1. Air Handling Systems
Heating
Ventilation and
Air Conditioning (HVAC)
Part 2: Components
Supplementary Training Modules
on GMP
Module 3, Part 2: Components Slide 1 of 20 WHO - EDM
2. Module 3, Part 2: Components Slide 2 of 20 WHO - EDM
Air Handling Systems
Purpose of an air handling system
Air Handling
System
Production Room
With
Defined
Requirements
Supply
Air
Outlet
Air
3. Module 3, Part 2: Components Slide 3 of 20 WHO - EDM
Air Handling Systems
Objectives
In the following slides, we will study the components of air
handling systems in order to:
1. become familiar with the components
2. know their functions
3. become aware of possible problems
4. Module 3, Part 2: Components Slide 4 of 20 WHO - EDM
Air Handling Systems
+
Production Room
Exhaust air treatment
Central air handling unit
Terminal air treatment
at production room level
Fresh air treatment
(make-up air)
Main subsystems
5. Module 3, Part 2: Components Slide 5 of 20 WHO - EDM
Air Handling Systems
Filter
Silencer
Terminal filter
Weather louvre Control damper
Fan
Flow rate controller
Humidifier
Heating
coil
Cooling coil
with droplet
separator
Production Room
Overview components
+
Prefilter
Exhaust Air Grille
Heater
Secondary Filter
Re-circulated air
6. Module 3, Part 2: Components Slide 6 of 20 WHO - EDM
Air Handling Systems
Weather louvre
Silencer
Flow rate controller
Control damper
To prevent insects, leaves, dirt and
rain from entering
To reduce noise caused by air
circulation
Automated adjustment of volume of
air (night and day, pressure control)
Fixed adjustment of volume of air
Components (1)
7. Module 3, Part 2: Components Slide 7 of 20 WHO - EDM
Air Handling Systems
Heating unit
Cooling unit
/dehumidifier
Humidifier
Filters
Ducts
To heat the air to the proper temperature
To cool the air to the required temperature
or to remove moisture from the air
To bring the air to the proper humidity, if
too low
To eliminate particles of pre-determined
dimensions and/or micro-organisms
To transport the air
Components (2)
8. Module 3, Part 2: Components Slide 8 of 20 WHO - EDM
Air Handling Systems
Flow rate controller
Control damper
Humidifier
Cooling battery
Filters
Ducts
Blocked
Poorly adjusted, bad pressure differential system
Bad water/steam quality/poor drainage
No elimination of condensed water/poor drainage
Incorrect retention rate/damaged/badly installed
Inappropriate material/internal insulator
leaking
Problems with components
9. Module 3, Part 2: Components Slide 9 of 20 WHO - EDM
Air Handling Systems
+
Production Room
Exhaust
air
Return air
(re-circulated)
Fresh air
(make-up air)
Supply
air
Air types
10. Module 3, Part 2: Components Slide 10 of 20 WHO - EDM
Air Handling Systems
Particles / m3
0.5µm
US 209D
non-
metric
US 209E
1992
metric
EC cGMP
Annex I
1997
Germany
VDI 2083
1990
UK
BS 5295
1989
Japan
JIS B 9920
1989
ISO 14644-
1
1
3,5 0 2 2
10 M 1
35 1 M 1.5 1 3 3
100 M 2
353 10 M 2.5 2 4 4
1.000 M 3
3.530 100 M 3.5 A, B
A= unidirectional
B= turbulent
3 E or F 5 5
10.000 M 4
35.300 1.000 M 4.5 4 G or H 6 6
100.000 M 5
353.000 10.000 M 5.5 C 5 J 7 7
1.000.000 M 6
3.530.000 100.000 M 6.5 D 6 K 8 8
10.000.000 M 7
Comparing International Cleanroom Classifications
11. Module 3, Part 2: Components Slide 11 of 20 WHO - EDM
Air Handling Systems
Filter classes Dust filters
Standard Aerosol
Fine
Coarse ULPA
HEPA
10 µ m > Dp > 1 µ m
Dp > 10 µ m Dp < 1 µ m
F5 - F9
G1 - G4 U 14- 17
H 11 - 13
EN 1822 Standard
EN 779 Standard
12. Module 3, Part 2: Components Slide 12 of 20 WHO - EDM
Air Handling Systems
Average Efficiency
Integral Value
Peak Arrestance
Local Value
Retention in
%
Penetration Efficiency Penetration
F9 85 0.15
H11 95 0.05
H12 99.5 5x10
-3
97.5 25x10
-3
H13 99.95 5x10
-4
99.75 25x10
-4
U14 99.995 5x10
-5
99.975 25x10
-5
Classification of filters according to their efficiency
13. Module 3, Part 2: Components Slide 13 of 20 WHO - EDM
Air Handling Systems
Primary panel filter
Secondary filter
HEPA or tertiaary filter
14. Module 3, Part 2: Components Slide 14 of 20 WHO - EDM
Air Handling Systems
Humidifier Silencer Heating and
cooling units
15. Module 3, Part 2: Components Slide 15 of 20 WHO - EDM
Air Handling Systems
Control damper for air flow
De-humidification
Filter Pressure
Gauges
AHU with fan Variable
Speed Controller
Humid room air
Air heater
Regeneration air
Humid room air
Adsorber wheel Dry air
Air handling unit
16. Module 3, Part 2: Components Slide 16 of 20 WHO - EDM
Air Handling Systems
Swirl Type air diffusors with
terminal filters
1 Filter
2 Tightening frame
3 Register outlet
4 Screw fixation for register
1
2
3
4
17. Module 3, Part 2: Components Slide 17 of 20 WHO - EDM
Air Handling Systems
Low induction
swirl diffusor
(preferred)
High induction
office type diffusor
(avoid)
18. Module 3, Part 2: Components Slide 18 of 20 WHO - EDM
Air Handling Systems
Annex 1, 17.26
Regulation of room pressure – pressure differentials concept
Room pressure
gauges
Room pressure indication panel
19. Module 3, Part 2: Components Slide 19 of 20 WHO - EDM
Air Handling Systems
Pressure cascade injectables
Protection from micro-organisms and particles
Note : Direction of door opening relative to room pressure
15 Pa
0 Pa
Air
Lock
30 Pa Passage
D
C
A
B
D
LF
Air Lock
Air Lock
45 Pa
Room 3
Room 2
Room 1
45 Pa
60 Pa
30 Pa
Annex 1, 17.24, 17.25
20. Module 3, Part 2: Components Slide 20 of 20 WHO - EDM
Air Handling Systems
Pressure cascade solids
Protection from cross-contamination
Note : Direction of door opening relative to room pressure
15Pa
15Pa
15Pa
E
30Pa
Passage
0Pa
Air
Lock
Room 3
Room 2
Room 1
15Pa
Air Lock
Air Lock
Editor's Notes
In the first part of this module, we have examined the purpose of cleanroom classes, and how the air handling systems constitute the main factor in reaching the requirements of the hygiene classes.
We now have to see how such systems are designed. However, in order to do this, we have to know what their components are, how they operate and what the risks associated with them are.
The suggested time for Part 2 is 45 - 60 minutes.
(Note for the trainer: the times noted are very approximate.)
You will recognize this picture from a previous slide, but we repeat it in order to emphasize the following:
An air handling system introduces pre-treated air, in order to provide a manufacturing environment with specified cleanliness, temperature and humidity in order to prevent product contamination and degradation. Air is then exhausted from the manufacturing environment.
Objectives:
For you, as inspectors, to be able to judge whether the air handling systems which you encounter during your factory inspections are adequate or not, it is necessary to know how such systems work, and to be aware of what problems may arise in terms of the components of the system.
Therefore, the objectives of this part of module 3 are to study the components of air handling systems in order to:
Become familiar with the components
Know their functions
Become aware of possible problems
To understand the air handling systems, it is necessary to know what their components are.
A conventional Air Handling System has 4 sub-systems:
1. Air handling of the incoming (fresh) air: elimination of coarse contaminants and protection from frost if necessary. In the case of air re-circulation, the fresh air is also called make-up air.
2. Central air handling unit (AHU), where the air will be conditioned (heated, cooled, humidified or de-humidified and filtered), and where fresh air and re-circulated air, if any, (indicated here by the dotted line) will be mixed.
3. Air handling in the rooms under consideration (pressure differential system, additional filtration, air distribution).
4. Air exhaust system (filtration).
Another way to look at an air handling system is to consider the different components and to know their function.
Some of the components, particularly the filters, are essential to ensure the quality of the air.
We will later consider individual components in detail.
Of course, a well-designed air handling system must not only be properly designed, but also properly installed, qualified and maintained (sealed ducts, tight filters).
(The trainer should make the audience aware that this slide is just an example, and that all components may not necessarily be present in each system.)
A typical HVAC unit consists of a small number of elements only.
It is important that these elements are compatible, properly installed, and fulfilling their goal.
Whereas a weather louvre and silencer are less critical elements, the components associated with the flow rate control are essential, as they allow adjustment of the air volumes supplied to the rooms, which in turn forms the base for a pressure differential concept: to have an automated or a fixed system is largely a financial matter, but a fixed system is more difficult to set up.
Silencer – check internal lining material of silencer as this can cause contamination.
Heating and cooling units (batteries), as well as humidifiers are used to adjust the climate in the room (temperature and humidity).
Special de-humidifiers, on a dessiccant base, will be addressed later.
Filters are one of the main components, as they determine the size of airborne particles that pass through them, and thus the hygiene class.
It is wise to protect the finer filters by pre-filters, thus extending their life cycles, and making them less prone to clogging.
Ducts transport the air from the air handling units to and from the rooms. Inspectors must verify that ducts do not have internal insulation as this is a great source of contamination.
Problems may arise with components, with the following consequences:
Flow rate controller Blocked No control of pressure differentials
Control damper Poorly adjusted Bad pressure differential systems
Humidifier Bad water/ Risks of microbial contamination
steam quality
Cooling Unit No elimination Risks of microbial contamination
of condensed water
Filters Incorrect retention Risks of contamination
rate (particles, micro-organisms)
Damaged Filter integrity fails
Badly installed Risks of contamination (particles, micro-organisms)
Ducts Inappropriate material Danger of corrosion
Leaking duct work Intake of unfiltered air
Internal insulation Inability to properly clean
There are different air types to be considered within the air handling system:
Fresh air (if the plant is of the re-circulation type, it is necessary to replace some of the re-circulating air with fresh air, which is then called make-up air).
A proportion of about 15% fresh air is normal, but this proportion can vary, depending on factors such as number of people, National Regulatory Authority requirements, the presence of certain substances in the air, leakage due to pressure control, etc.
Supply air to the rooms
Exhaust air from the rooms
Return air (about 85% is being re-circulated)
There are different norms for the number of particles in the air.
The table (refer to handout 3-2-10) shows that, for 0,5 micrometer particles, there are a number of names, those of the Federal Standard US 209 and the ISO guidelines being the most commonly in use at the moment.
However, in the years to come, the ISO nomenclature will be generally adopted.
The cleanroom classes for the pharmaceutical cleanrooms are highlighted in the table:
We can see for instance that a Cleanroom class of type A corresponds to
Non metric class 100 ( 100 particles / ft3 or 3.530 particles / m3)
Metric class 3,5 ( logarithmic calculation )
ISO class 5
The filtration efficacy depends on several mechanisms, and results in a rough filter classification.
The diagram shows the commonly used classification, with current abbreviations G = Gross, F= Fine, H= High, U= Ultra.
Filters are certified by the suppliers (challenge/efficiency test), but are often not properly installed or can be damaged. Leak tests (integrity tests), showing leakage of air through the filter itself or through its frame, therefore, have to be performed. Integrity tests are usually only carried out on the Aerosol filters (HEPA & ULPA).
Integrity or penetration testing is performed to detect leaks from the filter media, filter frame and seal. The challenge is a poly-dispersed aerosol usually composed of particles ranging in size from one to three microns. The test is done in place and the filter face is scanned with a photometer probe; the measured downstream leakage is taken as a percentage of the upstream challenge. Integrity tests should be carried out with filters installed in the system and should be carried out by an independent body (not the filter supplier).
The efficiency test, on the other hand, is used to determine the filter's rating. This test uses a mono-dispersed aerosol of 0.3 micron size particles, relates to filter media, and usually requires specialized equipment. Downstream readings represent an average over the entire filter surface. Therefore, leaks in a filter may not be detected by an efficiency test.
This table gives an idea of the efficiency of the filters, calculated across the entire surface (integral value) or in particular spots (local value).
Referring to filter ratings by percent efficiency is misleading, as there are so many different types of tests that give different efficiencies for the same filter. This can be very confusing and it is better to refer to the Committee of European Normalisation (EN) test rating i.e. G4, F8, H12, etc.
This slide shows
Primary Panel filters, which are used mainly for lower filtration efficiency or as pre-filters
Secondary filters, consisting of mini-pleated media or filter bags, and is used for higher filtration efficiency.
HEPA or tertiary filters, usually being the final filter in the system, providing the highest filtration efficiency.
Though there is a strong relationship between filter efficiency and cleanroom class, a filter of a high efficiency does not guarantee a high cleanroom class, as many other elements play a role, such as
Air flow (how the air is extracted, how well the room is “flushed”)
Air speed and number of air changes
Positions of air terminals
Layout and presence of objects
Personnel and clothing
Equipment (not all machines are designed to operate in a clean environment!)
Proper installation and proper maintenance
This slide shows additional elements of the air handling units.
For humidification purposes, especially in clean areas, high purity water should be used, to avoid contamination.
The silencer is not important from a GMP point of view, but from an environmental one, as ventilation units can be very noisy. Be sure that the silencers are manufactured of suitable materials as the linings of standard silencers can contaminate air with particulates.
Depending on the local legislation, the installation of silencers can be mandatory.
The cooling unit is important during the hot season. Be aware that stagnating water (condensed water) can bring bacterial growth, which can contaminate the filters, pass through them (depending on their retention properties) and end up contaminating production areas.
It is essential that there is no stagnating water. Cooling coils can be sanitized as well.
Do remember that, if filters are not properly maintained, micro-organisms may grow through the filters and be carried towards the production rooms.
Dampers to control pressure differentials are important. They can be automated or fixed. As filters get dirty the system pressure losses increase, and if airflow is not regulated, the flow decreases and pressure differentials change. This could cause flow reversal and cross-contamination. Variable speed drives for fan motors are also commonly used to control airflow.
In some cases, it is necessary to have very dry air for galenical reasons in certain rooms (production of effervescent tablets and humidity sensitive products in general).
To generate dry air, the air supplied to the production is passed over an adsorbant (silicagel, lithium chloride, etc.) where the humidity is removed from the air.
The adsorbant is then re-generated, on a continuous or on a batch-wise base.
The air flows into the rooms via so-called registers (diffusors), which are built and installed in such a way that the air is distributed evenly.
Machinery or furniture can block the passage of air from the register to the exhaust point, creating unflushed zones, where counts of particles and micro-organisms could be higher.
It is therefore important to consider the content of a clean room, when planning the HVAC system.
In many cases, the terminal filter panel and diffusors are incorporated into one unit.
It is also important that the air diffuser supplies air evenly and does not induce the circulation of dust in the room – as illustrated by the next slide.
The diffuser on the left is a normal office type diffuser which induces a lot of air to rise vertically from the floor towards the ceiling. The rising induced air has the potential for carrying a lot of dust upwards which is then spread throughout the room with the air supply. This type of diffuser readily spreads contaminants in the room and should be avoided.
The preferred type of diffuser for cleanroom applications is the swirl diffuser, or perforated plate diffuser. These types do not promote the spread of dust within the room.
One of the main points in the design of production rooms is the pressure differentials concept.
Pressure differentials must be defined, monitored and alarmed in critical cases.
The overpressure of each room is measured against a reference point in the factory (point zero). As discussed earlier, the pressure regulation can be fixed or automated. Pressure control can be by means of automatic air flow control dampers (as shown in slide 15) or by means of fan speed control. Whatever the means used it is important to ask the manufacturer how they ensure that the pressure cascade is maintained as the filters get dirty.
In the following slides, we are going to see that an overpressure concept can be very different for sterile products and for solid products.
This slide illustrates the pressure differential system in a sterile area where the overpressure is kept high in the rooms, mainly in the A/B class room, to prevent the entry of micro-organisms.
(The level of overpressure is reflected by the absolute pressure in Pascals).
To enter all rooms, it is necessary to go through airlocks.
In this particular example, the pressure differential in sterile areas is set up at 15 Pa between zones of different cleanliness, in accordance with FDA, EC and PIC/S regulations. Other values may apply in other regions.
It must be understood that high pressure differentials have an influence on the stability of building elements such as walls and doors.
Factory layouts must be carefully planned, in order not to have too high a pressure differential between entrance and exit of a sterilising or depyrogenating tunnel, as the air flow may significantly affect the temperature in a tunnel.
Pressure differentials must be constantly monitored.
The loss of overpressure in a filling room for injectables may mean the loss of the batches under production and the need for complete sanitation of the facility.
It is therefore essential that the systems are designed in such a way that there is no loss of overpressure in case of power loss (overpressure fan should be linked to emergency power grid).
This slide illustrates the pressure differential system in a solids area where the overpressure is kept high in the corridors, to prevent cross-contamination.
In this case, we are not too worried by the microbial contamination, but rather by dust coming out of rooms where process work is being done, and thus contaminating other rooms.
The entry into some rooms (containing dangerous products such as hormones, cytotoxics, low RH products or strongly coloured products) is protected by airlocks.
