Working document QAS/15.639/Rev.

2
July 2017
Revised document for comment

1
2 GUIDELINES ON
3 HEATING, VENTILATION AND AIR-CONDITIONING
4 SYSTEMS FOR NON-STERILE PHARMACEUTICAL
5 PRODUCTS
6
7 (June 2017)
8 REVISED DRAFT FOR COMMENT

10 Should you have any comments on the attached text, please send these to Dr S. Kopp, Group Lead,
Medicines Quality Assurance, Technologies, Standards and Norms (kopps@who.int) with a copy to
11 finnertyk@who.int by 15 September 2017.
Medicines Quality Assurance working documents will be sent out electronically only and will also
12 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)
13 and we will add it to our electronic mailing list.
14
15
16 ____________________________________________________________________________________________________________
17 World Health Organization 2017
18 All rights reserved.
19 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The
20 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole,
21 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and
22 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any
23 website.
24 Please send any request for permission to:
25 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Department of Essential
26 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730;
27 email: kopps@who.int
28
29 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
30 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or
31 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate
32 border lines for which there may not yet be full agreement.
33 The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or
34 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors
35 and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
36 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this
37 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The
38 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health
39 Organization be liable for damages arising from its use.
40 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
41
42
 Working document QAS/15.639/Rev.2
page 2

43 SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/15.639

44 GUIDELINES ON HEATING, VENTILATION AND AIR-CONDITIONING
45 SYSTEMS FOR NON-STERILE PHARMACEUTICAL PRODUCTS

Discussion of proposed need for revision in view of the current 29 June

trends in engineering and experience gained during the 1 July
implementation of this guidance in inspection during informal 2015
consultation on data management, bioequivalence, GMP and
medicines inspection
Preparation of draft proposal for revision by Mr D. Smith, consultant JulyAugust 2015
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 September 2015
Preliminary consolidation of comments received and review of 10 October 2015
feedback
Presentation to the fiftieth meeting of the WHO Expert Committee 1216 October
on Specifications for Pharmaceutical Preparations 2015
Final consolidation of comments received and review of feedback JanuaryMarch
2016
Discussion at the informal consultation on good practices for health 46 April 2016
products manufacture and inspection, Geneva
Preparation of revision by Mr D. Smith, based on comments May 2016
provided by Mr A. Kupferman and Dr A.J. Van Zyl, both
participants at the above-mentioned consultation.
Circulation of revised working document for public consultation May 2016
Consolidation of comments received and review of feedback August
September 2016
Presentation to the fifty-first meeting of the WHO Expert Committee 1721 October
on Specifications for Pharmaceutical Preparations 2016
Preparation of draft proposal for revision by Mr I. Thrussell, JanuaryMarch
consultant to the Medicines Quality Assurance group and 2017
Prequalification Team (PQT)-Inspections, based on the feedback
received during the meeting and from PQT-Inspections for further
discussion at the informal consultation on good practices for health
products manufacture and inspection, Geneva, April 2017.
Discussion at the informal consultation on good practices for health April 2017
products manufacture and inspection, Geneva, April 2017
Preparation of the next version of the guidelines based on the feed- May 2017
back received prior to and during the informal consultation, by
Dr A.J. van Zyl, May 2017
Circulation of revised working document for public consultation July 2017
 Working document QAS/15.639/Rev.2
page 3

Consolidation of comments received and review of feedback September 2017

Presentation to the fifty-second meeting of the WHO Expert October 2017
Committee on Specifications for Pharmaceutical Preparations
46

47
48

49
 Working document QAS/15.639/Rev.2
page 4

50 BACKGROUND

51 The World Health Organization (WHO) published the first edition of the WHO Guidelines on
52 good manufacturing practices for heating, ventilation and air-conditioning systems for non-
53 sterile pharmaceutical dosage forms in WHO Technical Report Series, No. 937, 2006. After
54 a revision, the second edition of the document was published in WHO Technical Report
55 Series, No. 961, 2011. Having considered various comments and questions related to good
56 manufacturing practices (GMP) for heating, ventilation and air-conditioning (HVAC)
57 systems, the document was opened for revision. After wide public consultation over the
58 recent years (see history of the process and timelines above), and considering comments
59 received from (but not limited to) various organizations, industry and individuals, the
60 document and comments were considered during an informal consultation in Geneva in
61 April 2017.

62 During this informal consultation the proposed changes based on comments received as well
63 as additional comments made during the consultation, were discussed. It was agreed that the
64 guidelines be amended to make provision for two documents. It was recommended that the
65 one document should consist of guidelines that contain recommendations for GMP for
66 HVAC systems for non-sterile products, while a second document should contain examples
67 and drawings that will clarify some of the recommendations included in the first document.

68 Therefore, the previous version of the WHO guidelines on good manufacturing practices for
69 heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage
70 forms as was published in WHO Technical Report Series, No. 961, Annex 5, 2011 is
71 proposed to be amended accordingly as set out in this draft guideline.

72 Summary of main changes

73 In accordance with the recommendation made during the informal consultation in April 2017,
74 the guidelines have been rewritten into two parts. This is the first part of the guidelines and
75 this part contains the recommendations that are to be considered as good practices in the
76 design, management, control and qualification over the life cycle of HVAC systems.
77
78 The second part will contain non-binding examples, clarifications and drawings in support of
79 Part one and is currently under preparation.
80
81 Due to the rewriting of the guidelines, a summary of changes is not provided here, as the
82 content in the previous guideline has been reorganized. In addition, all the comments received
83 during the last comment period were considered in rewriting the guidelines.
84
85 The illustrative guidance and explanations (Second part) will be published at a later stage.
86
87
 Working document QAS/15.639/Rev.2
page 5

88 Contents
89
90 page
91 1. Introduction
92 2. Scope
93 3. Glossary
94 4. Premises
95 5. Design of HVAC systems and components
96 6. Full fresh air and recirculation systems
97 7. Air filtration, airflow direction and pressure differentials
98 8. Temperature and relative humidity
99 9. Dust, vapour and fume control
100 10. Protection of the environment
101 11. Commissioning
102 12. Qualification
103 13. Maintenance
104 References and further reading
105
 Working document QAS/15.639/Rev.2
page 6

106 1. INTRODUCTION
107
108 Heating, ventilation and air-conditioning (HVAC) play an important role in ensuring the
109 manufacture of quality pharmaceutical products. The good manufacturing practice (GMP)
110 requirements of the prevention of contamination and cross-contamination are an essential
111 design consideration of an HVAC system. A well designed HVAC system also provides
112 environmental protection, operator protection as well as comfortable working conditions for
113 operators.
114
115 These guidelines mainly focus on recommendations for HVAC systems used in facilities for
116 the manufacture of non-sterile dosage forms which include tablets, capsules, powders,
117 liquids, creams and ointments. The general HVAC system design principles contained in the
118 guidelines may, however, also be applied to other dosage forms.
119
120 HVAC system design influences architectural building design and layouts with regard to, e.g.
121 airlock positions, doorways and lobbies. These in turn have an effect on room pressure,
122 pressure differential cascades, contamination and cross-contamination control. In view of
123 these aspects, the design of the HVAC system should be considered at the initial design stage
124 of a pharmaceutical manufacturing plant.
125
126 Temperature, relative humidity and ventilation should be appropriate and should not
127 adversely affect the quality of pharmaceutical products during their manufacture and storage,
128 or the accurate functioning of equipment and instruments.
129
130 A comprehensive science and risk-based approach should be followed throughout the
131 lifecycle of an HVAC system, including its design, qualification and maintenance. Risk
132 management principles should be applied throughout the life cycle. Risk assessment is
133 however not a substitute for GMP (WHO Technical Report Series, No. 957, Annex 3).
134
135 2. SCOPE
136
137 These guidelines focus primarily on GMP for the design, qualification, management and
138 maintenance of HVAC systems in facilities for the manufacture of non-sterile dosage forms.
139
140 These guidelines are intended to complement those provided for in GMP for pharmaceutical
141 products and should be read in conjunction with the parent guide. The additional standards
142 addressed in this guide should therefore be considered supplementary to the general
143 requirements set out in the main principles guide (WHO Technical Report Series, No. 961,
144 Annex 3).
145
146 Most of the system principles described in these guidelines may also be considered in
147 facilities manufacturing other dosage forms and products, including biological products,
148 herbal medicines, complimentary medicines and finishing processing steps for active
 Working document QAS/15.639/Rev.2
page 7

149 pharmaceutical ingredients (APIs). Additional, specific requirements apply for air-handling
150 systems of pharmaceutical hazardous, sterile and biological products. Guidelines for these are
151 covered in separate WHO guidelines (WHO Technical Report Series, No. 957, Annex 3;
152 WHO Technical Report Series, No. 961, Annex 6; and working document
153 WHO/BS/2015.2253, intended to replace WHO Technical Report Series, No. 822, Annex 1,
154 1992, respectively).
155
156 3. GLOSSARY
157
158 The definitions given below apply to terms used in this document. They may have different
159 meanings in other contexts.
160
161 acceptance criteria. Measurable terms under which a test result will be considered
162 acceptable.
163
164 action limit. The action limit is reached when the acceptance criteria of a critical
165 parameter have been exceeded. Results outside these limits will require specied action and
166 investigation.
167
168 air changes per hour. The flow rate of air supplied to a room, in m3/hr, divided by
169 the room volume, in m3.
170
171 air-handling unit. The air-handling unit serves to condition the air and provide the
172 required airflow within a facility.
173
174 airflow protection booth. A booth or chamber, typically for purposes of carrying out
175 sampling or weighing, in order to provide product containment and operator protection.
176
177 airlock. An enclosed space with two or more doors, which is interposed between two
178 or more rooms, e.g. of differing classes of cleanliness, for the purpose of controlling the
179 airow between those rooms when they need to be entered. An airlock is designed for and
180 used by either people or goods (personnel airlock (PAL); material airlock (MAL)).
181
182 alert limit. The alert limit is reached when the normal operating range of a critical
183 parameter has been exceeded, indicating that corrective measures may need to be taken to
184 prevent the action limit being reached.
185
186 as-built. Condition where the installation is complete with all services connected and
187 functioning but with no production equipment, materials or personnel present.
188
189 at-rest. Condition where the installation is complete with equipment installed and
190 operating in a manner agreed upon by the customer and supplier, but with no personnel
191 present.
 Working document QAS/15.639/Rev.2
page 8

192
193 central air-conditioning unit (see air-handling unit)
194
195 change control. A formal system by which qualied representatives of appropriate
196 disciplines review proposed or actual changes that might affect a validated status. The intent
197 is to determine the need for action that would ensure that the system is maintained in a
198 validated state.

199 clean area (cleanroom). An area (or room or zone) with dened environmental
200 control of particulate and microbial contamination, constructed and used in such a way as to
201 reduce the introduction, generation and retention of contaminants within the area.
202
203 clean-up (see recovery)
204
205 closed system. A system where the product or material is not exposed to the
206 manufacturing environment.
207
208 commissioning. Commissioning is the documented process of verifying that the
209 equipment and systems are installed according to specications, placing the equipment into
210 active service and verifying its proper action. Commissioning takes place at various stages
211 during the project construction but prior to validation.
212
213 containment. A process or device to contain product, dust or contaminants in one
214 zone, preventing it from escaping to another zone.
215
216 contamination. The undesired introduction of impurities of a chemical or microbial
217 nature, or of foreign matter, into or onto a starting material or intermediate, during
218 production, sampling, packaging or repackaging, storage or transport.
219
220 controlled area (classified area). An area within the facility in which specic
221 procedures and environmental parameters, including viable and non-viable particles, are
222 dened, controlled and monitored to prevent degradation, contamination or cross-
223 contamination of the product.
224
225 controlled not classified. An area where some environmental conditions are
226 controlled (such as temperature), but the area has no cleanroom classification.
227
228 critical parameter or component. A processing parameter (such as temperature or
229 relative humidity) that affects the quality of a product, or a component that may have a direct
230 impact on the quality of the product.
231
232 critical quality attribute. A physical, chemical, biological or microbiological
233 property or characteristic that should be within an appropriate limit, range or distribution to
234 ensure the desired product quality.
 Working document QAS/15.639/Rev.2
page 9

235
236 cross-contamination. Contamination of a starting material, intermediate product or
237 nished product with another starting material or product during production.
238
239 cross-over-bench. Cross-over or step-over bench in change room to demarcate the
240 barrier between different garment change procedures.
241
242 design condition. Design condition relates to the specied range or accuracy of a
243 controlled variable used by the designer as a basis for determining the performance
244 requirements of an engineered system.
245
246 design qualication. Design qualication is the documented check of planning
247 documents and technical specications for design conformity with the process,
248 manufacturing, good manufacturing practices and regulatory requirements.
249
250 differential pressure. The difference in pressure between two points such as the
251 pressure difference between an enclosed space and an independent reference point, or the
252 pressure difference between two enclosed spaces.
253
254 direct impact system. A system that is expected to have a direct impact on product
255 quality. These systems are designed and commissioned in line with good engineering practice
256 and, in addition, are subject to qualication practices.
257
258 exltration. Exltration is the egress of air from a controlled area to an external zone.
259
260 extract air. Air leaving a space, which could be either return air or exhaust air.
261 Return air means that the air is returned to the air-handling unit and exhaust air means that
262 the air is vented to atmosphere.
263
264 facility. The built environment within which the clean area installation and associated
265 controlled environments operate together with their supporting infrastructure.
266
267 good engineering practice. Established engineering methods and standards that are
268 applied throughout the project life cycle to deliver appropriate, cost-effective solutions.
269
270 hazardous substance or product. A product or substance that may present a
271 substantial risk of injury to health or to the environment.
272
273 HEPA filter. High efficiency particulate air filter.
274
275 HVAC. Heating, ventilation and air-conditioning. Also referred to as Environmental
276 control systems.
277
 Working document QAS/15.639/Rev.2
page 10

278 indirect impact system. This is a system that is not expected to have a direct impact
279 on product quality, but typically will support a direct impact system. These systems are
280 designed and commissioned according to good engineering practice only.
281
282 inltration. Inltration is the ingress of air from an external zone into a controlled
283 area.
284
285 installation qualication. Installation qualication is documented verication that
286 the premises, HVAC system, supporting utilities and equipment have been built and installed
287 in compliance with their approved design specication.
288
289 ISO 14644.The International Standards Organization has developed a set of standards
290 for the classification and testing of cleanrooms. Where ISO 14644 is referenced it implies the
291 latest revision and all the separate parts thereof.
292
293 no-impact system. This is a system that will not have any impact, either directly or
294 indirectly, on product quality. These systems are designed and commissioned according to
295 good engineering practice only.
296
297 non-critical parameter or component. A processing parameter or component within
298 a system where the operation, contact, data control, alarm or failure will have an indirect
299 impact or no impact on the quality of the product.
300
301 normal operating range. The range that the manufacturer selects as the acceptable
302 values for a parameter during normal operations. This range must be within the operating
303 range.
304
305 out-of-specification (OOS). In relation to HVAC systems this could refer to any of
306 the environmental conditions being OOS, i.e. falling outside of alert or action limits.
307
308 operating limits. The minimum and/or maximum values that will ensure that product
309 and safety requirements are met.
310
311 operating range. Operating range is the range of validated critical parameters within
312 which acceptable products can be manufactured.
313
314 operational condition. This condition relates to carrying out room classication tests
315 with the normal production process with equipment in operation and the normal staff present
316 in the specific room.
317
318 operational qualication. Operational qualication is the documentary evidence to
319 verify that the equipment operates in accordance with its design specications in its normal
320 operating range and performs as intended throughout all anticipated operating ranges.
 Working document QAS/15.639/Rev.2
page 11

321
322 oral solid dosage. Usually refers to oral solid dosage medicinal products such as
323 tablets, capsules and powders to be taken orally.
324
325 pass-through-hatch or pass box. A cabinet with two or more doors for passing
326 equipment, material or product, whilst maintaining the pressure cascade and segregation
327 between two controlled zones. A passive pass-through-hatch (PTH) has no air supply or
328 extract. A dynamic PTH has an air supply into the chamber.
329
330 performance qualication. Performance qualication is the documented verication
331 that the process and/or the total process related to the system performs as intended throughout
332 all anticipated operating ranges.
333
334 point extraction. Air extraction to remove dust with the extraction point located as
335 close as possible to the source of the dust.
336
337 pressure cascade. A process whereby air ows from one area, which is maintained at
338 a higher pressure, to another area maintained at a lower pressure.
339
340 qualication. Qualication is the planning, carrying out and recording of tests on
341 equipment and a system, which forms part of the validated process, to demonstrate that it will
342 perform as intended.
343
344 quality critical process parameter. A process parameter which could have an impact
345 on the critical quality attribute.
346
347 recovery. Room recovery or clean-up tests are performed to determine whether the
348 installation is capable of returning to a specified cleanliness level within a finite time, after
349 being exposed briefly to a source of airborne particulate challenge.
350
351 relative humidity. The ratio of the actual water vapour pressure of the air to the
352 saturated water vapour pressure of the air at the same temperature expressed as a percentage.
353 More simply put, it is the ratio of the mass of moisture in the air, relative to the mass at 100%
354 moisture saturation, at a given temperature.
355
356 standard operating procedure. An authorized written procedure, giving instructions
357 for performing operations, not necessarily specic to a given product or material, but of a
358 more general nature (e.g. operation of equipment, maintenance and cleaning, validation,
359 cleaning of premises and environmental control, sampling and inspection). Certain standard
360 operating procedures may be used to supplement product-specic master and batch
361 production documentation.
362
 Working document QAS/15.639/Rev.2
page 12

363 turbulent air ow. Turbulent ow, or non-unidirectional airow, is air distribution
364 that is introduced into the controlled space and then mixes with room air by means of
365 induction.
366
367 unidirectional airow. Unidirectional airow is a rectied airow over the entire
368 cross-sectional area of a clean zone with a steady velocity and approximately parallel
369 streamlines (see also turbulent ow). (Modern standards no longer refer to laminar flow, but
370 have adopted the term unidirectional airflow.)
371
372 validation. The documented act of proving that any procedure, process, equipment,
373 material, activity or system actually leads to the expected results.
374
375 validation master plan. Validation master plan is a high-level document which
376 establishes an umbrella validation plan for the entire project and is used as guidance by the
377 project team for resource and technical planning (also referred to as master qualication plan).
378
379 4. PREMISES
380
381 4.1. The manufacture of non-sterile pharmaceutical products should take place in a
382 controlled environment, as defined by the manufacturer.
383
384 4.2. The design of the HVAC system should be closely coordinated with the architectural
385 design of the building.
386
387 4.3. Infiltration of unfiltered air into a manufacturing facility should be prevented as this
388 can be a source of contamination.
389
390 4.4. Manufacturing facilities should normally be maintained at a positive pressure relative
391 to the outside, to prevent the ingress of contaminants. Where facilities are to be maintained at
392 negative pressures relative to the outside, special precautions should be taken to mitigate any
393 risks (see WHO Technical Report Series, No. 957, Annex 3).
394
395 4.5. Areas for the manufacture of products, or where open equipment is exposed, should
396 be of an appropriate level of cleanliness. The level of protection and air cleanliness for
397 different areas should be determined according to, but not limited to, the products
398 manufactured, the process used and product susceptibility to degradation.
399
400 Where a clean room classification is specified, the manufacturer should state whether the
401 classification is rated for the as-built, at-rest or operational condition.
402
403 4.6. HVAC systems should ensure that the specified room conditions are attained, e.g.
404 through heating, cooling, air filtration, air distribution, airflow rates and air exchange rates.
405
 Working document QAS/15.639/Rev.2
page 13

406 4.7. Any area where pharmaceutical starting materials, products, primary packing
407 materials, utensils and equipment are exposed to the environment should have the same
408 level of cleanliness or classification as that in which the products are produced.
409
410 4.8. Appropriate design and controls for the premises and HVAC systems should be in
411 place to achieve the required containment, cleanliness and the appropriate levels of product,
412 personnel and environmental protection.
413 (Note: For facilities where the highest level of containment is a requirement refer to the
414 WHO Technical Report Series, No. 957, Annex 3).
415
416 4.9. Containment, cleanliness and protection may be facilitated through, for example:
417
418 correct building layout;
419 building finishes;
420 the use of airlocks such as personnel airlocks (PAL) and/or material airlocks (MAL);
421 pass-through hatches (PTH);
422 change rooms and passages;
423 sufficient pressure cascades.
424
425 4.10. Detailed schematic diagrams should be maintained, indicating pressure cascades,
426 airflow directions and flow routes for personnel and materials.
427
428 4.11. Where possible, personnel and materials should not move from a higher cleanliness
429 zone to a lower cleanliness zone and back to a higher cleanliness zone. Where this is
430 unavoidable, risks should be identified and controlled.
431
432 4.12. The final change room should be at the same cleanliness level (at rest) as the area into
433 which it leads.
434
435 4.13. Where appropriate, such as where the simultaneous opening of airlock doors might
436 lead to a cross-contamination risk, airlock doors should not be opened at the same time. In
437 such cases, controls such as interlocking systems, warning systems and procedures should be
438 implemented.
439
440 4.14. Swing doors should normally open to the high-pressure side and be provided with
441 self-closers. Exceptions to the door swing direction should be justified and may include, e.g.
442 fire escapes or other health and safety constraints. In these cases, door closer mechanisms
443 should be carefully controlled and other controls should be in place to prevent any risk.
444
445 4.15. Sampling, weighing and dispensing areas should be appropriately designed with
446 required levels of containment, operator protection and product protection.
447
448 4.16. Sampling, weighing and dispensing should be performed under the same
 Working document QAS/15.639/Rev.2
page 14

449 environmental conditions as specified in the areas for further processing of the product.
450
451 4.17. Factors such as airflow should not disrupt the accuracy of balances.
452
453 4.18. The position of the operator, equipment and containers should not obstruct airflow
454 patterns.
455
456 4.19. Once an area is qualified with a specific layout for operators, equipment and
457 processes, this configuration should be ensured during routine activity.
458
459 4.20. Return and exhaust filters and grilles selected and installed should be appropriate and
460 their design should facilitate cleaning and maintenance.
461
462 4.21. The impact and risk to the HVAC system should be considered when changes are
463 planned to an existing facility. This includes upgrades and retrofitting of facilities.
464
465 5. DESIGN OF HVAC SYSTEMS AND COMPONENTS
466
467 HVAC systems should be appropriately designed and managed throughout their life cycle.
468 Documentation such as schematic drawings should be maintained to reflect the current
469 situation, including but not limited to, air supply and extraction, air handling units, room
470 pressure cascades, air flow direction, personnel and material movement, and waste removal.
471
472 5.1. Risk management principles should be applied during the design of an HVAC system.
473 This includes, but is not limited to, appropriate controls of the climatic conditions and the
474 prevention of contamination and cross-contamination.
475
476 5.2. The HVAC system capacity should be sufficient to ensure that the required
477 performance is maintained during normal use.
478
479 5.3. Materials of construction for components of an HVAC system should not become a
480 source of contamination.
481
482 5.4. Where possible, ducting, piping, fittings, sensors and other components should be
483 clearly marked or labelled for ease of identification, location and direction of flow as
484 appropriate.
485
486 5.5. Air intake and exhaust air terminals should be positioned in a manner in relation to
487 one another that assist in preventing cross-contamination.
488
489 5.6. Air-handling units (AHUs) should be provided with adequate drains to remove
490 condensate that may form in the AHU.
491
 Working document QAS/15.639/Rev.2
page 15

492 5.7. Conditions and limits for parameters such as temperature, relative humidity, air
493 cleanliness and recovery times should be specified and achieved, as needed, for the materials
494 and products handled, as well as process risks.
495
496 5.8. Room recovery rates should demonstrate that the HVAC system is capable of
497 returning an area to a specified level of cleanliness or classification, temperature, relative
498 humidity, room pressure and microbial limits, as appropriate, within the specified time.
499
500 5.9. Possible room pressure changes due to fan failure and partial system shut down with
501 an impact on ease of opening of doors for escape purposes should be considered.
502
503 5.10. The effectiveness of the air distribution and air flow patterns should be appropriate
504 and effective.
505
506 5.11. Air supply and extract grilles should be appropriately located to provide effective
507 room flushing and prevent zones of stagnant air.
508
509 5.12. The performance of HVAC systems should be controlled and monitored to ensure
510 ongoing compliance with defined parameters. Records should be maintained. Limits defined
511 should be justified.
512
513 5.13. Where automated monitoring systems are used, these should be capable of indicating
514 any out-of-specification (OOS) condition by means of an alarm or similar system. Where
515 these systems are identified as GXP systems, they should be appropriately validated.
516
517 5.14. Appropriate alarm systems should be in place to alert personnel in case a critical
518 component of the system fails, e.g. a fan.
519
520 5.15. The effect of fan failure on building and HVAC components should be assessed.
521 Where appropriate provision should be made for a fan interlock failure matrix.
522
523 5.16. Switching off of AHUs at intervals such as overnight or weekends, or reducing supply
524 air volumes during non-production hours, should not compromise product quality. Where this
525 is done, there should be appropriate justification and no risk to materials or products. The
526 procedure and acceptability should be proven through validation and qualification.
527
528 5.17. There should be procedures and records maintained for the start up and shut down
529 sequence of air handling units.
530
531 6. FULL FRESH AIR SYSTEMS AND RECIRCULATION SYSTEMS
532
533 6.1. Full fresh air, or recirculation type HVAC systems may be used. Where recirculation
534 systems are used, there should be no risk of contaminants in the return-air system. The
 Working document QAS/15.639/Rev.2
page 16

535 recirculated air should be adequately filtered.

536
537 6.2. HEPA filters may be installed (in the supply air stream or return air stream) to remove
538 contaminants and thus prevent cross-contamination. The HEPA filters in such an application
539 should have an EN 1822 classification of at least H13 or equivalent.
540
541 6.3. HEPA filters may not be required to control cross-contamination where there is
542 evidence that cross-contamination would not be possible due to other robust technical means,
543 or where the air-handling system is serving a single product facility.
544
545 6.4. The amount of fresh air intake required should be determined. As a minimum, the
546 following criteria should be considered:
547
548 sufficient volume of fresh air to compensate for leakage from the facility and loss
549 through exhaust air systems;
550 operator occupancy;
551 regional or national legislation.
552
553 6.5. Air that might be contaminated with organic solvents or highly hazardous materials
554 should normally not be recirculated.
555
556 6.6. The required degree of filtration of the exhaust air should be considered based on risk,
557 exhaust air contaminants and local environmental regulations.
558
559 6.7. Where energy-recovery wheels are used in multiproduct facilities, controls should be
560 in place to ensure that these do not become a source of cross-contamination.
561
562 7. AIR FILTRATION, AIRFLOW DIRECTION AND PRESSURE DIFFERENTIALS
563
564 7.1. Where different products are manufactured at the same time, such as in different areas
565 or cubicles in a multiproduct manufacturing site, measures should be taken to ensure that dust
566 cannot move from one cubicle to another. Appropriate levels of filtration, airflow direction
567 and a pressure cascade systems can assist in preventing cross-contamination.
568
569 7.2. Filters selected should be appropriate for their intended use and classified according
570 to current international classification (see Table 1 below).
571
572 7.3. Airflow directions should be appropriate, taking operator and equipment locations
573 into consideration.
574
575 7.4. The pressure cascade for areas in a facility should be individually assessed according
576 to the products handled and level of protection required. The pressure cascade regime and the
577 direction of airflow should be appropriate to the product and processing method used, and
 Working document QAS/15.639/Rev.2
page 17

578 should also provide operator and environmental protection.

579
580 7.5. The pressure cascade should be such that the direction of airflow is from the clean
581 area, resulting in dust containment, e.g. from the corridor to the cubicle.
582
583 7.6. The limits for the pressure differential between adjacent areas should be such that
584 there is no risk of overlap in the defined operating ranges.
585
586 7.7. Normally, for cubicles where dust is liberated, the corridor should be maintained at a
587 higher pressure than the cubicles and the cubicles at a higher pressure than atmospheric
588 pressure. (For negative pressure facilities refer to WHO Technical Report Series, No. 957,
589 Annex 3, for hazardous products guidelines and design conditions.)
590
591 Room pressure differential indication should be provided. The pressure indication gauges
592 should have a range and graduation scale which enables the reading to an appropriate
593 accuracy. The normal operating range, alert and action limits should be defined and displayed
594 at the point of indication.
595
596 Room pressure should be traced back to representative ambient pressure (by summation of
597 the room pressure differentials), in order to determine the room actual absolute pressure.
598
599 7.8. The pressure control and monitoring devices used should be calibrated. Compliance
600 with specifications should be regularly verified and the results recorded.
601
602 7.9. Pressure control devices should be linked to an alarm system which is set according to
603 the levels determined by a risk analysis and justified dead times.
604
605 7.10. Zero setting of gauges should be tamper proof. Zero setting should be checked at
606 regular intervals.
607
608 7.11. Where airlocks are used, the pressure cascade regimes selected should be appropriate.
609 In considering room pressure differentials, transient variations, such as machine extract
610 systems and their impact, should be taken into consideration.
611
612

613
614
615
 Working document QAS/15.639/Rev.2
page 18

616 Table 1. Comparison of filter test standards*

617
Eurovent
Eurovent 4/5
4/5
ASHRAE
Eurovent 4/5 ASHRAE ASHRAE
52.1 EN 779 & EN 1822
rating 52.2 52.1
BS6540 Part

ISO 29463
BS6540
1
Part 1
Average
Average
dust spot MPPS integral
Merv arrestance
(superseded) efficiency overall EN rating
rating Am (%)
Em (%) efficiency (%)
(superseded)
(superseded)
99.999995 U17 75E
99.99995 U16 65E

EN 1822: 2009
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
Merv 13 >98 85 MPPS = F7
most
EU 7 >98 80
penetrating
Merv 12 >95 75 particle size
EU 6 >95 70 M6
Merv 11 >95 65
>95 60
Merv 10 >95 55
EN 779: 2012

EU 5 Merv 9 >95 50 M5
Merv 8 >95 45
>95 40
Merv 7 >90 35
EU 4 >90 30 G4
Merv 6 90 25
EU 3 Merv 5 85 20 G3
80 <20
Merv 4 75
EU 2 Merv 3 70 G2
Merv 2 65
EU 1 Merv 1 <65 G1
618 *Ensure that the classification is current.

619 Note: The filter classifications referred to above relate to the EN1822:2009 and EN779: 2012
620 test standards (EN779 relates to filter classes G1 to F9 and EN1822 relates to filter classes
621 E10 to U17).
622
623 8. TEMPERATURE AND RELATIVE HUMIDITY
624
625 8.1. Where appropriate, temperature and relative humidity should be controlled, monitored
626 and recorded to ensure that the conditions are maintained pertinent to the materials and
627 products as required, and provide a comfortable environment for the operators.
 Working document QAS/15.639/Rev.2
page 19

628
629 8.2. Limits for minimum and maximum room temperatures and relative humidity should
630 be appropriate. Alert and action limits should be set appropriate to material and product
631 requirements, and to inhibit increased microbial loading.
632
633 8.3. Where steam or humidity is present, controls should be in place to ensure that the
634 HVAC system will remain effective. Precautions should be taken to prevent moisture
635 migration that may increase an uncontrolled load on the HVAC system.
636
637 Where humidification or dehumidification is required, this should be achieved by appropriate
638 means which does not become a source of contamination.
639
640 8.4. Dehumidification and cooling systems should be well drained. Condensate should not
641 accumulate in air-handling systems and should not become a source of contamination.
642
643 9. DUST, VAPOUR AND FUME CONTROL
644
645 The location of discharge exhaust points relative to air inlet points should be carefully
646 considered to prevent contamination and cross-contamination.
647
648 9.1. Dust, vapours and fumes could be possible sources of contamination and should be
649 appropriately controlled. Wherever possible, these should be removed at source. The HVAC
650 system should normally not serve as the primary mechanism of dust control.
651
652 9.2. Dust extraction systems should be appropriately designed and installed. Dust should
653 not flow back in the opposite direction, e.g. in the event of component failure or airflow
654 failure. The transfer velocity should be sufficient to ensure that dust is carried away and does
655 not settle in the ducting.
656
657 9.3. The positioning of dust extraction points should be appropriate to prevent dust and
658 powders dropping down from the extract point causing contamination or cross-
659 contamination.
660
661 9.4. Air should not flow through the dust extraction ducting or return air ducting from the
662 room with the higher pressure to the room with the lower pressure.
663
664 9.5. Periodic checks should be performed to ensure that there is no build-up of the dust in
665 the ducting.
666
667 9.6. Dust extraction systems should be interlocked, where appropriate, to the relevant air-
668 handling unit to avoid any risk and impact on pressure cascade imbalances.
669
670
 Working document QAS/15.639/Rev.2
page 20

671
672 10. PROTECTION OF THE ENVIRONMENT
673
674 Where exhaust air from equipment such as fluid bed driers, dust extraction systems and
675 facilities carry dust loads, adequate filtration should be provided to prevent contamination of
676 the ambient air.
677
678 10.1. Waste from wet and dry scrubbers should be disposed of in an appropriate manner.
679
680 10.2. Dust-slurry should be removed by suitable means, e.g. a drainage system or waste
681 removal contractor.
682
683 11. COMMISSIONING
684
685 Commissioning
686
687 Note: Commissioning is a precursor to system qualification and validation, and is normally
688 associated with good engineering practice (GEP).
689
690 12. QUALIFICATION
691
692 Note: For general notes on qualification and validation, see WHO Guideline on Validation .
693 (See WHO Technical Report Series, No. 937, Annex 4).
694
695 12.1. HVAC systems, including recirculation and full fresh air systems, should be qualified
696 to ensure continued performance in accordance with specifications and achieving the
697 conditions as specified.
698
699 12.2. The scope and extent of qualification should be determined based on risk management
700 principles.
701
702 12.3. The qualification of the HVAC system should be described in a master plan. The
703 master plan should define the nature and extent of testing, the test procedures and protocols to
704 be followed.
705
706 12.4. Where relevant, the procedures followed for the conduct of tests should be in
707 accordance with the appropriate parts as mentioned in ISO 14644 and relevant WHO
708 guidelines.
709
710 12.5. The design condition, operating ranges, alert and action limits should be defined.
711 Alert limits should be based on system capability.
712
713 12.6. Performance parameters to be included in qualification for the HVAC system should
 Working document QAS/15.639/Rev.2
page 21

714 be determined by means of a risk assessment.

715
716 12.7. Acceptable tolerances for system parameters, where appropriate, should be specified
717 prior to commencing the physical installation.
718
719 12.8. There should be standard operating procedures describing the action to be taken when
720 alert and action limits are reached. This may include, where relevant:
721
722 temperature;
723 relative humidity;
724 supply air quantities;
725 return air or exhaust air quantities;
726 room air-change rates;
727 room pressures and pressure differentials;
728 airflow pattern tests;
729 unidirectional air flow velocities;
730 containment system velocities;
731 HEPA filter penetration tests;
732 room particle count tests;
733 duct leakage tests;
734 materials of construction;
735 microbiological counts;
736 de-dusting and dust extraction systems.
737
738 12.9. Where routine or periodic revalidation is done, the frequency should be established
739 based on, e.g. risk, the type of facility, the level of product protection necessary, performance
740 of the system and the extent of routine ongoing monitoring activities.
741
742 12.10. Any change to the HVAC system should be handled according to a change control
743 procedure. The extent of qualification or requalification should be considered based on the
744 scope and impact of the change.
745
746 13. MAINTENANCE
747
748 13.1. Operation and maintenance (O&M) manuals, procedures and records should be
749 available and kept up to date, containing any system revisions made.
750
751 13.2. O&M manuals, schematic drawings, protocols and reports should be maintained as
752 reference documents for any future changes and upgrades to the system.
753
754 13.3. The O&M manuals may typically contain the following information:
 Working document QAS/15.639/Rev.2
page 22

755
756 system description;
757 operating instructions;
758 trouble shooting;
759 commissioning data;
760 maintenance instructions;
761 list of equipment suppliers;
762 spare parts list;
763 equipment data/capacity schedules;
764 suppliers literature;
765 control system description; e
766 electrical drawings;
767 as-built drawings.
768
769 13.4. There should be a planned preventive maintenance programme for the HVAC system.
770 The details of the maintenance programme should be commensurate with the criticality of the
771 system and components.
772
773 13.5. Maintenance activities should not have any negative impact on product quality and
774 should normally be scheduled to take place at appropriate times, e.g. outside production
775 hours.
776
777 In case of system stoppages, appropriate quality management system procedures should be
778 followed. Where necessary, the root cause and impact should be assessed and appropriate
779 corrective and preventive action taken. Where necessary, qualification or requalification
780 should be considered.
781
782 13.6. HEPA filters should be changed by a competent person followed by installed filter
783 leakage testing.
784
785 13.7. Records should be kept for a sufficient period of time.
786
787
788 REFERENCES AND FURTHER READING
789
790 1. Good manufacturing practices: quality assurance of pharmaceuticals. WHO guidelines,
791 good practices, related regulatory guidance and GXP training materials. CD-ROM,
792 update 2016.
793
794 2. ISO 14644 Cleanrooms and Associated Controlled Environments Package, including
795 ISO 14644-1 to ISO 14644-10 (updated regularly). International Standard
796 Organization, Geneva.
797
 Working document QAS/15.639/Rev.2
page 23

798 3. ICH Harmonised Tripartite Guideline on Quality Risk Management (Q9), 2005.
799
800 4. WHO guidelines on quality risk management, Annex 2, WHO Technical Report
801 Series, No. 981, 2013.
802
803 5. WHO GMP for sterile pharmaceutical products, WHO Technical Report Series, No.
804 961, Annex 6.
805
806 6. WHO good manufacturing practices for biological products, Annex 3, WHO
807 Technical Report Series, No. 996, 2016.
808
809 7. WHO Guideline on validation (see WHO Technical Report Series, No. 937, Annex 4)
810 (under revision).

***

811