GMP Guidelines For HVAC

Working document QAS/15.
639
August 2015
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
DRAFT FOR COMMENT
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(August 2015)
Should you have any comments on the attached text, please send these to Dr S. Kopp, Dr S. Kopp,
Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms
(kopps@who.int) with a copy to Ms Marie Gaspard (gaspardm@who.int) by 10 October 2015.
Medicines Quality Assurance working documents will be sent out electronically only and
will also be placed on the Medicines website for comment under Current projects. If you
do not already receive our draft working documents please let us have your email address
(to bonnyw@who.int) and we will add it to our electronic mailing list.
World Health Organization 2015

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
expression of any opinion whatsoever on the part of the World Health Organization concerning the
legal status of any country, territory, city or area or of its authorities, or concerning the delimitation
of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which
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The mention of specific companies or of certain manufacturers products does not imply that they
are endorsed or recommended by the World Health Organization in preference to others of a similar
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distinguished by initial capital letters.
All reasonable precautions have been taken by the World Health Organization to verify the
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This draft does not necessarily represent the decisions or the stated policy of the World Health
Organization.
Working document QAS/15.639

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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
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29 June
1 July 2015
Preparation of draft proposal for revision by D. Smith,

consultant to the Medicines Quality Assurance group and
Prequalification Team (PQT)-Inspections, based on the
feedback received during the meeting and from PQTInspections
July-August 2015
Circulation of revised working document for public

consultation
September 2015
Consolidation of comments received and review of

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

Committee on Specifications for Pharmaceutical
Preparations
1216 October 2015
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.
1. The Premises section has been moved towards the beginning of the document
due to its important impact on HVAC designs. In addition the text has been
expanded and a number of sample layouts have been included.
2. The HVAC sections have been re-arranged into a more logical sequence.
3. The Commissioning, Qualification and Validation (C, Q & V) section has
been aligned with the proposed revisions to the Supplementary GMP
Validation TRS937 Annex4 guideline.
4. Significant notes were added under the new Supplementary notes on test
procedures section.
5. The Maintenance section has been separated out of the C, Q & V section.
6. All the diagrams have been revised (mainly to achieve better clarity).
7. Throughout the document additional notes have been added and text revised
to provide better understanding and avoid ambiguity.
8. A list of abbreviations has been added.

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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 filtration
6.3
Unidirectional airflow
6.4
Infiltration
6.5
Cross-contamination
6.6
Displacement concept (low pressure differential,
high airflow)
6.7
Pressure differential concept (high pressure differential,
low airflow)
6.8
Physical barrier concept
6.9
Temperature and relative humidity
7.
Dust control
8.
Protection of the environment
8.1
General
8.2
Dust in exhaust air
8.3
Vapour and fume removal
9.
Commissioning, qualification and validation
9.1
General
9.2
Commissioning
9.3
Qualification
9.4
Supplementary notes on test procedures
10.
Maintenance
11.
Abbreviations
References
Further reading

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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 solid dosage forms. The guidelines also refer to other
systems or components which are not relevant to solid dosage form
manufacturing plants, but which may assist in providing a comparison
between the requirements for solid dosage-form plants and other systems.
HVAC system design influences 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, qualification 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
the present guidelines should, therefore, be considered supplementary to
the general requirements set out in the parent guide.
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 and other classes of products including
biological products, herbal medicines, complimentary medicines and
finishing process steps for APIs . Additional specific requirements apply
for handling of sterile products and hazardous products. Guidelines for
hazardous, sterile and biological product facilities are covered in separate

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

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

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Figure 1
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GMP compliance sequence diagram

PROJECT
INCEPTION
NC
USER
REQUIREMENT
SPECIFICATION
QUALIFICATION
&
VALIDATION
FACILITY
LAYOUTS
RISK
RISK
ASSESSMENT
ASSESSMENT
STUDIES
STUDIES
C OM
Installations
P
M
ENERGY
EFFICIENCY
STUDIES
G
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CE
208
HVAC &
SERVICES
DESIGNS
PL
I
M
CO
C OM PL I A
GM P
PL I A NC E
GM

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Figure 2
The guidelines address the various system criteria according to the
sequence set out in this diagram

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Glossary
The definitions 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
specified 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.
Similar to UDAF protection but not necessarily a Grade A condition.
airlock
An enclosed space with two or more doors, which is interposed between
two or more rooms, e.g. of differing classes of cleanliness, for the purpose
of controlling the airflow between those rooms when they need to be
entered. An airlock is designed for and used by either people or goods
(PAL, personnel airlock; MAL, material airlock).
alert limit
The alert limit is reached when the normal operating range of a critical
parameter has been exceeded, indicating that corrective measures may need
to be taken to prevent the action limit being reached.
as-built
Condition where the installation is complete with all services connected and
functioning but with no production equipment, materials or personnel present.
at-rest
Condition where the installation is complete with equipment installed and

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operating in a manner agreed upon by the customer and supplier, but with
no personnel present.
central air-conditioning unit (see air-handling unit)
change control
A formal system by which qualified representatives of appropriate
disciplines review proposed or actual changes that might affect a validated
status. The intent is to determine the need for action that would ensure that
the system is maintained in a validated state.
clean area (cleanroom)11
An area (or room or zone) with defined environmental control of particulate
and microbial contamination, constructed and used in such a way as to reduce
the introduction, generation and retention of contaminants within the area.
closed system
A system where the product or material is not exposed to the manufacturing
environment.
commissioning
Commissioning is the documented process of verifying that the equipment
and systems are installed according to specifications, placing the equipment
into active service and verifying its proper action. Commissioning takes
place at the conclusion of project construction but prior to validation.
containment
A process or device to contain product, dust or contaminants in one zone,
preventing it from escaping to another zone.
contamination
The undesired introduction of impurities of a chemical or microbial nature,
or of foreign matter, into or on to a starting material or intermediate, during
production, sampling, packaging or repackaging, storage or transport.
controlled area
An area within the facility in which specific environmental facility
conditions and procedures are defined, controlled, and monitored to prevent
degradation or cross-contamination of the product.
1
Note: Clean area standards, such as ISO 14644-1, provide details on how to classify air cleanliness by
means of particle concentrations, whereas the GMP standards provide a grading for air cleanliness in
terms of the condition (at-rest or operational), the permissible microbial concentrations, as well as
other factors such as gowning requirements. GMP and clean area standards should be used in
conjunction with each other to define and classify the different manufacturing environments.

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controlled-not classified
An area where some environmental conditions are controlled (such as
temperature), but the area has no cleanroom classification
critical parameter or component
A processing parameter (such as temperature or relative humidity) that
affects the quality of a product, or a component that may have a direct
impact on the quality of the product.
critical quality attribute
A physical, chemical, biological or microbiological property or characteristic
that should be within an appropriate limit, range or distribution to ensure
the desired product quality.
cross-contamination
Contamination of a starting material, intermediate product or finished
product with another starting material or product during production.
design condition
Design condition relates to the specified range or accuracy of a controlled
variable used by the designer as a basis for determining the performance
requirements of an engineered system.
design qualification
Design qualification is the documented check of planning documents and
technical specifications for conformity of the design with the process,
manufacturing, GMP and regulatory requirements.
direct impact system
A system that is expected to have a direct impact on product quality. These
systems are designed and commissioned in line with good engineering
practice and, in addition, are subject to qualification practices.
exfiltration
Exfiltration is the egress of air from a controlled area to an external zone.
facility
The built environment within which the clean area installation and associated
controlled environments operate together with their supporting infrastructure.
good engineering practice
Established engineering methods and standards that are applied throughout
the project life-cycle to deliver appropriate, cost-effective solutions.

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hazardous substance or product

A product or substance that may present a substantial risk of injury to health
or to the environment
HVAC
Heating, ventilation and air-conditioning. Also referred to as Environmental
control systems
indirect impact system
This is a system that is not expected to have a direct impact on product
quality, but typically will support a direct impact system. These systems are
designed and commissioned according to good engineering practice only.
infiltration
Infiltration is the ingress of air from an external zone into a controlled area.
installation qualification
Installation qualification is documented verification that the premises,
HVAC system, supporting utilities and equipment have been built and
installed in compliance with their approved design specification.
Most penetrating particle size (MPPS)
MPPS is a means of determining HEPA & ULPA filter efficiencies. The
MPPS is the particle size with the highest penetration for a defined filter
medium. (MPPS Integral overall efficiency is the efficiency, averaged over
the whole superficial face area of a filter element under a given operating
conditions of the filter. MPPS local efficiency is the efficiency, at a specific
point of the filter element under given operating conditions of the filter)
NLT
Not less than
NMT
Not more than
no-impact system
This is a system that will not have any impact, either directly or indirectly, on
product quality. These systems are designed and commissioned according
to good engineering practice only.
non-critical parameter or component
A processing parameter or component within a system where the operation,

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contact, data control, alarm or failure will have an indirect impact or no

impact on the quality of the product.
normal operating range
The range that the manufacturer selects as the acceptable values for a parameter
during normal operations. This range must be within the operating range.
OOS
Out of specification
operating limits
The minimum and/or maximum values that will ensure that product and
safety requirements are met.
operating range
Operating range is the range of validated critical parameters within which
acceptable products can be manufactured.
operational condition
This condition relates to carrying out room classification tests with the
normal production process with equipment in operation, and the normal
staff present in the specific room.
operational qualification (OQ)
Operational qualification is the documentary evidence to verify that the equipment
operates in accordance with its design specifications in its normal operating range
and performs as intended throughout all anticipated operating ranges.
oral solid dosage (OSD)
Usually refers to an OSD plant that manufactures medicinal products such
as tablets, capsules and powders to be taken orally.
pass-through-hatch (PTH) or pass box (PB)
A cabinet with two or more doors for passing equipment or product, whilst
maintaining the pressure cascade and segregation between two controlled
zones. A passive PTH has no air supply or extract. A dynamic PTH has an
air supply into the chamber.
performance qualification (PQ)
Performance qualification is the documented verification that the process and/
or the total process related to the system performs as intended throughout all
anticipated operating ranges.

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point extraction
Air extraction to remove dust with the extraction point located as close as
possible to the source of the dust.
pressure cascade
A process whereby air flows from one area, which is maintained at a higher
pressure, to another area at a lower pressure.
qualification
Qualification is the planning, carrying out and recording of tests on
equipment and a system, which forms part of the validated process, to
demonstrate that it will perform as intended.
quality critical process parameter (QCPP)
A process parameter which could have an impact on the critical quality
attribute.
relative humidity
The ratio of the actual water vapour pressure of the air to the saturated
water vapour pressure of the air at the same temperature expressed as a
percentage. More simply put, it is the ratio of the mass of moisture in
the air, relative to the mass at 100% moisture saturation, at a given
temperature.
standard operating procedure (SOP)
An authorized written procedure, giving instructions for performing
operations, not necessarily specific to a given product or material, but of a
more general nature (e.g. operation of equipment, maintenance and cleaning,
validation, cleaning of premises and environmental control, sampling and
inspection). Certain SOPs may be used to supplement product-specific
master and batch production documentation.
turbulent flow
Turbulent flow, or non-unidirectional airflow, is air distribution that is
introduced into the controlled space and then mixes with room air by means
of induction.
unidirectional airflow (UDAF)
Unidirectional airflow is a rectified airflow over the entire cross-sectional
area of a clean zone with a steady velocity and approximately parallel
streamlines (see also turbulent flow).
validation

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The documented act of proving that any procedure, process, equipment,

material, activity or system actually leads to the expected results.
validation master plan (VMP)
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 qualification plan).
Premises
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 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 co-ordinated with the
architectural designers. In addition the architectural layout must ensure that
the material flow is in a logical sequence, excluding material flow reversals
where possible.
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), change rooms and passages should be provided to protect
passage between different cleanliness conditions. 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.

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

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

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

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

page 20
583
584
Figure 7
Change rooms and ablution layouts
585
Figure 8
Compression cubicle with change room and MAL
L
R ow
et L
ur ev
n el
Ai
r
Passage
l
ve r
L e Ai
w rn
L o e tu
R
SOB
586
587
588

page 21
589
590
591
Figure 9
Compression cubicle without change room and MAL
(inclusion of airlocks dependant on risk assessment)
L
R ow
et L
ur ev
n el
Ai
r
15 Pa
592
593
30 Pa
Supply
Air
Grille
Passage
l
ve r
L e Ai
w rn
Lo etu
R
Compression
Cubicle

page 22
Passage
Figure 10
Wash-bay suite
Material Flow
594
595
596
597
5985.
599
5.1.
600
601
602
603
604
605
606
607
608
609
610
611
612
613
614
Design of HVAC systems and components

General
5.1.1. The required degree of air cleanliness in most OSD manufacturing
facilities can normally be achieved without the use of high-efficiency
particulate air (HEPA) filters, provided the air is not recirculated or in the
case of a single-product facility. Many open product zones of OSD 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 classified as such by manufacturers.
5.1.2. A risk assessment should be carried out to determine the cleanroom
conditions required and the extent of validation required.
5.1.3. There are two basic concepts of air delivery to pharmaceutical
production facilities: a recirculation system, and a full fresh air system

page 23
615
616
617
618
619
620
621
622
623
624
625
626
627
628
629
630
631
632
633
634
635
636
637
638
639
640
641
642
643
644
645
646
647
648
649
650
651
652
653
654
655
656
657
658
(100% outside air supply). For recirculation systems the amount of fresh air
should not be determined arbitrarily on a percentage basis, but, for example,
by the following criteria:
sufficient fresh air to compensate for leakage from the facility and
loss through exhaust air systems;
sufficient fresh air to comply with national building regulations
(depending on occupant density, between 1 and 2.5 ACPH will often
satisfy occupancy requirements);
sufficient fresh air for odour control;
sufficient fresh air to provide the required building pressurization
5.1.4. Where automated monitoring systems are used, these should be

capable of indicating any out-of-specification (OOS) condition without
delay by means of an alarm or similar system. Sophisticated computerbased data monitoring systems may be installed, which can aide with
planning of preventive maintenance and can also provide trend logging.
(This type of system is commonly referred to as a building management
system (BMS), building automation system (BAS) or system control and
data acquisition (SCADA) system. If these systems are used for critical
decision-making, they should be validated. If the BMS is not validated in
full (or in part for these critical parameters), an independent validated
environmental monitoring system (EMS) should be provided, specifically
for recording and alarming critical parameters. Critical parameters could
include for example, room temperature in production areas, humidity,
differential pressures, fan failure alarms, etc.)
,
5.1.5. Failure of a supply air fan, return air fan, exhaust air fan or dust
extract system fan can cause a system imbalance, resulting in a pressure
cascade malfunction with a resultant airflow reversal.
5.1.6. A fan interlock failure matrix should be set up, such that if a fan
serving a high pressure zone fails, then any fans serving surrounding lower
pressure areas should automatically stop, to prevent an airflow reversal and
possible cross-contamination. This fan stop-start matrix should apply to the
switching on and switching off of systems to ensure that there is no flow
reversal causing cross-contamination.
5.1.7. Appropriate alarm systems should be in place to alert personnel if a
critical fan fails All critical alarms should be easily identifiable and visible
and/or audible to relevant personnel.

page 24
Air distribution
5.2.1. The positioning of supply and extract grilles should be such as to
provide effective room flushing. 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 specified clean area condition, e.g. where
ceiling return air grilles are used.
5.2.2. There may be alternative locations for return air. For example,
referring to Figure 11, Room 1 (low-level return air) and Room 2 (ceiling
return air)..
HEPA Filter
Secondary
Filter
Supply Air
Fan
Figure 11
Air-handling system with high-efficiency particulate air filters in airhandling unit
Primary Filter
660
661
662
663
664
665
666
667
668
669
670
671
672
673
674
675
Cooling Coil
5.2.
659
676
677
678
679
680
681
682
683
The airflow schematics of the two systems (Figures 1 1 and 1 2) indicate

air-handling units with return air or recirculated air, having a percentage
of fresh air added. Depending on product characteristics and dust loading
it is sometimes preferable to fit filters on return air outlets or in return air
ducting.

page 25
Figure 12 is a schematic diagram of an air-handling system serving

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

page 26
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
5.4.
738
739
740
741
742
743
744
745
746
747
748
749
750
5.3.4. Recirculation of air from areas where pharmaceutical dust is not

generated such as secondary packing, may not require HEPA filters in the
system.
5.3.5. HEPA filters may be located in the air-handling unit or placed
terminally. Where H E P A fi l t e r s a r e t e r m i n a l l y m o u n t e d t h e y
s h o u l d preferably not be connected to the ducting by means of flexible
ducting. Due to the high air pressure required for the terminal filter, this
connection should preferably be a rigid duct connection. Where flexible
ducting is used, it should be as short as possible and properly fixed 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
monitor the filter pressure drop in individual HEPA filters.
5.3.6. Air containing dust from highly toxic processes and/or solvents or
flammable vapours should never be recirculated to the HVAC system.
Full fresh-air systems

5.4.1. The required degree of filtration of the exhaust air depends on the
exhaust air contaminants and local environmental regulations. HEPA filters
in the exhaust system would normally only be required when handling
hazardous materials.
Figure 13 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 27
751
752
753
754
755
756
757
Figure 13
Full fresh-air system

page 28
HEPA Filter
Secondary
Filter
Primary Filter
Secondary
Filter
HEPA Filter
Exhaust
Air Fan
Fresh Air
Cooling Coil
Supply Air
Fan
Figure 14
Full fresh-air system with energy recovery
Primary Filter
758
759
760
761
762
763
764
765
766
767
768
769
770
771
772
773
774
775
776
5.5.
777
778
779
780
781
782
783
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 14). Note:
Alternatives to the energy-recovery wheels, such as crossover plate heat
exchangers and water-coil heat exchangers, may be used in multiproduct
facilities.
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.
Additional system components
5.5.1. A schematic diagram of the airflow for a typical system serving a
low relative humidity suite is represented in Figure 15. 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 29
784
785
Figure 15
Air-handling system with chemical drying
CHEMICAL DRIER UNIT
Reactivation
Air Fan
Chemical Drier
Desiccant Wheel
= Supply Air
= Return Air
= Fresh Air
= Exhaust Air
F
E
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
786
787
788
789
790
791
792
793
794
795
796
797
798
799
800
801
802
803
804
805
806
807
808
5.5.2. The figure illustrates the chemical drier handling part of the fresh
air/return air mixture on a bypass flow. The location of the chemical drier
should be considered in the design phase. The practice of locating the
complete chemical drier unit in the production cubicle is not recommended
as this could be a source of contamination or cross-contamination. Examples
of appropriate locations for the drying wheel could include:
full flow of fresh/return air;
partial handling of fresh/return air (bypass airflow);
return air only;
fresh air only; or
pre-cooled air with any of the above alternatives.
5.5.3. Possible additional components that may be required in air handling
should be considered depending on the climatic conditions and locations.
These may include items such as:
frost coils on fresh air inlets in very cold climates to preheat the air;
reheaters for humidity control
automatic air volume control devices
sound attenuators

page 30
809
810
811
812
813
814
815
8166.
817
818
819
820
821
822
823
824
825
826
827
828
829
830
831
832
833
834
835
836
837
838
839
840
841
842
843
844
845
846
847
848
849
850
851
852
snow eliminators to prevent snow entering air inlets and

blocking airflow
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.
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 defined 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 qualification
stages. A suitable balance between the different criteria will be required in
order to create an efficient clean area.
6.1.3. Some of the basic criteria to be considered which affects room
cleanliness should include:
building finishes and structure dust control and containment

air filtration
air change rate or flushing rate
room pressure
location of air terminals and directional airflow
temperature
relative humidity
material flow
personnel flow
gowning procedures
equipment movement
process being carried out (open or closed system)
outside air conditions
occupancy
type of product
cleaning standard operating procedures (SOPs).
6.1.4. Air filtration and air change rates should be set to ensure that the
defined clean area condition is attained.

page 31
853
854
855
856
857
858
859
860
861
862
863
864
865
866
867
868
869
870
871
872
873
874
875
876
877
878
879
880
881
882
883
884
885
886
887
888
889
890
891
892
893
894
895
896
6.1.5. The air change rates should be determined by the manufacturer and
designer, taking into account the various critical parameters using a risk
based approach with due consideration of capital and running costs and
energy usage. Primarily the air change rate should be set to a level that will
achieve the required clean area condition.
6.1.6. Air change rates are normally determined by the following
considerations (could normally vary between 6 and 20 air changes per hour):
area condition required: whether a specific room cleanliness

condition is in fact required and whether the room condition is
rated for an at rest condition or an operational condition (air
change rate should be selected on need rather than tradition);
the product characteristics (e.g. odours, hygroscopicity, etc.);
the quality and filtration of the supply air;
particulates generated by the manufacturing process;
particulates generated by the operators;
configuration of the room and air supply and extract locations;
sufficient air to achieve containment effect and to clean up the area;
sufficient air to cope with the room heat load;
sufficient air to balance extract rates;
sufficient air to maintain the required room pressure.
6.1.7. If a cleanroom classification is specified, the manufacturer should

state whether this is achieved under as-built (Figure 16), at-rest (Figure
17) or operational (Figure 18) conditions.
6.1.8. Room classification tests in the as-built condition should be
carried out on the bare room, in the absence of any equipment or personnel.
6.1.9. Room classification tests in the at-rest condition should be carried
out with the equipment operating where relevant, but without any operators.
Because of the amounts of dust usually generated in a solid dosage facility,
the clean area classifications would be rated for the at-rest condition.
6.1.10. Room classification tests in the operational condition are
normally carried out during the normal production process with equipment
operating, and the normal number of personnel present in the room. When
qualifying for the operational condition details of the process operating,
number and positions of staff should be stipulated for each room, to enable
future qualifications to duplicate the same conditions.
6.1.11. Room clean-up or recovery tests are performed to determine
whether the installation is capable of returning to a specified cleanliness

page 32
897
898
899
900
901
902
903
904
905
906
907
908
909
910
911
912
913
914
915
916
917
918
919
920
level within a finite time, after being exposed briefly to a source of

airborne particulate challenge. Room clean-up or recovery tests should
demonstrate a change in particle concentration by a factor of 100 within
the prescribed time (as per ISO 14644-3 clause B.12) (3). The guidance
time period for clean-up or recovery is about 15 to 20 minutes.
In some instances it is not possible to increase the concentration by a factor
of 100 (such as for an ISO 14644 Class 8 condition) as the high particle
concentration can damage the particle counter. In this instance the particle
decay method can be used as per ISO 14644-3 clause B.12.3.2.
6.1.12. Materials and products should be protected from contamination
and cross-contamination during all stages of manufacture (see also section
6.5 for cross-contamination control).
Note: contaminants may result from inappropriate premises (e.g. poor design,
layout or finishing), poor cleaning procedures, contaminants brought in by
personnel, poor manufacturing process and a poor HVAC system.
Figure 16
As-built condition

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

page 34
928
929
930
931
932
933
934
935
936
937
938
939
940
941
942
943
944
945
946
947
948
949
950
951
6.1.13. Airborne contaminants should be controlled through effective

ventilation and filtration.
6.1.14. External contaminants should be removed by effective filtration of
the supply air (see Figure 19 for an example of a shell-like building
layout to enhance containment and protection from external
contaminants).
6.1.15. Internal contaminants should be controlled by dilution and
flushing of contaminants in the room, or by displacement airflow (See
Figures 20 and 21 for examples of methods for the flushing of airborne
contaminants).
6.1.16. Airborne particulates and the degree of filtration should be
considered critical parameters with reference to the level of product
protection required.
6.1.17. Personnel should not be a source of contamination.
6.1.18. The level of protection and air cleanliness for different areas should
be determined according to the product being manufactured, the process
being used and the products susceptibility to degradation (Table 3).

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

page 36
Table 1
Comparison of filter test standards
EU 14
EU 13
EU 12
EU 11
EU 10
EU 9
EU 9
EU 8
Merv rating
Average
arrestance
Am (%)
Average
dust spot
efficiency
Em (%)
Merv 18
Merv 17
Merv
Merv
Merv
Merv
16
15
14
13
EU 7
Merv 12
EU 6
Merv 11
EU 5
Merv 10
Merv 9
Merv 8
Merv 7
EU 4
EU 3
EU 2
EU 1
981
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
(supersede
d)
ASHRAE
52.2
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 rating
Eurovent 4/5
ASHRAE
52.1
BS6540 Part
1
F6
F5
G4
G3
G2
G1
EN 1822: 2009
977
978
979
980
75E
65E
55E
45E
35E
25E
15E

page 37
982
983
Table 2
Comparison of ISO and EN Filter Standards
ISO 29463
Global or Integral
Values for MPPS
Local Values for

MPPS
EN 1822
MPPS
Collection
Integral
Collection
Filter
EN
Penetrat
Penetrat
Efficiency
Efficiency
Overall
Class
ion (%)
ion (%)
Rating
(%)
(%)
Efficiency
(%)
ISO 75 E
99.9999 0.0001 99.999995 U17
99.999995 0.000005
ISO 70 E
99.9999 0.0001
99.99999 0.00001
ISO 65 E
99.99975
99.99995 U16
99.99995 0.00005
0.00025
ISO 60 E 99.9999 0.0001 99.9995 0.0005
ISO 55 E
984
985
986
0.0005 99.9975 0.0025

99.99995
99.9995
U15
ISO 50 E 99.999
0.001
99.995
0.005
ISO 45 E 99.995
0.005
99.975
0.025
99.995
H14
ISO 40 E
99.99
0.01
99.95
0.05
ISO 35 E
99.95
0.05
99.75
0.25
99.95
H13
ISO 30 E
99.9
0.1
ISO 25 E
99.5
0.5
99.5
E12
ISO 20 E
99
ISO 15 E
95
95
E11
The above all tested for MPPS (most penetrating

particle size)
Note: The filter classifications referred to above relate to the EN
1822:2009 and EN 779: 2002 test standards (EN 779 relates to filter
classes G1 to F9 and EN1822 relates to filter classes E10 to U17).

page 38
987
988
989
990
991
992
993
994
995
996
997
998
999
1000
1001
1002
6.2.3. In selecting filters, the manufacturer should have considered other

factors, such as particularly contaminated ambient conditions, local
regulations and specific product requirements. Good prefiltration extends
the life of the more expensive filters downstream.
6.2.4. Filters have an impact on the cleanroom class or Level of
Protection. The different levels of protection and recommended filters
grades are given in Tables 3 and 4 below.
Table 3
Examples of levels of protection (based on ISPE oral solid dosage
(OSD) guideline criteria)
Level
Condition
Example of area
Level 1
General
Area with normal housekeeping and
maintenance where there is no potential for
product contamination, e.g. warehousing.
Level 2
Protected
Area in which steps are taken to protect

the pharmaceutical starting material or
product from direct or indirect
contamination or degradation, e.g.
secondary packing, warehousing, first
stage change rooms.
Level 3
Controlled
Area in which specific environmental

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

page 39
1003
1004
1005
1006
1007
1008
1009
1010
1011
1012
1013
1014
1015
1016
1017
1018
1019
1020
1021
1022
1023
1024
Table 4
Levels of protection and recommended filtration
Level of protection Recommended filtration
Level 1
Primary filters only (e.g. EN 779 G4 filters)
Level 2
Protected areas operating on 100% outside air:

primary plus secondary filters (e.g. EN 779 G4
plus F8 or F9 filters)
Level 3
Production facility operating on recirculated

plus ambient air, where potential for crosscontamination exists: Primary plus secondary
plus tertiary filters (e.g. EN 779 G4 plus F8 plus
EN 1822 H13 filters) (for full fresh air system,
without recirculation, G4 and F8 or F9 filters are
acceptable)
6.2.5. Materials for components of an HVAC system should be selected

with care so that they do not become a source of contamination. Any
component with the potential for liberating particulate or microbial
contamination into the airstream should be located upstream of the final
filters.
6.2.6. Where possible ventilation dampers, filters and other services should
be designed and positioned so that they are accessible from outside the
manufacturing areas (service voids or service corridors) for maintenance
purposes.
6.2.7. Directional airflow within production or primary packing areas
should assist in preventing contamination. Airflows should be planned in
conjunction with operator locations, so as to minimize contamination of the
product by the operator and also to protect the operator from dust inhalation.
Different airflow patterns are indicated in Figures 20 & 21 below.

page 40
1025
1026
1027
1028
1029
1030
1031
1032
1033
1034
1035
Figure 20
Turbulent dilution of dirty air
Low-level extract is ideal for dust suppression purposes, but is not

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

page 41
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Figure 21
Unidirectional displacement of dirty air
6.2.8. HVAC air distribution components should be designed, installed

and located to prevent contaminants generated within the room from being
spread.
6.2.9. Supply air diffusers should be selected with care taking consideration
of, e.g. room requirements and positions of equipment and operators in the
room. Supply air diffusers of the high induction type (e.g. those typically
used for office-type air-conditioning) should where possible not be used
in clean areas where dust is liberated. Air diffusers should be of the noninduction type, introducing air with the least amount of induction so as to
maximize the flushing effect. In rooms where the process results in high
dust liberation; perforated plates or low induction swirl diffusers with
low level extract or return should be used (to contain the dust at the lower
level of the room) (see Figures 2224 for illustrations of the three types of
diffuser). In cases where dust liberation is low, ceiling return air grilles may
be acceptable.

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

page 43
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Figure 23
Perforated plate diffuser

page 44
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1100
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1102
1103
1104
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Figure 24
Swirl diffuser
6.3.
Unidirectional airflow
6.3.1. Unidirectional airflow (UDAF) should be used for weighing booths

or sampling booths to provide operator and product protection and should
also have a slight air in-flow from the room to enhance containment. Dust
containment at the weigh booth should be demonstrated by smoke airflow
pattern tests, or other appropriate tests. UDAF can also be used to provide
protection of other dusty processes.
6.3.2. Sampling of materials such as starting materials, primary packaging
materials and products, should be carried out in the same environmental
conditions that are required for the further processing of the product.
6.3.3. In a weighing booth situation, the aim of the UDAF is to provide
dust containment and operator protection.
Example: in Figure 25 the dust generated at the weighing station is
immediately extracted through the perforated worktop, thus protecting the
operator from dust inhalation, but at the same time protecting the product
from contamination by the operator by means of the vertical unidirectional
airflow stream.

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

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

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1170
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 9 shows that a solid worktop can sometimes cause deflection of
the vertical unidirectional airflow resulting in a flow reversal. A possible
solution would be to have a 100 mm gap between the back of the table and
the wall, with the air being extracted here.
Figure 27
Operator subject to powder inhalation due to obstruction

page 48
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Figure 28
Operator subject to powder contamination due to airflow reversal in
bin

page 49
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Figure 29
Operator subject to powder inhalation due to worktop obstruction
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1184
1185
6.3.8 The manufacturer should select either vertical or horizontal

unidirectional airflow (Figure 30) and an appropriate airflow pattern to
provide the best protection for the particular application.
1186

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

page 51
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1201
1202
6.4.
1203
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1209
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1211
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1214
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1222
6.5.
1223
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1226
1227
1228
1229
1230
1231
1232
1233
1234
1235
1236
1237
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 filters can either be installed at the room terminal or in
the air-handling unit. Maintenance and cleaning of filters and ducts should
be addressed to ensure constant airflow.
Infiltration
6.4.1. Air infiltration of unfiltered 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
infiltrate into the controlled zone.
Cross-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 airflow 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.

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6.6.
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6.5.4. Containment can normally be achieved by application of the

displacement concept (low pressure differential, high airflow), or the
pressure differential concept (high pressure differential, low airflow), or the
physical barrier concept.
6.5.5. The pressure cascade regime and the direction of airflow should be
appropriate to the product and processing method used.
6.5.6. Highly potent products should be manufactured under a pressure
cascade regime that is negative relative to atmospheric pressure.
6.5.7. The pressure cascade for each facility should be individually
assessed according to the product handled and level of protection required.
6.5.8. Building structure should be given special attention to accommodate
the pressure cascade design.
6.5.9. Ceilings and walls, close fitting doors and sealed light fittings should
be in place, to limit ingress or egress of air.
Displacement concept (low pressure differential, high airflow)
Note: This method of containment is not the preferred method, as the
measurement and monitoring of airflow velocities in doorways is difficult.
This concept is commonly found in production processes where large
amounts of dust are generated.
6.6.1. Under this concept the air should be supplied to the corridor,
flow through the doorway, and be extracted from the back of the cubicle.
Normally the cubicle door should be closed and the air should enter the
cubicle through a door grille, although the concept can be applied to an
opening without a door. (With the door open the pressure differential will
effectively be zero.)
6.6.2. The velocity should be high enough to prevent turbulence within the
doorway resulting in dust escaping.
6.6.3. This displacement airflow should be calculated as the product of
the door area and the velocity through the doorway, which generally
results in fairly large air quantities.
Note: Although this method of containment may still exist on older facilities,
it is not the preferred method, as the measurement and monitoring of doorway
velocities is difficult. In addition, simultaneously maintaining the correct
room pressure and the correct room air change rate is often not achieved.

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6.7.
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1300
1301
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1322
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Pressure differential concept (high pressure differential, low airflow)

Note: The pressure differential concept may normally be used in zones where
little or no dust is being generated. It may be used alone or in combination
with other containment control techniques and concepts, such as a double
door airlock.
6.7.1. The high pressure differential between the clean and less clean
zones should be generated by leakage through the gaps of the closed doors
to the cubicle.
6.7.2. The pressure differential should be of sufficient magnitude to ensure
containment and prevention of flow reversal, but should not be so high as to
create turbulence problems.
6.7.3. In considering room pressure differentials, transient variations, such
as machine extract systems, should be taken into consideration.
6.7.4. A pressure differential of 15 Pa is often used for achieving
containment between two adjacent zones, but pressure differentials of
between 5 Pa and 20 Pa may be acceptable. Where the design pressure
differential is too low and tolerances are at opposite extremities, a flow
reversal can take place. For example, where a control tolerance of 3 Pa
is specified, 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 flow reversal is unlikely to occur.
6.7.5. 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 first room is at the maximum
pressure limit and the second room is at its minimum pressure limit.
6.7.6. Low p r e s s u r e d i f f e r e n t i a l s m a y b e a c c e p t a b l e
w h e n a i r l o c k s (pressure sinks or pressure bubbles) are used to
segregate areas.
6.7.7. The effect of room pressure tolerances are illustrated in Figure 31.
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

page 54
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.
Air Leakage
Air Leakage
Figure 31
Examples of pressure cascades
Air Leakage
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Air Leakage
Air Leakage
Air Leakage
Air Leakage
Air Leakage
Air Leakage
Image of room pressure gauge

indicating colour coded normal,
alert & action parameters
6.7.8. The pressure control and monitoring devices used should be

calibrated and qualified. Compliance with specifications should be regularly
verified and the results recorded. Pressure control devices should be linked
to an alarm system set according to the levels determined by a risk analysis.
6.7.9. Manual control systems, where used, should be set up during
commissioning, with set point marked, and should not change unless other
system conditions change.
6.7.10. Airlocks can be important components in setting up and maintaining
pressure cascade systems and also to limit cross-contamination.
6.7.11. Airlocks with different pressure cascade regimes include the
cascade airlock, sink airlock and bubble airlock (Figures 3234):
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

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both outer sides;

bubble airlock: higher pressure inside the airlock and lower
pressure on both outer sides.
Figure 32
Example of cascade airlock
(In most cases the internal pressure of the airlock is not critical. The
pressure differential between the two outer sides is the important criteria.)

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Figure 33
Example of sink airlock

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

page 58
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6.8.
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1439
6.9.
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6.7.15. Air should not flow 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 flowing back
in the opposite direction in the event of component failure or airflow failure.
6.7.16. 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, such as a pressure gauge installed to
indicate the pressure differential from a central corridor to the outside.
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 defined 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-specification condition should be
easily identifiable.
6.7.17. Material pass-through-hatches (PTH) 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.
6.7.18. 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.
Physical barrier concept
6.8.1. Where appropriate, an impervious barrier to prevent crosscontamination between two zones, such as closed systems, pumped or
vacuum transfer of materials, should be used.
Temperature and relative humidity
6.9.1. 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.

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1493
6.9.2. Maximum and minimum room temperatures and relative humidity

should be appropriate. Alert and action limits on temperatures and
humidities should be set, as appropriate.
6.9.3. The operating band, or tolerance, between the acceptable minimum
and maximum temperatures should not be made too close. Tight control
tolerances may be difficult to achieve and can also add unnecessary
installation and running costs.
6.9.4. Cubicles, or suites, in which products requiring low relative humidity
are processed, should have well-sealed walls and ceilings and should also
be separated from adjacent areas with higher relative humidity by means of
suitable airlocks.
6.9.5. Precautions should be taken to prevent moisture migration that
increases the load on the HVAC system.
6.9.6. Humidity control should be achieved by removing moisture from
the air, or adding moisture to the air, as relevant.
6.9.7. Dehumidification (moisture removal) may be achieved by means of
either refrigerated dehumidifiers or chemical dehumidifiers.
6.9.8. Appropriate cooling media for dehumidification such as low
temperature chilled water/glycol mixture or refrigerant should be used.
6.9.9. Humidifiers should be avoided if possible as they may become a
source of contamination (e.g. microbiological growth). Where humidification
is required, this should be achieved by appropriate means such as the injection
of steam into the air stream. A product-contamination assessment should be
done to determine whether pure or clean steam is required for the purposes
of humidification.
6.9.10. Where steam humidifiers are used, chemicals such as corrosion
inhibitors or chelating agents, which could have a detrimental effect on
the product, should not be added to the boiler system. Only appropriate
additives should be added to the boiler system.
6.9.11. Humidification systems should be well drained. No condensate
should accumulate in air-handling systems.
6.9.12. Other humidification appliances such as evaporative systems,
atomizers and water mist sprays, should not be used because of the potential
risk of microbial contamination.
6.9.13. Duct material in the vicinity of the humidifier should not add
contaminants to air that will not be removed by filtration further downstream.

page 60
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1499
1500
1501
1502
1503
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1505
15067.
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1508
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1530
1531
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1533
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1536
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1540
6.9.14. Air filters should not be installed immediately downstream of

humidifiers, as moisture on the filters could lead to bacterial growth.
6.9.15. Cold surfaces should be insulated to prevent condensation within
the clean area or on air-handling components.
6.9.16. When specifying relative humidity, the associated temperature
should also be specified.
6.9.17. Chemical driers using silica gel or lithium chloride are acceptable,
provided that they do not become sources of contamination.
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 fixed,
high-velocity extraction point or an articulated arm with movable hood or a
fixed extraction hood.
7.3.
Dust extraction ducting should be designed with sufficient 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.
Airflow 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 sufficient to capture all of
the contaminants, and general directional airflow should be used to assist
in removing dust and vapours from the room.
7.7.
Typically, in a room operating with turbulent airflow, 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
flushing effect in the room. Correct flushing of the rooms may be verified
by airflow visualization smoke tests.

page 61
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15458.
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8.1.
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8.2.
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1586
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.
Protection of the environment
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.
Dust in exhaust air
8.2.1. Exhaust air discharge points on pharmaceutical equipment and
facilities, such as from fluid bed driers and tablet-coating equipment, and
exhaust air from dust extraction systems, carry heavy dust loads and should be
provided with adequate filtration to prevent contamination of the ambient air.
8.2.2. Where the powders are not highly potent, final filters on a dust
exhaust system should be fine dust filters with a filter classification of F9
according to EN 779 filter 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
filters containing a compressed air lance, and be capable of continuous
operation without interrupting the airflow.
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 airflow during a
production run as the loss of airflow could disrupt the pressure cascade.
8.2.5. Mechanical-shaker dust collectors should not be used for applications
where continuous airflow is required, in order to avoid unacceptable
fluctuations 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.

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

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

page 64
1675
1676
1677
1678
1679
1680
1681
1682
1683
1684
1685
1686
1687
1688
1689
1690
1691
1692
1693
1694
1695
1696
1697
1698
9.4.
1699
9.5.
1700
9.6.
1701
1702
1703
1704
1705
commissioning data schedules;

maintenance instructions;
list of equipment suppliers;
spare parts lists;
equipment capacity and data schedules;
suppliers literature;
control system operation;
electrical drawings;
as-built drawings;
maintenance records.
9.3.7. 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.
9.3.8. Training should be provided to personnel after installation of the
system, and should include how to perform operation and maintenance.
9.3.9. Commissioning should be a precursor to system qualification and
validation.
Qualification
9.6.1. Manufacturers should qualify HVAC systems using a risk-based
approach. The basic concepts of qualification of HVAC systems are set out
in Figure 35 below.

page 65
1706
1707
Figure 35
Qualification is a part of validation
1708
1709
1710
1711
1712
1713
1714
1715
1716
1717
1718
1719
1720
9.6.2. The qualification of the HVAC system should be described in a

validation master plan (VMP), or a subsection of the VMP.
9.6.3. The validation master plan should define the nature and extent of
testing and the test procedures and protocols to be followed.
9.6.4. Stages of the qualification of the HVAC system should include
design qualification (DQ), installation qualification (IQ), operational
qualification (OQ) and performance qualification (PQ). The relationship
between the development stage of a project and the qualification/validation
stage is given in the V-Diagram (Figure 36) below.

page 66
1721
Figure 36
V-Model for Direct Impact Systems
PQ Test Plan
User Requirement
Specification
Performance
Qualification
(incl. UAT)
Design
Qualification
Functional Design
Specification
OQ Test Plan
Operational
Qualification
(incl. FAT)
DQ Test Plan
Detail Design and

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

Implementation
1722
1723
1724
1725
1726
1727
1728
1729
1730
1731
1732
1733
1734
1735
9.6.5. Critical and non-critical parameters for all HVAC installation

components, subsystems and controls should be determined by means of a
risk analysis.
1736
Example
1737
1738
1739
1740
1741
1742
9.6.6. Any parameter that may affect the quality of the pharmaceutical
product should be considered a critical parameter.
9.6.7. All critical parameters should be included in the qualification
process.
Note: A realistic approach to differentiating between critical and
noncritical parameters, systems or components is required, to avoid
making the validation process unnecessarily complex.
The humidity of the room where the product is exposed should be

considered a critical parameter when a humidity-sensitive product
is being manufactured. The humidity sensors and the humidity
monitoring system should, therefore, be qualified. Components or
equipment such as the heat transfer system, chemical drier or
steam humidifier, which is producing the humidity-controlled air, is

page 67
1743
1744
1745
1746
1747
1748
1749
1750
1751
1752
1753
1754
1755
1756
1757
1758
1759
1760
1761
1762
1763
1764
1765
1766
1767
1768
1769
1770
1771
1772
1773
1774
1775
1776
1777
further removed from the product and may not require operational
qualification.
A room cleanliness classification is a critical parameter and,
therefore, the room air-change rates and high-efficiency particulate
air (HEPA) filters should be considered critical parameters and
components, and therefore require qualification. Items such as the
fan generating the airflow and the primary and secondary filters
are considered non-critical components, and may not require
operational qualification.
9.6.8. Non-critical systems and components should be subject to

verification by good engineering practice (GEP) and may not necessarily
require full qualification.
9.6.9. A change control procedure should be followed when changes are
planned to the HVAC system, its components and controls, that may affect
critical parameters.
9.6.10. The design condition, normal operating ranges, operating range
and alert and action limits should be defined and be realistic. Alert limits
should be based on system capability.
.
9.6.11. All parameters should fall within the design condition range
during system operational qualification. Conditions may go out of the
design condition range during normal operating procedures but they should
remain within the operating range.
9.6.12. Out-of-limit results (e.g. alert or action limit deviations) should be
recorded and form part of the batch manufacturing records, and their
impact should be investigated.
9.6.13. The relationships between design conditions, operating range and
qualified acceptance criteria are given in Figure 37. There should be SOPs
to determine action to be taken when alert and action limits are reached.

page 68
1778
1779
Figure 37
System operating ranges
1780
1781
1782
1783
1784
1785
1786
1787
1788
1789
1790
1791
1792
1793
1794
1795
1796
1797
1798
1799
1800
1801
1802
1803
1804
1805
9.6.14. A narrow range of relative humidities coupled with a wide range of

temperatures is unacceptable as changes in temperature will automatically
give rise to variations in the relative humidity.
1806
1807
1808
1809
9.6.16. The maximum time interval between tests and re-qualification

should be defined by the manufacturer. The type of facility under test and
the product level of protection should be considered.
9.6.15. Some of the typical HVAC system parameters, based on a risk

assessment, that should be qualified for a pharmaceutical facility may
include:
temperature
relative humidity
supply air quantities for all diffusers
return air or exhaust air quantities
room air-change rates
room pressures (pressure differentials)
room airflow patterns
unidirectional flow velocities
containment system velocities
HEPA filter penetration tests
room particle counts
room clean-up or recovery rates
microbiological air and surface counts where appropriate
operation of de-dusting
warning/alarm systems where applicable.

page 69
1810
1811
1812
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.
1813
1814
Table 5
Strategic tests to demonstrate continued compliance
1815
1816
(Time intervals given for re-qualification are for reference purposes only.
The actual tests required will depend on specific facility requirements)
Test parameter
Particle count test

(verification of
cleanliness)
Air pressure
difference (to verify
absence of crosscontamination)
Airflow volume
(to verify air change
rates)
Airflow velocity
(to verify
unidirectional flow or
containment
conditions)
Max. time Test procedure

interval
between tests
(all classes)
6 months Dust particle counts to be carried
(ISO 5) out and result printouts produced.
12 months No. of readings and positions of
(>ISO 5) tests to be in accordance with ISO
14644-1 Annex B.2
Log of pressure differential
12 months readings to be produced - critical
plants should be logged daily,
preferably continuously. In
accordance with ISO 14644-3
Airflow readings for supply air and
return air grilles to be measured
12 months and air change rates to be
calculated. In accordance with
ISO 14644-3 Annex B.4
Air velocities for containment
systems and unidirectional flow
12 months protection systems to be measured.
In accordance with ISO 14644-3
Annex B.4

page 70
Filter penetration tests to be carried

out by a competent person to
12 months demonstrate filter media, filter seal
(to verify filter
and filter frame integrity.. In
integrity)
Annex B.6
Demonstrate that contaminant is
Containment leakage
(to verify absence of
maintained within a room by
cross-contamination)
means of:
12 months airflow direction smoke tests
HEPA filter leakage
tests
room air pressures. In

Annex B.13
Recovery
(to verify clean-up
time)
Room temperatures
(to verify temperature
tolerance adherence)
Warehouse and store

temperatures
(to verify temperature
mapping conditions)
Room Humidities
(To verify humidity
tolerance adherence)
Test to establish time that a

12 months cleanroom takes to recover from a
contaminated condition to the
specified cleanroom condition. In
Demonstrate that room
temperatures at determined
12 months locations comply with specified
tolerances. In accordance with
ISO 14644-3 Annex B.8.2
Demonstrate that store
temperatures are uniform within
specified tolerances
In accordance with WHO 45th
36 months report (WHO Technical Report
Series, No. 961), Annex 9 and
WHO 49th report (WHO Technical
Report Series, No. 992), Annex 5
plus Supplements 1 to 16
Demonstrate that room humidities
at determined locations comply
12 months with specified tolerances. In
Annex B.9.2

page 71
1817
1818
1819
1820
1821
1822
1823
1824
1825
1826
1827
1828
9.6.17. Requalification should also be done when any change, which could
affect system performance, takes place.
1829
1830
1831
1832
In some instances it is not possible to increase the concentration by a

factor of 100 (such as for an ISO 14644 Class 8 condition) as the high
particle concentration can damage the particle counter. In this instance the
particle decay method can be used as per ISO 14644-3 clause B.12.3.2.
1833
1834
1835
1836
1837
9.6.19. If energy-saving procedures such as reducing the airflow during

non-production hours are used, precautionary measures should be in place
to ensure that the systems are not operated outside the defined relevant
environmental conditions.
1838
1839
1840
1841
1842
These precautionary measures should be based on a risk assessment to

ensure that there is no negative impact on the quality of the product.
Qualification tests should be carried out to demonstrate that there are no
flow reversals, loss of room pressurisation cascade, temperature, humidity
excursions, etc.
1843
1844
1845
1846
1847
1848
9.6.20. Additional documents that should be included in the qualification

manuals should include system airflow schematics, room pressure cascade
drawings, zone concept drawings, air-handling system allocation drawings,
particle count mapping drawings, etc.
9.6.18. Room clean-up or recovery tests are performed to determine

whether the installation is capable of returning to a specified cleanliness
level within a finite time, after being exposed briefly to a source of
airborne particulate challenge.
Room clean-up or recovery tests should demonstrate a change in particle
concentration by a factor of 100 within the prescribed time (as per ISO
14644-3 clause B.12) (3). The guidance time period for clean-up or
recovery is about 15 to 20 minutes.

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

page 73
1890
1891
1892
1893
1894
1895
1896
1897
1898
1899
1900
1901
1902
1903
1904
1905
1906
1907
1908
1909
1910
1911
1912
1913
1914
1915
1916
1917
1918
1919
1920
1921
1922
1923
1924
1925
1926
1927
1928
10.1.
1929
1930
1931
determine if additional sample locations are warranted. Consider aspects

such as personnel and/or production activities and air flow dead spots.
9.7.3.5.
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.
9.7.3.6.
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.
9.7.4. HEPA filter integrity tests
9.7.4.1.
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.
9.7.4.2.
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.)
9.7.4.3.
the product.
10.
The test procedure should not compromise the quality of
Maintenance
Maintenance records, maintenance procedures and Operating &

Maintenance 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

page 74
1932
1933
1934
1935
10.2.
1936
1937
1938
1939
1940
10.3.
1941
1942
1943
1944
1945
1946
10.4.
1947
1948
1949
10.5.
1950
1951
1952
10.6.
1953
1954
1955
10.7.
1956
1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975
1976
1977
system. Records should be kept for a sufficient length of time should they
be required for any product defect analysis.
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.
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.
Maintenance personnel should receive appropriate training, and training
records should be kept.
HEPA filters should be changed either by a specialist or a trained person,
and then followed by installed filter leakage testing.
Any maintenance activity should be assessed critically to determine any
impact on product quality including possible contamination.
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 requalification 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 Specifications 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
Organization, 2007; and Quality assurance of pharmaceuticals. A
compendium of guidelines and related materials. Geneva, World
Health Organization, 2015 (CD-ROM) (in print).
2.
Expert Committee on Specifications for Pharmaceutical

Preparations.Fortieth report. Geneva, World Health Organization,
2005 (WHO Technical Report Series, No. 937)

page 75
1978
1979
http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf.
1980 3.
1981
1982
1983
1984
1985
Technical supplements to Model guidance for the storage and

transport of time- and temperature-sensitive pharmaceutical
products. WHO Expert Committee on Specifications for
Pharmaceutical Preparations. Forty Ninth report. Geneva, World
Health Organization, 2015 (WHO Technical Report Series, No. 992),
Annex 5.
1986 4.
1987
1988
1989
1990
1991
Model guidance for the storage and transport of time- and

temperature-sensitive pharmaceutical products (jointly with the
Expert Committee on Biological Standardization). WHO Expert
Committee on Specifications for Pharmaceutical Preparations.
Forty-fifth report. Geneva, World Health Organization, 2011 (WHO
Technical Report Series, No. 961), Annex 9.
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
Further reading
Quality assurance of pharmaceuticals. A compendium of guidelines and
related materials, Volume 1. Geneva, World Health Organization, 1997.
Quality Assurance of Pharmaceuticals. A compendium of guidelines and
related materials, Volume 2, Second updated edition. Good manufacturing
practices and inspection. Geneva, World Health Organization, 2007.
http://
www.who.int/medicines/areas/quality_safety/quality_assurance/productio
n/ en/index.html; and Quality Assurance of Pharmaceuticals. A
compendium of guidelines and related materials. Geneva, World Health
Organization, 2015 (CD-ROM) (in print).
World Health Organization. Supplements and updates available at:
www.who.int/medicines.
ASHRAE handbook 1999. HVAC Applications, SI edition. Atlanta, GA,
ASHRAE, 2007. http://www.ashrae.org/technology/page/548.
ASHRAE handbook 2000. HVAC Systems and Equipment. Atlanta, GA,
ASHRAE, 2008. http://www.ashrae.org/technology/page/548.
Daly BB. Woods practical guide to fan engineering. Colchester, Woods of
Colchester Ltd. Third impression, June 1985. Cambridge, Cambridge
University Press. www.flaktwoods.com.

page 76
2018
2019
2020
2021
2022
2023
2024
2025
2026
2027
2028
2029
2030
2031
2032
2033
2034
2035
2036
2037
2038
2039
2040
2041
2042
2043
2044
2045
2046
2047
2048
2049
2050
2051
European Commission. The rules governing medicinal products in the

European Community, Volume IV. Good manufacturing practice for
medicinal products. European Commission, Brussels, 2005.
http://www.cen.eu/cenorm/ sectors/sectors/healthcare/index.asp.
ISPE Baseline pharmaceutical engineering guides, Volume 2. Oral solid
dosage forms, Second Edition / November 2009, International Society for
Pharmaceutical Engineering. http://www.ispe.org/.
ISPE Baseline pharmaceutical engineering guides for new and
renovated facilities, Volume 5. Commissioning and qualification, 1st ed.
Tampa, Fl, International Society for Pharmaceutical Engineering, 2001.
http://www.ispe.org/.
International Cleanroom Standards, ISO 14644. Geneva, International
Organization for Standardization. http://www.iso.org/iso/standards_
development.htm.
Luwa. Introduction to high efficiency filtration. Bulletin 50.10.10, Sheet
020. Pharmaceutical Inspectorate Convention/Pharmaceutical Inspection
Co-operation Scheme. Guide to Good Manufacturing Practice for
Medicinal Products. PH 1/97 (Rev. 3), 15 January 2002.
PIC/s GMP Guide (PE 009)
http://www.picscheme.org/publication.php?id=4.
ICH Q9: Quality Risk Management, November 2005
http://www.ich.org.
World Health Organization. Guidelines on quality risk management,
Geneva, World Health Organization, 2013 (WHO Technical Report Series,
No. 981), Annex 2).
***

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Working document QAS/15.

DRAFT FOR COMMENT

World Health Organization 2015

Working document QAS/15.639

SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF

Preparation of draft proposal for revision by D. Smith,

Circulation of revised working document for public

Consolidation of comments received and review of

Presentation to fiftieth meeting of the WHO Expert

1216 October 2015

Any other follow-up action as required

Working document QAS/15.639

During the consultation on data management, bioequivalence, GMP and

Summary of main changes

Working document QAS/15.639

Working document QAS/15.639

Working document QAS/15.639

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

Working document QAS/15.639

GMP compliance sequence diagram

Working document QAS/15.639

Working document QAS/15.639

Working document QAS/15.639

Working document QAS/15.639

Working document QAS/15.639

hazardous substance or product

Working document QAS/15.639

contact, data control, alarm or failure will have an indirect impact or no

Working document QAS/15.639

Working document QAS/15.639

The documented act of proving that any procedure, process, equipment,

Working document QAS/15.639

Working document QAS/15.639

Dispensary Pre-Staging Room

Return Air Shaft

Working document QAS/15.639

Return Air Shaft

Return Air Shaft

Dispensary Pre-Staging Room

Working document QAS/15.639

Working document QAS/15.639

Working document QAS/15.639

Working document QAS/15.639

Design of HVAC systems and components

Working document QAS/15.639

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

Working document QAS/15.639

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

Working document QAS/15.639

Figure 12 is a schematic diagram of an air-handling system serving

Working document QAS/15.639

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

Full fresh-air systems

Working document QAS/15.639

Working document QAS/15.639

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

Working document QAS/15.639

AIR HANDLING UNIT

Working document QAS/15.639

snow eliminators to prevent snow entering air inlets and

Products and personnel

6.1.1. Areas for the manufacture of pharmaceuticals, where pharmaceutical

building finishes and structure dust control and containment