exhaust air depends on the 741

exhaust air contaminants and local environmental regulations. HEPA filters 742

in the exhaust system would normally only be required when handling 743

hazardous materials. 744

745

Figure 13 indicates a system operating on 100% fresh air and would 746

normally be used in a facility dealing with toxic products or solvents, where 747

recirculation of air with contaminants should be avoided. 748

749 750

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751

Full fresh-air system 752 753 754 755 756 757

(28)

Figure 14 758

Full fresh-air system with energy recovery 759 760 P ri m a ry F ilt e r S u p p ly A ir F a n S e c o n d a ry F ilt e r H E P A F ilt e r P ri m a ry F ilt e r E x h a u s t A ir F a n S e c o n d a ry F ilt e r H E P A F ilt e r F re sh A ir C o o lin g C o il 761 762

5.4.2. Energy-recovery wheels if used in multiproduct facilities should 763

have been subjected to a risk assessment to determine if there is any 764

risk of cross-contamination. When such wheels are used they should 765

not become a source of possible contamination (see Figure 14). Note: 766

Alternatives to the energy-recovery wheels, such as crossover plate heat

767

exchangers and water-coil heat exchangers, may be used in multiproduct

768

facilities.

769 770

5.4.3. The potential for air leakage between the supply air and exhaust air 771

as it passes through the wheel should be prevented. The relative pressures 772

between supply and exhaust air systems should be such that the exhaust air 773

system operates at a lower pressure than the supply system. 774

775 776

5.5.777 Additional system components 778

5.5.1. A schematic diagram of the airflow for a typical system serving a 779

low relative humidity suite is represented in Figure 15. Air can be dried 780

with a chemical drier (e.g. a rotating desiccant wheel which is continuously 781

regenerated by means of passing hot air through one segment of the wheel). 782

Alternative methods of drying air are also available. 783

(29)

Working document QAS/15.639 page 29 Figure 15

784

Air-handling system with chemical drying 785 S u p p ly A ir F a n S e c o n d a ry F ilt e r H E P A F ilt e r

AIR HANDLING UNIT

LOW HUMIDITY PRODUCTION FACILITY P ro c e s s A ir F a n

CHEMICAL DRIER UNIT Reactivation Air Fan P ri m a ry F ilt e r P ri m a ry F ilt e r Fresh Air Chemical Drier Desiccant Wheel S R F = Supply Air = Return Air = Fresh Air E= Exhaust Air E F S S R R R R C o o lin g C o il -+ + R e a c ti v a ti o n H e a te r 786 787

5.5.2. The figure illustrates the chemical drier handling part of the fresh 788

air/return air mixture on a bypass flow. The location of the chemical drier 789

should be considered in the design phase. The practice of locating the 790

complete chemical drier unit in the production cubicle is not recommended 791

as this could be a source of contamination or cross-contamination. Examples 792

of appropriate locations for the drying wheel could include: 793

794

— full flow of fresh/return air; 795

— partial handling of fresh/return air (bypass airflow); 796

— return air only; 797

— fresh air only; or 798

— pre-cooled air with any of the above alternatives. 799

800

5.5.3. Possible additional components that may be required in air handling 801

should be considered depending on the climatic conditions and locations. 802

These may include items such as: 803

804

‒ frost coils on fresh air inlets in very cold climates to preheat the air; 805

‒ reheaters for humidity control 806

‒ automatic air volume control devices 807

‒ sound attenuators 808

(30)

‒ snow eliminators to prevent snow entering air inlets and 809

blocking airflow 810

‒ dust eliminators on air inlets in arid and dusty locations 811

‒ moisture eliminators in humid areas with high rainfall 812

‒ fresh air precooling coils for very hot or humid climates. 813 814 815 6. Protection 816 817

6.1. Products and personnel 818

819

6.1.1. Areas for the manufacture of pharmaceuticals, where pharmaceutical 820

starting materials and products, utensils, primary packing materials and 821

equipment are exposed to the environment, should be defined as “clean 822

areas”, “clean zones”, “controlled areas” or “cleanrooms”. 823

824

6.1.2. The achievement of a particular clean area condition depends on a 825

number of criteria that should be addressed at the design and qualification 826

stages. A suitable balance between the different criteria will be required in 827

order to create an efficient clean area. 828

829

6.1.3. Some of the basic criteria to be considered which affects room 830

cleanliness should include: 831

832

• building finishes and structure• dust control and containment 833

• air filtration 834

• air change rate or flushing rate 835

• room pressure 836

• location of air terminals and directional airflow 837 • temperature 838 • relative humidity 839 • material flow 840 • personnel flow 841 • gowning procedures 842 • equipment movement 843

• process being carried out (open or closed system) 844

• outside air conditions 845

• occupancy 846

• type of product 847

• cleaning standard operating procedures (SOPs). 848

849

6.1.4. Air filtration and air change rates should be set to ensure that the 850

defined clean area condition is attained. 851

(31)

Working document QAS/15.639 page 31 6.1.5. The air change rates should be determined by the manufacturer and 853

designer, taking into account the various critical parameters using a risk 854

based approach with due consideration of capital and running costs and 855

energy usage. Primarily the air change rate should be set to a level that will 856

achieve the required clean area condition. 857

858

6.1.6. Air change rates are normally determined by the following 859

considerations (could normally vary between 6 and 20 air changes per hour): 860

861

• area condition required: whether a specific room cleanliness 862

condition is in fact required and whether the room condition is 863

rated for an “at rest” condition or an “operational” condition (air 864

change rate should be selected on need rather than tradition); 865

• the product characteristics (e.g. odours, hygroscopicity, etc.); 866

• the quality and filtration of the supply air; 867

• particulates generated by the manufacturing process; 868

• particulates generated by the operators; 869

• configuration of the room and air supply and extract locations; 870

• sufficient air to achieve containment effect and to clean up the area; 871

• sufficient air to cope with the room heat load; 872

• sufficient air to balance extract rates; 873

• sufficient air to maintain the required room pressure. 874

875

6.1.7. If a cleanroom classification is specified, the manufacturer should 876

state whether this is achieved under “as-built” (Figure 16), “at-rest” (Figure 877

17) or “operational” (Figure 18) conditions. 878

879

6.1.8. Room classification tests in the “as-built” condition should be 880

carried out on the bare room, in the absence of any equipment or personnel. 881

882

6.1.9. Room classification tests in the “at-rest” condition should be carried 883

out with the equipment operating where relevant, but without any operators. 884

Because of the amounts of dust usually generated in a solid dosage facility, 885

the clean area classifications would be rated for the “at-rest” condition. 886

887

6.1.10. Room classification tests in the “operational” condition are 888

normally carried out during the normal production process with equipment 889

operating, and the normal number of personnel present in the room. When 890

qualifying for the operational condition details of the process operating, 891

number and positions of staff should be stipulated for each room, to enable 892

future qualifications to duplicate the same conditions. 893

894

6.1.11. Room clean-up or recovery tests are performed to determine 895

whether the installation is capable of returning to a specified cleanliness 896

(32)

level within a finite time, after being exposed briefly to a source of 897

airborne particulate challenge. Room “clean-up” or “recovery” tests should 898

demonstrate a change in particle concentration by a factor of 100 within 899

the prescribed time (as per ISO 14644-3 clause B.12) (3). The guidance 900

time period for clean-up or recovery is about 15 to 20 minutes. 901

In some instances it is not possible to increase the concentration by a factor 902

of 100 (such as for an ISO 14644 Class 8 condition) as the high particle 903

concentration can damage the particle counter. In this instance the particle 904

decay method can be used as per ISO 14644-3 clause B.12.3.2. 905

906

6.1.12. Materials and products should be protected from contamination 907

and cross-contamination during all stages of manufacture (see also section 908

6.5 for cross-contamination control). 909

910

Note: contaminants may result from inappropriate premises (e.g. poor design,

911

layout or finishing), poor cleaning procedures, contaminants brought in by

912

personnel, poor manufacturing process and a poor HVAC system.

913 914 Figure 16 915 “As-built” condition 916 917 918 919 920

(33)

Working document QAS/15.639 page 33 Figure 17 921 “At-rest” condition 922 923 924 Figure 18 925 “Operational” condition 926 927

(34)

928 929

6.1.13. Airborne contaminants should be controlled through effective 930

ventilation and filtration. 931

932

6.1.14. External contaminants should be removed by effective filtration of 933

the supply air (see Figure 19 for an example of a shell-like building 934

layout to enhance containment and protection from external 935

contaminants). 936

937

6.1.15. Internal contaminants should be controlled by dilution and 938

flushing of contaminants in the room, or by displacement airflow (See 939

Figures 20 and 21 for examples of methods for the flushing of airborne 940

contaminants). 941

942

6.1.16. Airborne particulates and the degree of filtration should be 943

considered critical parameters with reference to the level of product 944

protection required. 945

946

6.1.17. Personnel should not be a source of contamination. 947

948

6.1.18. The level of protection and air cleanliness for different areas should 949

be determined according to the product being manufactured, the process 950

being used and the product’s susceptibility to degradation (Table 3). 951

(35)

952

Shell-like containment control concept 953 954 W a s te E x it P e rs o n n e l M o v e m e n t P e rs o n n e l M o v e m e n t 955 956 957 6.2. Air filtration 958 959

Note: The degree to which air is filtered plays an important role in the

960

prevention of contamination and the control of cross-contamination.

961 962

6.2.1. The type of filters required for different applications depends on 963

the quality of the ambient air and the return air (where applicable) and 964

also on the air change rates. Table 4 gives the recommended filtration 965

levels for different levels of protection in a pharmaceutical facility. 966

Manufacturers should determine and prove the appropriate use of 967

filters. 968

969

6.2.2. Filter classes should always be linked to the standard test method 970

because referring to actual filter efficiencies can be very misleading (as 971

different test methods each result in a different efficiency value for the 972

same filter). (Referring to filter classifications such as an 85% filter or a 5 µm 973

filter are not valid classifications and should not be used, as this can lead to 974

the incorrect filter being installed. Only the EN 779 and EN 1822 or ISO 975

29463 classifications, as per Tables 1 and 2, should be used.) 976

(36)

Working document QAS/15.639 page 36 977 978 Table 1 979

Comparison of filter test standards 980 Eurovent 4/5 rating ASHRAE 52.2 Eurovent 4/5 ASHRAE 52.1 BS6540 Part 1 Eurovent 4/5 ASHRAE 52.1 BS6540 Part 1 EN 779 & EN 1822 IS O 2 9 4 6 3 (supersede d) Merv rating Average arrestance Am (%) Average dust spot efficiency Em (%) MPPS integral overall efficiency (%) EN Rating 99.999995 U17 E N 1 8 2 2 : 2 0 0 9 75E 99.99995 U16 65E EU 14 99.9995 U15 55E EU 13 Merv 18 99.995 H14 45E EU 12 Merv 17 99.95 H13 35E EU 11 99.5 E12 25E EU 10 95 E11 15E EU 9 Merv 16 >95 85 E10 EU 9 Merv 15 95 F9 E N 1 8 2 2 : 2 0 0 9 EU 8 Merv 14 90 MPPS = most penetrating particle Size F8 Merv 13 >98 85 F7 EU 7 >98 80 Merv 12 >95 75 EU 6 >95 70 F6 Merv 11 >95 65 >95 60 Merv 10 >95 55 EU 5 Merv 9 >95 50 F5 Merv 8 >95 45 >95 40 Merv 7 >90 35 EU 4 >90 30 G4 Merv 6 90 25 EU 3 Merv 5 85 20 G3 80 <20 Merv 4 75 EU 2 Merv 3 70 G2 Merv 2 65 EU 1 Merv 1 <65 G1 981

(37)

Working document QAS/15.639 page 37 Table 2

982

Comparison of ISO and EN Filter Standards 983

ISO 29463

EN 1822 Global or Integral

Values for MPPS

Local Values for MPPS Filter Class Collection Efficiency (%) Penetrat ion (%) Collection Efficiency (%) Penetrat ion (%) MPPS Integral Overall Efficiency (%) EN Rating ISO 75 E ≥ 99.999995 ≤ 0.000005 ≥ 99.9999 ≤ 0.0001 99.999995 U17 ISO 70 E ≥ 99.99999 ≤ 0.00001 ≥ 99.9999 ≤ 0.0001 - - ISO 65 E ≥ 99.99995 ≤ 0.00005 ≥ 99.99975 ≤ 0.00025 99.99995 U16 ISO 60 E ≥ 99.9999 ≤ 0.0001 ≥ 99.9995 ≤ 0.0005 - - ISO 55 E ≥ 99.99995 ≤ 0.0005 ≥ 99.9975 ≤ 0.0025 99.9995 U15 ISO 50 E ≥ 99.999 ≤ 0.001 ≥ 99.995 ≤ 0.005 - - ISO 45 E ≥ 99.995 ≤ 0.005 ≥ 99.975 ≤ 0.025 99.995 H14 ISO 40 E ≥ 99.99 ≤ 0.01 ≥ 99.95 ≤ 0.05 - - ISO 35 E ≥ 99.95 ≤ 0.05 ≥ 99.75 ≤ 0.25 99.95 H13 ISO 30 E ≥ 99.9 ≤ 0.1 - - ISO 25 E ≥ 99.5 ≤ 0.5 99.5 E12 ISO 20 E ≥ 99 ≤ 1 - - ISO 15 E ≥ 95 ≤ 5 95 E11

The above all tested for MPPS (most penetrating particle size)

Note: The filter classifications referred to above relate to the EN

984

1822:2009 and EN 779: 2002 test standards (EN 779 relates to filter

985

classes G1 to F9 and EN1822 relates to filter classes E10 to U17).

(38)

987

6.2.3. In selecting filters, the manufacturer should have considered other 988

factors, such as particularly contaminated ambient conditions, local 989

regulations and specific product requirements. Good prefiltration extends 990

the life of the more expensive filters downstream. 991

992

6.2.4. Filters have an impact on the cleanroom class or Level of 993

Protection. The different levels of protection and recommended filters 994

grades are given in Tables 3 and 4 below. 995

996

Table 3 997

Examples of levels of protection (based on ISPE oral solid dosage 998

(OSD) guideline criteria) 999

1000

Level Condition Example of area

Level 1 General Area with normal housekeeping and maintenance where there is no potential for product contamination, e.g. warehousing. Level 2 Protected Area in which steps are taken to protect

the pharmaceutical starting material or product from direct or indirect

contamination or degradation, e.g. secondary packing, warehousing, first stage change rooms.

Level 3 Controlled Area in which specific environmental conditions are defined, controlled and monitored to prevent contamination or degradation of the pharmaceutical starting material or product, e.g. where product, starting materials and components are exposed to the room environment; plus equipment wash and storage areas for equipment product contact parts.

1001 1002

(39)

Working document QAS/15.639 page 39 Table 4

1003

Levels of protection and recommended filtration 1004

1005

Level of protection Recommended filtration

Level 1 Primary filters only (e.g. EN 779 G4 filters) Level 2 Protected areas operating on 100% outside air:

primary plus secondary filters (e.g. EN 779 G4 plus F8 or F9 filters)

Level 3 Production facility operating on recirculated plus ambient air, where potential for cross-contamination exists: Primary plus secondary plus tertiary filters (e.g. EN 779 G4 plus F8 plus EN 1822 H13 filters) (for full fresh air system, without recirculation, G4 and F8 or F9 filters are acceptable)

1006

6.2.5. Materials for components of an HVAC system should be selected 1007

with care so that they do not become a source of contamination. Any 1008

component with the potential for liberating particulate or microbial 1009

contamination into the airstream should be located upstream of the final 1010

filters. 1011

1012

6.2.6. Where possible ventilation dampers, filters and other services should 1013

be designed and positioned so that they are accessible from outside the 1014

manufacturing areas (service voids or service corridors) for maintenance 1015

purposes. 1016

1017

6.2.7. Directional airflow within production or primary packing areas 1018

should assist in preventing contamination. Airflows should be planned in 1019

conjunction with operator locations, so as to minimize contamination of the 1020

product by the operator and also to protect the operator from dust inhalation. 1021

Different airflow patterns are indicated in Figures 20 & 21 below. 1022

1023 1024

(40)

Figure 20 1025

Turbulent dilution of dirty air 1026

1027

1028 1029 1030

Low-level extract is ideal for dust suppression purposes, but is not 1031

essential. (Low-level extract is essential for Grade A, B & C classified 1032

areas.) 1033

1034 1035

(41)

1036

Unidirectional displacement of dirty air 1037 1038 1039 1040 1041 1042

6.2.8. HVAC air distribution components should be designed, installed 1043

and located to prevent contaminants generated within the room from being 1044

spread. 1045

1046

6.2.9. Supply air diffusers should be selected with care taking consideration 1047

of, e.g. room requirements and positions of equipment and operators in the 1048

room. Supply air diffusers of the high induction type (e.g. those typically 1049

used for office-type air-conditioning) should where possible not be used 1050

in clean areas where dust is liberated. Air diffusers should be of the non- 1051

induction type, introducing air with the least amount of induction so as to 1052

maximize the flushing effect. In rooms where the process results in high 1053

dust liberation; perforated plates or low induction swirl diffusers with 1054

low level extract or return should be used (to contain the dust at the lower 1055

level of the room) (see Figures 22–24 for illustrations of the three types of 1056

diffuser). In cases where dust liberation is low, ceiling return air grilles may 1057 be acceptable. 1058 1059 1060 1061

(42)

6.2.10. Induction and certain swirl diffusers induce room air vertically 1062

up to the diffuser to mix with the supply air. These diffusers create good 1063

dilution of contaminants in the room and may be used in rooms where there 1064

is low dust liberation. However, if used in rooms where excessive dust is 1065

generated, the distribution of dust in the room could be hazardous for the 1066

operators in the room, as dust is drawn up into the supply air stream and 1067

then spread throughout the room. Airflow patterns for different diffuser 1068

types are indicated in figures 22, 23 & 24 below. 1069 1070 Figure 22 1071 Induction diffuser 1072 1073 1074 1075 1076

(43)

1077

Perforated plate diffuser 1078

1079 1080 1081