SUPPLEMENTARY GUIDELINES ON

August 2015 Draft document for comment 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS (August 2015) World Health Organization 2015 All rights reserved. DRAFT FOR COMMENT 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 (kopps@who.int) with a copy to Ms Marie Gaspard (gaspardm@who.int) 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 bonnyw@who.int) and we will add it to our electronic mailing list. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. Please send any request for permission to: Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730; email: kopps@who.int The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.

page 2 41 42 43 44 45 46 47 SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/15.639 SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR- CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE FORMS. PROPOSAL FOR REVISION 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 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 Circulation of revised working document for public consultation Consolidation of comments received and review of feedback Presentation to fiftieth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations Any other follow-up action as required 29 June 1 July 2015 July-August 2015 September 2015 10 October 2015 12 16 October 2015 48 49 50 51

page 3 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 BACKGROUND During the consultation on data management, bioequivalence, GMP and medicines inspection held in 2015 the possible revision of the guidance for (WHO Technical Report Series, No. 961, Annex 5, 2011) was discussed with the inspectors. It was suggested that in light of the new developments a draft for revision be prepared. This new proposal for revision was drafted based on the feedback received, the new, current trends in engineering and the experience gained during the implementation of this guidance in inspection. At the same time, the opportunity was used to improve the graphic images and make them more readable in e-version as well as in print. Summary of main changes Below is a list of the main changes that have been made to the WHO Technical Report Series, No. 961, 2011, Annex 5: Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms. 1. The Premises section has been moved towards the beginning of the document due to its important impact on HVAC designs. In addition the text has been expanded and a number of sample layouts have been included. 2. The HVAC sections have been re-arranged into a more logical sequence. 3. The Commissioning, Qualification and Validation (C, Q & V) section has been aligned with the proposed revisions to the Supplementary GMP Validation TRS937 Annex4 guideline. 4. Significant notes were added under the new Supplementary notes on test procedures section. 5. The Maintenance section has been separated out of the C, Q & V section. 6. All the diagrams have been revised (mainly to achieve better clarity). 7. Throughout the document additional notes have been added and text revised to provide better understanding and avoid ambiguity. 8. A list of abbreviations has been added.

91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 Working document QAS/15.639 page 4 Contents 1. Introduction 2. Scope of document 3. Glossary 4. Premises 5. Design of HVAC systems and components 5.1 General 5.2 Air distribution 5.3 Recirculation system 5.4 Full fresh-air systems 5.5 Additional system components 6. Protection 6.1 Products and personnel 6.2 Air filtration 6.3 Unidirectional airflow 6.4 Infiltration 6.5 Cross-contamination 6.6 Displacement concept (low pressure differential, high airflow) 6.7 Pressure differential concept (high pressure differential, low airflow) 6.8 Physical barrier concept 6.9 Temperature and relative humidity 7. Dust control 8. Protection of the environment 8.1 General 8.2 Dust in exhaust air 8.3 Vapour and fume removal 9. Commissioning, qualification and validation 9.1 General 9.2 Commissioning 9.3 Qualification 9.4 Supplementary notes on test procedures 10. Maintenance 11. Abbreviations References Further reading page

page 5 1301. Introduction 131 132 Heating, ventilation and air-conditioning (HVAC) play an important role in 133 ensuring the manufacture of quality pharmaceutical products. A well designed 134 135 HVAC system will also provide comfortable conditions for operators. 136 These guidelines mainly focus on recommendations for systems for 137 manufacturers of solid dosage forms. The guidelines also refer to other 138 systems or components which are not relevant to solid dosage form 139 manufacturing plants, but which may assist in providing a comparison 140 141 between the requirements for solid dosage-form plants and other systems. 142 HVAC system design influences architectural layouts with regard to items 143 such as airlock positions, doorways and lobbies. The architectural components 144 have an effect on room pressure, differential cascades and cross- 145 contamination control. The prevention of contamination and cross- 146 contamination is an essential design consideration of the HVAC system. In 147 view of these critical aspects, the design of the HVAC system should be 148 considered at the concept design stage of a pharmaceutical manufacturing 149 150 plant. 151 Temperature, relative humidity and ventilation should be appropriate and 152 should not adversely affect the quality of pharmaceutical products during 153 154 their manufacture and storage, or the accurate functioning of equipment. 155 This document aims to give guidance to pharmaceutical manufacturers 156 and inspectors of pharmaceutical manufacturing facilities on the design, 157 installation, qualification and maintenance of the HVAC systems. 158 These guidelines are intended to complement those provided in Good 159 manufacturing practices for pharmaceutical products (1) and should be read 160 in conjunction with the parent guide. The additional standards addressed by 161 the present guidelines should, therefore, be considered supplementary to 162 the general requirements set out in the parent guide. 163 1642. Scope of document 165 166 These guidelines focus primarily on the design and good manufacturing 167 practices (GMP) requirements for HVAC systems for facilities for the 168 manufacture of solid dosage forms. Most of the system design principles 169 for facilities manufacturing solid dosage forms also apply to facilities 170 manufacturing other dosage forms and other classes of products including 171 biological products, herbal medicines, complimentary medicines and 172 finishing process steps for APIs. Additional specific requirements apply 173 for handling of sterile products and hazardous products. Guidelines for 174 hazardous, sterile and biological product facilities are covered in separate

page 6 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 WHO guidelines (WHO Technical Report Series, No. 957, Annex 3, Technical Report Series, No. 961 Annex 6 and working document WHO/BS/2015.2253, intended to replace Technical Report Series, No. 822, Annex 1, 1992, respectively). These guidelines are intended as a basic guide for use by pharmaceutical manufacturers and GMP inspectors. They are not intended to be prescriptive in specifying requirements and design parameters. There are many parameters affecting a clean area condition and it is, therefore, difficult to lay down the specific requirements for one particular parameter in isolation. Many pharmaceutical manufacturers have their own engineering design and qualification standards, and requirements may vary from one manufacturer to the next. Design parameters and user requirements should, therefore, be set realistically for each project, with a view to creating a cost-effective design, yet still complying with all regulatory standards and ensuring that product quality and safety are not compromised. The three primary aspects addressed in this manual are the roles that the HVAC system plays in product protection, personnel protection and environmental protection (Figure 2). Cognizance should be taken of the products to be manufactured when establishing system design parameters. A facility manufacturing multiple different products may have more stringent design parameters with respect to cross-contamination control, compared with a single product facility. Risk assessment studies should be an integral part of the facility design and implementation, from the URS stage right through to validation, as indicated in the diagram below (Figure 1). Validation protocols and criteria should be justified by links to a written risk assessment. 205

L Working document QAS/15.639 page 7 206 207 Figure 1 GMP compliance sequence diagram PROJECT INCEPTION G M P C O M P USER REQUIREMENT SPECIFICATION L I A NC E A NC E I QUALIFICATION & VALIDATION RISK ASSESSMENT STUDIES FACILITY LAYOUTS G M P P M Installations C O C O G M P HVAC & SERVICES DESIGNS ENERGY EFFICIENCY STUDIES A NC E L M P I 208 209 210

page 8 211 212 213 214 Figure 2 The guidelines address the various system criteria according to the sequence set out in this diagram 215

page 9 2163. Glossary 217 218 The definitions given below apply to terms used in these guidelines. They 219 may have different meanings in other contexts. 220 221 acceptance criteria 222 Measurable terms under which a test result will be considered acceptable. 223 224 action limit 225 The action limit is reached when the acceptance criteria of a critical 226 parameter have been exceeded. Results outside these limits will require 227 specified action and investigation. 228 229 air changes per hour 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 The volume of air supplied to a room, in m 3 /hr, divided by the room volume, in m 3. air-handling unit The air-handling unit serves to condition the air and provide the required air movement within a facility. airflow protection booth A booth or chamber, typically for purposes of carrying out Sampling or Weighing, in order to provide product containment and operator protection. Similar to UDAF protection but not necessarily a Grade A condition. airlock An enclosed space with two or more doors, which is interposed between two or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the airflow between those rooms when they need to be entered. An airlock is designed for and used by either people or goods (PAL, personnel airlock; MAL, material airlock). alert limit The alert limit is reached when the normal operating range of a critical parameter has been exceeded, indicating that corrective measures may need to be taken to prevent the action limit being reached. as-built Condition where the installation is complete with all services connected and functioning but with no production equipment, materials or personnel present. at-rest Condition where the installation is complete with equipment installed and

page 10 259 260 261 262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 operating in a manner agreed upon by the customer and supplier, but with no personnel present. central air-conditioning unit (see air-handling unit) change control A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state. clean area (cleanroom)1 1 An area (or room or zone) with defined environmental control of particulate and microbial contamination, constructed and used in such a way as to reduce the introduction, generation and retention of contaminants within the area. closed system A system where the product or material is not exposed to the manufacturing environment. commissioning Commissioning is the documented process of verifying that the equipment and systems are installed according to specifications, placing the equipment into active service and verifying its proper action. Commissioning takes place at the conclusion of project construction but prior to validation. containment A process or device to contain product, dust or contaminants in one zone, preventing it from escaping to another zone. contamination The undesired introduction of impurities of a chemical or microbial nature, or of foreign matter, into or on to a starting material or intermediate, during production, sampling, packaging or repackaging, storage or transport. controlled area An area within the facility in which specific environmental facility conditions and procedures are defined, controlled, and monitored to prevent degradation or cross-contamination of the product. 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.

page 11 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 controlled-not classified An area where some environmental conditions are controlled (such as temperature), but the area has no cleanroom classification critical parameter or component A processing parameter (such as temperature or relative humidity) that affects the quality of a product, or a component that may have a direct impact on the quality of the product. critical quality attribute A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range or distribution to ensure the desired product quality. cross-contamination Contamination of a starting material, intermediate product or finished product with another starting material or product during production. design condition Design condition relates to the specified range or accuracy of a controlled variable used by the designer as a basis for determining the performance requirements of an engineered system. design qualification Design qualification is the documented check of planning documents and technical specifications for conformity of the design with the process, manufacturing, GMP and regulatory requirements. direct impact system A system that is expected to have a direct impact on product quality. These systems are designed and commissioned in line with good engineering practice and, in addition, are subject to qualification practices. exfiltration Exfiltration is the egress of air from a controlled area to an external zone. facility The built environment within which the clean area installation and associated controlled environments operate together with their supporting infrastructure. good engineering practice Established engineering methods and standards that are applied throughout the project life-cycle to deliver appropriate, cost-effective solutions.

page 12 342 343 344 345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 hazardous substance or product A product or substance that may present a substantial risk of injury to health or to the environment HVAC Heating, ventilation and air-conditioning. Also referred to as Environmental control systems indirect impact system This is a system that is not expected to have a direct impact on product quality, but typically will support a direct impact system. These systems are designed and commissioned according to good engineering practice only. infiltration Infiltration is the ingress of air from an external zone into a controlled area. installation qualification Installation qualification is documented verification that the premises, HVAC system, supporting utilities and equipment have been built and installed in compliance with their approved design specification. Most penetrating particle size (MPPS) MPPS is a means of determining HEPA & ULPA filter efficiencies. The MPPS is the particle size with the highest penetration for a defined filter medium. (MPPS Integral overall efficiency is the efficiency, averaged over the whole superficial face area of a filter element under a given operating conditions of the filter. MPPS local efficiency is the efficiency, at a specific point of the filter element under given operating conditions of the filter) NLT Not less than NMT Not more than no-impact system This is a system that will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned according to good engineering practice only. non-critical parameter or component A processing parameter or component within a system where the operation,

page 13 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 contact, data control, alarm or failure will have an indirect impact or no impact on the quality of the product. normal operating range The range that the manufacturer selects as the acceptable values for a parameter during normal operations. This range must be within the operating range. OOS Out of specification operating limits The minimum and/or maximum values that will ensure that product and safety requirements are met. operating range Operating range is the range of validated critical parameters within which acceptable products can be manufactured. operational condition This condition relates to carrying out room classification tests with the normal production process with equipment in operation, and the normal staff present in the specific room. operational qualification (OQ) Operational qualification is the documentary evidence to verify that the equipment operates in accordance with its design specifications in its normal operating range and performs as intended throughout all anticipated operating ranges. oral solid dosage (OSD) Usually refers to an OSD plant that manufactures medicinal products such as tablets, capsules and powders to be taken orally. pass-through-hatch (PTH) or pass box (PB) A cabinet with two or more doors for passing equipment or product, whilst maintaining the pressure cascade and segregation between two controlled zones. A passive PTH has no air supply or extract. A dynamic PTH has an air supply into the chamber. performance qualification (PQ) Performance qualification is the documented verification that the process and/ or the total process related to the system performs as intended throughout all anticipated operating ranges.

page 14 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 point extraction Air extraction to remove dust with the extraction point located as close as possible to the source of the dust. pressure cascade A process whereby air flows from one area, which is maintained at a higher pressure, to another area at a lower pressure. qualification Qualification is the planning, carrying out and recording of tests on equipment and a system, which forms part of the validated process, to demonstrate that it will perform as intended. quality critical process parameter (QCPP) A process parameter which could have an impact on the critical quality attribute. relative humidity The ratio of the actual water vapour pressure of the air to the saturated water vapour pressure of the air at the same temperature expressed as a percentage. More simply put, it is the ratio of the mass of moisture in the air, relative to the mass at 100% moisture saturation, at a given temperature. standard operating procedure (SOP) An authorized written procedure, giving instructions for performing operations, not necessarily specific to a given product or material, but of a more general nature (e.g. operation of equipment, maintenance and cleaning, validation, cleaning of premises and environmental control, sampling and inspection). Certain SOPs may be used to supplement product-specific master and batch production documentation. turbulent flow Turbulent flow, or non-unidirectional airflow, is air distribution that is introduced into the controlled space and then mixes with room air by means of induction. unidirectional airflow (UDAF) Unidirectional airflow is a rectified airflow over the entire cross-sectional area of a clean zone with a steady velocity and approximately parallel streamlines (see also turbulent flow). validation

page 15 472 The documented act of proving that any procedure, process, equipment, 473 material, activity or system actually leads to the expected results. 474 475 validation master plan (VMP) 476 Validation master plan is a high-level document which establishes an 477 umbrella validation plan for the entire project, and is used as guidance by 478 the project team for resource and technical planning (also referred to as 479 master qualification plan). 480 4814. Premises 482 483 4.1. There is a close relationship between architectural design and HVAC 484 design, as they both have an impact on the functionality of the other. 485 HVAC system design influences architectural layouts with regard to items 486 such as airlock positions, doorways and lobbies. The architectural layouts 487 and building components have an effect on room pressure differential 488 cascades and cross-contamination control. The prevention of contamination 489 and cross-contamination is an essential design consideration of the HVAC 490 system. In view of these critical aspects, the design of the HVAC system 491 should be considered at the concept design stage of a pharmaceutical 492 manufacturing plant, and the design should be closely co-ordinated with the 493 architectural designers. In addition the architectural layout must ensure that 494 the material flow is in a logical sequence, excluding material flow reversals 495 where possible. 496 497 4.2. As the efficient operation of the air-handling system and cleanliness levels 498 attained are reliant on the correct building layout and building finishes, the 499 following items should be considered. 500 501 4.2.1. Adequate airlocks, such as personnel airlocks (PAL) and/or material 502 airlocks (MAL), change rooms and passages should be provided to protect 503 passage between different cleanliness conditions. These should have supply 504 and extract air systems as appropriate. 505 506 4.2.2. Areas such as airlocks, change rooms and passages, should be 507 designed so that the required pressure cascades can be achieved. 508 509 4.2.3. Detailed diagrams depicting pressure cascades, air flow directions 510 and flow routes for personnel and materials should be prepared and 511 maintained. 512

page 16 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 4.2.4. Where possible, personnel and materials should not move from a higher cleanliness zone to a lower cleanliness zone and back to a higher cleanliness zone (if moving from a lower cleanliness zone to a higher cleanliness zone, changing /decontamination procedures should be followed). 4.2.5. The final stage of the changing room should be the same GMP classification grade as the area into which it leads. Changing rooms should be of a sufficient size to allow for ease of changing. Changing rooms should be equipped with mirrors so that personnel can confirm the correct fit of garments before leaving the changing room. Appropriate hand wash and sanitizing facilities should be provided. Hand-wash basins should be provided with elbow taps or sensor operated taps. 4.2.6. Door gaps around the door perimeter have a marked impact on the pressure differential across the doorway. The fit of the doors should be agreed upon between the architect and the HVAC designer to ensure that the correct leakages are allowed for. Likewise the maintenance of doors is a critical factor in room pressure control (a poorly fitting door can severely compromise a room pressure differential). 4.2.7. Where the opening and closing of airlock doors could lead to crosscontamination, these airlock doors should not be opened simultaneously. An interlocking system and a visual and/or audible warning system should be operated to prevent the opening of more than one door at a time. 4.2.8. Doors should be carefully designed to avoid un-cleanable recesses; sliding doors may be undesirable for this reason. Swing doors should open to the high-pressure side and be provided with self-closers. Exceptions are permitted based on egress and site environmental, fire, health and safety containment requirements. 4.2.9. The choice of building finishes and materials also has an impact on air conditioning performance and air cleanliness. Materials should be selected that will provide a well-sealed building to facilitate room pressure control. Materials and paint finishes should also be non-dust and particle liberating as this impacts on room cleanliness. Finishes should be easy to clean and non-absorbent. To reduce the accumulation of dust and to facilitate cleaning, there should be no un-cleanable recesses and a minimum of projecting ledges, shelves, cupboards and equipment.

page 17 4.3. 554 The following diagrams illustrate some typical room and suite layouts with 555 their associated room pressures. These are purely examples and other 556 factors may dictate different room arrangements and room pressures. 557 558 Figure 3 559 Typical weigh booth layout 560 Change Room SOB 35 Pa Dispensary Post-Staging Room Wash Bay 35 Pa Pallet BIN BIN BIN 35 Pa BIN BIN Dispensary Pre-Staging Room Perforated Worktop Weigh Booth 25 Pa Airflow Protection Plenum 15 Pa Material Flow Material Flow Table Scale BIN Floor Scale BIN Return Air Shaft 561 562 563 564 565

page 18 566 567 568 Figure 4 Typical dispensary suite Production Passage Dispensary Post-Staging Room MAL Change Room MAL Change Room Weigh Booth 1 Airflow Protection Plenum Return Air Shaft Weigh Booth 2 Airflow Protection Plenum Return Air Shaft Brocken Bulk Store MAL Wash Bay MAL Wash Bay Dispensary Pre-Staging Room MAL 569 570 571 Material Flow MAL Warehouse Area

page 19 572 573 574 Figure 5 Sampling booth for small volumes SOB Return Air Shaft 575 576 577 578 579 Figure 6 Sampling Booth for larger volumes 580 581 582

page 20 583 584 Figure 7 Change rooms and ablution layouts 585 586 587 Figure 8 Compression cubicle with change room and MAL Low Level Return Air Passage SOB Low Level Return Air 588

page 21 589 590 591 Figure 9 Compression cubicle without change room and MAL (inclusion of airlocks dependant on risk assessment) Low Level Return Air Compression Cubicle Supply Air Grille 30 Pa Passage 15 Pa Low Level Return Air 592 593

page 22 594 595 Figure 10 Wash-bay suite Material Flow Passage 596 597 5985. Design of HVAC systems and components 599 5.1. 600 General 601 602 5.1.1. The required degree of air cleanliness in most OSD manufacturing 603 facilities can normally be achieved without the use of high-efficiency 604 particulate air (HEPA) filters, provided the air is not recirculated or in the 605 case of a single-product facility. Many open product zones of OSD form 606 facilities are capable of meeting ISO 14644-1 Class 8 or Grade D, at-rest 607 condition, measured against particle sizes of 0.5 µm and 5 µm, but 608 cleanliness may not necessarily be classified as such by manufacturers. 609 610 5.1.2. A risk assessment should be carried out to determine the cleanroom 611 conditions required and the extent of validation required. 612 613 5.1.3. There are two basic concepts of air delivery to pharmaceutical 614 production facilities: a recirculation system, and a full fresh air system

page 23 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 (100% outside air supply). For recirculation systems the amount of fresh air should not be determined arbitrarily on a percentage basis, but, for example, by the following criteria: sufficient fresh air to compensate for leakage from the facility and loss through exhaust air systems; sufficient fresh air to comply with national building regulations (depending on occupant density, between 1 and 2.5 ACPH will often satisfy occupancy requirements); sufficient fresh air for odour control; sufficient fresh air to provide the required building pressurization 5.1.4. Where automated monitoring systems are used, these should be capable of indicating any out-of-specification (OOS) condition without delay by means of an alarm or similar system. Sophisticated computerbased data monitoring systems may be installed, which can aide with planning of preventive maintenance and can also provide trend logging. (This type of system is commonly referred to as a building management system (BMS), building automation system (BAS) or system control and data acquisition (SCADA) system. If these systems are used for critical decision-making, they should be validated. If the BMS is not validated in full (or in part for these critical parameters), an independent validated environmental monitoring system (EMS) should be provided, specifically for recording and alarming critical parameters. Critical parameters could include for example, room temperature in production areas, humidity, differential pressures, fan failure alarms, etc.), 5.1.5. Failure of a supply air fan, return air fan, exhaust air fan or dust extract system fan can cause a system imbalance, resulting in a pressure cascade malfunction with a resultant airflow reversal. 5.1.6. A fan interlock failure matrix should be set up, such that if a fan serving a high pressure zone fails, then any fans serving surrounding lower pressure areas should automatically stop, to prevent an airflow reversal and possible cross-contamination. This fan stop-start matrix should apply to the switching on and switching off of systems to ensure that there is no flow reversal causing cross-contamination. 5.1.7. Appropriate alarm systems should be in place to alert personnel if a critical fan fails All critical alarms should be easily identifiable and visible and/or audible to relevant personnel.

page 24 5.2. 659 Air distribution 660 661 5.2.1. The positioning of supply and extract grilles should be such as to 662 provide effective room flushing. Low-level return or exhaust air grilles are 663 usually preferred. However, where this is not possible, a higher air change 664 rate may be needed to achieve a specified clean area condition, e.g. where 665 ceiling return air grilles are used. 666 667 5.2.2. There may be alternative locations for return air. For example, 668 referring to Figure 11, Room 1 (low-level return air) and Room 2 (ceiling 669 return air).. 670 671 672 Figure 11 673 674 675 Air-handling system with high-efficiency particulate air filters in airhandling unit Primary Filter Cooling Coil Supply Air Fan Secondary Filter HEPA Filter 676 677 678 679 680 681 682 683 The airflow schematics of the two systems (Figures 11 and 12) indicate air-handling units with return air or recirculated air, having a percentage of fresh air added. Depending on product characteristics and dust loading it is sometimes preferable to fit filters on return air outlets or in return air ducting.

page 25 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 Figure 12 is a schematic diagram of an air-handling system serving rooms with horizontal unidirectional flow, vertical unidirectional flow and turbulent flow, for rooms 3, 4 and 5, respectively. In this case the HEPA filters are terminally mounted at the rooms, and not in the AHU. Terminally mounted HEPA filters can assist with preventing crosscontamination from room to room in the event of a fan failure condition. The decision whether to install terminal HEPA filters should be based on a risk-assessment study. Figure 12 Horizontal unidirectional flow, vertical unidirectional flow and turbulent flow HEPA Filters Primary Filter Cooling Coil Supply Air Fan Secondary Filter 699 700 5.3. 701 Recirculation system 702 703 5.3.1. There should be no risk of contamination or cross-contamination 704 705 (including by fumes and volatiles) due to recirculation of air. 706 5.3.2. Depending on the airborne contaminants in the return-air system 707 it may be acceptable to use recirculated air, provided that HEPA filters 708 are installed in the supply air stream (or return air stream) to remove 709 contaminants and thus prevent cross-contamination. The HEPA filters for 710 711 this application should have an EN 1822 classification of H13. 712 5.3.3. HEPA filters may not be required where the air-handling system 713 714 715 is serving a single product facility and there is evidence that crosscontamination would not be possible.

page 26 716 5.3.4. Recirculation of air from areas where pharmaceutical dust is not 717 generated such as secondary packing, may not require HEPA filters in the 718 719 system. 720 5.3.5. HEPA filters may be located in the air-handling unit or placed 721 terminally. Where HEPA filters are terminall y mounted they 722 should preferably not be connected to the ducting by means of flexible 723 ducting. Due to the high air pressure required for the terminal filter, this 724 connection should preferably be a rigid duct connection. Where flexible 725 ducting is used, it should be as short as possible and properly fixed to 726 withstand duct pressure. When HEPA filters are terminally mounted, it 727 should be possible to carry out filter integrity tests from within the room. 728 The filter housings will therefore require ports for measuring appropriate 729 upstream concentration (refer to ISO 14644.3) and penetration 730 concentration from within the room. In addition it should be possible to 731 732 monitor the filter pressure drop in individual HEPA filters. 733 5.3.6. Air containing dust from highly toxic processes and/or solvents or 734 flammable vapours should never be recirculated to the HVAC system. 735 736 737 5.4. 738 Full fresh-air systems 739 740 741 5.4.1. The required degree of filtration of the exhaust air depends on the 742 exhaust air contaminants and local environmental regulations. HEPA filters 743 in the exhaust system would normally only be required when handling 744 hazardous materials. 745 746 Figure 13 indicates a system operating on 100% fresh air and would 747 normally be used in a facility dealing with toxic products or solvents, where 748 recirculation of air with contaminants should be avoided. 749 750

page 27 751 752 753 754 Figure 13 Full fresh-air system 755 756 757

page 28 758 759 760 Figure 14 Full fresh-air system with energy recovery HEPA Filter Secondary Filter Primary Filter Exhaust Air Fan Fresh Air Primary Filter Cooling Coil Supply Air Fan Secondary Filter HEPA Filter 761 762 763 5.4.2. Energy-recovery wheels if used in multiproduct facilities should 764 have been subjected to a risk assessment to determine if there is any 765 risk of cross-contamination. When such wheels are used they should 766 not become a source of possible contamination (see Figure 14). Note: 767 Alternatives to the energy-recovery wheels, such as crossover plate heat 768 exchangers and water-coil heat exchangers, may be used in multiproduct 769 770 facilities. 771 5.4.3. The potential for air leakage between the supply air and exhaust air 772 as it passes through the wheel should be prevented. The relative pressures 773 between supply and exhaust air systems should be such that the exhaust air 774 system operates at a lower pressure than the supply system. 775 776 5.5. 777 778 Additional system components 779 5.5.1. A schematic diagram of the airflow for a typical system serving a 780 low relative humidity suite is represented in Figure 15. Air can be dried 781 with a chemical drier (e.g. a rotating desiccant wheel which is continuously 782 regenerated by means of passing hot air through one segment of the wheel). 783 Alternative methods of drying air are also available.

+ Working document QAS/15.639 page 29 784 785 Figure 15 Air-handling system with chemical drying CHEMICAL DRIER UNIT E Reactivation Air Fan Chemical Drier Desiccant Wheel Reactivation Heater Primary Filter Fresh Air S = Supply Air R = Return Air F = Fresh Air E = Exhaust Air F Primary Filter Process Air Fan - Cooling Coil AIR HANDLING UNIT Supply Air Fan Secondary Filter HEPA Filter S R + LOW HUMIDITY PRODUCTION FACILITY S R R 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 5.5.2. The figure illustrates the chemical drier handling part of the fresh air/return air mixture on a bypass flow. The location of the chemical drier should be considered in the design phase. The practice of locating the complete chemical drier unit in the production cubicle is not recommended as this could be a source of contamination or cross-contamination. Examples of appropriate locations for the drying wheel could include: full flow of fresh/return air; partial handling of fresh/return air (bypass airflow); return air only; fresh air only; or pre-cooled air with any of the above alternatives. 5.5.3. Possible additional components that may be required in air handling should be considered depending on the climatic conditions and locations. These may include items such as: frost coils on fresh air inlets in very cold climates to preheat the air; reheaters for humidity control automatic air volume control devices sound attenuators R

page 30 809 snow eliminators to prevent snow entering air inlets and 810 blocking airflow 811 dust eliminators on air inlets in arid and dusty locations 812 moisture eliminators in humid areas with high rainfall 813 814 fresh air precooling coils for very hot or humid climates. 815 8166. Protection 817 818 819 6.1. Products and personnel 820 6.1.1. Areas for the manufacture of pharmaceuticals, where pharmaceutical 821 starting materials and products, utensils, primary packing materials and 822 equipment are exposed to the environment, should be defined as clean 823 824 areas, clean zones, controlled areas or cleanrooms. 825 6.1.2. The achievement of a particular clean area condition depends on a 826 number of criteria that should be addressed at the design and qualification 827 stages. A suitable balance between the different criteria will be required in 828 829 order to create an efficient clean area. 830 6.1.3. Some of the basic criteria to be considered which affects room 831 cleanliness should include: 832 833 building finishes and structure dust control and containment 834 air filtration 835 air change rate or flushing rate 836 room pressure 837 location of air terminals and directional airflow 838 temperature 839 relative humidity 840 material flow 841 personnel flow 842 gowning procedures 843 equipment movement 844 process being carried out (open or closed system) 845 outside air conditions 846 occupancy 847 type of product 848 cleaning standard operating procedures (SOPs). 849 850 6.1.4. Air filtration and air change rates should be set to ensure that the 851 defined clean area condition is attained. 852

page 31 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 6.1.5. The air change rates should be determined by the manufacturer and designer, taking into account the various critical parameters using a risk based approach with due consideration of capital and running costs and energy usage. Primarily the air change rate should be set to a level that will achieve the required clean area condition. 6.1.6. Air change rates are normally determined by the following considerations (could normally vary between 6 and 20 air changes per hour): area condition required: whether a specific room cleanliness condition is in fact required and whether the room condition is rated for an at rest condition or an operational condition (air change rate should be selected on need rather than tradition); the product characteristics (e.g. odours, hygroscopicity, etc.); the quality and filtration of the supply air; particulates generated by the manufacturing process; particulates generated by the operators; configuration of the room and air supply and extract locations; sufficient air to achieve containment effect and to clean up the area; sufficient air to cope with the room heat load; sufficient air to balance extract rates; sufficient air to maintain the required room pressure. 6.1.7. If a cleanroom classification is specified, the manufacturer should state whether this is achieved under as-built (Figure 16), at-rest (Figure 17) or operational (Figure 18) conditions. 6.1.8. Room classification tests in the as-built condition should be carried out on the bare room, in the absence of any equipment or personnel. 6.1.9. Room classification tests in the at-rest condition should be carried out with the equipment operating where relevant, but without any operators. Because of the amounts of dust usually generated in a solid dosage facility, the clean area classifications would be rated for the at-rest condition. 6.1.10. Room classification tests in the operational condition are normally carried out during the normal production process with equipment operating, and the normal number of personnel present in the room. When qualifying for the operational condition details of the process operating, number and positions of staff should be stipulated for each room, to enable future qualifications to duplicate the same conditions. 6.1.11. Room clean-up or recovery tests are performed to determine whether the installation is capable of returning to a specified cleanliness

page 32 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 level within a finite time, after being exposed briefly to a source of airborne particulate challenge. Room clean-up or recovery tests should demonstrate a change in particle concentration by a factor of 100 within the prescribed time (as per ISO 14644-3 clause B.12) (3). The guidance time period for clean-up or recovery is about 15 to 20 minutes. In some instances it is not possible to increase the concentration by a factor of 100 (such as for an ISO 14644 Class 8 condition) as the high particle concentration can damage the particle counter. In this instance the particle decay method can be used as per ISO 14644-3 clause B.12.3.2. 6.1.12. Materials and products should be protected from contamination and cross-contamination during all stages of manufacture (see also section 6.5 for cross-contamination control). Note: contaminants may result from inappropriate premises (e.g. poor design, layout or finishing), poor cleaning procedures, contaminants brought in by personnel, poor manufacturing process and a poor HVAC system. Figure 16 As-built condition 917 918 919 920

page 33 921 922 Figure 17 At-rest condition 923 924 925 926 Figure 18 Operational condition 927

page 34 928 929 930 931 932 933 934 935 936 937 938 939 940 941 942 943 944 945 946 947 948 949 950 951 6.1.13. Airborne contaminants should be controlled through effective ventilation and filtration. 6.1.14. External contaminants should be removed by effective filtration of the supply air (see Figure 19 for an example of a shell-like building layout to enhance containment and protection from external contaminants). 6.1.15. Internal contaminants should be controlled by dilution and flushing of contaminants in the room, or by displacement airflow (See Figures 20 and 21 for examples of methods for the flushing of airborne contaminants). 6.1.16. Airborne particulates and the degree of filtration should be considered critical parameters with reference to the level of product protection required. 6.1.17. Personnel should not be a source of contamination. 6.1.18. The level of protection and air cleanliness for different areas should be determined according to the product being manufactured, the process being used and the product s susceptibility to degradation (Table 3).

page 35 952 953 954 Figure 19 Shell-like containment control concept Waste Exit Personnel Movement Personnel Movement 955 956 957 958 959 960 961 962 963 964 965 966 967 968 969 970 971 972 973 974 975 976 6.2. Air filtration Note: The degree to which air is filtered plays an important role in the prevention of contamination and the control of cross-contamination. 6.2.1. The type of filters required for different applications depends on the quality of the ambient air and the return air (where applicable) and also on the air change rates. Table 4 gives the recommended filtration levels for different levels of protection in a pharmaceutical facility. Manufacturers should determine and prove the appropriate use of filters. 6.2.2. Filter classes should always be linked to the standard test method because referring to actual filter efficiencies can be very misleading (as different test methods each result in a different efficiency value for the same filter). (Referring to filter classifications such as an 85% filter or a 5 µm filter are not valid classifications and should not be used, as this can lead to the incorrect filter being installed. Only the EN 779 and EN 1822 or ISO 29463 classifications, as per Tables 1 and 2, should be used.)

977 978 979 980 Eurovent 4/5 rating (supersede d) Working document QAS/15.639 page 36 Table 1 Comparison of filter test standards ASHRAE 52.2 Merv rating Eurovent 4/5 ASHRAE 52.1 BS6540 Part 1 Average arrestance Am (%) Eurovent 4/5 ASHRAE 52.1 BS6540 Part 1 Average dust spot efficiency Em (%) EN 779 & EN 1822 MPPS integral overall efficiency (%) EN Rating ISO 29463 99.999995 U17 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 EU 8 Merv 14 90 F8 EU 7 Merv 13 >98 85 MPPS = F7 most >98 80 penetrating Merv 12 >95 75 particle Size 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 75 981 EU 2 Merv 3 70 G2 Merv 2 65 EU 1 Merv 1 <65 G1 EN 1822: 2009 EN 1822: 2009

page 37 982 983 Table 2 Comparison of ISO and EN Filter Standards Filter Class ISO 75 E ISO 70 E ISO 65 E ISO 29463 Global or Integral Values for MPPS Collection Efficiency (%) 99.999995 99.99999 99.99995 Penetrat ion (%) 0.000005 0.00001 0.00005 Local Values for MPPS Collection Efficiency (%) Penetrat ion (%) EN 1822 MPPS Integral Overall Efficiency (%) 99.9999 0.0001 99.999995 EN Rating U17 99.9999 0.0001 - - 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 - - 984 985 986 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 1822:2009 and EN 779: 2002 test standards (EN 779 relates to filter classes G1 to F9 and EN1822 relates to filter classes E10 to U17).

page 38 987 988 989 990 991 992 993 994 995 996 997 998 1000 999 6.2.3. In selecting filters, the manufacturer should have considered other factors, such as particularly contaminated ambient conditions, local regulations and specific product requirements. Good prefiltration extends the life of the more expensive filters downstream. 6.2.4. Filters have an impact on the cleanroom class or Level of Protection. The different levels of protection and recommended filters grades are given in Tables 3 and 4 below. Table 3 Examples of levels of protection (based on ISPE oral solid dosage (OSD) guideline criteria) 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

page 39 1003 1004 1005 Table 4 Levels of protection and recommended filtration Level of protection Recommended filtration Level 1 Primary filters only (e.g. EN 779 G4 filters) Level 2 Level 3 Protected areas operating on 100% outside air: primary plus secondary filters (e.g. EN 779 G4 plus F8 or F9 filters) Production facility operating on recirculated plus ambient air, where potential for crosscontamination 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 1007 1008 1009 1010 1011 1012 1013 1014 1015 1016 1017 1018 1019 1020 1021 1022 1023 1024 6.2.5. Materials for components of an HVAC system should be selected with care so that they do not become a source of contamination. Any component with the potential for liberating particulate or microbial contamination into the airstream should be located upstream of the final filters. 6.2.6. Where possible ventilation dampers, filters and other services should be designed and positioned so that they are accessible from outside the manufacturing areas (service voids or service corridors) for maintenance purposes. 6.2.7. Directional airflow within production or primary packing areas should assist in preventing contamination. Airflows should be planned in conjunction with operator locations, so as to minimize contamination of the product by the operator and also to protect the operator from dust inhalation. Different airflow patterns are indicated in Figures 20 & 21 below.

page 40 1025 1026 1027 Figure 20 Turbulent dilution of dirty air 1028 1029 1030 1031 1032 1033 1034 1035 Low-level extract is ideal for dust suppression purposes, but is not essential. (Low-level extract is essential for Grade A, B & C classified areas.)

page 41 1036 1037 1038 Figure 21 Unidirectional displacement of dirty air 1039 1040 1041 1042 1043 1044 1045 1046 1047 1048 1049 1050 1051 1052 1053 1054 1055 1056 1057 1058 1059 6.2.8. HVAC air distribution components should be designed, installed and located to prevent contaminants generated within the room from being spread. 6.2.9. Supply air diffusers should be selected with care taking consideration of, e.g. room requirements and positions of equipment and operators in the room. Supply air diffusers of the high induction type (e.g. those typically used for office-type air-conditioning) should where possible not be used in clean areas where dust is liberated. Air diffusers should be of the noninduction type, introducing air with the least amount of induction so as to maximize the flushing effect. In rooms where the process results in high dust liberation; perforated plates or low induction swirl diffusers with low level extract or return should be used (to contain the dust at the lower level of the room) (see Figures 22 24 for illustrations of the three types of diffuser). In cases where dust liberation is low, ceiling return air grilles may be acceptable. 1060 1061

page 42 1062 1063 1064 1065 1066 1067 1068 1069 1070 1071 1072 1073 6.2.10. Induction and certain swirl diffusers induce room air vertically up to the diffuser to mix with the supply air. These diffusers create good dilution of contaminants in the room and may be used in rooms where there is low dust liberation. However, if used in rooms where excessive dust is generated, the distribution of dust in the room could be hazardous for the operators in the room, as dust is drawn up into the supply air stream and then spread throughout the room. Airflow patterns for different diffuser types are indicated in figures 22, 23 & 24 below. Figure 22 Induction diffuser 1074 1075 1076

page 43 1077 1078 Figure 23 Perforated plate diffuser 1079 1080 1081

page 44 1082 1083 Figure 24 Swirl diffuser 1084 1085 1086 1087 1088 1089 1090 1091 1092 1093 1094 1095 1096 1097 1098 1099 1100 1101 1102 1103 1104 1105 1106 1107 6.3. Unidirectional airflow 6.3.1. Unidirectional airflow (UDAF) should be used for weighing booths or sampling booths to provide operator and product protection and should also have a slight air in-flow from the room to enhance containment. Dust containment at the weigh booth should be demonstrated by smoke airflow pattern tests, or other appropriate tests. UDAF can also be used to provide protection of other dusty processes. 6.3.2. Sampling of materials such as starting materials, primary packaging materials and products, should be carried out in the same environmental conditions that are required for the further processing of the product. 6.3.3. In a weighing booth situation, the aim of the UDAF is to provide dust containment and operator protection. Example: in Figure 25 the dust generated at the weighing station is immediately extracted through the perforated worktop, thus protecting the operator from dust inhalation, but at the same time protecting the product from contamination by the operator by means of the vertical unidirectional airflow stream.

page 45 1108 1109 Figure 25 Operator protection at weighing station 1110 1111 1112 1113 1114 1115 1116 1117 1118 1119 1120 1121 1122 1123 1124 1125 1126 1127 1128 6.3.4 The unidirectional flow velocity should be such that it does not disrupt the sensitivity of balances in weighing areas. Where necessary the velocity may be reduced to prevent inaccuracies during weighing, provided that sufficient airflow is maintained to provide containment. Conventional unidirectional airflow systems, where a Grade A condition is required, have a guidance airflow velocity of 0.36 to 0.54 m/s. However, in a weigh booth or sampling booth a lower velocity can be used as a Grade A condition is not required. It is often necessary to reduce velocities to a lower level in order not to influence balance readings. The airflow velocity and directional flow should still ensure product containment. For this type of application it is sometimes better to refer to the unit as an airflow protection booth (APB) rather than a UDAF, in order to avoid confusion, with a Grade A requirement. To assist with containment for weighing and sampling operations there should be a slight inflow of air into the UDAF protected zone from the surrounding room in order to prevent dust escaping. Thus the amount of air extracted from below the UDAF/APB should exceed the amount of air supplied. (Unless the hazardous or sterile nature of the product dictates otherwise.)

page 46 1129 1130 1131 1132 1133 1134 1135 6.3.5 The position in which the operator stands relative to the source of dust liberation and airflow should be determined to ensure that the operator is not in the path of an airflow that could lead to contamination of the product (Figure 26). Figure 26 Operator protection by horizontal airflow 1136 1137 1138 1139 1140 1141 1142 1143 1144 1145 1146 1147 1148 1149 1150 1151 1152 1153 6.3.6 Once the system has been designed and qualified with a specific layout for operators and processes, this should be maintained in accordance with an SOP. 6.3.7 There should be no obstructions in the path of a unidirectional flow air stream that may cause the operator to be exposed to dust. Figure 27 illustrates the incorrect use of a weighing scale which has a solid back. The back of the weighing scale should not block the return air path as this obstructs the airflow and causes air to rise vertically carrying dust, resulting in a hazardous situation for the operator. Figure 28 illustrates a situation where an open bin is placed below a vertical unidirectional flow distributor. The downward airflow should be prevented from entering the bin, and then being forced to rise again, as this would carry light dust up towards the operator s face. In such an occurrence it

page 47 1154 1155 1156 1157 1158 1159 1160 1161 1162 1163 1164 1165 may be necessary to add a partial cover over the bin to limit the entry of air. Point extraction could also be used but this can result in the excessive loss of product. Figure 29 shows that a solid worktop can sometimes cause deflection of the vertical unidirectional airflow resulting in a flow reversal. A possible solution would be to have a 100 mm gap between the back of the table and the wall, with the air being extracted here. Figure 27 Operator subject to powder inhalation due to obstruction 1166 1167 1168 1169 1170

page 48 1171 1172 1173 Figure 28 Operator subject to powder contamination due to airflow reversal in bin 1174 1175 1176 1177

page 49 1178 1179 Figure 29 Operator subject to powder inhalation due to worktop obstruction 1180 1181 1182 1183 1184 1185 6.3.8 The manufacturer should select either vertical or horizontal unidirectional airflow (Figure 30) and an appropriate airflow pattern to provide the best protection for the particular application. 1186

page 50 1187 1188 Figure 30 Diagram indicating horizontal and vertical unidirectional flow 1189 1190 1191 1192 1193 1194

page 51 1195 6.3.9 Return or exhaust air grilles in rooms or at weigh or sampling booths 1196 should preferably be of the perforated grille types, which are easy to clean. 1197 Return/exhaust air filters can either be installed at the room terminal or in 1198 the air-handling unit. Maintenance and cleaning of filters and ducts should 1199 be addressed to ensure constant airflow. 1200 1201 1202 6.4. Infiltration 1203 1204 6.4.1. Air infiltration of unfiltered air into a pharmaceutical plant should 1205 not be a source of contamination. 1206 1207 6.4.2. Manufacturing facilities should normally be maintained at a positive 1208 pressure relative to the outside, to limit the ingress of contaminants. Where 1209 facilities are to be maintained at negative pressures relative to the ambient 1210 pressure, special precautions should be taken. Refer to the WHO 1211 guidelines for hazardous products, for further guidance on negative 1212 pressure facilities. 1213 1214 6.4.3. The location of the negative pressure facility should be carefully 1215 considered with reference to the areas surrounding it, particular attention 1216 being given to ensuring that the building structure is well sealed. 1217 1218 6.4.4. Negative pressure zones should, as far as possible, be encapsulated 1219 by surrounding areas with clean air supplies, so that only clean air can 1220 infiltrate into the controlled zone. 1221 1222 6.5. 1223 Cross-contamination 1224 6.5.1. Where different products are manufactured at the same time, in 1225 different areas or cubicles, in a multiproduct OSD manufacturing site, 1226 measures should be taken to ensure that dust cannot move from one cubicle 1227 to another. 1228 1229 6.5.2. Correct directional air movement and a pressure cascade system 1230 can assist in preventing cross-contamination. The pressure cascade should 1231 be such that the direction of airflow is from the clean corridor into the 1232 cubicles, resulting in dust containment. 1233 1234 6.5.3. For cubicles where dust is liberated, the corridor should be 1235 maintained at a higher pressure than the cubicles and the cubicles at a 1236 higher pressure than atmospheric pressure. 1237

page 52 1238 6.5.4. Containment can normally be achieved by application of the 1239 displacement concept (low pressure differential, high airflow), or the 1240 pressure differential concept (high pressure differential, low airflow), or the 1241 physical barrier concept. 1242 1243 6.5.5. The pressure cascade regime and the direction of airflow should be 1244 appropriate to the product and processing method used. 1245 1246 6.5.6. Highly potent products should be manufactured under a pressure 1247 cascade regime that is negative relative to atmospheric pressure. 1248 1249 6.5.7. The pressure cascade for each facility should be individually 1250 assessed according to the product handled and level of protection required. 1251 1252 6.5.8. Building structure should be given special attention to accommodate 1253 the pressure cascade design. 1254 1255 6.5.9. Ceilings and walls, close fitting doors and sealed light fittings should 1256 1257 be in place, to limit ingress or egress of air. 1258 6.6. 1259 Displacement concept (low pressure differential, high airflow) 1260 Note: This method of containment is not the preferred method, as the 1261 measurement and monitoring of airflow velocities in doorways is difficult. 1262 This concept is commonly found in production processes where large 1263 1264 amounts of dust are generated. 1265 6.6.1. Under this concept the air should be supplied to the corridor, 1266 flow through the doorway, and be extracted from the back of the cubicle. 1267 Normally the cubicle door should be closed and the air should enter the 1268 cubicle through a door grille, although the concept can be applied to an 1269 opening without a door. (With the door open the pressure differential will 1270 1271 effectively be zero.) 1272 6.6.2. The velocity should be high enough to prevent turbulence within the 1273 1274 doorway resulting in dust escaping. 1275 6.6.3. This displacement airflow should be calculated as the product of 1276 the door area and the velocity through the doorway, which generally 1277 1278 results in fairly large air quantities. 1279 Note: Although this method of containment may still exist on older facilities, 1280 it is not the preferred method, as the measurement and monitoring of doorway 1281 velocities is difficult. In addition, simultaneously maintaining the correct 1282 room pressure and the correct room air change rate is often not achieved.

page 53 1283 1284 1285 6.7. 1286 Pressure differential concept (high pressure differential, low airflow) 1287 Note: The pressure differential concept may normally be used in zones where 1288 little or no dust is being generated. It may be used alone or in combination 1289 with other containment control techniques and concepts, such as a double 1290 1291 door airlock. 1292 6.7.1. The high pressure differential between the clean and less clean 1293 zones should be generated by leakage through the gaps of the closed doors 1294 to the cubicle. 1295 1296 6.7.2. The pressure differential should be of sufficient magnitude to ensure 1297 containment and prevention of flow reversal, but should not be so high as to 1298 1299 create turbulence problems. 1300 6.7.3. In considering room pressure differentials, transient variations, such 1301 1302 as machine extract systems, should be taken into consideration. 1303 6.7.4. A pressure differential of 15 Pa is often used for achieving 1304 containment between two adjacent zones, but pressure differentials of 1305 between 5 Pa and 20 Pa may be acceptable. Where the design pressure 1306 differential is too low and tolerances are at opposite extremities, a flow 1307 reversal can take place. For example, where a control tolerance of ± 3 Pa 1308 is specified, the implications of adjacent rooms being operated at the upper 1309 and lower tolerances should be evaluated. It is important to select pressures 1310 1311 and tolerances such that a flow reversal is unlikely to occur. 1312 6.7.5. The pressure differential between adjacent rooms could be 1313 considered a critical parameter, depending on the outcome of risk analysis. 1314 The limits for the pressure differential between adjacent areas should be 1315 such that there is no risk of overlap in the acceptable operating range, e.g. 1316 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting 1317 in the failure of the pressure cascade, where the first room is at the maximum 1318 1319 pressure limit and the second room is at its minimum pressure limit. 1320 6.7.6. Low p r e s s u r e d i f f e r e n t i a l s m a y b e a c c e p t a b l e 1321 w h e n a i r l o c k s (pressure sinks or pressure bubbles) are used to 1322 1323 segregate areas. 1324 6.7.7. The effect of room pressure tolerances are illustrated in Figure 31. 1325 If one room is at the higher side of the tolerance and the other at the lower 1326 side of the tolerance, it could result in either a high or a low pressure 1327 differential. When setting tolerances it is also important to specify if the 1328 tolerance is applicable to the absolute room pressures or the pressure 1329 differentials. In the diagram below the tolerances have been based on a ±

page 54 1330 1331 1332 1333 1334 1335 1336 1337 3 Pa tolerance on absolute room pressures, resulting in pressure differential variances of between 21 and 9 Pa.. For a room pressure differential of 15 Pa and a tolerance based on ± 3 Pa of differential pressure, then the resultant variances would only be between 12 and 18 Pa. Figure 31 Examples of pressure cascades Air Leakage Air Leakage Air Leakage Air Leakage Air Leakage Air Leakage Air Leakage Air Leakage Air Leakage Image of room pressure gauge indicating colour coded normal, alert & action parameters 1338 1339 1340 1341 1342 1343 1344 1345 1346 1347 1348 1349 1350 1351 1352 1353 1354 1355 1356 1357 6.7.8. The pressure control and monitoring devices used should be calibrated and qualified. Compliance with specifications should be regularly verified and the results recorded. Pressure control devices should be linked to an alarm system set according to the levels determined by a risk analysis. 6.7.9. Manual control systems, where used, should be set up during commissioning, with set point marked, and should not change unless other system conditions change. 6.7.10. Airlocks can be important components in setting up and maintaining pressure cascade systems and also to limit cross-contamination. 6.7.11. Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock and bubble airlock (Figures 32 34): cascade airlock: higher pressure on one side of the airlock and lower pressure on the other; sink airlock: lower pressure inside the airlock and higher pressure on

page 55 1358 1359 1360 1361 1362 1363 1364 1365 1366 both outer sides; bubble airlock: higher pressure inside the airlock and lower pressure on both outer sides. Figure 32 Example of cascade airlock (In most cases the internal pressure of the airlock is not critical. The pressure differential between the two outer sides is the important criteria.) 1367 1368 1369

page 56 1370 1371 1372 Figure 33 Example of sink airlock 1373 1374

page 57 1375 1376 1377 1378 Figure 34 Example of bubble airlock Air Leakage Air Leakage 15 Pa Material Airlock 30 Pa 15 Pa Bubble Airlock 1379 1380 1381 1382 1383 1384 1385 1386 1387 1388 1389 1390 1391 1392 1393 1394 1395 1396 1397 1398 1399 1400 Note: The diagrams above and the differential pressures shown here are for illustration purposes only. Pressures indicated in these examples are absolute pressures, whereas the local pressure indication would most likely be pressure differential from room to room. 6.7.12. Doors should open to the high pressure side, so that room pressure assists in holding the door closed and in addition be provided with selfclosers. Should the doors open to the low pressure side, the door closer springs should be sufficient to hold the door closed and prevent the pressure differential from pushing the door open. There should be a method to indicate if both doors to airlocks are open at the same time, or alternatively these should be interlocked. The determination of which doors should be interlocked should be the subject of a risk assessment study. 6.7.13. Central dust extraction systems should be interlocked with the appropriate air-handling systems, to ensure that they operate simultaneously. 6.7.14. Room pressure differential between adjacent cubicles, which are linked by common dust extraction ducting, should be avoided.

page 58 1401 6.7.15. Air should not flow through the dust extraction ducting or return 1402 air ducting from the room with the higher pressure to the room with the 1403 lower pressure (this would normally occur only if extract or return systems 1404 were inoperative). Systems should be designed to prevent dust flowing back 1405 1406 in the opposite direction in the event of component failure or airflow failure. 1407 6.7.16. Adequate room pressure differential indication should be provided 1408 so that each critical room pressure can be traced back to ambient pressure 1409 (by summation of the room pressure differentials), in order to determine the 1410 room actual absolute pressure, such as a pressure gauge installed to 1411 indicate the pressure differential from a central corridor to the outside. 1412 Room pressure indication gauges should have a range and graduation scale 1413 which enables the reading to an appropriate accuracy. Normal operating 1414 range, alert and action limits should be defined and displayed at the point of 1415 1416 indication. A colour coding of these limits on the gauge may be helpful. 1417 Room pressure indication may be either analogue or digital, and may be 1418 represented as either pressure differentials or absolute pressures. 1419 Whichever system is used any out-of-specification condition should be 1420 1421 easily identifiable. 1422 6.7.17. Material pass-through-hatches (PTH) or pass boxes (PB) can also 1423 be used for separating two different zones. PTHs fall into two categories, 1424 namely a dynamic PTH or a passive PTH. Dynamic PTHs have an air 1425 supply to or extraction from them, and can then be used as bubble, sink or 1426 cascade PTHs. 1427 1428 6.7.18. Room pressure differential tolerances should always be set with a 1429 maximum and minimum tolerance. Setting tolerances as NMT or NLT can 1430 easily lead to an OOS condition. 1431 1432 6.8. 1433 Physical barrier concept 1434 6.8.1. Where appropriate, an impervious barrier to prevent cross- 1435 contamination between two zones, such as closed systems, pumped or 1436 vacuum transfer of materials, should be used. 1437 1438 1439 6.9. 1440 Temperature and relative humidity 1441 6.9.1. Where appropriate, temperature and relative humidity should be 1442 controlled, monitored and recorded, where relevant, to ensure compliance 1443 with requirements pertinent to the materials and products and provide a 1444 1445 comfortable environment for the operator where necessary.

page 59 1446 1447 1448 1449 1450 1451 1452 1453 1454 1455 1456 1457 1458 1459 1460 1461 1462 1463 1464 1465 1466 1467 1468 1469 1470 1471 1472 1473 1474 1475 1476 1477 1478 1479 1480 1481 1482 1483 1484 1485 1486 1487 1488 1489 1490 1491 1492 1493 6.9.2. Maximum and minimum room temperatures and relative humidity should be appropriate. Alert and action limits on temperatures and humidities should be set, as appropriate. 6.9.3. The operating band, or tolerance, between the acceptable minimum and maximum temperatures should not be made too close. Tight control tolerances may be difficult to achieve and can also add unnecessary installation and running costs. 6.9.4. Cubicles, or suites, in which products requiring low relative humidity are processed, should have well-sealed walls and ceilings and should also be separated from adjacent areas with higher relative humidity by means of suitable airlocks. 6.9.5. Precautions should be taken to prevent moisture migration that increases the load on the HVAC system. 6.9.6. Humidity control should be achieved by removing moisture from the air, or adding moisture to the air, as relevant. 6.9.7. Dehumidification (moisture removal) may be achieved by means of either refrigerated dehumidifiers or chemical dehumidifiers. 6.9.8. Appropriate cooling media for dehumidification such as low temperature chilled water/glycol mixture or refrigerant should be used. 6.9.9. Humidifiers should be avoided if possible as they may become a source of contamination (e.g. microbiological growth). Where humidification is required, this should be achieved by appropriate means such as the injection of steam into the air stream. A product-contamination assessment should be done to determine whether pure or clean steam is required for the purposes of humidification. 6.9.10. Where steam humidifiers are used, chemicals such as corrosion inhibitors or chelating agents, which could have a detrimental effect on the product, should not be added to the boiler system. Only appropriate additives should be added to the boiler system. 6.9.11. Humidification systems should be well drained. No condensate should accumulate in air-handling systems. 6.9.12. Other humidification appliances such as evaporative systems, atomizers and water mist sprays, should not be used because of the potential risk of microbial contamination. 6.9.13. Duct material in the vicinity of the humidifier should not add contaminants to air that will not be removed by filtration further downstream.

page 60 1494 6.9.14. Air filters should not be installed immediately downstream of 1495 1496 humidifiers, as moisture on the filters could lead to bacterial growth. 1497 6.9.15. Cold surfaces should be insulated to prevent condensation within 1498 1499 the clean area or on air-handling components. 1500 6.9.16. When specifying relative humidity, the associated temperature 1501 1502 should also be specified. 1503 6.9.17. Chemical driers using silica gel or lithium chloride are acceptable, 1504 provided that they do not become sources of contamination. 1505 15067. Dust control 1507 1508 7.1. Wherever possible, dust or vapour contamination should be 1509 removed at source. Point-of-use extraction, i.e. as close as possible to the 1510 point where the dust is generated, should be employed. Spot ventilation or 1511 capture hoods may be used as appropriate. The HVAC system should not 1512 1513 serve as the primary mechanism of dust control. 1514 7.2. Point-of-use extraction should be either in the form of a fixed, 1515 high-velocity extraction point or an articulated arm with movable hood or a 1516 1517 fixed extraction hood. 1518 7.3. Dust extraction ducting should be designed with sufficient transfer 1519 velocity to ensure that dust is carried away, and does not settle in the ducting. 1520 Periodic checks should be performed to ensure that there is no build-up of 1521 1522 the dust in the ducting. 1523 7.4. The required transfer velocity should be determined: it is dependent 1524 on the density of the dust (the denser the dust, the higher the transfer 1525 1526 velocity should be, e.g. 15 20 m/s). 1527 7.5. Airflow direction should be carefully chosen, to ensure that the 1528 operator does not contaminate the product, and also so that the operator is 1529 not put at risk by the product. 1530 1531 7.6. Point extraction alone is usually not sufficient to capture all of 1532 the contaminants, and general directional airflow should be used to assist 1533 1534 in removing dust and vapours from the room. 1535 7.7. Typically, in a room operating with turbulent airflow, the air should 1536 be introduced from ceiling diffusers, located at the door entry side of the 1537 room and extracted from the rear of the room at low level to help give a 1538 flushing effect in the room. Correct flushing of the rooms may be verified 1539 1540 by airflow visualization smoke tests.

page 61 1541 7.8. When dealing with particularly harmful products, additional steps, 1542 such as handling the products in glove boxes or using barrier isolator 1543 technology, should be used. 1544 15458. Protection of the environment 1546 1547 8.1. 1548 General 1549 8.1.1. It should be noted that protection of the environment is not addressed 1550 in this guideline, and discharges into the atmosphere should be compliant 1551 1552 with relevant local and national environmental legislation and standards. 1553 8.1.2. Dust, vapours and fumes could be possible sources of contamination; 1554 therefore, care should be taken when deciding on the location of the inlet 1555 and exhaust points relative to one other. 1556 1557 8.2. Dust in exhaust air 1558 1559 8.2.1. Exhaust air discharge points on pharmaceutical equipment and 1560 facilities, such as from fluid bed driers and tablet-coating equipment, and 1561 exhaust air from dust extraction systems, carry heavy dust loads and should be 1562 1563 provided with adequate filtration to prevent contamination of the ambient air. 1564 8.2.2. Where the powders are not highly potent, final filters on a dust 1565 exhaust system should be fine dust filters with a filter classification of F9 1566 1567 according to EN 779 filter standards. 1568 8.2.3. Where reverse-pulse dust collectors are used for removing dust from 1569 dust extraction systems, they should usually be equipped with cartridge 1570 filters containing a compressed air lance, and be capable of continuous 1571 1572 operation without interrupting the airflow. 1573 8.2.4. Alternative types of dust collectors (such as those operating with a 1574 mechanical shaker, requiring that the fan be switched off when the mechanical 1575 shaker is activated) should be used in such a manner that there is no risk 1576 of cross-contamination. There should be no disruption of airflow during a 1577 production run as the loss of airflow could disrupt the pressure cascade. 1578 1579 8.2.5. Mechanical-shaker dust collectors should not be used for applications 1580 where continuous airflow is required, in order to avoid unacceptable 1581 fluctuations in room pressures, except in the case where room pressures are 1582 1583 automatically controlled. 1584 8.2.6. When wet scrubbers are used, the dust-slurry should be removed by 1585 1586 a suitable means, e.g. a drainage system or waste removal contractor.

page 62 1587 8.2.7. The quality of the exhaust air should be determined to see whether the 1588 filtration efficiency is adequate with all types of dust collectors and wet 1589 1590 scrubbers. 1591 8.2.8. Where necessary, additional filtration may be provided downstream 1592 of the dust collector. 1593 1594 8.3. Vapour and fume removal 1595 1596 8.3.1. Vapour should be extracted at the point of generation. When planning 1597 the system for the extraction of residual vapours, the density of the vapour 1598 should be taken into account. If the vapour is lighter than air, the extract 1599 1600 grilles should be at a high level, or possibly at both high and low levels. 1601 8.3.2. The systems for fume, dust and effluent control should be designed, 1602 installed and operated in such a manner that they do not become possible 1603 sources of contamination or cross-contamination, e.g. an exhaust-air 1604 1605 discharge point located close to the HVAC system fresh air inlet. 1606 8.3.3. Fumes should be removed by means of wet scrubbers or dry 1607 1608 chemical scrubbers (deep-bed scrubbers). 1609 8.3.4. Wet scrubbers for fume removal normally require the addition of 1610 various chemicals to the water to increase the adsorption efficiency. 1611 1612 8.3.5. Deep-bed scrubbers should be designed with activated carbon filters 1613 or granular chemical adsorption media. The chemical media for deep-bed 1614 scrubbers should be specific to the effluent being treated. 1615 1616 8.3.6. The type and quantity of the vapours to be removed should be 1617 known to enable the appropriate filter media, as well as the volume of media 1618 required to be determined. 1619 1620 1621 1622 9. Commissioning, qualification and validation 1623 9.1. General 1624 9.2. 1625 9.2.1. The heating, ventilation and air-conditioning (HVAC) system plays 1626 an important role in the protection of the product, the personnel and the 1627 environment. 1628 1629 9.2.2. For all HVAC installation components, subsystems or parameters, 1630 critical parameters and non-critical parameters should be determined. 1631 1632 9.2.3. Some of the parameters of a typical HVAC system that should be 1633 qualified include:

1634 1635 room temperature and humidity; 1636 supply air and return air quantities; Working document QAS/15.639 page 63 1637 room pressure, air change rate, flow patterns, particle count and clean-up 1638 rates; 1639 unidirectional flow velocities and HEPA filter penetration tests; and 1640 critical alarms, etc. 1641 1642 1643 9.3. Commissioning 1644 9.3.1. Commissioning should involve the setting up, balancing, 1645 adjustment and testing of the entire HVAC system, to ensure that the 1646 system meets all the requirements, as specified in the user requirement 1647 specification, and capacities as specified by the designer or developer. The 1648 commissioning plan should start at the early stages of a project so that it 1649 can be integrated with qualification and verification procedures. 1650 1651 9.3.2. Acceptable tolerances for all system parameters should be specified 1652 and agreed by the user prior to commencing the physical installation. 1653 These tolerances should be specified in the User Requirement 1654 Specifications 1655 1656 9.3.3. Acceptance criteria should be set for all system parameters. The 1657 measured data should fall within the acceptance criteria. 1658 1659 9.3.4. System installation records should provide documented evidence 1660 of all measured capacities of the system. 1661 1662 9.3.5. The i n s t a l l a t i o n r e c o r d s should include items such as the 1663 design and measured figures for airflows, water flows, system pressures 1664 electrical amperages, etc. These should be contained in the operating 1665 and maintenance manuals (O & M manuals). The installation records of 1666 the system should provide documented evidence of all measured capacities 1667 of the system. 1668 1669 9.3.6. Typical information that should be contained in the O&M 1670 manuals is the following: 1671 1672 system description; 1673 operating instructions, 1674 trouble shooting;

page 64 1675 commissioning data schedules; 1676 maintenance instructions; 1677 list of equipment suppliers; 1678 spare parts lists; 1679 equipment capacity and data schedules; 1680 supplier s literature; 1681 control system operation; 1682 electrical drawings; 1683 as-built drawings; 1684 maintenance records. 1685 1686 9.3.7. O & M manuals, schematic drawings, protocols and reports should 1687 be maintained as reference documents for any future changes and upgrades 1688 to the system. As-built drawings should be available and should be kept up 1689 to date with all the latest system changes. Any changes from the originally 1690 approved system should be covered by change control documentation and 1691 risk assessment studies where deemed necessary. 1692 1693 9.3.8. Training should be provided to personnel after installation of the 1694 system, and should include how to perform operation and maintenance. 1695 1696 9.3.9. Commissioning should be a precursor to system qualification and 1697 validation. 1698 9.4. 1699 9.5. Qualification 1700 9.6. 1701 9.6.1. Manufacturers should qualify HVAC systems using a risk-based 1702 approach. The basic concepts of qualification of HVAC systems are set out 1703 in Figure 35 below. 1704 1705

page 65 1706 1707 Figure 35 Qualification is a part of validation 1708 1709 1710 1711 1712 1713 1714 1715 1716 1717 1718 1719 1720 9.6.2. The qualification of the HVAC system should be described in a validation master plan (VMP), or a subsection of the VMP. 9.6.3. The validation master plan should define the nature and extent of testing and the test procedures and protocols to be followed. 9.6.4. Stages of the qualification of the HVAC system should include design qualification (DQ), installation qualification (IQ), operational qualification (OQ) and performance qualification (PQ). The relationship between the development stage of a project and the qualification/validation stage is given in the V-Diagram (Figure 36) below.

page 66 1721 Figure 36 V-Model for Direct Impact Systems User Requirement Specification PQ Test Plan (incl. UAT) Performance Qualification Design Qualification Functional Design Specification OQ Test Plan (incl. FAT) Operational Qualification DQ Test Plan Detail Design and Configuration Specifications IQ Test Plan (incl. PDI) Installation Qualification 1722 1723 1724 1725 1726 1727 1728 1729 1730 1731 1732 1733 1734 1735 1736 1737 1738 1739 1740 1741 1742 Build & Project Implementation 9.6.5. Critical and non-critical parameters for all HVAC installation components, subsystems and controls should be determined by means of a risk analysis. 9.6.6. Any parameter that may affect the quality of the pharmaceutical product should be considered a critical parameter. 9.6.7. All critical parameters should be included in the qualification process. Note: A realistic approach to differentiating between critical and noncritical parameters, systems or components is required, to avoid making the validation process unnecessarily complex. Example The humidity of the room where the product is exposed should be considered a critical parameter when a humidity-sensitive product is being manufactured. The humidity sensors and the humidity monitoring system should, therefore, be qualified. Components or equipment such as the heat transfer system, chemical drier or steam humidifier, which is producing the humidity-controlled air, is

page 67 1743 1744 1745 1746 1747 1748 1749 1750 1751 1752 1753 1754 1755 1756 1757 1758 1759 1760 1761 1762 1763 1764 1765 1766 1767 1768 1769 1770 1771 1772 1773 1774 1775 1776 1777 further removed from the product and may not require operational qualification. A room cleanliness classification is a critical parameter and, therefore, the room air-change rates and high-efficiency particulate air (HEPA) filters should be considered critical parameters and components, and therefore require qualification. Items such as the fan generating the airflow and the primary and secondary filters are considered non-critical components, and may not require operational qualification. 9.6.8. Non-critical systems and components should be subject to verification by good engineering practice (GEP) and may not necessarily require full qualification. 9.6.9. A change control procedure should be followed when changes are planned to the HVAC system, its components and controls, that may affect critical parameters. 9.6.10. The design condition, normal operating ranges, operating range and alert and action limits should be defined and be realistic. Alert limits should be based on system capability.. 9.6.11. All parameters should fall within the design condition range during system operational qualification. Conditions may go out of the design condition range during normal operating procedures but they should remain within the operating range. 9.6.12. Out-of-limit results (e.g. alert or action limit deviations) should be recorded and form part of the batch manufacturing records, and their impact should be investigated. 9.6.13. The relationships between design conditions, operating range and qualified acceptance criteria are given in Figure 37. There should be SOPs to determine action to be taken when alert and action limits are reached.

page 68 1778 1779 Figure 37 System operating ranges 1780 1781 1782 1783 1784 1785 1786 1787 1788 1789 1790 1791 1792 1793 1794 1795 1796 1797 1798 1799 1800 1801 1802 1803 1804 1805 1806 1807 1808 1809 9.6.14. A narrow range of relative humidities coupled with a wide range of temperatures is unacceptable as changes in temperature will automatically give rise to variations in the relative humidity. 9.6.15. Some of the typical HVAC system parameters, based on a risk assessment, that should be qualified for a pharmaceutical facility may include: temperature relative humidity supply air quantities for all diffusers return air or exhaust air quantities room air-change rates room pressures (pressure differentials) room airflow patterns unidirectional flow velocities containment system velocities HEPA filter penetration tests room particle counts room clean-up or recovery rates microbiological air and surface counts where appropriate operation of de-dusting warning/alarm systems where applicable. 9.6.16. The maximum time interval between tests and re-qualification should be defined by the manufacturer. The type of facility under test and the product level of protection should be considered.

page 69 1810 1811 1812 1813 1814 1815 1816 Note: Table 5 gives intervals for reference purposes only. The actual test periods may be more or less frequent, depending on the product and process and subject to risk assessment. Table 5 Strategic tests to demonstrate continued compliance (Time intervals given for re-qualification are for reference purposes only. The actual tests required will depend on specific facility requirements) Test parameter Max. time Test procedure interval between tests (all classes) Particle count test (verification of cleanliness) Air pressure difference (to verify absence of crosscontamination) Airflow volume (to verify air change rates) Airflow velocity (to verify unidirectional flow or containment conditions) 6 months (ISO 5) 12 months (>ISO 5) 12 months 12 months 12 months Dust particle counts to be carried out and result printouts produced. No. of readings and positions of tests to be in accordance with ISO 14644-1 Annex B.2 Log of pressure differential readings to be produced - critical plants should be logged daily, preferably continuously. In accordance with ISO 14644-3 Airflow readings for supply air and return air grilles to be measured and air change rates to be calculated. In accordance with ISO 14644-3 Annex B.4 Air velocities for containment systems and unidirectional flow protection systems to be measured. In accordance with ISO 14644-3 Annex B.4

page 70 HEPA filter leakage tests (to verify filter integrity) Containment leakage (to verify absence of cross-contamination) Recovery (to verify clean-up time) Room temperatures (to verify temperature tolerance adherence) Warehouse and store temperatures (to verify temperature mapping conditions) Room Humidities (To verify humidity tolerance adherence) 12 months 12 months 12 months 12 months 36 months 12 months Filter penetration tests to be carried out by a competent person to demonstrate filter media, filter seal and filter frame integrity.. In accordance with ISO 14644-3 Annex B.6 Demonstrate that contaminant is maintained within a room by means of: airflow direction smoke tests room air pressures. In accordance with ISO 14644-3 Annex B.13 Test to establish time that a cleanroom takes to recover from a contaminated condition to the specified cleanroom condition. In Demonstrate that room temperatures at determined locations comply with specified tolerances. In accordance with ISO 14644-3 Annex B.8.2 Demonstrate that store temperatures are uniform within specified tolerances In accordance with WHO 45th report (WHO Technical Report Series, No. 961), Annex 9 and WHO 49th report (WHO Technical Report Series, No. 992), Annex 5 plus Supplements 1 to 16 Demonstrate that room humidities at determined locations comply with specified tolerances. In accordance with ISO 14644-3 Annex B.9.2

page 71 1817 1818 1819 1820 1821 1822 1823 1824 1825 1826 1827 1828 1829 1830 1831 1832 1833 1834 1835 1836 1837 1838 1839 1840 1841 1842 1843 1844 1845 1846 1847 1848 9.6.17. Requalification should also be done when any change, which could affect system performance, takes place. 9.6.18. Room clean-up or recovery tests are performed to determine whether the installation is capable of returning to a specified cleanliness level within a finite time, after being exposed briefly to a source of airborne particulate challenge. Room clean-up or recovery tests should demonstrate a change in particle concentration by a factor of 100 within the prescribed time (as per ISO 14644-3 clause B.12) (3). The guidance time period for clean-up or recovery is about 15 to 20 minutes. In some instances it is not possible to increase the concentration by a factor of 100 (such as for an ISO 14644 Class 8 condition) as the high particle concentration can damage the particle counter. In this instance the particle decay method can be used as per ISO 14644-3 clause B.12.3.2. 9.6.19. If energy-saving procedures such as reducing the airflow during non-production hours are used, precautionary measures should be in place to ensure that the systems are not operated outside the defined relevant environmental conditions. These precautionary measures should be based on a risk assessment to ensure that there is no negative impact on the quality of the product. Qualification tests should be carried out to demonstrate that there are no flow reversals, loss of room pressurisation cascade, temperature, humidity excursions, etc. 9.6.20. Additional documents that should be included in the qualification manuals should include system airflow schematics, room pressure cascade drawings, zone concept drawings, air-handling system allocation drawings, particle count mapping drawings, etc.

page 72 1849 1850 1851 1852 1853 1854 1855 1856 1857 1858 1859 1860 1861 1862 1863 1864 1865 1866 1867 1868 1869 1870 1871 1872 1873 1874 1875 1876 1877 1878 1879 1880 1881 1882 1883 1884 1885 1886 1887 1888 1889 9.7. Supplementary notes on test procedures 9.7.1. General 9.7.1.1. Tests should be carried as described in ISO 14644-3. However below are some supplementary notes and aspects that provide additional guidance. 9.7.2. Airflow measurements 9.7.2.1. The ISO 14644 method - "B.4.3.3 Supply airflow rate calculated from filter face velocity" - should not be used to measure the airflow at diffuser outlets. The diffuser air directional blades or swirl outlets result in highly inaccurate measurements. 9.7.2.2. The cone and anemometer method is more accurate. Other methods can be used such as volume flow regulators with built in orifice and pressure differential ports, whereby airflow can be read off a graph from the corresponding pressure differentials. 9.7.3. Non-viable air particle counts 9.7.3.1. Particle count test results should be calculated using the UCL (upper confidence level) formulas as described in ISO 14644-3, if there are up to nine locations. The practice of using the average value of all particle count readings as the pass criteria is not acceptable. 9.7.3.2. Ensure that the test certificate states the condition under which the test was taken i.e. as built, at-rest or operational. The operational condition should be clearly defined for each room. (For example: number of staff, staff locations, manner of equipment operating, etc.) 9.7.3.3. ISO 14644-1 clause B.4.3.42 states that when only one test location is determined by formula, take a minimum of three single sample volumes (B.4.2) at that location. A more representative result would be obtained by taking a single sample at each of three different locations in that room. The actual locations should be based on a risk assessment. 9.7.3.4. In addition to determining the number of the sampling locations based on the area of the clean room, a risk assessment should

page 73 1890 determine if additional sample locations are warranted. Consider aspects 1891 such as personnel and/or production activities and air flow dead spots. 1892 1893 9.7.3.5. Where a UDAF is located within a room the UDAF and its 1894 background environment should be considered separately in terms of 1895 sampling location calculations, and should be individually certified. 1896 1897 9.7.3.6. The mapping drawing indicating test location should be 1898 included with the test certificate, and the same mapping locations should 1899 be used for future tests for comparative purposes. 1900 1901 9.7.4. HEPA filter integrity tests 1902 1903 9.7.4.1. Filter media, frame and seal should be tested for each filter 1904 and results for media, frame and seal penetration reflected separately on 1905 the test certificates. 1906 1907 9.7.4.2. When HEPA filters are terminally mounted at the room, it 1908 should be possible to carry out filter integrity tests from within the room. 1909 The filter housings will therefore require ports for measuring appropriate 1910 upstream concentration and penetration concentration from within the 1911 room. In addition it should be possible to measure the filter pressure drop 1912 in individual HEPA filters, also preferably from within the room. These 1913 pressure drops should be recorded on the filter test certificate as an 1914 indication of the filter life. (The practice of measuring the appropriate 1915 upstream concentration from the ceiling void or at the air handling plant- 1916 room, and then measuring the filter penetration concentration in the room 1917 is unacceptable. The time lag between measuring the upstream 1918 concentration and the penetration concentration could mean that by the 1919 time the room penetration is measured, the upstream concentration is no 1920 longer the required concentration.) 1921 1922 9.7.4.3. The test procedure should not compromise the quality of 1923 1924 1925 the product. 1926 1927 10. Maintenance 1928 10.1. Maintenance records, maintenance procedures and Operating & 1929 Maintenance Manuals should be sufficient to indicate that the company 1930 has control over the HVAC systems. There should be a planned 1931 preventive maintenance programme, procedures and records for the HVAC

page 74 1932 system. Records should be kept for a sufficient length of time should they 1933 1934 be required for any product defect analysis. 1935 10.2. O&M manuals, schematic drawings, protocols and reports should be 1936 maintained as reference documents for any future changes and upgrades 1937 to the system. These documents should be kept up to date, containing 1938 any system revisions made. 1939 1940 10.3. The O&M manuals should typically contain the following information: 1941 system description, operating instructions, trouble shooting, 1942 commissioning data, maintenance instructions, list of equipment suppliers, 1943 spare parts list, equipment data/capacity schedules, supplier s literature, 1944 control system description, electrical drawings and as-built drawings. 1945 1946 10.4. Maintenance personnel should receive appropriate training, and training 1947 1948 records should be kept. 1949 10.5. HEPA filters should be changed either by a specialist or a trained person, 1950 1951 and then followed by installed filter leakage testing. 1952 10.6. Any maintenance activity should be assessed critically to determine any 1953 impact on product quality including possible contamination. 1954 1955 10.7. Maintenance activities should normally be scheduled to take place outside 1956 production hours, and any system stoppage should be assessed with a view 1957 to the possible need for requalification of an area as a result of an 1958 interruption of the service. 1959 1960 1961 1962 References 1963 1. Good manufacturing practices for pharmaceutical products: main 1964 principles. In: WHO Expert Committee on Specifications for 1965 Pharmaceutical Preparations Thirty-seventh report. Geneva, World 1966 Health Organization, 2003 (WHO Technical Report Series, No. 908), 1967 Annex 4. http://whqlibdoc.who.int/trs/who_ TRS_908_eng.pdf; 1968 Quality assurance of pharmaceuticals. A compendium of guidelines 1969 and related materials. Volume 2, Second updated edition. Good 1970 manufacturing practices and inspection. Geneva, World Health 1971 Organization, 2007; and Quality assurance of pharmaceuticals. A 1972 compendium of guidelines and related materials. Geneva, World 1973 Health Organization, 2015 (CD-ROM) (in print). 1974 1975 2. Expert Committee on Specifications for Pharmaceutical 1976 Preparations.Fortieth report. Geneva, World Health Organization, 1977 2005 (WHO Technical Report Series, No. 937)

page 75 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 http://whqlibdoc.who.int/trs/who_trs_937_eng.pdf. 3. Technical supplements to Model guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products. WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty Ninth report. Geneva, World Health Organization, 2015 (WHO Technical Report Series, No. 992), Annex 5. 4. Model guidance for the storage and transport of time- and temperature-sensitive pharmaceutical products (jointly with the Expert Committee on Biological Standardization). WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-fifth report. Geneva, World Health Organization, 2011 (WHO Technical Report Series, No. 961), Annex 9. Further reading Quality assurance of pharmaceuticals. A compendium of guidelines and related materials, Volume 1. Geneva, World Health Organization, 1997. Quality Assurance of Pharmaceuticals. A compendium of guidelines and related materials, Volume 2, Second updated edition. Good manufacturing practices and inspection. Geneva, World Health Organization, 2007. http:// www.who.int/medicines/areas/quality_safety/quality_assurance/productio n/ en/index.html; and Quality Assurance of Pharmaceuticals. A compendium of guidelines and related materials. Geneva, World Health Organization, 2015 (CD-ROM) (in print). World Health Organization. Supplements and updates available at: www.who.int/medicines. ASHRAE handbook 1999. HVAC Applications, SI edition. Atlanta, GA, ASHRAE, 2007. http://www.ashrae.org/technology/page/548. ASHRAE handbook 2000. HVAC Systems and Equipment. Atlanta, GA, ASHRAE, 2008. http://www.ashrae.org/technology/page/548. Daly BB. Woods practical guide to fan engineering. Colchester, Woods of Colchester Ltd. Third impression, June 1985. Cambridge, Cambridge University Press. www.flaktwoods.com.

page 76 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 European Commission. The rules governing medicinal products in the European Community, Volume IV. Good manufacturing practice for medicinal products. European Commission, Brussels, 2005. http://www.cen.eu/cenorm/ sectors/sectors/healthcare/index.asp. ISPE Baseline pharmaceutical engineering guides, Volume 2. Oral solid dosage forms, Second Edition / November 2009, International Society for Pharmaceutical Engineering. http://www.ispe.org/. ISPE Baseline pharmaceutical engineering guides for new and renovated facilities, Volume 5. Commissioning and qualification, 1st ed. Tampa, Fl, International Society for Pharmaceutical Engineering, 2001. http://www.ispe.org/. International Cleanroom Standards, ISO 14644. Geneva, International Organization for Standardization. http://www.iso.org/iso/standards_ development.htm. Luwa. Introduction to high efficiency filtration. Bulletin 50.10.10, Sheet 020. Pharmaceutical Inspectorate Convention/Pharmaceutical Inspection Co-operation Scheme. Guide to Good Manufacturing Practice for Medicinal Products. PH 1/97 (Rev. 3), 15 January 2002. PIC/s GMP Guide (PE 009) http://www.picscheme.org/publication.php?id=4. ICH Q9: Quality Risk Management, November 2005 http://www.ich.org. World Health Organization. Guidelines on quality risk management, Geneva, World Health Organization, 2013 (WHO Technical Report Series, No. 981), Annex 2). ***