WORLD HEALTH ORGANIZATION

Technical Report Series

937, 2006

WHO EXPERTS MEETING

ABOUT SPECIFICATIONS FOR
PHARMACEUTICAL PREPARATIONS
REPORT No. 40

Annex 2

SUPPLEMENTARY GUIDELINES ON GOOD

MANUFACTURING PRACTICES ON SYSTEMS
HEATING, VENTILATION, AND AIR CONDITIONING
IN UNSTERILE PHARMACEUTICAL FORMS.
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World Health Organization

WHO Technical Report. Series No. 937, 2006

Annex 2
Supplementary guidelines on good practices of
manufacturing for heating, ventilation, and air conditioning systems
packaged in non-sterile pharmaceutical forms.

1. Introduction.

2. Scope of the document.

3. Glossary.

4. Protection.
4.1. Products and personnel.
4.2. Air filtration.
4.3. Unidirectionality of flow.
4.4. Infiltration.
4.5. Cross-contamination.
4.6. Temperature and relative humidity.

5. Dust control.

6. Environmental protection.
6.1. Dust and expelled air.
6.2. Gas extraction.

7. Systems and components.

7.1. General.
7.2. Recirculation system.
7.3. Loss air systems(full fresh air system).
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1. Introduction.
Heating, ventilation, and air conditioning (HVAC) systems
(by its acronym in English) have an important role in ensuring the
manufacturing of quality pharmaceutical products. An HVAC system
well designed, can also offer comfortable conditions of
work for the operators. The guidelines described here focus on
your recommendations mainly to the systems used by the
manufacturers of solid dosage forms laboratories. They also
it refers to other systems or components that, although they are not
relevant in solid form manufacturing plants, serve us
as a point of comparison between the requirements of these and others
systems.
The design of HVAC systems influences the architectural layout in
relation to certain elements such as the position of the air locks,
the entrances and the lobbies. The architectural components have
an effect on the differential pressure cascades and on the control of the
pollution. The most important consideration within the design of
HVAC systems are the prevention of pollution and contamination.
crusade. It is in view of these critical aspects that the design of
HVAC system must be considered from the concept stage
design of a pharmaceutical plant.
The conditions of temperature, relative humidity, and ventilation must
be appropriate, in such a way that they do not adversely affect the
quality of pharmaceutical products during their manufacturing and
storage, or the accuracy of the operation of the equipment.
This document aims to serve as a guide for manufacturers and
to the design inspectors of installations in the pharmaceutical industry.
These guidelines are intended to complement those provided.
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2.Scope of the document.

The guidelines described here focus mainly on design and
requirements for good manufacturing practices (GMP) of systems
HVAC for solid shape manufacturing facilities. Most
From the design principles applied to solid forms, it also
applied to other manufacturing facilities such as in the case of
liquid and semi-solid preparations or ointments. These regulations do not
they encompass the requirements for production plants of products
sterile pharmaceuticals.
These regulations aim to serve as a basic guide for the
BPM inspectors. They are not made with the purpose of serving as precepts.
in the specification of specific requirements or parameters of
design. There are many parameters that affect the conditions of an area
clean, and it is therefore very difficult to determine the requirements
specific for a particular parameter separately.
Many manufacturers have their own design engineering, in addition to the
grading standards and their requirements may vary from one
manufacturer to another. The design parameters must therefore
to establish realistically for each project, with a view to the
creation of a cost-effective design that is maintained according to the
regulatory standards and ensure the quality and safety of the product.
are not affected.
The three main aspects mentioned in this manual are the
functions that HVAC systems fulfill in protection of the
product, personal protection and environmental protection (see Figure 1).
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CONDITIONALS

Protection of Protection of Protection

product personal environmental

Pollution Prevent contact Avoid download of

(Product and Personnel) with the dust dust

Protect from the Prevent contact Avoid download of

with the smoke/gas gases
Pollution
crusade
Conditions
acceptable of Avoid downloading
Correct temperature and effluents
humidity comfort

Systems

System validation

3. GLOSSARY
The definitions given below apply to terms used in
these guidelines. Each of them can have different meanings
depending on the context.

Acceptance criteria
Measurement term under which the result of a test will be
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Air treatment unitAir-handling unit

The air handling unit (AHU,by its initials in Englishit is used for
condition the air and provide the required displacement of it within
a facility.

Excludedairlock
It is an open space with two or more doors, that is situated between two or
more rooms; for example, of different degrees of cleanliness, with the purpose of
control the airflow between these when it is necessary to enter one of them
They. A lock is designed to be used by both people and for
materials (People lock, PAL, and material lock, MAL).

Alert limit.
The alert limit is reached when the normal operating range of a
critical parameter has been exceeded, this limit indicates that is needed
take corrective measures to avoid reaching the action limit.

As-built
Condition where the installation is complete, with all services.
installed and working but without the presence of production equipment,
materials or personnel.

At rest.
Condition where the installation is complete, with equipment installed and
operating in the manner anticipated by the client and the supplier,
but without the presence of personnel.

Central air handling unit (see air-handling unit)

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the necessary actions that could ensure that the system remains in
a validated state.

Clean area (clean room)

It is an area (or room) with a defined environmental control regarding particles and
microbial contamination; it is built and used in such a way that it is reduced
the introduction, generation, and retention of pollutants within it.

Start-up
Commissioning
The startup orCommissioningit is the documented process of
verification that the equipment and systems are installed according to the
specifications, putting the equipment into active service and verifying its
actions proper to themselves. Thecommissioningis carried out at the end of the
construction project but prior to validation.

Containment
It is a process or mechanism to contain a product, powder, or contaminants.
in a specific area, preventing its escape to another area.

Pollution
It is the unwanted entry of impurities, whether of a chemical nature or
microbiological, or of a foreign substance, inside or on the raw materials,
intermediate products, during production, sampling, packaging or re-
packaging, storage or transportation.

Critical parameters or components

It is a parameter of processes (such as temperature or humidity) that affect
 8

Design conditions
The design conditions relate to a specific range or to accuracy.
of a variable controlled by the designer, as well as a base for
determine the performance requirements of an engineering system.

Design Quality Rating (DQ)

The design qualification (DQ) is the review
documented plans and technical specifications to ensure compliance
of the design concerning the process, manufacturing and regulations of the good
manufacturing practices.

Direct impact systems

It is a system that is expected to have a direct impact on quality of the
product. These systems are designed and implemented online, within
of good engineering practices (GEP; for its acronym in English) and,
they are also subject to grading practices.

Installation.
It is an area of the building within which the cleanroom installation and the
control of the environmental conditions operate together through a
support infrastructure.

Good practices of Engineering

(GEP, for its initials in English)
They are established standards and methods that are applied throughout the life cycle.
from an engineering project to adequately achieve cost solutions
effective.
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Infiltration
Infiltration is the entry of contaminated air coming from an area.
external towards a clean area.

Installation rating(IQ)
The installation qualification (IQ) is the verification
documented that the premises, support systems, and equipment have been
constructed and installed according to the design specifications
previously approved.

Impact-free system
(no-impact system)
It is a system that has no direct or indirect impact on the quality of
product. These systems are designed and implemented following the
GEP standards.

Non-critical parameters or components

It is a process parameter or component within the system where the
operation contact, data control, the alarm or failure will have an impact
indirect or none about the quality of the product.

Normal operating range

It is the range that manufacturers select as an acceptable value for
certain parameters during their normal operations. This range must
to be within the operating range.

Operation limits
They are the minimum and/or maximum values that will ensure the achievement of
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Operational condition
This condition refers to carrying out the area classification tests.
within a normal production process, with the equipment operating and the
operational staff present.

Operation rating (OQ)

The Operational Qualification (OQ) is the evidence
verified documentation that the equipment operates in accordance with
design specifications, within their normal operating ranges and that
performs as expected throughout the entire operating range
previously determined.

Oral dosage in solid form (OSD)

It usually refers to a drug manufacturing plant.
solid for oral dosage (OSD, for its acronym in English), for example
tablets, capsules, and powders that are administered orally.

Performance rating(PQ)
Performance qualification (PQ) is the evidence
documented verification that the procedure and/or the total processes
related to the system function as expected, within the range of
previously determined operation.

Extraction point
Air extraction to remove dust, whose extraction point is located
as close as possible to the source of the dust.

Pressure cascade
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Rating.
Assessment is the planning, execution, and recording of the tests conducted.
to the team and system, which is part of the validation process, in order to
demonstrate that this will perform as expected.

Relative humidity.
It is the relationship between the vapor pressure of water in the air and the saturated pressure.
of the water vapor in the air at the same temperature, expressed as a percentage.
More simply, it is the relationship of the mass of water in the air, regarding
the mass at 100% saturation, at a certain temperature.

Standard Operating Procedure(SOP)

It is a written and authorized procedure that provides instructions for the
development of operations, not necessarily specific to a certain
product or material, but in a general way (example: operation of a equipment,
maintenance and cleaning, validation, cleaning of rooms and environmental control,
sampling and inspection). Certain procedures can be used to
complementing the master's degree of a specific product and the documentation of a
production batch.

Turbulent flow
Turbulent flow or non-unidirectional air flow is the distribution of air that
is introduced into a controlled space and then mixed with the air of the
environment through induction.

Unidirectional airflow
(UDAF, for its English acronym )
The unidirectional airflow is a rectified airflow that falls at speed
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Validation.
It is the documented act of demonstrating that any procedure,
process, team, material, activity or system, really leads to results
expected.

Master validation plan (VMP).

The master validation plan (MVP) is a document
high-level, which establishes a comprehensive validation plan for everything
project, and it is used as a guide by the project team as a source and
technical planning (also known as master grading plan).

4. Protection

4.1. Product and staff

4.1.1. The areas of pharmaceutical product manufacturing, where the
raw materials or inputs and products, utensils and equipment are
exposed to the environment, must be classified as 'clean area'.

4.1.2. The classification determination of the clean area depends on a

number of critical criteria that must be considered in the stages of
design and qualification. An appropriate balance will be required between the
different criteria in order to create an efficient clean area.

4.1.3. Some of the basic criteria to be considered must include:

- Finishes and structure of the building.
- Air filtration.
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- The processes that are carried out.

- Air conditions outside.
- Capacity
- Type of product.

4.1.4. The air filtration and the number of air changes must ensure
that the defined clean area classification is achieved.

4.1.5. The number of air changes per hour must be determined by

the manufacturer and the designer, taking into account the variables of the
critical parameters. Mainly, the number of air changes
It should be established at the level that achieves clean room classification.
requested.

4.1.6. The number of air changes usually varies between 6 and 20.
air changes per hour and is normally determined under the
following considerations:
- Required level of protection.
- The quality and filtration of the air supply.
- Particles generated by manufacturing processes.
- Particles generated by the operators.
- Room setup, air supply, and location of the
extractors
- The sufficient air to achieve the containment effect.
- The air sufficient to face the hot load of the area.
- The sufficient air to maintain the required pressure of the room.

4.1.7. In the classification of environments, the manufacturer must establish whether

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4.1.9.The area classification tests in conditionat-restthey must

to be carried out with the teams in operation, when relevant,
but without the presence of operators. Due to the amount of dust that
it is generated in a solid forms manufacturing facility, great
part of the area classifications are estimated based on the
conditionat-rest

4.1.10. The classification tests of areas in condition

“operationalmust be carried out during the normal manufacturing process,
with the teams operating and the usual number of people present
in the room. Generally a room that is tested under condition
"operational" should be able to be cleaned until a clean room is achieved.
of classificationat restafter a short cleaning period. The
cleaning time must be determined through validation and it is
generally around 20 minutes.

4.1.11. Materials and products must be protected from the

pollution and cross-contamination during all stages of
the manufacturing (see also section 5.5. for the control of the
cross-contamination)
Note: Pollutants can come from inappropriate locations
bad (e.g.: due to poor design, distribution, or finish)
cleaning procedures, contaminants coming from the personnel and
due to an inadequate HVAC system.

4.1.12. Air pollutants must be controlled through a

effective ventilation system.
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Table 1
Examples of levels of protection

Level Condition Example of area

Level 1 General Normal cleaning and maintenance area. For
example: warehouse, secondary packaging.
Level 2 Protected Area where measures are taken to protect
the input or pharmaceutical product exposed from the
pollution or degradation. For example: areas
manufacturing, primary packaging, dispensing.
Level 3 Controlled area where environmental conditions are
defined, they are also controlled and
monitored to prevent pollution or
degradation of the raw material or product
pharmaceutical.

Table 2
Recommended levels of protection and filtration

Level of protection Recommended filtration

Level 1 Primary filters only (example: filters of
class EN779 G4
Level 2 and 3 Manufacturing facilities operating at 100%
from outside air: primary filters plus filters
secondary (for example: classification filters)
EN779 G4 and F8
Level 2 and 3 Manufacturing facility operating with air
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4.1.14. Internal contaminants must be controlled by dilution or

(flushingwashing of contaminants in the area, or by displacement of
air flow (see figures 6 and 7: Examples of elimination methods
airborne pollutants.

4.1.15. The particles transported in the air and the degree of filtration
critical parameters must be considered with reference to the degree of
protection that the product requires.

4.1.16. The level of air protection and cleanliness for the different
areas should be determined according to the product that will be manufactured, the
process to be used and the susceptibility of the product to degradation.

4.2. Air Filtration.

Note: the air filtration degree plays an important role in the
prevention of pollution and control of cross-contamination.

4.2.1. The type of filter required for different applications

it depends on the quality of the ambient air and the return air (where
is applicable) and also the number of air changes. The table
Number 2 shows the recommended filtration levels for different
protection grades in a pharmaceutical laboratory. The manufacturers
they must determine and test the use of the appropriate filters.

4.2.2. The classification of the filter must always be related to

standardized testing methods, as they refer to the
real efficiency of the filter, which can be very misleading (according to different
 17

of the product. Good pre-filtration extends the lifespan of the filters

more expensive posters.

4.2.4. The type of material for the components of an HVAC system is

must be carefully selected so that they do not
become a source of pollution. Any component with the
potential to release particles or microbial contamination within the
Airflow must be located before reaching the final filters.

4.2.5. The ventilation regulators, filters, and other services must be

designed and located so that they are accessible from outside
the manufacturing areas (in the cavities or service corridors)
for maintenance purposes.

4.2.6. Personnel must not be a source of contamination.

4.2.7. The directional airflow within the production areas or

Packaging should help in the prevention of pollution. It should
jointly plan the airflow and the operator's location, so that
so that the product contamination by the operator is minimized and
the operator is also protected from inhaling dust.

4.2.8. The components of the HVAC system for air distribution are
they must design, install, and locate to prevent contaminants
generated in the area are scattered.

4.2.9. High induction type air supply diffusers

(example: those commonly used in air conditioning)
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4.2.10. Whenever possible, the air in the rooms should be

expelled from a low level to help achieve the effect of
washing(flushing effect).

4.3. Unidirectional airflow.

4.3.1. The unidirectional airflow (UDAF, for its acronym in English) is

should be used when it is necessary to protect the product by means of the
supply of clean air over this, so that
minimize the entry of pollutants from the area
surrounding.

4.3.2. When appropriate, the unidirectional flow must protect the

pollution operator from the product.

4.3.3. The sampling of raw materials, packaging materials and

intermediate products must be carried out under the same conditions
environmental requirements for the other processing stages of
product.

4.3.4. Within the installation of a weighing cabin, the objective of the

design using UDAF must ensure dust containment.

4.3.5. A dispensary or weighing booth must be equipped with a flow

from unidirectional air for the protection of the product and the operator.
 19

time protects the product from contamination by the operator by

in the middle of a vertical unidirectional airflow.

4.3.7. The speed of the unidirectional flow must be such that it does not affect the
sensitivity of scales in the weighing area. Whenever it is
necessary, the speed can be reduced to prevent failures in the
accuracy during the weighing process, ensuring sufficient flow of
air to maintain dust containment.

4.3.8. The location of the personnel must be determined in advance.

operator in relation to the dust release source and the airflow
to ensure that the operator does not interrupt the trajectory of the flow of
air, which could lead to product contamination (see
figure 13).

4.3.9. Once the system has been designed and qualified with a
specific distribution for operators and processes, these must
maintain according to a standard operating procedure

4.3.10. There should be no obstructions in the current path.

of air with unidirectional flow, that may cause the personnel
worker is exposed to dust.
Figure 14 shows the incorrect use of a back scale.
solid. The backrest of the scale should not block the path of
return of the air that causes the air to rise vertically, resulting in
resulting in a dangerous situation for the operator.
Figure 15 shows us a situation where an open container is
Place under a vertical unidirectional flow distributor. It must be
 20

have holes of 100mm between the backrest of the work table and the
pared, so that air can be extracted from there.

4.3.11. The manufacturer must select either a unidirectional flow.

vertical or horizontal (see fig. 17), and an appropriate pattern of the flow of
air to provide the best protection in specific applications.

4.4. Infiltration.

4.4.1 The infiltration of air or unfiltered air inside a plant

pharmaceuticals should not be a source of contamination.

4.4.2 The manufacturing facilities must be maintained with a

positive pressure with respect to the outdoors to limit the ingress of
pollutants. Special precautions should be taken when the
installations have a negative pressure relative to the pressure of the
environment to prevent the escape of hazardous products into the
exterior (such as penicillin and hormones).

4.4.3 The location of negative pressure facilities must be

carefully considered with reference to the surrounding areas to
she should be given special attention to ensure that the structure
The building is well sealed.

4.4.4 Negative pressure zones should, as far as possible,

to be encapsulated by surrounding areas with a supply of clean air,
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4.5. Cross-contamination

4.5.1. When different products are manufactured at the same time in

different areas or cubicles within a manufacturing plant for
solid dosage forms, measures must be taken to ensure
that dust does not move from one cubicle to another.

4.5.2. The correct directional movement of air and system of

pressure differentials can help prevent contamination
crusade. The pressure differential must be such that the direction of
air flow comes from the clean corridor to the cubicles,
resulting in the containment of dust.

4.5.3. The tires must be kept at higher pressures than in

the cubicles, and in the cubicles maintain a higher pressure with
regarding atmospheric pressure.

4.5.4. Containment is usually achieved through the application of the concept.

of displacement (low differential pressure, high air flow), or by the
concept of pressure differentials (high differential pressure, low flow)
of air), or the concept of physical barriers.

4.5.5. The pressure cascade system and the direction of air flow
It must be suitable for the product and the processing method used.

4.5.6. High-power products must be manufactured under a

negative pressure cascade regime with respect to pressure
atmospheric.
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4.5.8. The structure of the building must pay special attention to

adapt the design of pressure cascades.

4.5.9. Airtight ceilings and walls, tight-closing doors and lights

A hermetic seal must be placed in the location.

Concept of displacement (low differential pressure, high flow)

air
Note: this containment method is not the preferred method, as the
measurement and monitoring of air flow velocity in the channels of
entry is difficult. This concept should ideally be applied in the
production processes where large amounts of dust are generated.

4.5.10. Under this concept, air must be supplied to the corridor,

flow from the entrance and be extracted from the back of the
cubicle. Normally the cubicle door should be closed and the
air entering the cubicle through the door grille, although the concept
it can be applied to an open cubicle without a door.

4.5.11. The speed must be high enough to prevent the

turbulence inside the entrance that may cause the escape of the
dust.

4.5.12. The airflow displacement must be calculated as the

product of the area of the door and the speed, which generally
results in large amounts of air.

Concept of pressure differentials (high differential pressure, low

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4.5.13. The differential pressure between clean and less clean areas
it should be generated by leakage through the empty spaces(gaps)
behind the closed doors of the cubicles.

4.5.14. The differential pressure must be of a sufficient magnitude to

ensure containment and prevent reverse flow, but it should not be
as high as to create turbulence problems.

4.5.15. When considering the pressure differentials in the room, it must be taken into account

consider the transitional variations such as the extraction systems.

Note. The most widely accepted differential pressure to achieve the
the containment between two adjacent zones is 15 Pascal, but also
Differential pressures between 5 Pa and 20 Pa can be acceptable.
When the differential pressure design is very low and the tolerances
they are at opposite extremes, it is possible that the inversion takes place
flow. For example, where a tolerance control of + is specified
3Pa, the implications of the containment tolerances must be evaluated.
maximums and minimums.

4.5.16. The differential pressure between adjacent rooms is due to

consider as a critical parameter, depending on the result of
risk analysis. The limits for the differential pressure between areas
adjacent must be such that there is no risk of overlap or
value coincidence, example: in a room with 5Pa at 15Pa and in the
adjacent room from 15Pa to 30Pa does not result in a cascade of
pressure, as in the first quarter it is at the maximum tolerance and in
the second quarter is at the minimum tolerance.
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4.5.19. The control devices must be calibrated and qualified.

pressure maintenance that are used. According to the specifications
it must be verified and recorded regularly the results. The
pressure control mechanisms must be connected to a system
the fixed alarms according to the levels determined by the
risk analysis.

4.5.20. Wherever a manual control system is employed, it must

pay attention during the startup phase (commissioning) and no
It must change unless other conditions of the system change.

4.5.21. The locks can be important components for

establish and maintain pressure cascade systems.

4.5.22. The locks with different pressure cascade regimes

includes: cascade exclusion, in fall and bubble type (see fig.19 and 21)
Cascade lock: High pressure on one side of the lock and low pressure on the other.

pressure on the other.

Lock in fall: Low pressure on one side of the lock and high pressure
on both outer sides.
Bubble-type lock: High pressure inside the lock and low pressure
on both external sides.

4.5.23. Doors must open toward the side of higher pressure, and
they must have automatic closing devices. The door closers of
springs should be designed to keep the doors closed and
prevent the pressure difference from pushing the door open.
 25

4.5.25. Pressure differentials in the room must be prevented between the

adjacent cubicles that are connected by a common duct of
dust extraction.

4.5.26. Through dust extraction ducts, air should not flow

from the area of higher pressure to the area of lower pressure (this
it could normally occur only if the dust extraction system does not
it was operational.)

Concept of physical barriers

4.5.27. A waterproof barrier should be used when necessary.
to prevent cross-contamination between two areas, for example
an insulating barrier or through transfer of vented materials or
inflated.

4.5.28. The ventilation points or the capture covers (caps)

they must be used appropriately.

4.6. Temperature and relative humidity.

4.6.1. When relevant, it should be controlled, monitored, and recorded.
temperature and relative humidity to ensure compliance with the
relevant requirements for materials and products, and when applicable
necessary to provide comfortable environmental conditions to
operator.

4.6.2. The maximum and minimum temperature and relative humidity inside
 26

4.6.4. The operating range or tolerance between the minimum temperature

acceptable and the maximum should not be too tight.

4.6.5. The cubicles or rooms where the product requires low

Humidity for their process must have walls and ceilings.
hermetic, they must also be separated from adjacent high areas
humidity through appropriate sluices.

4.6.6. Precautions must be taken to prevent migration of

humidity that increases the load on the HVAC system.

4.6.7. Humidity control should be achieved by removal of

humidity of the air, or addition of humidity to the air, as applicable.

4.6.8. Dehumidification (removal of moisture) can be achieved already

by means of refrigerated or chemical dehumidifiers.

4.6.9. Appropriate cooling methods must be used to

dehumidify the environment, such as low temperature, frost mix
of water and polyethylene glycol or coolants.

4.6.10. As much as possible, humidifiers should be avoided.

turn into a source of pollution (Example: in growth
bacterial). When the use of humidifiers is required, this must be
achieve by appropriate means such as steam injection in the
air current. An assessment of the pollution must be made
product to determine whether clean steam or pure steam is required for
purposes of humidification.
 27

4.6.12. The humidification systems must be drained well. Inside the

The air handling system should not accumulate condensates.

4.6.13. Other humidification devices, such as

evaporation systems and water sprinklers, due to the risk
potential for microbial contamination.

4.6.14. The material of the ducts in the surroundings del

humidiifier should not add pollutants to the air that could be
subsequently filtered in the current.

4.6.15. Air filters should not be installed immediately behind the

humidifiers.

4.6.16. Cold surfaces must be insulated to prevent

condensation inside the clean area or on the components of the unit
air handler.

4.6.17. Where a relative humidity is specified, it must

also specify the associated temperature.

4.6.18. Chemical desiccators that use silica gel or lithium chloride

are acceptable, as long as they do not become sources of
pollution.

5. Dust control.
 28

5.2. The extraction at the point of use must be either in the form of
high-speed extraction fixed point or an articulated arm with
movable cap or fixed extraction cap.

5.3. The dust extraction ducts must be designed to

a sufficient transfer speed, so that the dust is
taken outside and does not settle in the ducts.

5.4. The required transfer speed must be determined: it

it depends on the density of the dust (the thicker the dust is)
the transfer speed should be higher, for example 15-20
m/s.

5.5. The direction of the airflow must be carefully

selected, to ensure that the operator does not contaminate the product and
so that the operator is not at risk due to the product.

5.6. The hazards caused by dust that must be assessed

operators may be subject. A type analysis must be done
of dust and its toxicity; the direction of the airflow must
determine as it corresponds.

5.7. Usually a single extraction point is not enough to

capture all pollutants, and the airflow should be used
general guidance to help extract dust and vapors
from the room.

5.8. Normally, in an operating room with an airflow

 29

strategically locate to carry the air away from the operator, but to
at the same time protect the operator from contamination by the product.

5.10. In the planning of the vapor extraction system, it should be

take into account the density of the vapor. If the vapor is lighter than the
air, the extraction grille should be at a high level or possibly in
both high and low levels.

5.11. When handling particularly harmful products, it is necessary to

use additional protective measures such as handling products with
gloves or using barrier isolation technology.

5.12. When working with exposed products such as hormones or

highly potent products. Operators must wear clothing
totally closed, as indicated in figure 22. The operators only
they must be equipped with a breathing system that provides them
filtered air conditioning. The air of this type is normally due to
supply through an air compressor. It must be controlled the
filtration, temperature, and humidity to ensure safety and
operator comfort.

5.13. The average number of times fresh air is supplied to the

installation must comply with national regulations,
regional and international, to provide workers with levels
acceptable levels of comfort and safety and also remove odors and fumes.

5.14. The number of air changes must be determined by exhaust.

leakageof the building for pressure control purposes.
 30

6.1.1. The air discharge points in equipment

pharmaceuticals and facilities, such as fluid bed dryers, and
tablet coating equipment, and the air expelled by the
dust extraction systems can carry very heavy loads, so
that must be properly filtered to prevent contamination
of the environment.

6.1.2. When it comes to powders that are not highly potent, the
final filters in the dust expulsion system must be filters of
fine powder with an F9 classification, in accordance with the EN779 standard.

6.1.3. Where hazardous substances such as penicillins are manufactured

hormones, toxic powders and enzymes, the final filters must be filters
HEPA and at least classification H12 according to the standard
EN1822 for filters, as appropriate

6.1.4. For discharge systems where the polluting discharge

is considered particularly dangerous, it will be necessary to install two
HEPA filter stations in series, to provide additional protection
in case of a possible failure of the first filter.

6.1.5. When handling hazardous compounds, they must be used

safe exchange filter housings, also called filters bag
in-bag-out.

6.1.6. All filter banks must have pressure indicators

differential in order to indicate the dust load of the filter.
 31

to dust to pass through the filtering medium or cause it to burst, giving

as a result of environmental pollution.

6.1.9. Sophisticated monitoring systems can be installed based on

on computers, with which preventive maintenance is planned
through trend tracking (these types of systems commonly
known as building management system (BMS, for its initials)
building automation system (BAS, for its initials)
in English), or the data acquisition and supervisory control system
(SCADA, for its acronym in English).

6.1.10. An automated monitoring system must be able to

indicate without delay any condition that is outside of
specification, either through an alarm or similar system.

6.1.11. When using dust collectors with automated system

cleaning ("reverse-pulse"), to remove dust from the systems of
air extraction, these usually must have filter cartridges
containing a compressed air launcher and must be able to
to operate continuously and without interrupting the airflow.

6.1.12. The alternative types of dust collectors (such as those that

they work with a mechanical stirrer, require the fan to be turned off
when the agitator is activated) they should be used in such a way that there is no
risk of cross contamination. There should be no interruption of the flow
of air during the production process as the decrease or
Airflow loss can interrupt the cascading pressure.
 32

6.1.15. The quality of the expelled air must be determined to see if the
filtration efficiency is suitable with all types of collectors
dust and wet scrubbers.

6.1.16. When necessary, filtration must be carried out.

additional in the direction of the dust collector current.

6.2. Gas extraction.

6.2.1. The systems for gases, powders, and emission control must
designed, installed, and operated in such a way that they do not become a
possible source of contamination or cross-contamination. For example:
the air discharge point located near the entrance of
fresh air from the HVAC system.

6.2.2. The gases must be extracted through wet scrubbers or

chemicals (multiple bed purifiers)deep-bed scrubbers).

6.2.3. The wet scrubbers for gas extraction,

they normally require the addition of several chemicals to the water to
increase adsorption efficiency.

6.2.4. Multi-bed purifiers ( Deep-bed scrubbers they must

designed with activated carbon filters or granular chemicals of
medium adsorption. The chemical medium for these purifiers must be
specific to the effluent to be treated.
 33

7. Systems and components.

Note: The level of air cleanliness required in most
oral solid dosage (OSD) manufacturing facilities are achieved
usually without the use of high-efficiency filters (HEPA, for its acronym
in English) as long as the air is not recirculated. Many open areas
product in OSD facilities are capable of reaching the
classification 8 of ISO 14644-1, in condition " at rest, measured against
particles of between 0.5ųm y 5ųbut the cleaning cannot be
classified as such by the manufacturers.

7.1. General.
7.1.1. There should be no failures in the air supply fan, for
the return air, for the expelled air or for the extraction system of
air. Faults can cause an imbalance in the system, leading to
a malfunction of the pressure cascade with a reverse flow of
air as a result.

7.1.2. Figure 23 shows a schematic diagram of the flow.

of air for a typical service system in a low humidity room.

7.1.3. The air should be dried with a chemical desiccant (for example: the
rotary desiccant that is continuously regenerated by
the passage of hot air through a segment of the wheel.

7.1.4. The figure illustrates part of the chemical drying process of the air
fresh air return in a flow deviation. The location of
Chemical desiccant should be considered in the design phase. Examples of
 34

7.1.5. The additional components that may be

requirements must be considered depending on the conditions
climatic and location. These may include elements such as:
- Cooling coil over the fresh air intakes
very cold climates to preheat the air;
- Snow eliminators to prevent snow from entering the
air intakes and block the airflow.
- Dust removers at air intakes and locations
dusty.
- Dehumidifiers in wet areas with a lot of rain; and
- Fresh air pre-cooling serpentine for very climates
hot or humid.

7.1.6. Appropriate alarm systems should be installed to alert the

personnel in case of critical ventilation failures.

They are usually preferred low-level returns or grids for

air expulsion. However, when this is not possible, a number
higher air change rates per hour may be necessary to achieve a
specific classification of clean area. For example: when used
air return grilles in the ceiling.

7.1.8. There may be alternative locations for air return.

example, figure 24 referring to room D (low air return
level) and room E (air return in the ceiling).
The schematic airflow of the two systems (see figures 24 and 25)
indicates an air handling unit with air return or air
recirculated, with a percentage of fresh air added. Figure 25
 35

Note: There are two basic concepts in air distribution for

pharmaceutical production facilities: a recirculation system, and
a loss air system or completely fresh (100% outside of the
air supply.

7.2. Recirculation system.

7.2.1. There should be no risk of contamination or cross-contamination.
(including those for gases and volatile compounds) due to the
air recirculation.

7.2.2. Depending on the airborne pollutants within the

air return system, the use of recirculated air can be accepted,
as long as HEPA filters are installed in the supply line
air to extract pollutants and thus prevent the
cross contamination. The HEPA filters for this application must
to have an H13 classification in the EN1822 scale.

7.2.3. HEPA filters may not be required when the system

air handler is being used in a manufacturing installation
exclusive and there is evidence that there will be no cross-contamination.

7.2.4. Air recirculation from areas where dust is not generated

pharmaceutical as in the secondary packaging area, it may not
require HEPA filters in the system.

7.2.5. HEPA filters can be located in the handling system

air or located terminally.
 36

7.3. Loss air systems(full fresh air system).

Figure 26 shows a system operating at 100% fresh air and it
would normally be used in a facility where products are handled
toxins, where the recirculation of air with contaminants should be avoided.

7.3.1. The required degree of filtration for the expelled air depends on
the pollutants present in it and the environmental regulations
locales.

7.3.2. Energy recovery rings should not normally be

use in facilities for multiple products. When such
rings are used, these should not become a source of possible
pollution (see figure 27). Note: In this type of facilities there
They can use alternatives, such as interchangeable connector plates.
heating or water coil heat exchangers.

7.3.3. Potential air leakage between the supply must be prevented.

air and the expelled air, when it passes through the ring. The pressure
the ratio between the supplied and extracted air must be such that the system
expelled air operates at lower pressure than the system of
supply.

8. Commissioning, qualification and

maintenance.
 37

by its initials in English), and the capacity specified by the designer or

development area.

8.1.2. The system installation records must document

evidence that all the system's capabilities have been measured.

8.1.3. The data must include elements such as design and figures of
measurement for air flows, water flows, system pressures and
electric currents. These should be included in the manuals of
operation and maintenance (O&M Manuals, for its acronym in English).

8.1.4. Acceptable tolerances must be specified for all

system parameters before starting the physical installation.

8.1.5. Training must be provided to the staff before the installation of

system and must include operation and maintenance.

8.1.6. The operation and maintenance manuals, schematics,

protocols and reports must be kept as documents of
reference for any future changes and improvements to the system.

8.1.7. The start-up orcommissioningmust be a precursor of the

system rating and validation process.

8.2. Rating.
 38

Manufacturers must qualify HVAC systems using an approach

based on risks. The basic concepts of system qualification
HVAC is explained below.

8.2.2. The qualification of the HVAC system must be defined in the plan
validation master (VMP, for its initials in English).

8.2.3. The nature and scope of the tests must be defined, the
analysis procedures, and the protocols to follow.

8.2.4. The phases of the HVAC system qualification must include the
design qualifications (DQ), installation (IQ), operation (OQ) and
performance (PQ).

8.2.5. Critical and non-critical parameters must be determined by

through a risk analysis for all components of
HVAC system installation, subsystems and controls.

8.2.6. Any parameter that may affect product quality

pharmaceutical, or have a component of direct impact, must be
considered as a critical parameter.

8.2.7. All critical parameters must be included in the

classification of processes.
Note: A realistic approach is required to differentiate between a
critical and non-critical parameter, thus avoiding that the validation process is
make it unnecessarily complex.
Example:
 39

the controlled humidity air is even more extracted from

the product and may not require an operational qualification.
The cleanliness classification of a room is a critical parameter and, therefore,
both the number of air changes and HEPA filters must be parameters
critical and require qualification. Elements like the fan
airflow generator and the primary and secondary filters are
non-critical parameters and may not require a qualification of
operation.

8.2.8. Non-critical systems and components must be subject to the

Good Engineering Practices (GEP, for its acronym in English) and not
necessarily require grading.

8.2.9. A change control procedure must be followed when

it is expected that the change made will have a direct impact on the
HVAC system or how its components and controls can affect the
critical parameters.

8.2.10. The acceptance criteria and limits must be defined during

the design stage.

8.2.11. The manufacturer must define the design conditions, the ranges
of normal operation, the operating ranges and limits of action and
alert.

8.2.12. The design conditions and normal operating ranges are

they must identify and realistically set as parameters
achievable.
 40

8.2.14. Results outside the limit must be recorded (for example:

deviations from action limits) and must be part of the record of the
manufacturing batch.

8.2.15. The relationships between design conditions, ranges of

qualified acceptance criteria and operation are shown in the figure
29.

8.2.16. A narrow range of relative humidity is unacceptable along with

a wide range of temperature as temperature changes
would automatically cause variations in relative humidity.

8.2.17. For a pharmaceutical installation, based on analysis of

risks, some of the typical parameters of the HVAC system to qualify
include:
- Temperature
- Relative humidity
- Air supply quantity for all diffusers
- Amount of return air or expelled air
- Number of air changes
- Room pressure (pressure differentials)
- Airflow patterns in the room
- Unidirectional flow velocity
- Speed of the containment system
- HEPA filter penetration tests
- Particle counting
- Cleaning frequency
 41

8.2.18. The maximum time interval between tests must be defined by

the manufacturer. The type of installation to be analyzed and the
product protection level.
Note:Table 3 shows intervals for reference purposes
only. The real test intervals should be more frequent or
less frequent, depending on the product and the process.

Periodic reassessment of the parameters should be carried out at

regular intervals, for example annually.

8.2.20. The reclassification should also be carried out when it occurs

any change that may affect the system performance.

8.2.21. The cleaning or recovery times are normally

they relate to the time it takes to clean the room from a condition
to another; for example, the relationship between the "at-rest" conditions and
"operational" in the clean area can be used as a criterion for the
cleaning tests. Therefore, the cleaning time may be
expressed as the time it takes to change from one condition
operational to a condition at-rest.

8.3. Maintenance.

A preventive maintenance program should be planned,

procedures and records for the HVAC system. They must be maintained.
the records of maintenance performed.
 42

8.3.4. Any maintenance activity must be assessed for

critical way to determine any impact on the quality of
product, including possible contamination.

8.3.5. Maintenance activities must be scheduled to

to be carried out outside of production hours, and any obstruction
it should be assessed with a view to a possible reclassification of the area as
result of a service interruption.

Table 3.
Section A: Test programming to demonstrate compliance.
(For reference only)
Testing schedule to demonstrate continued compliance
Essay Classif. Area Max interval. Procedure
Counting of All classes 6 months The counting of particles must be carried out.
particles of dust and print the results.
verification of Number of readings and locations of the
cleaning test, according to ISO14644-1 Annex B.
Difference of All classes 12 The pressure readings log
air pressures months differentials produced in plants
verification of daily criticisms, preferably
absence of continuation. A recommendation is made for a

pollution pressure differential of 15 Pascal

crusade between different zones.
According to the ISO146644-3 standard
Annex B5
Flow volume ofAll classes 12 Air flow readings are measured from
air months supply and return through the grilles and
(Verification of the number of changes is calculated
number of changes air.