Hvac Qas15-639 31082015 2

Working document QAS/15.639/Rev.
1
May 2016
Draft document for comment
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SUPPLEMENTARY GUIDELINES ON
GOOD MANUFACTURING PRACTICES FOR HEATING,
VENTILATION AND AIR-CONDITIONING SYSTEMS FOR
NON-STERILE PHARMACEUTICAL DOSAGE FORMS
REVISED DRAFT FOR COMMENT
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(May 2016)
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 Ms Marie Gaspard (gaspardm@who.int) by 12 July 2016.
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.
World Health Organization 2016

All rights reserved.
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
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Organization.
Working document QAS/15.639/Rev.1

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SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF

DOCUMENT QAS/15.639
SUPPLEMENTARY GUIDELINES ON GOOD MANUFACTURING
PRACTICES FOR HEATING, VENTILATION AND AIRCONDITIONING 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
29 June
1 July 2015
Preparation of draft proposal for revision by Mr 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
JulyAugust 2015
Circulation of revised working document for public

consultation
September 2015
Consolidation of comments received and review of

feedback
10 October 2015
Presentation to the fiftieth meeting of the WHO Expert

Committee on Specifications for Pharmaceutical
Preparations
1216 October 2015

feedback
JanuaryMarch
2016
Discussion at the informal consultation on good

practices for health products manufacture and inspection,
Geneva,
46 April 2016
Preparation of revision by Mr D. Smith, based on

comments provided by Mr A. Kupferman and Dr A.J.
Van Zyl, both participants at the above-mentioned
consultation.
May 2016
Circulation of revised working document for public

consultation
May 2016

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feedback
AugustSeptember
2016
Presentation to the fifty-first meeting of the WHO Expert

Committee on Specifications for Pharmaceutical
Preparations
1721 October 2016
Any other follow-up action as required

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BACKGROUND
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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.
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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.
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Summary of main changes
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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.
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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 TRS, No. 937, Annex 4 guidelines.
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.

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Contents
page
1.
2.
3.
4.
5.
Introduction
Scope of document
Glossary
Premises
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 ltration and air patterns
6.3
Unidirectional airow
6.4
Inltration
6.5
Cross-contamination and contamination
6.6
Pressure differential concept (high pressure differential,
low airow)
6.7
Physical barrier concept
6.8
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, qualication and validation
9.1
General
9.2
Commissioning
9.3
Qualication
9.4
Supplementary notes on test procedures
9.4.1 General
9.4.2 Airflow measurements
9.4.3 Non-variable air particle counts
9.4.4 HEPA filter integrity tests
10.
Maintenance
References
Further reading

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1.
INTRODUCTION
Heating, ventilation and air-conditioning (HVAC) play an important role in

ensuring the manufacture of quality pharmaceutical products. A well designed
HVAC system will also provide comfortable conditions for operators.
These guidelines mainly focus on recommendations for systems for
manufacturers of non-sterile dosage forms, and include tablets, capsules,
powders, liquids, creams, ointments, etc. The HVAC design principles
contained in the guidelines may be applied to other dosage forms.
HVAC system design inuences architectural layouts with regard to items
such as airlock positions, doorways and lobbies. The architectural components
have an effect on room pressure, differential cascades and crosscontamination control. The prevention of contamination and crosscontamination is an essential design consideration of the HVAC system. In
view of these critical aspects, the design of the HVAC system should be
considered at the concept design stage of a pharmaceutical manufacturing
plant.
Temperature, relative humidity and ventilation should be appropriate and
should not adversely affect the quality of pharmaceutical products during
their manufacture and storage, or the accurate functioning of equipment.
This document aims to give guidance to pharmaceutical manufacturers
and inspectors of pharmaceutical manufacturing facilities on the design,
installation, qualication and maintenance of the HVAC systems.
These guidelines are intended to complement those provided in Good
manufacturing practices for pharmaceutical products (1) and should be read
in conjunction with the parent guide. The additional standards addressed by
this guide should, therefore, be considered supplementary to the general
requirements set out in the main principles guide (WHO Technical Report
Series, No. 961, Annex 3)
2.
SCOPE OF DOCUMENT
These guidelines focus primarily on the design and good manufacturing

practices (GMP) requirements for HVAC systems for facilities for the
manufacture of solid dosage forms. Most of the system design principles
for facilities manufacturing solid dosage forms also apply to facilities
manufacturing other dosage forms (such as liquids, cream, ointments) and
other classes of products including biological products, herbal medicines,
complementary medicines and finishing process steps for APIs.
Non-sterile forms typically include:

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products with low water activity (less subject to microbial

contamination), e.g. oral solid dosage forms, suppositories;
products with high water activity (more subject to microbial
contamination, depending on the formulation), e.g. liquids,
drops, syrups, ointments and creams.
Additional specic requirements apply for air-handling systems of

pharmaceutical sterile products and hazardous products. Guidelines for
hazardous, sterile and biological product facilities are covered in separate
WHO guidelines (WHO Technical Report Series, No. 957, Annex 3; WHO
Technical Report Series, No. 961, Annex 6; and working document
WHO/BS/2015.2253, intended to replace WHO Technical Report Series,
No. 822, Annex 1, 1992, respectively).
These guidelines 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, difcult to lay down the specic requirements
for one particular parameter in isolation.
Many pharmaceutical manufacturers have their own engineering design and
qualication 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 guideline are the roles that the HVAC system plays in
product protection, personnel protection and environmental protection
(Figure 1).
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 user requirement specification stage right
through to validation, as indicated in the diagram below (Figure 2).
Validation protocols and criteria should be justified by links to a written
risk assessment.

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Figure 1. The guidelines address the various system criteria according to

the sequence set out in this diagram
GMP MANUFACTURING
ENVIRONMENT
PRODUCT
PROTECTION
PERSONNEL
PROTECTION
PROTECTION OF
EXTERNAL
ENVIRONMENT
Contamination
(Product & Staff)
Prevent Contact
with Dust
Avoid Dust
Discharge
Protect from
Product
Contamination
Prevent Contact
with Fumes
Avoid Fume
Discharge
Correct Temperature
& Humidity
Acceptable Comfort
Conditions
Avoid Effluent
Discharge
SYSTEMS
SYSTEM VALIDATION
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Figure 2. GMP compliance sequence diagram

PROJECT
INCEPTION
QUALIFICATION
&
VALIDATION
RISK
RISK
ASSESSMENT
ASSESSMENT
STUDIES
STUDIES
HVAC &
SERVICES
DESIGNS
ENERGY
EFFICIENCY
STUDIES
CE
N
M
CO
Installations &
Commissioning
CO
G
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FACILITY
LAYOUTS
IA
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USER
REQUIREMENT
SPECIFICATION
CE
MP
L
222
C OM PL I A N
GM P
PL I A NC E
GM

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3.
GLOSSARY
The denitions given below apply to terms used in these guidelines. They
may have different meanings in other contexts.
acceptance criteria. Measurable terms under which a test result
will be considered acceptable.
action limit. The action limit is reached when the acceptance
criteria of a critical parameter have been exceeded. Results outside these
limits will require specied action and investigation.
air changes per hour. The volume of air supplied to a room, in m3/hr,
divided by the room volume, in m3.
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.
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 airow between those rooms
when they need to be entered. An airlock is designed for and used by
either people or goods (personnel airlock (PAL); material airlock (MAL)).
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 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 qualied 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

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would ensure that the system is maintained in a validated state.
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clean area (cleanroom). An area (or room or zone) with dened

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.
clean-up (see recovery)
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
specications, 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 (classified area). An area within the facility in
which specic environmental parameters, conditions and procedures are
dened, controlled and monitored to prevent degradation or crosscontamination of the product.
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 nished product with another starting material or

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product during production.

cross-over-bench. Cross-over or step-over bench in change room to
demarcate the barrier between different garment change procedures.
design condition. Design condition relates to the specied range or
accuracy of a controlled variable used by the designer as a basis for
determining the performance requirements of an engineered system.
design qualication. Design qualication is the documented check
of planning documents and technical specications for design conformity
with the process, manufacturing, good manufacturing practices and
regulatory requirements.
differential pressure. The difference in pressure between two
points such as the pressure difference between an enclosed space and an
independent reference point, or the pressure difference between two
enclosed spaces.
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
qualication practices.
exltration. Exltration is the egress of air from a controlled area to
an external zone.
extract air. Air leaving a space, which could be either return air or
exhaust air. Return air means that the air is returned to the air-handling unit
and exhaust air means that the air is vented to atmosphere.
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.
hazardous substance or product. A product or substance that may
present a substantial risk of injury to health or to the environment.
HEPA filter. High efficiency particulate air filter.

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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.
inltration. Inltration is the ingress of air from an external zone
into a controlled area.
installation qualication. Installation qualication is documented
verication that the premises, HVAC system, supporting utilities and
equipment have been built and installed in compliance with their approved
design specication.
ISO 14644. The International Standards Organization has developed
a set of standards for the classification and testing of cleanrooms. The
standard comprises 12 separate parts. Where ISO 14644 is referenced it
implies the latest revision.
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, 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. In relation to HVAC systems this could
refer to any of the environmental conditions being OOS, i.e. falling outside of
alert or action limits.
operating limits. The minimum and/or maximum values that will
ensure that product and safety requirements are met.

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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
classication tests with the normal production process with equipment in
operation and the normal staff present in the specific room.
operational qualication. Operational qualication is the documentary
evidence to verify that the equipment operates in accordance with its design
specications in its normal operating range and performs as intended throughout
all anticipated operating ranges.
oral solid dosage. Usually refers to an oral solid dosage plant that
manufactures medicinal products such as tablets, capsules and powders to
be taken orally.
pass-through-hatch or pass box. A cabinet with two or more doors
for passing equipment, material or product, whilst maintaining the pressure
cascade and segregation between two controlled zones. A passive passthrough-hatch (PTH) has no air supply or extract. A dynamic PTH has an
air supply into the chamber.
performance qualication. Performance qualication is the
documented verication that the process and/or the total process related to the
system performs as intended throughout all anticipated operating ranges.
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 ows from one area,
which is maintained at a higher pressure, to another area maintained at a
lower pressure.
qualication. Qualication 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. A process parameter which
could have an impact on the critical quality attribute.
recovery. Room recovery or clean-up 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.

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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. An authorized written procedure,
giving instructions for performing operations, not necessarily specic 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 standard operating
procedures may be used to supplement product-specic master and batch
production documentation.
turbulent ow. Turbulent ow, or non-unidirectional airow, is air
distribution that is introduced into the controlled space and then mixes with
room air by means of induction.
unidirectional airow. Unidirectional airow is a rectied airow
over the entire cross-sectional area of a clean zone with a steady velocity
and approximately parallel streamlines (see also turbulent ow). (Modern
standards no longer refer to laminar flow, but have adopted the term
unidirectional airflow.)
validation. The documented act of proving that any procedure,
process, equipment, material, activity or system actually leads to the
expected results.
validation master plan. Validation master plan is a high-level
document which establishes an umbrella validation plan for the entire
project and is used as guidance by the project team for resource and
technical planning (also referred to as master qualication plan).
4.
PREMISES
4.1.
There is a close relationship between architectural design and
HVAC design, as they both have an impact on the functionality of the
other. HVAC system design influences architectural layouts with regard to
items such as airlock positions, doorways and lobbies. The architectural
layouts and building components have an effect on room pressure
differential cascades and cross-contamination control. The prevention of
contamination and cross-contamination is an essential design consideration

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of the HVAC system. In view of these critical aspects, the design of the
HVAC system should be considered at the concept design stage of a
pharmaceutical manufacturing plant, and the design should be closely
coordinated with the architectural designers. The above design
considerations should also be applicable to facility upgrades or the
retrofitting of facilities.
4.2.
As the efficient operation of the air-handling system and cleanliness
levels attained are reliant on the correct building layout and building
finishes, the following items should be considered.
4.2.1. Adequate airlocks, such as personnel airlocks (PAL) and/or material
airlocks (MAL), pass-through hatches (PTH), change rooms and passages
should be provided to limit air transfer between different cleanliness zones,
and may be provided to limit cross-contamination within the same
cleanliness zone. These should have supply and extract air systems as
appropriate.
4.2.2. Areas such as airlocks, change rooms and passages should be
designed so that the required pressure cascades can be achieved.
4.2.3. Detailed diagrams depicting pressure cascades, air flow directions
and flow routes for personnel and materials should be prepared and
maintained.
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 change room should be the same good manufacturing
practices (GMP) classification grade (at rest) as the area into which it leads.
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).

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536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
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/or a visual and/or audible warning system
should be operated to prevent the opening of more than one door at a time.
556
557
558
559
560
561
Room pressure differentials could be lower or higher depending on the

specific design and operations. The purpose of a pressure differential is to
enhance the separation between areas with different levels of cleanliness
and also to provide containment to prevent cross-contamination. Where
there is no difference in cleanliness level, and no potential for cross
contamination, a zero pressure differential can be applied.
562
4.2.8. Doors should be carefully designed to avoid un-cleanable recesses.

Swing doors should open to the high-pressure side and be provided with
self-closers. Exceptions are permitted based on site environmental, fire,
health and safety containment requirements. Cognizance should be taken of
possible room pressure changes due to fan failure and the impact on ease of
opening doors for escape purposes.
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 uncleanable recesses and a minimum
of projecting ledges, shelves, cupboards and equipment.
The following diagrams are examples of room and suite layouts with their
associated room pressures. These are purely examples and other factors
may dictate different room arrangements and room pressures.

page 18
Figure 3. Example of a weigh booth layout
Material Flow
Dispensary Post-Staging
Room
Staff Flow
563
564
35 Pa
Change
Room
Pallet
COB
Perforated Worktop
25 Pa
BIN
BIN
BIN
BIN
BIN
Table Scale
Staff Flow
25 Pa
35 Pa
BIN
BIN
Airflow Protection
Plenum
Wash Bay
Floor
Scale
Material Flow
25 Pa
Dispensary Pre-Staging Room
565
566
567
568
569
15 Pa
Note: Similar air handling and product protection principles apply to

sampling suites.
Return Air Shaft
Weigh Booth
Airlock

page 19
570
Figure 4. Example of a dispensary suite
Staff Flow
Material Flow
Production Passage
Staff Flow
Wash
Bay
Staff Flow
Staff Flow
Dispensary Pre-Staging Room
Wash
Bay
Optional
location
Material Flow
Staff Flow
W/h Staff
MAL
Material Flow
571
572
573
574
575
576
577
578
579
Warehouse
Area
Optional
location
MAL
Staff Flow
Wash
Bay
Material Flow
Material Flow
Broken
Bulk
Store
Staff Flow
Airflow
Protection
Plenum
Staff Flow
Airflow
Protection
Plenum
Return Air Shaft
Weigh
Booth 2
Return Air Shaft
Weigh
Booth 1
MAL
Change
Room
MAL
Staff Flow
MAL
Optional
location
Material Flow
Staff Flow
Change
Room
COB
Material Flow
Dispensary
Post-Staging
Room
Notes:
1. Two alternative locations are indicated for the wash bays.
2. The broken bulk store is optional. Alternatively partially used
containers can be returned to the warehouse.
3. The inclusion of MALs at entrance and exit to weigh booths depend on
containment risks and the pressure cascade design.

page 20
580
Figure 5. Change rooms and washing area layouts
Production
Passage
Female
Toilets
15 Pa
COB
-10 Pa
Female
Change
Room
Lobby
30 Pa
0 Pa
-10 Pa
15 Pa
COB
Male
Toilets
Male
Change
Room
Un-classified Zone
581
582

page 21
Figure 6. Example of a compression cubicle with change room and MAL,

for higher risk materials.
COB
l
ve r
L e Ai
w rn
Lo etu
R
Compression
Cubicle
L
R ow
et L
ur ev
n el
Ai
r
15 Pa
Change
Room
25 Pa
35 Pa
Supply
Air
Grille
MAL
Production Passage
583
584
25 Pa
585
586
587
588
589
590
Note: The inclusion of the PAL and MAL is dependent on product risk,
range of products handled in adjacent cubicles, pressure cascade and open
vs closed manufacturing processes.

page 22
Figure 7. Example of compression cubicle without change room and MAL,

for lower risk materials (inclusion of airlocks dependant on risk assessment)
l
ve r
L e Ai
w rn
Lo etu
R
Compression
Cubicle
L
R ow
et L
ur ev
n el
Ai
r
15 Pa
593
594
595
596
30 Pa
Supply
Air
Grille
Production Passage
591
592
Note the supply air from the ceiling towards the front of the cubicle and air
extract at low level at the back corners of the cubicle.

page 23
Figure 8. Example of wash-bay suite
Material Flow
Material Flow
Dirty
Equipment
Store
Wash Bay
25 Pa
Material Flow
15 Pa
30 Pa
Clean Equipment
Store
Equipment
Drying
Production Passage
597
45 Pa
35 Pa
Material Flow
Material Flow
598
599
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
615
616
5.
DESIGN OF HVAC SYSTEMS AND COMPONENTS
5.1.
General
5.1.1. The required degree of air cleanliness in most non-sterile dosage

form manufacturing facilities can normally be achieved without the use of
high-efciency particulate air (HEPA) lters, provided the air is not
recirculated or in the case of a single-product facility. Many open product
zones of non-sterile dosage form facilities are capable of meeting ISO
14644-1 Class 8 or Grade D, at-rest condition, measured against particle
sizes of 0.5 m and 5 m, but cleanliness may not necessarily be classied
as such by manufacturers.
Grade D conditions usually have a maximum viable particle concentration of
200 cfu/m3. Alternative microbiological levels as per the table below could be
used depending on risk assessments.

page 24
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618
Table 1. Microbiological air quality in production premises for the manufacture of

non-sterile medicinal products
Area
Limits
in operation
Manufacture of
nonsterile,
semi-solid4 and
liquid dosage
forms2
Manufacture of
tablets, capsules
and coated
tablets3
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
Limits
at rest
Alert limit
(cfu1/m3)
Action
limit
(cfu/m3)
(cfu/m3)
Routine
monitoring
frequency of
testing
250
500
100
Weekly
500
800
400
Monthly
Colony-forming unit.
In analogy to WHO GMP guidelines, this area can also be classified as grade E.
3
In analogy to WHO GMP guidelines, this area can also be classified as grade F.
4 Depending on the product properties it may be necessary to define stricter limits for water-based semi-solid
dosage.
2
5.1.2. A risk assessment should be carried out to determine the room

cleanliness conditions required and the extent of validation required. Once
room cleanliness and environmental conditions have been determined,
qualification of these conditions should be carried out.
5.1.3. There are two basic concepts of air delivery to pharmaceutical
production facilities: a recirculation system; and a full fresh air system
(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:
sufcient fresh air to compensate for leakage from the facility and
loss through exhaust air systems;
sufcient fresh air to comply with national building regulations
(depends on occupant density);
sufcient 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-specication (OOS) condition by means of
an alarm or similar system. Sophisticated computer-based data monitoring
systems may be installed, which can aide with planning of preventive
maintenance and can also provide trend logging.

page 25
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657
658
659
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661
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663
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667
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683
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691
(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. The EMS for monitoring of
critical parameters could be a computerized system or a more manual
means of recording data. 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 airow reversal.
5.1.6. Appropriate alarm systems should be in place to alert personnel if a
critical fan fails. Critical alarms should be easily identiable and visible
and/or audible to relevant personnel. There should be an action plan for such
alarms i.e. stop production, close up open product, move product, etc., and may
include corrective and preventive action (CAPA).
5.1.7. Based on a risk assessment 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 airow reversal and possible cross-contamination. This fan stopstart matrix should apply to the switching on and switching off of systems
to ensure that there is no flow reversal causing cross-contamination. The
effect of fan failure on building and HVAC components should also be
assessed. A failure of one fan could cause excessive positive or negative
pressures resulting in damage such as structural failure of components.
5.1.8. 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 nal
lters.
5.1.9. Where possible ventilation dampers, lters 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.

page 26
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697
698
699
700
701
702
703
704
705
706
707
5.2.
Air distribution
5.2.1. The positioning of supply and extract grilles should be such as to

provide effective room ushing. Low-level return or exhaust air grilles are
usually preferred. However, where this is not possible, a higher air change
rate may be needed to achieve a specied clean area condition, e.g. where
ceiling return air grilles are used.
5.2.2. There may be alternative locations for return air leaving the room.
For example, referring to Figure 9, room 1 (low-level return air) and room 2
(ceiling return air).
Figure 9. Air-handling system with high-efciency particulate air lters in
air-handling unit
HEPA Filter
Secondary
Filter
Cooling Coil
Supply Air
Fan
Primary Filter
AIR HANDLING UNIT

S
R
F
= Supply Air
= Return Air
= Fresh Air
R
S
Room with low

level return air
Room with
ceiling return air
ROOM 1
ROOM 2
708
709
710
711
712
713
714
715
716
The airow schematics of the two systems (Figures 9 and 1 0 ) 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 t lters on return air outlets or in return air
ducting.

page 27
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718
719
720
721
722
723
724
725
726
727
728
729
Figure 10 is a schematic diagram of an air-handling system serving

rooms with horizontal unidirectional ow, vertical unidirectional ow and
turbulent ow, 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 supply air 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 10. Horizontal unidirectional ow, vertical unidirectional ow and
turbulent ow
Secondary
Filter
Cooling Coil
Supply Air
Fan
Primary Filter
AIR HANDLING UNIT

S
= Supply Air
= Return Air
= Fresh Air
R
F
R
+
+
HEPA Filters
S
Room with
Horizontal UDAF
HEPA Filters
Room with low

level return air
Room with
Vertical UDAF
ROOM 3
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
746
747
748
5.3.
ROOM 4
ROOM 5
Recirculation system
5.3.1. The risk of contamination a n d / or cross-contamination (including

by fumes and volatiles) due to recirculation of air should be evaluated to
determine if recirculation of air is acceptable.
5.3.2. Depending on the airborne contaminants in the return-air system
it may be acceptable to use recirculated air, provided that HEPA lters
are installed in the supply air stream (or return air stream) to remove
contaminants and thus prevent cross-contamination. The HEPA lters for
this application should have an EN 1822 classication of H13.
5.3.3. HEPA lters may not be required where the air-handling system
is serving a single product facility and there is evidence that crosscontamination would not be possible.
5.3.4. Recirculation of air in areas where pharmaceutical dust is not

page 28
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756
757
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763
764
765
generated such as secondary packing, may not require HEPA lters in the
system.
766
767
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769
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771
772
773
774
775
776
777
778
779
780
781
782
783
784
5.3.6. Air containing solvents or flammable vapours should not be recirculated
5.3.5. HEPA lters may be located in the air-handling unit or placed

terminally. Where H E P A l t e r s a r e t e r m i n a l l y m o u n t e d t h e y
s h o u l d preferably not be connected to the ducting by means of exible
ducting. Due to the high air pressure required for the terminal lter, this
connection should preferably be a rigid duct connection. Where exible
ducting is used, it should be as short as possible and properly xed to
withstand duct pressure.
When HEPA filters are terminally mounted, it should be possible to carry
out filter integrity tests from within the room. The filter housings will
therefore require ports for measuring appropriate upstream concentration
(refer to ISO 14644.3) and penetration concentration from within the room.
In addition it should be possible to measure the filter pressure drop in
individual HEPA filters by means of test ports provided.
to the HVAC system. Air containing dust from highly toxic processes should only
be recirculated if risk assessments shows adequate protection and special
precautions are in place (e.g. triple HEPA filtration).
5.4.
Full fresh-air systems
5.4.1. The required degree of ltration of the exhaust air depends on the
exhaust air contaminants and local environmental regulations. HEPA lters
in the exhaust system would normally only be required when handling
hazardous materials.
Figure 11 indicates a system operating on 100% fresh air and would
normally be used in a facility dealing with toxic products or solvents, where
recirculation of air with contaminants should be avoided.

page 29
785
786
787
Figure 11. Full fresh-air system
F
Fresh Air
HEPA Filter
Secondary
Filter
Supply Air
Fan
Cooling Coil
Primary Filter
AIR HANDLING UNIT

R
F
E
= Supply Air
= Return Air
= Fresh Air
= Exhaust Air
PRODUCTION
FACILITY
Primary Filter
Secondary
Filter
HEPA Filter
Exhaust Air
Fan
EXHAUST AIR HANDLING UNIT

E
Exhaust Air
Degree of filtration required

depends on exhaust air contaminants
788
789
790
791
792
793
794
795
796
797
798
799
800
Note: A HEPA filter on supply air is optional for a full fresh-air system.
A HEPA filter on the exhaust air is dependent on type of contaminants in the
exhaust leaving the room.
5.4.2. Energy-recovery wheels if used in multiproduct facilities should

have been subjected to a risk assessment to determine if there is any
risk of cross-contamination. When such wheels are used they should
not become a source of possible contamination (see Figure 12).
Note: Alternatives to the energy-recovery wheels, such as crossover plate
heat exchangers and water-coil heat exchangers, may be used in
multiproduct facilities.

page 30
801
802
Figure 12. Full fresh-air system with energy recovery
R
F
E
= Supply Air
= Return Air
= Fresh Air
= Exhaust Air
Fresh Air
HEPA Filter
Cooling Coil
Secondary
Filter
Supply Air
Fan
Primary Filter
AIR HANDLING UNIT
Energy
Recovery
Wheel
PRODUCTION
FACILITY
Exhaust Air
Exhaust
Air Fan
Primary Filter
Secondary
Filter
HEPA Filter
EXHAUST AIR FILTER UNIT

E
Degree of filtration required

depends on exhaust air contaminants
803
804
805
806
807
808
809
810
811
812
813
814
815
816
817
818
819
5.4.3. The potential for air leakage between the supply air and exhaust air
as it passes through the wheel should be prevented. The relative pressures
between supply and exhaust air systems should be such that the exhaust air
system operates at a lower pressure than the supply system.
5.5.
Additional system components
5.5.1. A schematic diagram of the airow for a typical system serving a

low relative humidity suite is represented in Figure 13. Air can be dried
with a chemical drier (e.g. a rotating desiccant wheel which is continuously
regenerated by means of passing hot air through one segment of the wheel).
Alternative methods of drying air are also available.

page 31
820
821
Figure 13. Air-handling system with chemical drying

CHEMICAL DRIER UNIT
Reactivation
Air Fan
Chemical Drier
Desiccant Wheel
S
F
E
= Supply Air
= Return Air
= Fresh Air
= Exhaust Air
Secondary
Filter
HEPA Filter
AIR HANDLING UNIT
Supply Air
Fan
Primary Filter
Cooling Coil
Fresh Air
Process
Air Fan
Primary Filter
Reactivation
Heater
R
+
LOW HUMIDITY
PRODUCTION
FACILITY
822
823
824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
5.5.2. The gure illustrates the chemical drier handling part of the fresh
air/return air mixture on a bypass ow. 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 ow of fresh/return air;
partial handling of fresh/return air (bypass airow);
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;

page 32
845
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847
848
849
850
851
852
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
snow eliminators to prevent snow entering air inlets and

blocking airow;
dust eliminators on air inlets in arid and dusty locations;
moisture eliminators in humid areas with high rainfall;
fresh air precooling coils for very hot or humid climates.
Air-handling units should be provided with adequate drains to remove
condensate.
6.
PROTECTION
6.1.
Products and personnel
6.1.1. Areas for the manufacture of pharmaceuticals, where pharmaceutical

starting materials and products, utensils, primary packing materials and
equipment are exposed to the environment, should be dened as clean
areas, clean zones, controlled areas or cleanrooms.
6.1.2. The achievement of a particular clean area condition depends on a
number of criteria that should be addressed at the design and qualication
stages. A suitable balance between the different criteria will be required in
order to create an efcient clean area.
6.1.3. Some of the basic criteria to be considered which affects room
cleanliness should include:
building nishes and structure;

dust control and containment;
air ltration;
air change rate or ushing rate;
air flow pattern;
recovery capability;
room pressure;
location of air terminals and directional airow;
temperature;
relative humidity;
material ow;
personnel ow;
gowning procedures;
equipment movement;
process being carried out (open or closed system);
outside air conditions;
occupancy;
type of product;
cleaning standard operating procedures (SOPs).

page 33
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891
892
893
894
895
896
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
921
922
923
924
925
926
927
928
929
930
931
6.1.4. Air ltration and air change rates should be set to ensure that the
dened room conditions are attained.
6.1.5. The air change rates should be determined by the manufacturer and
designer, taking into account the various critical parameters using a riskbased 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 room condition.
6.1.6. Air change rates are normally determined by the following
considerations (could normally vary between 10 and 20 air changes per
hour):
area condition required: whether a specic 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 ltration of the supply air;
particulates generated by the manufacturing process;
particulates generated by the operators;
conguration of the room and air supply and extract locations;
sufcient air to achieve containment effect and to flush the area;
sufcient air to cope with the room heat load;
sufcient air to balance extract rates;
sufcient air to maintain the required room pressure.
6.1.7. If a cleanroom classication is specied, the manufacturer should

state if the classification is rated for the as-built (Figure 14), at-rest (Figure
15) or operational (Figure 16) conditions.
6.1.8. Room classication tests in the as-built condition should be
carried out on the bare room, in the absence of any equipment if feasible.
Due to equipment size the rooms are constructed around the equipment and
therefore the equipment is included in the as-built condition.
6.1.9. Room classication 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 classications would be rated for the at-rest condition.

page 34
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934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
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950
951
952
953
954
955
956
957
958
959
960
961
962
963
964
965
966
6.1.10. Room classication 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 recovery tests are performed to determine whether the
installation is capable of returning to a specified cleanliness level,
temperature, humidity, microbial limits, room pressure, etc. where
appropriate, within a finite time. This test is carried out after the above
room conditions have reached an OOS state after the HVAC system has
been switched off. Room recovery tests should demonstrate a reduction 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 recovery is
about 15 to 20 minutes.
In some instances it is not possible to increase the particle 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.
Risk assessments should be carried out to determine which rooms should
be subject to recovery tests. Recovery tests are also required to determine
how long it takes for specified conditions to be achieved after power
failure or system start up.
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 nishing), poor cleaning procedures, contaminants brought in by
personnel, poor manufacturing process and a poor HVAC system.

page 35
967
Figure 14. As-built condition
968
969
970
971
Figure 15. At-rest condition
972
973
974

page 36
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979
980
981
982
983
984
985
986
987
988
989
990
991
992
993
994
995
996
997
998
Figure 16. Operational condition
6.1.13. Airborne contaminants should be controlled through effective

ventilation and ltration.
6.1.14. External contaminants should be removed by effective ltration of
the supply air.
6.1.15. Airborne particulates and the degree of ltration should be
considered critical parameters with reference to the level of product
protection required.
6.1.16. Internal contaminants should be controlled by dilution and
ushing of contaminants in the room, or by displacement airow (see
Figures 10, 17 and 21 for examples of methods for the ushing of
airborne contaminants).
6.1.17. 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 products susceptibility to degradation (Table 3).

page 37
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1000
1001
1002
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
6.2.
Air ltration and air patterns
Note: The degree to which air is ltered 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 lter efciencies can be very misleading (as
different test methods each result in a different efficiency value for the
same lter). (Referring to lter classications such as an 85% lter or a 5 m
lter are not valid classications and should not be used, as this can lead to
the incorrect lter being installed. Only the EN 779 and EN 1822 or ISO
29463 classications, or ASHRAE Merv classifications, as per Tables 1 and
2, should be used.)

page 38
Table 2. Comparison of filter test standards
EU 14
EU 13
EU 12
EU 11
EU 10
EU 9
EU 9
EU 8
Merv
Merv
Merv
Merv
16
15
14
13
Merv 12
EU 6
Merv 11
Merv 10
Merv 9
Merv 8
Merv 7
EU 4
EU 3
EU 2
EU 1
1024
1025
1026
Average
dust spot
efficiency
Em (%)
Merv 18
Merv 17
EU 7
EU 5
Average
arrestance
Am (%)
Merv 6
Merv 5
Merv 4
Merv 3
Merv 2
Merv 1
>98
>98
>95
>95
>95
>95
>95
>95
>95
>95
>90
>90
90
85
80
75
70
65
<65
>95
95
90
85
80
75
70
65
60
55
50
45
40
35
30
25
20
<20
EN 779 & EN 1822
MPPS integral
overall
efficiency (%)
99.999995
99.99995
99.9995
99.995
99.95
99.5
95
85
MPPS =
most
penetrating
particle size
ISO 29463
(superseded)
Merv
rating
Eurovent
4/5
ASHRAE
52.1
BS6540
Part 1
EN rating
U17
U16
U15
H14
H13
E12
E11
E10
F9
F8
F7
EN 1822: 2009
Eurovent 4/5
ASHRAE
Eurovent 4/5 ASHRAE
52.1
rating
52.2
BS6540 Part
1
75E
65E
55E
45E
35E
25E
15E
M6
M5
G4
EN 779: 2012
1022
1023
G3
G2
G1
Note: The lter classications referred to above relate to the

EN 1822:2009 and EN 779: 2012 test standards (EN 779 relates to lter

page 39
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1029
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1031
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1033
1034
1035
1036
1037
1038
1039
1040
1041
1042
1043
1044
1045
1046
1047
1048
1049
1050
classes G1 to F9 and EN 1822 relates to lter classes E10 to U17).

Most penetrating particle size (MPPS) is a means of determining HEPA
and ultra low penetration air (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).
Note: ULPA filters are not applicable to pharmaceutical installations.
6.2.3. In selecting lters, the manufacturer should have considered other
factors, such as particularly contaminated ambient conditions, local
regulations and specic product requirements. Good preltration extends
the life of the more expensive lters 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, rst
stage change rooms.

page 40
Level 3
Controlled
Area in which specic environmental

conditions are dened, 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.
1051
1052
1053
1054
Table 4. Levels of protection and recommended ltration

Level of protection
Level 1
Recommended ltration
Primary lters only (e.g. EN 779 G4 lters)
Level 2
Protected areas operating on recirculated or full

fresh air
Primary plus secondary lters (e.g. EN 779 G4
plus F8 or F9 lters)
Level 3
1055
1056
1057
1058
1059
1060
1061
1062
1063
1064
1065
1066
Production facility operating on recirculated

plus ambient air, where potential for crosscontamination exists: Primary plus secondary
plus tertiary lters (e.g. EN 779 G4 plus F8 plus
EN 1822 H13 lters) (for full fresh air system,
without recirculation, G4 and F8 or F9 lters are
acceptable)
6.2.5. Directional airow within production or primary packing areas

should assist in preventing contamination. Airows 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.
An example of flushing effect with turbulent airflow and low level extract
is indicated in Figure 17 below.
6.2.6. At airlocks and change rooms supply air and extract air terminals
should be positioned such that air flows from the clean side of the room to
the less clean side, to enhance the separation between the two adjoining
rooms.

page 41
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1075
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1077
1078
1079
1080
1081
1082
1083
1084
1085
1086
1087
1088
1089
1090
Figure 17. Turbulent dilution of dirty air
Low-level extract is ideal for dust suppression purposes, but is not

essential where no dust is liberated. (Low-level extract is essential for
Grade C classified areas for information only.)
6.2.7. 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 ofce-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 ushing 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 1820 for illustrations of the three types of
diffuser). Although ceiling returns are generally avoided in cases where dust
liberation is low, ceiling return air grilles may be acceptable.

page 42
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1100
1101
1102
6.2.8. The type of diffusers used for each room should be carefully
selected considering their air flow patterns and the amount of dust
liberated in the room. Induction and certain swirl diffusers create good
dilution of room air and may be used where dust liberation is minimal. If
used in rooms where significant dust is generated, their use may draw dust
up into the air stream and spread it throughout the room, presenting
increased hazards to containment and to operators. Some swirl type
diffusers have less induction (as indicated in Figure 20)
1103
Figure 18. Induction diffuser
1104
1105
1106
1107
6.2.9. Airflow patterns for different diffuser types are indicated in Figures
18, 19 and 20 below.

page 43
1108
Figure 19. Perforated plate diffuser
1109
1110
1111
1112
1113
Figure 20. Swirl diffuser

page 44
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1121
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1125
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1132
1133
1134
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1136
1137
1138
6.3.
Unidirectional airow
6.3.1. Unidirectional airow (UDAF) should be used for weighing booths

or sampling booths to provide operator and product protection and should
also have a slight air in-ow from the room to enhance containment. Dust
containment at the weigh booth should be demonstrated by smoke airow
pattern tests (AFPT), 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. The weigh booth and dispensary
should have the same environmental conditions that are required for the
further processing of the product.
Example: in Figure 21 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
airow stream.
Figure 21. Operator protection at weighing station

page 45
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6.3.4 The unidirectional ow velocity should be such that it does not

disrupt the sensitivity of balances in weighing areas. However, the airow
velocity and directional ow should be appropriate to ensure product
containment and operator protection. For this type of application it is
sometimes better to refer to the unit as an airow 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.
1152
1153
1154
1155
6.3.5 The position in which the operator stands relative to the source of
dust liberation and airow should be determined to ensure that the operator
is not in the path of an airow that could lead to contamination of the
product (Figure 22).
1156
Figure 22. Operator protection by horizontal airow

page 46
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1175
6.3.6 Once the system has been designed and qualied with a specic
layout for operators and processes, this configuration should be maintained
in accordance with an SOP.
6.3.7 There should be no obstructions in the path of a unidirectional ow
air stream that may cause the operator to be exposed to dust.
Figure 23 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 24 illustrates a situation where an open bin is placed below a vertical
unidirectional airow distributor. The downward airow should be
prevented from entering the bin, and then being forced to rise again, as this

page 47
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1183
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1187
would carry light dust up towards the operators face. In such an

occurrence it 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 2 5 shows that a solid worktop can sometimes cause deection of
the vertical unidirectional airow resulting in a ow 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, or have a perforated worktop
with extraction below..

page 48
1188
Figure 23. Operator subject to powder inhalation due to obstruction
1189
1190
1191
1192
Figure 24. Operator subject to powder contamination due to airow

reversal in bin
1193

page 49
1194
1195
1196
1197
Figure 25. Operator subject to powder inhalation due to worktop

obstruction
1198
1199
1200
1201
6.3.8 The manufacturer should select either vertical or horizontal

unidirectional airow (Figure 26), and an appropriate airow pattern to

page 50
1202
1203
1204
1205
1206
1207
1208
provide the best protection for the particular application.

Figure 26. Diagram indicating horizontal and vertical unidirectional ow

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1222
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1227
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1234
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1251
6.3.9 Return or exhaust air grilles in rooms or at weigh or sampling booths

should preferably be of the perforated grille types, which are easy to clean.
Return/exhaust air lters can either be installed at the room terminal or in
the air-handling unit. Maintenance and cleaning of lters and ducts should
be addressed to ensure constant airow.
6.4.
Inltration
6.4.1. Air infiltration of unltered air into a pharmaceutical plant should

not be a source of contamination.
6.4.2. Manufacturing facilities should normally be maintained at a positive
pressure relative to the outside, to limit the ingress of contaminants. Where
facilities are to be maintained at negative pressures relative to the ambient
pressure, special precautions should be taken. Refer to the WHO
guidelines for hazardous products, for further guidance on negative
pressure facilities.
6.4.3. The location of the negative pressure facility should be carefully
considered with reference to the areas surrounding it, particular attention
being given to ensuring that the building structure is well sealed.
6.4.4. Negative pressure zones should, as far as possible, be encapsulated
by surrounding areas with clean air supplies, so that only clean air can
inltrate into the controlled zone.
6.5.
Cross-contamination and contamination
6.5.1. Where different products are manufactured at the same time, in

different areas or cubicles, in a multiproduct OSD manufacturing site,
measures should be taken to ensure that dust cannot move from one cubicle
to another.
6.5.2. Correct directional air movement and a pressure cascade system
can assist in preventing cross-contamination. The pressure cascade should
be such that the direction of airow is from the clean corridor into the
cubicles, resulting in dust containment.
6.5.3. For cubicles where dust is liberated, the corridor should be
maintained at a higher pressure than the cubicles and the cubicles at a
higher pressure than atmospheric pressure. (For negative pressure facilities

page 52
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1262
1263
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1265
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1268
1269
1270
1271
1272
1273
1274
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1276
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1279
1280
1281
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1287
1288
1289
1290
1291
1292
1293
1294
1295
refer to WHO Technical Report Series, No. 957, Annex 3 for hazardous
products guidelines and design conditions.)
6.5.4. Containment can normally be achieved by application of the
pressure differential concept (high pressure differential, low airow), or the
displacement concept (low pressure differential, high airow), or the
physical barrier concept, as described in ISO 14644-4. However, the low
pressure differential, high airow method is no longer used as a means of
room segregation.
6.5.5. The pressure cascade for each facility should be individually
assessed according to the product handled and level of protection required.
The pressure cascade regime and the direction of airow should be
appropriate to the product and processing method used, and should also
provide operator and environmental protection.
6.5.6. Building structure should be given special attention to accommodate
the pressure cascade design.
6.5.7. Ceilings and walls, close tting doors and sealed light ttings should
be in place, to limit ingress or egress of air.
6.6.
Pressure differential concept (high pressure differential, low

airow)
Note: The pressure differential concept may be used alone or in

combination with other containment control techniques and concepts, such
as a double door airlock.
6.6.1. The high pressure differential between the clean and less clean
zones should be generated by balancing the supply and extract air quantities in
the two adjoining rooms, thus resulting in the pressure gradient. Leakage through
the cracks around the door, as a result of the pressure differential, is acceptable.
6.6.2. The pressure differential should be of sufcient magnitude to ensure

containment and prevention of ow reversal, but should not be so high as to
create turbulence problems.
6.6.3. In considering room pressure differentials, transient variations, such
as machine extract systems, should be taken into consideration.
6.6.4. A pressure differential of 15 Pa is often used for achieving
containment between two adjacent zones, but pressure differentials of

page 53
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1300
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1305
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1312
1313
1314
1315
1316
1317
1318
1319
1320
1321
1322
1323
1324
1325
between 5 Pa and 20 Pa may be acceptable. Where the design pressure

differential is too low and tolerances are at opposite extremities, a ow
reversal can take place. For example, where a control tolerance of 3 Pa
is specied, the implications of adjacent rooms being operated at the upper
and lower tolerances should be evaluated. It is important to select pressures
and tolerances such that a ow reversal is unlikely to occur.
6.6.5. The pressure differential between adjacent rooms could be
considered a critical parameter, depending on the outcome of risk analysis.
The limits for the pressure differential between adjacent areas should be
such that there is no risk of overlap in the acceptable operating range, e.g.
5 Pa to 15 Pa in one room and 15 Pa to 30 Pa in an adjacent room, resulting
in the failure of the pressure cascade, where the rst room is at the maximum
pressure limit and the second room is at its minimum pressure limit.
6.6.6. Low pressure differentials may be acceptable when airlocks
(pressure sinks or pressure bubbles) are used to segregate areas.
6.6.7. The effect of room pressure tolerances are illustrated in Figure 27.
If one room is at the higher side of the tolerance and the other at the lower
side of the tolerance, it could result in either a high or a low pressure
differential. When setting tolerances it is also important to specify if the
tolerance is applicable to the absolute room pressures or the pressure
differentials. In the diagram below the tolerances have been based on a
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.

page 54
Figure 27. Examples of pressure cascades

Encapsulation
15 Pa 3 Pa
15 Pa 3 Pa
15 Pa 3 Pa
Air Leakage
Tablet
Compression
Airlock
Air Leakage
Production Corridor
Air Leakage
15 Pa 3 Pa
30 Pa 3 Pa
Image of room pressure gauge

indicating colour coded normal,
alert & action parameters
Design Condition (15 Pa Pressure Differential)
Production Corridor
12 Pa
Air Leakage
18 Pa
Airlock
Air Leakage
Air Leakage
Tablet
Compression
Encapsulation
18 Pa
18 Pa
Air Leakage
Tablet
Compression
Encapsulation
12 Pa
Air Leakage
Air Leakage
12 Pa
Tablet
Compression
Air Leakage
Tablet
Compression
Production Corridor
12 Pa
33 Pa
1327
1328
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1330
1331
1332
1333
1334
1335
1336
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1339
1340
1341
1342
1343
1344
1345
1346
1347
1348
1349
1350
1351
Maximum Differential (21 Pa Pressure Differential)
Air Leakage
Air Leakage
Tablet
Compression
Air Leakage
1326
Airlock
Air Leakage
Air Leakage
18 Pa
27 Pa
Minimum Differential (9 Pa Pressure Differential)
6.6.8. The pressure control and monitoring devices used should be

calibrated and qualied. Compliance with specications should be regularly
veried and the results recorded. Pressure control devices should be linked
to an alarm system set according to the levels determined by a risk analysis.
6.6.9. Manual control systems, where used, should be set up during
commissioning, with set point marked, and should not change unless other
system conditions change.
6.6.10. Airlocks can be important components in setting up and maintaining
pressure cascade systems and also to limit cross-contamination.
6.6.11. Airlocks with different pressure cascade regimes include the
cascade airlock, sink airlock and bubble airlock (Figures 2830):
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
both outer sides;
bubble airlock: higher pressure inside the airlock and lower
pressure on both outer sides.

page 55
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Figure 28. 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.)
Air Leakage
15 Pa
Air Leakage
Material Airlock
22.5 Pa
Cascade Airlock
1357
1358
30 Pa

page 56
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Figure 29. Example of sink airlock
Air Leakage
30 Pa
Air Leakage
Material Airlock
15 Pa
Sink Airlock
1361
1362
30 Pa

page 57
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Figure 30. Example of bubble airlock
Air Leakage
15 Pa
Air Leakage
Material Airlock
15 Pa
30 Pa
Bubble Airlock
1365
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1368
1369
1370
1371
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1376
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1378
1379
1380
1381
1382
1383
1384
1385
1386
1387
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.
6.6.12. 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 sufcient 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 such that only one door can be opened at a
time. The determination of which doors should be interlocked should be
the subject of a risk assessment study.
6.6.13. Risk assessment should be done to determine whether dust
extraction systems should be interlocked to the appropriate air-handling
systems. Failure to interlock fans could result in pressure cascade
imbalances.

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6.6.14. Air should not ow through the dust extraction ducting or return
air ducting from the room with the higher pressure to the room with the
lower pressure (this would normally occur only if extract or return systems
were inoperative). Systems should be designed to prevent dust owing back
in the opposite direction in the event of component failure or airow failure.
6.6.15. Adequate room pressure differential indication should be provided
so that each critical room pressure can be traced back to ambient pressure
(by summation of the room pressure differentials), in order to determine the
room actual absolute pressure. A pressure gauge installed to indicate the
pressure differential from a central corridor to ambient could serve to trace
pressures to ambient.
6.6.16. Room pressure indication gauges should have a range and
graduation scale which enables the reading to an appropriate accuracy.
Normal operating range, alert and action limits should be dened and
displayed at the point of indication. A colour coding of these limits on the gauge
may be helpful.
Room pressure indication may be either analogue or digital, and may be
represented as either pressure differentials or absolute pressures.
Whichever system is used any out-of-specication (OOS) condition should
be easily identiable. Zero setting of gauges should be frequently checked (such
as, weekly) and zero setting should preferably be tamper proof.
6.6.17. Material PTHs or pass boxes (PB) can also be used for separating
two different zones. PTHs fall into two categories, namely a dynamic PTH
or a passive PTH. Dynamic PTHs have an air supply to or extraction from
them, and can then be used as bubble, sink or cascade PTHs.
6.6.18. Room pressure differential tolerances should always be set with a
maximum and minimum tolerance. Setting tolerances as NMT or NLT can
easily lead to an OOS condition.
6.7.
Physical barrier concept
6.7.1. Where appropriate, an impervious barrier to prevent crosscontamination between two zones, such as closed manufacturing and
transfer systems, pumped or vacuum transfer of materials, should be
used.

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6.8.
Temperature and relative humidity
6.8.1. Where appropriate, temperature and relative humidity should be

controlled, monitored and recorded, where relevant, to ensure compliance
with requirements pertinent to the materials and products and provide a
comfortable environment for the operator where necessary.
6.8.2. Maximum and minimum room temperatures and relative humidity
should be appropriate. Alert and action limits on temperatures and
humidities should be set, as appropriate.
6.8.3. The operating band, or tolerance, between the acceptable minimum
and maximum temperatures should not be made too close. Tight control
tolerances may be difcult to achieve and can also add unnecessary
installation and running costs.
6.8.4. 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.
6.8.5. Precautions should be taken to prevent moisture migration that
increases the load on the HVAC system.
6.8.6. Humidity control should be achieved by removing moisture from
the air, or adding moisture to the air, as relevant.
6.8.7. Dehumidication (moisture removal) may be achieved by means of
either refrigerated dehumidiers (cooling coils) or chemical dehumidiers.
6.8.8. Humidiers should be avoided if possible as they may become a
source of contamination (e.g. microbiological growth). Where humidication
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 purified water or clean steam is required for the
purposes of humidication.
6.8.9. Humidication systems should be well drained. No condensate
should accumulate in air-handling systems.
6.8.10. Other humidication appliances such as evaporative systems,
atomizers and water mist sprays, should not be used because of the potential
risk of microbial contamination.
6.8.11. Duct material in the vicinity of the humidier should not add
contaminants to air that will not be removed by ltration further downstream.

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6.8.12. Air lters should not be installed immediately downstream of

humidiers, as moisture on the lters could lead to bacterial growth.
6.8.13. Cold surfaces should be insulated to prevent condensation within
the clean area or on air-handling components.
6.8.14. When specifying relative humidity, the associated temperature
should also be specied.
6.8.15. Chemical driers using silica gel or lithium chloride are acceptable,
provided that they do not become sources of contamination.
7.
DUST CONTROL
7.1.
Wherever possible, dust or vapour contamination should be
removed at source. Point-of-use extraction, i.e. as close as possible to the
point where the dust is generated, should be employed. Spot ventilation or
capture hoods may be used as appropriate. The HVAC system should not
serve as the primary mechanism of dust control.
7.2.
Point-of-use extraction should be either in the form of a xed,
high-velocity extraction point or an articulated arm with movable hood or a
xed extraction hood. Care should be taken in the design and positioning of
dust extract points to prevent cross-contamination by powders dropping down
from the extract point.
7.3.
Dust extraction ducting should be designed with sufcient transfer
velocity to ensure that dust is carried away, and does not settle in the ducting.
Periodic checks should be performed to ensure that there is no build-up of
the dust in the ducting.
7.4.
The required transfer velocity should be determined: it is dependent
on the density of the dust (the denser the dust, the higher the transfer
velocity should be, e.g. 1520 m/s).
7.5.
Airow direction should be carefully chosen, to ensure that the
operator does not contaminate the product, and also so that the operator is
not put at risk by the product.
7.6.
Point extraction alone is usually not sufcient to capture all of
the contaminants, and general directional airow should be used to assist
in removing dust and vapours from the room.
7.7.
Typically, in a room operating with turbulent airow, the air should
be introduced from ceiling diffusers, located at the door entry side of the
room and extracted from the rear of the room at low level to help give a

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ushing effect in the room. Correct ushing of the rooms may be veried
by airow visualization smoke tests.
7.8.
When dealing with particularly harmful products, additional steps,
such as handling the products in glove boxes or using barrier isolator
technology, should be used (refer to WHO Technical Report Series, No.
957, Annex 3 for additional guidance on handling hazardous products).
8.
PROTECTION OF THE ENVIRONMENT
8.1.
General
8.1.1. It should be noted that protection of the environment is not addressed

in this guideline, and discharges into the atmosphere should be compliant
with relevant local and national environmental legislation and standards.
8.1.2. Dust, vapours and fumes could be possible sources of contamination;
therefore, care should be taken when deciding on the location of the inlet
and exhaust points relative to one other.
8.2.
Dust in exhaust air
8.2.1. Exhaust air discharge points on pharmaceutical equipment and

facilities, such as from uid bed driers and tablet-coating equipment, and
exhaust air from dust extraction systems, carry heavy dust loads and should be
provided with adequate ltration to prevent contamination of the ambient air.
8.2.2. Where the powders are not highly potent, nal lters on a dust
exhaust system should be ne dust lters with a lter classication of F9
according to EN 779 lter standards.
8.2.3. Where reverse-pulse dust collectors are used for removing dust from
dust extraction systems, they should usually be equipped with cartridge
lters containing a compressed air lance, and be capable of continuous
operation without interrupting the airow.
8.2.4. Alternative types of dust collectors (such as those operating with a
mechanical shaker, requiring that the fan be switched off when the mechanical
shaker is activated) should be used in such a manner that there is no risk
of cross-contamination. There should be no disruption of airow during a
production run as the loss of airow could disrupt the pressure cascade.
8.2.5. Mechanical-shaker dust collectors should not be used for applications
where continuous airow is required, in order to avoid unacceptable

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uctuations in room pressures, except in the case where room pressures are
automatically controlled.
8.2.6. When wet scrubbers are used, the dust-slurry should be removed by
a suitable means, e.g. a drainage system or waste removal contractor.
8.2.7. The quality of the exhaust air should be determined to see whether the
ltration efciency is adequate with all types of dust collectors and wet
scrubbers.
8.2.8. Where necessary, additional ltration may be provided downstream
of the dust collector.
8.3.
Vapour and fume removal
8.3.1. Vapour should be extracted at the point of generation. When planning

the system for the extraction of residual vapours, the density of the vapour
should be taken into account. If the vapour is lighter than air, the extract
grilles should be at a high level, or possibly at both high and low levels.
8.3.2. The systems for fume, dust and efuent control should be designed,
installed and operated in such a manner that they do not become possible
sources of contamination or cross-contamination, e.g. an exhaust-air
discharge point located close to the HVAC system fresh air inlet.
8.3.3. Fumes should be removed by means of wet scrubbers or dry
chemical scrubbers (deep-bed scrubbers).
8.3.4. Wet scrubbers for fume removal normally require the addition of
various chemicals to the water to increase the adsorption efciency.
8.3.5. Deep-bed scrubbers should be designed with activated carbon lters
or granular chemical adsorption media. The chemical media for deep-bed
scrubbers should be specic to the efuent being treated.
8.3.6. The type and quantity of the vapours to be removed should be
known to enable the appropriate lter media, as well as the volume of media
required to be determined.
9.
COMMISSIONING, QUALIFICATION AND VALIDATION
9.1.
General
9.1.1. The HVAC system plays an important role in the protection of the
product, the personnel and the environment.

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9.1.2. For all HVAC installation components, subsystems or parameters,

critical parameters and non-critical parameters should be determined.
9.2.
Commissioning
9.2.1. Commissioning should involve the setting up, balancing,

adjustment and testing of the entire HVAC system, to ensure that the
system meets all the requirements, as specied in the user requirement
specication, and capacities as specied by the designer or developer. The
commissioning plan should start at the early stages of a project so that it
can be integrated with qualification and verification procedures.
9.2.2. Acceptable tolerances for all system parameters should be specied
and agreed by the user prior to commencing the physical installation.
These tolerances should be specified in the user requirement specifications
9.2.3. Acceptance criteria should be set for all system parameters. The
measured data should fall within the acceptance criteria.
9.2.4. System installation records should provide documented evidence
of all measured capacities of the system.
9.2.5. 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
design and measured gures for airows, water ows, system pressures
electrical amperages, etc. These should be contained in the operating
and maintenance manuals (O & M manuals). The installation records of
the system should provide documented evidence of all measured capacities
of the system.
9.2.6. Typical information that should be contained in the O&M
manuals is the following:
system description;
operating instructions;
trouble shooting;
commissioning data schedules;
maintenance instructions;
list of equipment suppliers;
spare parts lists;
equipment capacity and data schedules;
suppliers literature;

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Figure 31. Qualification is a part of validation
control system operation;

electrical drawings;
as-built drawings;
maintenance records.
9.2.7. O & M manuals, schematic drawings, protocols and reports should

be maintained as reference documents for any future changes and upgrades
to the system. As-built drawings should be available and should be kept up
to date with all the latest system changes. Any changes from the originally
approved system should be covered by change control documentation and
risk assessment studies where deemed necessary.
9.2.8. Training should be provided to personnel after installation of the
system, and should include how to perform operation and maintenance.
9.2.9. Commissioning should be a precursor to system qualication and
validation.
Qualication
9.3.
Equipment
2
Equipment
3
Equipment
4
System 1
Equipment
5
Equipment
6
Equipment
7
System 2
Process
A number of Qualified systems make up a Validated process.

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9.3.2. The qualication of the HVAC system should be described in a

validation master plan (VMP), or a subsection of the VMP.
Validation
Equipment
1
Qualification
9.3.1. Manufacturers should qualify HVAC systems using a risk-based

approach. The basic concepts of qualication of HVAC systems are set out
in Figure 31 below.

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9.3.3. The VMP should dene the nature and extent of testing and the test
procedures and protocols to be followed.
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Figure 32.
9.3.4. Stages of the qualication of the HVAC system should include

design qualication (DQ), installation qualication (IQ), operational
qualication (OQ) and performance qualication (PQ). The relationship
between the development stage of a project (user requirement
specification, functional design specification, detail design and
configuration specifications, build & project implementation) and the
qualification stages are given in the V-diagram (Figure 32) below. The Vmodel is one example of an approach to qualification and validation.
V-Model for Direct Impact Systems
PQ Test Plan
User Requirement
Specification
Performance
Qualification
Design
Qualification
(incl. UAT)
Functional Design
Specification
OQ Test Plan
Operational
Qualification
(incl. SAT)
DQ Test Plan
Detail Design and

Configuration
Specifications
IQ Test Plan
Installation
Qualification
(incl. FAT/PDI)
Build & Project

Implementation
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SAT, FAT & PDI where applicable, could take place at different stages depending on the application
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UAT=user acceptance tests; FAT=factory acceptance tests; SAT=site

acceptance tests; PDI=pre-delivery inspections.
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9.3.5. Critical and non-critical parameters for all HVAC installation

components, subsystems and controls should be determined by means of a
risk analysis.

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9.3.6. Any parameter that may affect the quality of the pharmaceutical
product should be considered a critical parameter.
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Example
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9.3.7. All critical parameters should be included in the qualication

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.
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 qualied. Components or
equipment such as the heat transfer system, chemical drier or
steam humidier, which is producing the humidity-controlled air, is
further removed from the product and may not require operational
qualication.
A room cleanliness classication is a critical parameter and,
therefore, the room air-change rates and high-efciency particulate
air (HEPA) lters should be considered critical parameters and
components, and therefore require qualication. Components such
as the fan generating the airow and the primary and
secondary lters are considered non-critical components, and may
not require operational qualication.
9.3.8. Non-critical systems and components should be subject to

verification by good engineering practice and may not necessarily require
full qualication.
9.3.9. A change control procedure should be followed when changes are
planned to the HVAC system, its components and controls, that may affect
critical parameters.
9.3.10. The design condition, normal operating ranges, operating range
and alert and action limits should be dened and be realistic. Alert limits
should be based on system capability.

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.
9.3.11. All parameters should fall within the design condition range
during system operational qualication. Conditions may go out of the
design condition range during normal operating procedures but they should
remain within the operating range.
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Figure 33. System operating ranges
9.3.12. OOS 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. Such incidents should be handled in accordance
with a deviation procedure.
9.3.13. The relationships between design conditions, operating range and

qualied acceptance criteria are given in Figure 33. There should be SOPs
to determine action to be taken when alert and action limits are reached.
ACTION
LIMIT
ALERT
LIMIT
DESIGN
SET-POINT
DESIGN
SET-POINT
ALERT
LIMIT
ACTION
LIMIT
Design Condition
Normal Operating Range
Operating Range Validated Acceptance Criteria
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9.3.14. 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.
9.3.15. Some of the typical HVAC system parameters, based on a
quality risk assessment, that should be qualied for a pharmaceutical
facility may include:
temperature;
relative humidity;
supply air quantities for all diffusers;
return air or exhaust air quantities;

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9.3.16. The maximum time interval between tests and requalification

should be dened by the manufacturer. The type of facility under test and
the product level of protection should be considered.
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Table 5. Strategic tests to demonstrate continued compliance

(Time intervals given for requalification are for reference purposes only.
The actual tests required will depend on specific facility requirements)
room air-change rates;

room pressures (pressure differentials);
room airow patterns;
unidirectional ow velocities;
containment system velocities;
HEPA lter penetration tests;
room particle counts;
room recovery rate tests;
duct leakage tests;
materials of construction;
microbiological air and surface counts where appropriate;
operation of de-dusting;
warning/alarm systems where applicable.
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.
Test parameter
Particle count test

(verication of
cleanliness)
Example of Test procedure

time intervals
between tests
(all classes)
6 months Dust particle counts to be carried out
( ISO 5) and result printouts produced.
12 months
(> ISO 5) No. of readings and positions of tests
ISO 5 not to be in accordance with ISO 14644-1
applicable to A.3
non-steriles

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Air pressure difference
(to verify absence of
cross-contamination)
Log of pressure differential readings

to be produced critical plants
should be logged daily, preferably
12 months continuously. In accordance with
ISO 14644-3 Annex B.5
Airow volume
Airow readings for supply air and

return air grilles to be measured and
12 months air change rates to be calculated. In
accordance with ISO 14644-3 Annex
B.4
(to verify air change

rates)
Airow velocity
(to verify unidirectional
ow or containment
conditions)
HEPA filter leakage
tests
(to verify lter integrity)
Containment leakage
(to verify absence of
cross-contamination)
Air velocities for containment systems

and unidirectional ow protection
12 months systems to be measured. In
B.4
Filter penetration tests to be carried
out by a competent person to
12 months demonstrate lter media, lter seal
and lter frame integrity. In
B.6
Demonstrate that contaminant is
maintained within a room by means
of:
12 months airow direction smoke tests
room air pressures. In accordance
with ISO 14644-3 Annex B.13
Recovery
Test to establish time that a cleanroom

takes to recover from a contaminated
12 months condition to the specied cleanroom
condition. In accordance with ISO
14644-3 Annex B.12

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Room temperatures
(to verify temperature
tolerance adherence)
Warehouse and store

temperatures
(to verify temperature
mapping conditions)
Room Humidities
(To verify humidity
tolerance adherence)
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Demonstrate that room temperatures

at determined locations comply with
12 months 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 Technical
36 months Report Series, No. 961, Annex 9 and
WHO Technical Report Series, No.
992, Annex 5 plus Supplements 1 to
16
Demonstrate that room humidities at

determined locations comply with
12 months specified tolerances. In accordance
with ISO 14644-3 Annex B.9.2
9.3.17. Any change to the HVAC system should be handled according to

change procedure, and requalification should be considered. Risk
assessments should be performed with such changes that affect system
performance and documented with specific change controls. Justification and
rationale should also be captured if no requalification is performed.
9.3.18. If energy-saving procedures such as reducing the airow during

non-production hours are used, precautionary measures should be in place
to ensure that the systems are not operated outside the dened relevant
environmental conditions.
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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 pressurization cascade, temperature, humidity
excursions, etc.
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Additional documents that should be included in the qualication

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manuals should include system airow schematics, room pressure cascade

drawings, zone concept drawings, air-handling system allocation drawings,
particle count mapping drawings, airflow direction diagrams, man,
material and waste flow routes, etc.
9.4.
Supplementary notes on test procedures
9.4.1.
General
9.4.1.1.
Tests should be carried as described in ISO 14644-3.
However below are some supplementary notes and aspects that provide
additional guidance.
9.4.2. Airflow measurements
9.4.2.1.
The ISO 14644-3 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.
9.4.2.2.
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.
9.4.3.
Non-viable air particle counts
9.4.3.1.
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.
9.4.3.2.
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.)
9.4.3.3.
The number of test sample location is determined based on

the area of the room as per Table A1in ISO 14644-1 2015. The sampling
locations should be chosen representatively, meaning that features such as

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cleanroom or clean zone layout, equipment positions and airflow systems

should be considered when selecting sampling locations
9.4.3.4.
In addition to determining the number of the sampling
locations based on the area of the clean room, a risk assessment should
determine if additional sample locations are warranted. Consider aspects
such as personnel and/or production activities and air flow dead spots.
9.4.3.5.
Where a UDAF is located within a room the UDAF and its
background environment should be considered separately in terms of
sampling location calculations, and should be individually certified.
9.4.3.6.
The mapping drawing indicating test location should be
included with the test certificate, and the same mapping locations should
be used for future tests for comparative purposes.
9.4.4. HEPA filter integrity tests
9.4.4.1.
Filter media, frame and seal should be tested for each filter
and results for media, frame and seal penetration reflected separately on
the test certificates.
9.4.4.2.
When HEPA filters are terminally mounted at the room, it
should be possible to carry out filter integrity tests from within the room.
The filter housings will therefore require ports for measuring appropriate
upstream concentration and penetration concentration from within the
room. In addition it should be possible to measure the filter pressure drop
in individual HEPA filters, also preferably from within the room. These
pressure drops should be recorded on the filter test certificate as an
indication of the filter life. (The practice of measuring the appropriate
upstream concentration from the ceiling void or at the air handling plantroom, and then measuring the filter penetration concentration in the room
is unacceptable. The time lag between measuring the upstream
concentration and the penetration concentration could mean that by the
time the room penetration is measured, the upstream concentration is no
longer the required concentration.)
9.4.4.3.
The implementation of the tests should not compromise the
quality of the product.
10.
MAINTENANCE

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10.1. Maintenance records, maintenance procedures and O&M manuals

should be sufficient to indicate that the company has control over the
HVAC systems. There should be a planned preventive maintenance
programme, procedures and records for the HVAC system. The details of
the maintenance programme should be commensurate with the criticality of the
system and components. Records should be kept for a sufficient length of
time should they be required for any product defect analysis.

10.2. O&M manuals, schematic drawings, protocols and reports should
be maintained as reference documents for any future changes and
upgrades to the system. These documents should be kept up to date,
containing any system revisions made.
10.3. The O&M manuals should typically contain the following
information: system description; operating instructions; trouble shooting;
commissioning data; maintenance instructions; list of equipment suppliers;
spare parts list; equipment data/capacity schedules; suppliers literature;
control system description; electrical drawings; and as-built drawings.
10.4. Maintenance personnel should receive appropriate training and
training records should be kept.
10.5. HEPA lters should be changed either by a specialist or a trained
person and then followed by installed lter leakage testing.
10.6. Any maintenance activity should be assessed critically to determine
any impact on product quality including possible contamination.
10.7. Maintenance activities should normally be scheduled to take place
outside production hours and any system stoppage should be assessed with
a view to the possible need for requalication of an area as a result of an
interruption of the service.
References
1.
Good manufacturing practices for pharmaceutical products: main

principles. In: WHO Expert Committee on Specications for
Pharmaceutical Preparations. Thirty-seventh report. Geneva, World
Health Organization, 2003 (WHO Technical Report Series, No. 908),
Annex 4. http://whqlibdoc.who.int/trs/WHO_ TRS_908_eng.pdf;
Quality assurance of pharmaceuticals. A compendium of guidelines
and related materials. Volume 2, Second updated edition. Good
manufacturing practices and inspection. Geneva, World Health

page 74
1944
1945
1946
1947
1948
1949
2.
1950
1951
1952
1953
1954 3.
1955
1956
1957
1958
1959
Organization, 2007; and Quality assurance of pharmaceuticals. WHO

guidelines, good practices, related regulatory guidance and GXP
training materials. Geneva, World Health Organization, 2015 (CDROM).
1960 4.
1961
1962
1963
1964
1965
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 Specications for Pharmaceutical Preparations.
Forty-fifth report. Geneva, World Health Organization, 2011 (WHO
Technical Report Series, No. 961), Annex 9.
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
1978
1979
1980
1981
1982
1983
Expert Committee on Specications for Pharmaceutical

Preparations. Fortieth report. Geneva, World Health Organization,
2005 (WHO Technical Report Series, No. 937)
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf.
Technical supplements to Model guidance for the storage and
transport of time- and temperature-sensitive pharmaceutical
products. WHO Expert Committee on Specications for
Pharmaceutical Preparations. Forty-ninth report. Geneva, World
Health Organization, 2015 (WHO Technical Report Series, No. 992),
Annex 5.
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/prod
uction/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.

page 75
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
2018
2019
2020
2021
2022
2023
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.aktwoods.com.
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 qualication, 1st ed.
Tampa, Fl, International Society for Pharmaceutical Engineering, 2001.
http://www.ispe.org/.
ISPE Good Practice Guide: Heating, Ventilation, and Air Conditioning
(HVAC) 2009 International Society for Pharmaceutical Engineering.
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 efciency ltration. 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.

page 76
2024
2025
2026
2027
World Health Organization. Guidelines on quality risk management,

Geneva, World Health Organization, 2013. WHO Technical Report Series,
No. 981, Annex 2.
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Working document QAS/15.639/Rev.

REVISED DRAFT FOR COMMENT

World Health Organization 2016

Working document QAS/15.639/Rev.1

SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF

Preparation of draft proposal for revision by Mr D.

Circulation of revised working document for public

Consolidation of comments received and review of

Presentation to the fiftieth meeting of the WHO Expert

1216 October 2015

Consolidation of comments received and review of

Discussion at the informal consultation on good

Preparation of revision by Mr D. Smith, based on

Circulation of revised working document for public

Working document QAS/15.639/Rev.1

Consolidation of comments received and review of

Presentation to the fifty-first meeting of the WHO Expert

1721 October 2016

Any other follow-up action as required

Working document QAS/15.639/Rev.1

During the consultation on data management, bioequivalence, GMP and

Summary of main changes

Working document QAS/15.639/Rev.1

Working document QAS/15.639/Rev.1

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

These guidelines focus primarily on the design and good manufacturing

Working document QAS/15.639/Rev.1

products with low water activity (less subject to microbial

Additional specic requirements apply for air-handling systems of

Working document QAS/15.639/Rev.1

Figure 1. The guidelines address the various system criteria according to

Working document QAS/15.639/Rev.1

Figure 2. GMP compliance sequence diagram

Working document QAS/15.639/Rev.1

Working document QAS/15.639/Rev.1

would ensure that the system is maintained in a validated state.

clean area (cleanroom). An area (or room or zone) with dened

closed system. A system where the product or material is not

Working document QAS/15.639/Rev.1

product during production.

Working document QAS/15.639/Rev.1

HVAC. Heating, ventilation and air-conditioning. Also referred to

Working document QAS/15.639/Rev.1

operating range. Operating range is the range of validated critical

Working document QAS/15.639/Rev.1

relative humidity. The ratio of the actual water vapour pressure of

Working document QAS/15.639/Rev.1

Working document QAS/15.639/Rev.1

Room pressure differentials could be lower or higher depending on the

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

Working document QAS/15.639/Rev.1

Figure 3. Example of a weigh booth layout

Dispensary Pre-Staging Room

Note: Similar air handling and product protection principles apply to

Return Air Shaft

Working document QAS/15.639/Rev.1

Figure 4. Example of a dispensary suite

Dispensary Pre-Staging Room

Return Air Shaft

Return Air Shaft

Working document QAS/15.639/Rev.1

Figure 5. Change rooms and washing area layouts

Working document QAS/15.639/Rev.1