Working document QAS/18.

759
February 2018
Draft document for comment

1
2
3 GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION
4 AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE
5 PHARMACEUTICAL DOSAGE FORMS: PART 2
6
7 INTERPRETATION OF PART 1 – GMP FOR HVAC SYSTEMS
8
9 (February 2018)
10 DRAFT FOR COMMENT

11 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 Mrs Xenia Finnerty (finnertyk@who.int)
12 by 26 April 2018.
Medicines Quality Assurance working documents will be sent out electronically only and
13 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.
14
15

16 © World Health Organization 2018

17 All rights reserved.
18 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The
19 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole,
20 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and
21 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any
22 website.
23 Please send any request for permission to:
24 Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies Standards and Norms, Department of Essential
25 Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) 791 4730;
26 email: kopps@who.int
27
28 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion
29 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or
30 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate
31 border lines for which there may not yet be full agreement.
32 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or
33 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors
34 and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
35 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this
36 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The
37 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health
38 Organization be liable for damages arising from its use.
39 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.
40
 Working document QAS/18.759
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41
42 SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/18.757:
43 GOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION AND AIR-
44 CONDITIONING SYSTEMS FOR NON-STERILE PHARMACEUTICAL DOSAGE
45 FORMS: PART 2
46
47 INTERPRETATION OF PART 1 – GMP FOR HVAC SYSTEMS
48
49
Preparation of document by Dr A. J. van Zyl, January–
consultant February
2018
Circulation of working document for public
consultation February 2018
Consolidation of comments received and review of
feedback May 2018
Discussion during the informal consultation on July 2018
GXPs for medicines and inspection tools
Circulation of working document for public August 2018
consultation
Consolidation of comments received and review of September 2018
feedback
Presentation to the 53rd meeting of the WHO Expert 22–26 October
Committee on Specifications for Pharmaceutical 2018
Preparations
Any further action …
 Working document QAS/18.759
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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, in 2006.

54 Having considered various comments and the recommendations through public consultation
55 over several years, the WHO Expert Committee on Specifications for Pharmaceutical
56 Preparations (ECSPP) agreed during its 51st meeting held in October 2017, that the Good
57 manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile
58 pharmaceutical dosage forms guidelines, as amended, be adopted as Part 1.

59 It was agreed that Part 1 consists of guidelines that contain good manufacturing practices
60 (GMP) recommendations for heating, ventilation and air-conditioning (HVAC) systems for
61 non-sterile products, and further agreed that Part 1 be supported by an additional document
62 that reflects the interpretation of the recommendations in Part 1.

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

64
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65 Contents
66 page
67 Section 1 and 2. Introduction and Scope
68 3. Glossary
69 4. Premises
70 5. Design of HVAC systems and components
71 6. Full fresh air and recirculation systems
72 7. Air filtration, airflow direction and pressure differentials
73 8. Temperature and relative humidity
74 9. Dust, vapour and fume control
75 10. Protection of the environment
76 11. Commissioning
77 12. Qualification
78 13. Maintenance
79
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80 Section 1 and 2 : Introduction and Scope

81
82 This document represents Part 2 of the HVAC systems guidelines. It contains non-binding
83 examples, drawings, technical representations and interpretation in support of Part 1 of the
84 HVAC systems guidelines.
85
86 It is intended to be a basic and explanatory guide for use by pharmaceutical manufacturers
87 and GMP inspectors. It is not intended to be prescriptive in specifying requirements and design
88 parameters but it attempts to facilitate a harmonized understanding of expectations for HVAC
89 systems for manufacturers of non-sterile products.
90
91 Part 1 and Part 2 focus on good practices for HVAC systems for non-sterile products. Where
92 applicable, some of the principles referred to may be considered in the HVAC design and
93 approach for other dosage forms. These two documents are, however, not intended to be used
94 as enforceable criteria for the design or review of HVAC systems for, e.g. APIs or sterile
95 products.
96
97 Other relevant national and international standards, as applicable, should be considered when
98 Part 1 and Part 2 are used. These include, but are not limited to, the current publications such
99 as ISO 14644 and ASHRAE standards.
100
101 In general, HVAC systems can play an important role in facilitating a suitable environment
102 for the manufacture of quality pharmaceutical products. Therefore careful consideration should
103 be given to the design of the HVAC system. When designing an HVAC system, careful
104 consideration should also be given to the building design and layout of areas as these may
105 influence the decision and design relating to, for example, the number of air handling units
106 (AHUs), components in AHUs, room pressure, pressure differentials, pressure cascades,
107 levels of filtration, humidification, dehumidification, heating and cooling of air. These may in
108 turn have an impact on the quality of materials and products as well as the functioning of
109 equipment and instruments.
110
111 The conditions of areas should be defined and should be appropriate for the storage,
112 manufacturing and use, as appropriate, for equipment, instruments, materials and products. It
113 should further ensure that comfortable conditions are maintained for operators.
114
115 Risk assessment
116
117 In line with the current approach in GMP, risk identification should be done for utilities such
118 as HVAC systems. A science-based, comprehensive exercise of risk assessment should be
119 used to determine risks related to possible failure of the HVAC system and AHUs (including
120 their components and subcomponents). An appropriate risk assessment tool such as failure
121 modes and effects analysis (FMEA) or fault tree analysis (FTA) should be selected. Controls
122 should be identified to eliminate the risks, or minimize the risk to an acceptable level. For
123 example, the effect of the failure of one or more AHUs in the HVAC system; the failure of
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124 dust extraction systems; the failure of AHU components such as filters, heating coils, cooling
125 coils and fans should be assessed and appropriate controls should be identified and
126 implemented.
127
128 For more information on risk assessment, refer the current WHO guidelines on Quality risk
129 management.
130
131 Design parameters
132
133 Manufacturers should define the design parameters of the HVAC system to ensure
134 appropriate operation and functioning of the system that is needed for all the areas. Special
135 consideration should be given to the required conditions for storage and handling of materials
136 and products, equipment and instrument functioning, personnel requirements and
137 contamination control.
138
139 Section 3. Glossary
140
141 For definitions and abbreviations, see Part 1.
142
143
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144 Section 4. Premises

145
146 Premises design
147
148 Both the architectural design of the building and that of the HVAC system should be
149 carefully considered when attempting to achieve the general objectives of preventing
150 contamination, cross-contamination and ensuring an appropriate environment for the
151 production and control of pharmaceutical products. The layout of the premises should
152 facilitate unidirectional flow of material and personnel; building finishes should not result in
153 contamination (e.g. through shedding of particles) and should ensure that the required
154 environmental conditions, cleanliness and containment are achieved and maintained.
155
156 Air infiltration of unfiltered air into production areas should be prevented. Manufacturing
157 facilities should normally be maintained at a positive pressure relative to the outside, to limit
158 the ingress of contaminants. Where facilities are to be maintained at negative pressures
159 relative to the ambient pressure, special precautions should be taken.
160
161 Where necessary, air locks, change rooms and pass-through hatches may be considered and
162 provided with effective ventilation and filtered air. Special attention should be given to door
163 design as gaps between doors and floors, doors opening into low pressure areas and sliding
164 doors can result in changes in pressure differential between areas. An interlocking system and
165 a visual and/or audible warning system may be used to prevent the opening of more than one
166 door at a time where required.
167
168 In addition to the design of the premises, general controls should be in place to ensure
169 protection of materials, products and personnel. The HVAC system can play a role in
170 achieving this objective. Where identified, areas should be maintained within defined limits
171 for temperature, relative humidity, viable and non-viable particles. In such cases, the areas
172 are considered to be “clean areas” (also referred to as “zones, rooms”, etc.). To ensure that
173 the clean area is maintained at the defined limits, areas are normally classified. When
174 classifying the area, the manufacturer should state whether the classification is for the “as
175 built”, “at rest” or “in operation” condition. For details including definitions, see ISO 14644.

176 The following describes approaches (and illustrations by means of diagrams) of different
177 room arrangements and room pressures.

178 Weighing/dispensing and sampling areas

179 A room for weighing (e.g. dispensing of materials), should be of appropriate design. It is
180 often advantageous to have several rooms associated with the weighing activity. These may
181 include a pre-weighing staging area, personnel airlock, material airlock, weighing area with a
182 containment booth, post-weighing staging area, washing area and provision for waste
183 removal. The HVAC system for such areas should ensure that the areas have at least the same
184 area classification as other production areas where materials and products are exposed to the
185 environment, logical flow of material and personnel, appropriate number of AHUs, pressure
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186 differentials, containment, dust control, and air exchange rate.

187
188 The objective of having a booth in a weighing room is to provide dust containment and
189 operator protection. For example, the dust generated at the weighing location should be
190 extracted through a perforated worktop, thus protecting the operator from dust inhalation, but
191 at the same time protecting the product from contamination by the operator by means of the
192 vertical airflow stream. The airflow velocity should be such that it does not disrupt the
193 sensitivity of balances. The operator should neither obstruct the airflow nor become a source
194 of contamination of the materials or products.
195
196
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197 Figure 1. Example of a weighing area

198
Dispensary Post-Staging

Material Flow
Room
35 Pa

Change
Room Pallet
SOB
Perforated Worktop
BIN
35 Pa BIN BIN

Table Scale
BIN BIN

Return Air Shaft

Weigh Booth

25 Pa

BIN

Airflow Protection
Plenum
BIN

Wash Bay
Floor
35 Pa
Scale
Material Flow

Dispensary Pre-Staging Room 15 Pa

199
200 Figure 2. Example of a weighing area
201
Production Passage

Dispensary
Post-Staging
Room

Change Change
MAL Room MAL Room

Weigh Weigh
Return Air Shaft

Brocken
Return Air Shaft

Booth 1 Booth 2 Bulk

Airflow Airflow Store
Protection Protection
Plenum Plenum

Wash Wash
MAL MAL Bay
Bay

MAL
Dispensary Pre-Staging Room
Warehouse
Area

MAL
Material Flow

202
203 Similar aspects may be considered when designing a sampling area, as materials and primary
204 components may be exposed to the environment during sampling.
205
206 Sampling of materials such as starting materials, primary packaging materials and products,
207 should be carried out in the same environmental conditions that are required for the further
208 processing of the product
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209 Figure 3. Example of a sampling area

Change

SOB
25 Pa
Room
Warehouse Wash Bay
30 Pa
Area

5 Pa

Perforated
Worktop

Return Air Shaft

Material Flow Sampling
PTH Booth
Airflow Protection
Material Flow 15 Pa Booth Plenum

210
211
212 Figure 4. Example of a sampling area
Write-up Worktop
Return Air Plenum

Change
Room
SOB

25 Pa
Wash Bay
5 Pa

30 Pa
Warehouse Area

APB (Airflow
Protection Booth)

Sampling Booth

15 Pa

Material Flow
Material Flow
25 Pa Entry MAL 25 Pa Exit MAL
213

214
215 A clean corridor concept is usually recommended for non-sterile oral solid dosage form
216 production areas where there is then a higher pressure in the corridor compared to airlocks or
217 production rooms. This is to facilitate containment of dust and contaminants that may have
218 been generated in production rooms (see also the principles mentioned in the section on
219 sampling and dispensing).
220
221 To further support containment, consideration may also be given to have material airlocks
222 (MAL) and personnel airlocks (PAL), where needed, for entry and exiting processing areas.
223 Appropriately designed airlocks can assist in ensuring containment. Additional controls such
224 as pressure differentials between areas, an appropriate number of air changes in an area and
225 sufficient filtration of air should be in place.
226
227
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228 Figure 5. Example of a change room and some production areas

Female
SOB 15 Pa Ablution
-10 Pa
Female
Production Change
Passage Room

30 Pa Lobby

0 Pa

-10 Pa
15 Pa
SOB
Male
Ablution
Male
Change
Room

Un-classified Zone

229

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

Change
Room
Lo etu

SOB
w rn
R

L e Ai

25 Pa
ve r
l

Passage

35 Pa
Compression Supply
Air
Cubicle Grille

15 Pa MAL
n el

25 Pa
ur ev
r
Ai
et L
R ow
L

232

233
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234 Washing areas should be designed and used in such a manner that equipment and components
235 will not be re-contaminated after cleaning. The system supplying and extracting air from the
236 area(s) should be suitably designed to ensure that this objective is achieved. Principles that
237 may be considered include (but are not limited to) filtration of air, pressure differentials
238 between areas and airflow directions.

239 Figure 7. Example of a washing area

Material Flow Material Flow

Wash Bay Dirty

Equipment
25 Pa
Store

Passage
15 Pa
30 Pa
Material Flow

Clean Equipment
Store

Equipment 45 Pa

Drying

35 Pa
Material Flow Material Flow

240

241
242 Section 5. Design of HVAC systems and components
243
244 The HVAC system should be appropriately designed, taking into consideration the design of
245 the facility with various rooms or areas for the storage of materials and in-process materials
246 or products, processing, movement of materials, products and personnel. The required
247 cleanliness classification should be achieved, as well as other parameters such as airflow
248 direction, air filtration, air exchange rate, airflow velocity, air volumes, pressure differentials,
249 temperature and relative humidity, viable and non-viable particle counts and containment.
250 Conditions and limits should be specified based on need. Manufacturers should determine
251 and define limits for these. These should be realistic, appropriate and scientifically justifiable.
252 In determining these, relevant factors and risks should be considered including but not limited
253 to possible failures of AHUs, seasonal variations, properties and types of materials and
254 products, number of personnel and risks of cross-contamination.
255
256 Other aspects such as the number of AHUs, dust collecting or dust extraction systems, the
257 need for recirculation of air, percentage of fresh air (in the case of recirculated air) and the
258 level of filtration of air should be defined by the manufacturer when considering the design of
259 the facility and activities in different areas and rooms.
260
261 Manufacturers should maintain schematic drawings of the HVAC system, AHUs and
262 components. These should reflect the initial design and installation, as well as the current
263 situation. Changes made during the life cycle of the system should be reflected in change
 Working document QAS/18.759
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264 control records and qualification protocols and reports as appropriate.

265
266 The components selected in an HVAC system should be of sufficient capacity to ensure that
267 the design objectives are met (e.g. for heating, cooling, humidification, dehumidification, air
268 flow volumes), taking impacting factors into consideration such as loss of air due to leakage
269 and seasonal variations. Materials of construction for components and their placement should
270 be such that these do not become the source of contamination. For example, components
271 should not shed particles and the sequence of components should be logical, e.g. filters
272 should be placed in such a manner that any possible contaminants generated in the system
273 can be retained by filters and not be introduced into the production area.
274
275 To prevent contamination of areas, access to components such as ventilation dampers, filters
276 and other services should be accessible from outside the manufacturing areas (such as service
277 corridors).
278
279 The overall design should be such that there is no possibility of undesired, unfiltered air or
280 contaminants entering into manufacturing areas.

281 Containment
282
283 Manufacturers should ensure that appropriate measures are taken to contain product dust in a
284 manufacturing area, thus preventing or minimizing the risk of contamination of other areas
285 and possible cross-contamination. In some cases, it may be advisable to have airlocks or pass
286 through hatches between rooms or areas. In addition, sufficient dilution, pressure differentials
287 (recommended minimum values of 5 to 15 Pa) and airflow directions can further support
288 containment in an area.
289
290 Cleanliness
291
292 Areas should be maintained at the defined levels of cleanliness and classifications. The
293 HVAC system can support this through, e.g. appropriate levels of filtration of air, airflow
294 directions, dilution, dust removal and air exchange rate. Equipment, containers, personnel and
295 other related components should be appropriately located or placed in areas so as not to
296 obstruct airflow and effectiveness of the HVAC system.
297
298 Recontamination should be prevented by ensuring that material and personnel movement is
299 within the same area classification and not back and forth between areas of different
300 classification. Where such back-and-forth movement is unavoidable, appropriate controls
301 should be identified and implemented to ensure that moving from a higher class to a lower
302 classified area and back to a higher classified area will not result in contaminants being
303 brought into the cleaner classified area.
304
305 Automated monitoring systems
306
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307 The performance of the HVAC system achieving and maintaining the desired results for
308 parameters such as temperature, relative humidity, airflow and pressure differential should be
309 carefully controlled and monitored. This is to ensure that there is no departure from these
310 limits during manufacturing. Monitoring systems should be in place to ensure that the system
311 operates within its design limits. Manual or automated (computerized) systems may be used.
312
313 Manual systems of monitoring may not always provide sufficient proof that the system is able
314 to maintain all conditions throughout the manufacturing period.
315
316 Automated monitoring systems may provide ongoing monitoring possibilities with better
317 assurance of compliance with the defined limits. Where these automated systems are
318 considered to be GXP systems, these should be appropriately validated. The scope and extent
319 of validation of the computerized system should be determined, be justifiable and
320 appropriately executed. This includes, but is not limited to, access and privileges to the
321 software, setting of limits, monitoring and acknowledging alarms, audit trails, controls,
322 monitoring and reporting.
323
324 Switching off of AHUs
325
326 It is recommended that the HVAC system be operational on an ongoing basis. Where a
327 manufacturer decides to use energy saving modes or switch some selected AHUs off at
328 specified intervals such as overnight, weekends or extended periods of time, care should be
329 taken to ensure that materials and products are not affected. In such cases, the decision,
330 procedures and records should be sufficiently documented and should include risk
331 assessment, standard operating procedures (SOPs), records and validation. This includes
332 procedures and records for the start-up and shut-down sequence of air handling units.
333
334 Section 6. Full fresh air and recirculation systems
335
336 Manufacturers may select to have full fresh air systems or recirculate treated air supplied to
337 production areas (In a full fresh air system, no air is recirculated. In recirculation systems, a
338 defined percentage of the air is recirculated.). In both cases, the air supplied to the production
339 areas should be appropriately treated to ensure that the environmental conditions specified are
340 met and that the risks for contamination and cross-contamination are controlled.
341
342 Manufacturers using recirculation systems should determine the percentage of fresh air to be
343 supplied to the relevant manufacturing areas, as required by national and international
344 standards. This volume of air should be verified during qualification.
345
346 In both scenarios, appropriate levels of filtration should be applied to prevent contamination
347 and cross-contamination. Manufacturers should ensure that when HEPA filters are used that
348 these are appropriately installed, not damaged and thus suitable for the intended use (see tests
349 described below under the section of qualification).
350
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351 Figure 8. Example of a full fresh-air system

352
AIR HANDLING UNIT
Primary Filter S = Supply Air

HEPA Filter
= Return Air

Supply Air

Secondary
R

Filter
Fan
-
F = Fresh Air
Cooling Coil E = Exhaust Air

F
Fresh Air

PRODUCTION
FACILITY

EXHAUST AIR HANDLING UNIT

Exhaust Air

Primary Filter
Secondary
HEPA Filter

E E
Filter
Fan

Exhaust Air

Degree of filtration required

depends on exhaust air contaminants
353
354
355 Section 7. Air filtration, airflow direction and pressure differentials
356
357 Effective ventilation and appropriate levels of filtration are recommended in basic GMP
358 guidelines. Manufacturers should determine which classes of filters should be used in
359 ensuring that contaminants from outside are not introduced into manufacturing areas and that
360 where recirculation systems are used, filtration of recirculated air should be effectively
361 treated to ensure that there is no risk of cross-contamination. Where different products are
362 manufactured in different rooms in the same facility at the same time, appropriate controls
363 should be in place to ensure containment and the prevention of contamination and cross-
364 contamination.
365
366 Filters selected for air filtration, air changes and airflow direction should be determined and
367 specified. When a manufacturer chooses to install high efficiency particulate air (HEPA) filters
368 to achieve the desired degree of filtration of air, these filters may be placed in the AHU or
369 may be installed terminally near the supply grille.
370
371 The number of air changes or air exchange rates should be sufficient. A guidance value is
372 between 6 and 20 air changes per hour. Manufacturers should also establish how much time it
373 takes for a room, which is out of its classification, to return within the specified class. This is
374 often referred to as clean-up or recovery time. A guidance time period for clean-up or
375 recovery is about 15 to 20 minutes
376
377 Airflow directions should be specified and proven to promote containment and not be
378 adversely affected or obstructed by equipment, utilities, containers or personnel. The location
379 of supply and return or exhaust air grilles should facilitate appropriate airflow directions in an
380 area.
381
382 Figure 9 is a schematic diagram of air-handling system serving rooms with horizontal
383 directional flow, vertical directional flow and turbulent flow, for rooms 3, 4 and 5,
384 respectively. In these room, the HEPA filters are indicate to have been placed terminally
 Working document QAS/18.759
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385 mounted at the rooms and not in the AHU. Terminally-mounted HEPA filters can assist with
386 preventing cross-contamination from room to room in the event of a fan failure condition.
387
388 Figure 9. Example of horizontal airflow, vertical flow and turbulent flow
389
AIR HANDLING UNIT

Primary Filter

Supply Air

Secondary
S = Supply Air

Filter
Fan
- R = Return Air

Cooling Coil
F = Fresh Air
F

+ +
+
S S
R

HEPA Filters
S
Room with low
S level return air
S
HEPA Filters

Room with
R S
Room with Vertical UDAF
Horizontal UDAF
R
R
R

ROOM 4 ROOM 5
ROOM 3
390
391
392 The pressure differential should be of sufficient magnitude to ensure containment and
393 prevention of flow reversal, but should not be so high as to create turbulence problems. It is
394 suggested that pressure differentials of between 5 Pa and 20 Pa be considered. Where the
395 design pressure differential is too low and tolerances are at opposite extremities a flow
396 reversal can take place. There should be no risk of overlap in the acceptable operating range,
397 e.g. 5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting in the failure
398 of the pressure cascade. The upper and lower limits for pressure differentials between areas in
399 a facility should be defined by the manufacturer. Where there are interleading rooms the
400 limits should be appropriate to ensure that there is no overlap in actual values as this may
401 result in loss in pressure differential between areas and even reversal of air flow.
402
403 The pressure control and monitoring devices used should be calibrated and where possible, be
404 linked to an alarm system set according to the determined levels.
405
406 Figure 10: Examples of pressure cascades
407
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Tablet Tablet
Compression Compression Encapsulation

15 Pa ± 3 Pa 15 Pa ± 3 Pa 15 Pa ± 3 Pa
Air Leakage

Air Leakage

Air Leakage
Airlock
Air Leakage Air Leakage
Production Corridor
30 Pa ± 3 Pa 15 Pa ± 3 Pa

Image of room pressure gauge

Design Condition (15 Pa Pressure Differential) indicating colour coded normal,
alert & action parameters

Tablet Tablet Tablet Tablet

Compression Compression Encapsulation Compression Compression Encapsulation

12 Pa 12 Pa 12 Pa 18 Pa 18 Pa 18 Pa
Air Leakage

Air Leakage

Air Leakage

Air Leakage

Air Leakage

Air Leakage
Airlock Airlock
Air Leakage Air Leakage Air Leakage Air Leakage
Production Corridor Production Corridor
12 Pa 18 Pa
33 Pa 27 Pa

408 Maximum Differential (21 Pa Pressure Differential) Minimum Differential (9 Pa Pressure Differential)

409
410 Airlocks
411
412 Airlocks with different pressure cascade regimes include the cascade airlock, sink airlock and
413 bubble airlock:
414
415  cascade airlock: higher pressure on one side of the airlock and lower pressure on
416 the other;
417  sink airlock: lower pressure inside the airlock and higher pressure on both outer sides;
418  bubble airlock: higher pressure inside the airlock and lower pressure on both outer
419 sides.
420
421 Figure 11: Example of cascade airlock
422 (In most cases the internal pressure of the airlock is not critical. The pressure differential
423 between the two outer sides is the important criteria.)
424

Air Leakage Air Leakage

Material Airlock 30 Pa
15 Pa
22.5 Pa

Cascade Airlock

425
426

427
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428 Figure 12: Example of sink airlock

429

Air Leakage
Air Leakage

Material Airlock
30 Pa 30 Pa
15 Pa

Sink Airlock

430
431
432

433 Figure 13: Example of bubble airlock

434

Air Leakage Air Leakage

15 Pa Material Airlock
15 Pa
30 Pa

Bubble Airlock

435
436
437 Note: The diagrams above and the differential pressures shown here are for illustration
438 purposes only. Pressures indicated in these examples are absolute pressures, whereas the
439 local pressure indication would most likely be pressure differential from room to room.
440
441 Additional controls should be identified through risk identification and risk assessment. For
442 example, where possible, personnel should not move between different areas during
443 production (such as compression rooms and in process control laboratories) unless there is no
444 risk of contamination of other areas. Personnel often become sources of contamination as
445 they may carry dust from one area to another. Controls may include airlocks or gowning
446 procedures.
447
448 Section 8: Temperature and relative humidity
449
450 Manufacturers should set appropriate upper and lower limits for temperature and relative
451 humidity for different areas. The required storage conditions specified for the materials and
452 products should be considered when the limits are defined. The HVAC system should be
453 designed in such a manner that these limits can be achieved and be maintained through all
454 seasons.
455
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456 Systems for dehumidification or humidification require special considerations due to their
457 contamination risk (e.g. condensate formation, bacterial and fungal contamination,
458 contaminated steam and risks when using mobile systems between different areas).
459 Chemicals such as corrosion inhibitors or chelating agents, which could have a
460 detrimental effect on the product, should not be added to the boiler system. Humidification
461 systems should be well drained. No condensate should accumulate in air-handling systems.
462 Other humidification appliances such as evaporative systems, atomizers and water mist sprays,
463 should not be used because of the potential risk of microbial contamination. Air filters should
464 not be installed immediately downstream of humidifiers as moisture on the filters could lead
465 to bacterial growth. Cold surfaces should be insulated to prevent condensation within the
466 clean area or on air-handling components. Chemical driers using silica gel or lithium chloride
467 are acceptable provided that they do not become sources of contamination.
468
469 Section 9. Dust, vapour and fume control
470
471 Manufacturers should ensure that dust-generated vapours and fumes are effectively removed
472 from the manufacturing areas. Extraction or collecting systems should be designed and
473 qualified to demonstrate this. Sufficient air velocity should be maintained in such systems to
474 effectively remove dust and vapours.
475
476 A dust extractor should normally not serve different rooms where different products can be
477 processed at the same time due to the risks such as backflow or flow from room to room
478 resulting in possible contamination and cross-contamination.
479
480 Wherever possible, dust or vapour contamination should be removed at source, i.e. as close as
481 possible to the point where the dust is generated. Dust extraction ducting should be designed
482 with sufficient transfer velocity (determined by the manufacturer depending on materials and products
483 processed) to ensure that dust is carried away, and does not settle in the ducting (a guidance value
484 is 15–20 m/s). As vapours can be problematic, extraction may be supported by directional
485 airflow to assist in the removal. The density of the vapour should be taken into consideration
486 with extract grilles at a high level or possibly at both high and low levels.
487
488 Section 10. Protection of the environment
489
490 Manufacturers should have controls in place to ensure that air from production areas,
491 including contaminated air from equipment such as fluid bed driers, is passed through
492 appropriate levels of filtration to ensure that the environment is not polluted. Manufacturers
493 should consult national and international environmental legislation.
494
495 Section 11. Commissioning
496
497 Where manufacturers perform commissioning, this should be clearly documented.
498
499 Section 12. Qualification
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500
501 Manufacturers should consider all stages of qualification for their HVAC systems. This
502 includes, where appropriate, user requirement specification, design qualification, factory
503 acceptance test, site acceptance test, installation qualification, operational qualification and
504 performance qualification. Qualification to be done over the life cycle of the HVAC system
505 should be described and executed including, e.g. when changes are made to the system.
506
507 Validation master plan(s), protocols, reports and source data for tests should be available. The
508 scope and extent of qualification should be determined based on risk assessment. Parameters
509 with limits included in qualification (such as temperature test, airflow direction, viable and
510 non-viable particle counts) should be justified by manufacturers. The procedures followed for
511 the performance of the tests should generally be in line with the standard as described in ISO
512 14644
513
514 Some of the typical HVAC system parameters that should be included in the tests during
515 qualification are listed below. It is recommended that the tests be done at defined intervals.
516 The tests typically cover:
517
518 — temperature;
519 — relative humidity;
520 — supply air quantities;
521 — return air or exhaust air quantities;
522 — room air-change rates;
523 — pressure differentials;
524 — airflow direction test;
525 — installed filter leakage tests;
526 — particle counts;
527 — clean-up or recovery rates;
528 — microbiological counts;
529 — warning/alarm systems.
530
531 Table 1. Considerations in testing
532
Test parameter Test procedure Note

Temperature ISO 14644 and WHO Consider the

Technical Report temperature mapping
Series, No. 961 test as described in
WHO Technical
Report Series
Relative humidity ISO 14644 and WHO See Temperature
Technical Report mapping test for
Series, No. 961 principles
 Working document QAS/18.759
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Pressure differential ISO 14644

Airflow volumes ISO 14644
Installed filter leakage ISO 14644
Particle counts ISO 14644
Airflow direction ISO 14644 or Where a smoke test is
company procedure performed, ensure a
(smoke test) continuous capture of
the process, e.g.
video, with correct
angles to demonstrate
flow direction and
identification of date,
time and area filmed
and recorded in a
traceable manner
Air flow velocity ISO 14644
Recovery

533
534 Section 13. Maintenance
535
536 Manufacturers should maintain current documentation for HVAC systems which include
537 operation and maintenance manuals, schematic drawings, procedures and records.
538
539 Repairs, maintenance and preventive maintenance (including cleaning, replacement of
540 components, changes, qualification) should be executed in accordance with procedures.
541 Records for these should be maintained for an appropriate time.
542
543 ***
544
545
546