HVAC Overview

HVAC
H-V-A-C
H-VAK
Pharmaceutical plant air quality
Management
Air Conditioning
www.pharmatechbd.blogspot.com
HVAC
H = Heating
V = Ventilation
A = Air
C = Conditioning
HVAC
What is HVAC?
Controlling components and parameters of air
Why?
As it has great effects on product quality
How?
By using AHU
HVAC
Definition
The simultaneous control of various
components and parameters of air to the
specific limit as required for the
manufacturing of quality medicine is
known as air conditioning.
Component of Air
Gases
Component
Quantity
Harmful Effects Examples
Nitrogen
78.02%
Oxygen
20.71%
Oxidation
Carbon dioxide
0.03%
Carboxylation
Argon
0.001%
Fe++ Fe+++
Component of Air
Solid
Component
Quantity Harmful Effects
Dust Particles
0.01%
Examples
Contamination
All products
Drug Particle
Cross Contamination
All products
Microorganism
Microbial contamination, Antacid &

Endotoxin contamination Sterile
Preparation
Component of Air
Liquid
Component
Quantity
Moisture
0-1.5%
Harmful
Examples
Effects
Hydrolysis,
Aspirin,
Dissolution,
Ranitidine
Microbial
growth
Parameters of Air
Component
Quantity Harmful Effects Examples
Temperature 30-400
C
Light
Pressure
Flow
Movement
Drug
Degradation,
Microbial
growth.
Photo
degradation
Contamination
Contamination
Contamination
Thermo labile
Drugs.
Vitamins,
Antibiotics.
Nimesulide
All products
All products
All products
Zone
Grade
Process
Particles
Limit
Air
change/hr
Filter
Aseptic filling in
final container
Class 100
40
HEPA
Background of
Zone A
Class 100
20
HEPA
Sterile solution
preparation
Class 10,000
20
HEPA
Dispensing of
starting materials
for products
terminally
sterilized.
Class 100,000
20
HEPA
Production and
packing of non
sterile products.
Class 100,000
EU 12
Secondary
packaging
Optically
Clean
EU 9
Warehousing, QC
Labs, General Area.
General Area
Depends
on heat
load
EU 6
Zone
Grade
Process
Particles
Limit(> 0.5
micron /M3
Air
change/hr
Filter
Aseptic filling in
final container
Class 100
40
HEPA
Background of
Zone A
Class 100
20
HEPA
Sterile solution
preparation
Class 10,000
20
HEPA
Dispensing of
starting materials
for products
terminally
sterilized.
Class 100,000
20
HEPA
Production and
packing of non
sterile products.
Class 100,000
Secondary
packaging
Optically
Clean
Warehousing, QC
Labs, General Area.
General Area
Depends
on heat
load
Area
Temperature
(0c)
Humidity
( % RH)
Particles
( per M3)
Air
Change
Aseptic filling
15-25
30-45
100
>40
Weighing, Processing
( Aseptic)& Filtration
of Sterile product
15-25
45-55
10,000
20-40
Weighing, Processing
of Sterile product with
terminally sterilization.
15-25
45-55
100,000
20-40
Ophthalmic ointment
20-28
30-40
10,000
5-20
Weighing, processing
and packing of nonsterile product.
20-28
45-75
100,000
5-20
a. Capsule
20-25
40-50
100,000
5-20
b. Hygroscopic Tablet
20-25
40-50
100,000
5-20
c. Dry Syrup
20-25
40-50
100,000
5-20
d. Liquid
20-28
45-75
100,000
5-20
Secondary Packing
20-28
45-75
Clean
5-20
a. Cool store
0-8
45-75
Clean
5-20
b. Controlled store
20-25
45-75
Clean
5-20
c. Normal store
30-35
45-75
Clean
Warehouse
5-20
HVAC
Product quality depends on air quality
Products can only be as pure as the
environments in which they are produced.
Product Quality
Efficacy
Product Stability
Patients safety
Product Purity
Patients Acceptability
Regulatory Compliance
Harmful Effects of Air

Purity : Product will not be pure due to
contaminants
Stability : Product will be physically and
chemically unstable
Efficacy : Less effective due to decomposition
Safety : May not be safe for patient
Shelf life: Less Shelf life due to decomposition
Acceptability : May be unacceptable to patients
Factors that contribute to quality

products:
i.
ii.
iii.
iv.
v.
vi.
vii.
Starting materials and packaging materials

Validated processes
Personnel
Procedures
Equipment
Design and quality of premises
Manufacturing environment
Factors contributing
to quality products
Personnel
Validated processes
Procedures
Starting materials
Equipment
Packing materials
Premises
Environment
Environmental factors have a direct

influence on a product:
Some environmental factors have a direct influence on a
product:
1. Light, for light sensitive products (photo-degradation)
2. Temperature, for temperature sensitive products (many
injectables,
vaccines)
3. Humidity, often for capsules and always for effervescent
tablets
4. Air movement, affecting contamination and crosscontamination
5. Microbial contamination can lead to the destruction of
the product and to grave accidents in the case of
injectables or sterile products.
6. Particulate contamination is critical in injectable forms
Environmental factors have a direct

influence on a product:
These factors, if not properly controlled, can lead

to:
- product degradation (Physical-Chemical

change)
- product contamination
- sensitization or allergic reactions.
- loss of product and profit
Cross contamination In the case of highly potent

drugs, can lead to grave accidents.
Harmful effects of temperature
Thermal degradation of Drugs:
Microbial Growth

Chemical Change: Thermo labile drugs
are decomposed if they are stored in
higher temperature.
Physical Change: Temperature may
change the color, odor and taste of drugs

Safety: The degradation may produce toxic
product
Efficacy: Drug will be less effective due to
thermal degradation
Stability: Both physical and chemical stability
of some drugs are affected by temperature
Shelf life: Thermal Degradation will decrease
the shelf life of drugs and dosage form

Microbial load:
Microbial growth is accelerated by the
optimum temperature. 370c temperature
promotes the bacterial growth. Microbial
load of some drugs, excipients or dosage
form will increase if they are stored to
370c.
Dust Particle Control
Harmful effects of dust particle:
Cross contamination:
Microbial contamination:
Particulate contamination:
Sensitization or allergic reaction:
Product loss
1. Microbial contamination can lead to the

destruction of the product and to grave
accidents in the case of injectables or sterile
products.
2. Particulate contamination is critical in
injectable forms
Harmful Effects of Moisture
Hydrolysis of drugs: Hydrolysis is considered

as the major cause of drug decomposition. It
may be defined as the reaction of drugs with
water. A prime example of this phenomenon is
the decomposition of aspirin into salicylic acid
and acetic acid.
Aspirin ------ Salicylic Acid + Acetic Acid
Many drugs are susceptible to hydrolysis and
degraded by moisture present in the air.
Oxidation of drugs: Moisture can

increase the rate of oxidation of some
drugs. Ferrous Sulphate crystals are
more rapidly oxidized in moist air.
Fe++ ---- Fe+++

Physical changes due to chemical
decomposition:
Color Change
Odor Change
Taste Change
Production of Toxic Chemicals
Physical Stability
Drug dissolution: Moisture is rapidly
absorbed on the surface of hygroscopic
drugs causing solution of the drug in that
moisture. Ranitidine, Ascorbic Acid,
Cloxacillin, Flucloxacillin are very
hygroscopic drugs that absorb moisture
from air and dissolved in it.

Physical Stability:
Agglomeration of powder: Fine powder may

form lump due to the absorption of moisture
from air.
Moisture regain: Materials may regain

moisture from air after drying if it is exposed to
humid air.
Cake Formation: Fine powder may form cake
due to the absorption of moisture from air.

Microbial Growth: Microbial growth is

accelerated by the presence of moisture.
Above 60% RH promotes the bacterial
growth. Microbial load of some drugs,
excipients or dosage form will increase if
they are exposed to humid air.
What are contaminants ?

Contaminants are
1. Products or substances other
than product manufactured
2. Foreign products
3. Particulate matter
4. Micro-organisms
5. Endotoxins (degraded microorganisms)
Contaminants
Contaminants can be:
1. Products or substances other than the product
manufactured (e.g. products resulting from air pollution).
2. Foreign products, such as metal parts from equipment,
paint chips,etc.
3. Particulate matter, especially dangerous in injectables.
4. Micro-organisms a particular problem for sterile
products.
5. Endotoxins: Even if killed by thermal treatment, microorganisms are degraded to endotoxins and can cause
damage.
Contaminants
Contaminants are in fact the
presence of anything in the
manufactured product which should
not be there.
Cross-contamination is a particular
case of contamination
Sources of contaminants
Contaminants can originate from:
Environment
particles,
micro-organisms,
dust containing other products.
Equipment
residues of other products,
oil,
particles,
rust,
gaskets,
Metal
leaching of plastic components, metal parts (broken
sieves in granulators), brittle gaskets, oil, chips of paint,
etc.
Contamination can be brought by operators
objects falling into the product,
skin particles,
dandruff,
fibres from uniforms.
Contamination can be brought by premises
Particle shading
Paint chips
Construction material
Cross-Contamination (1)
What is Cross-Contamination ?
Definition of Cross-Contamination:
Contamination of a starting
material, intermediate product, or
finished product with another
starting material or product during
production.
(WHO)
Annex 1, Glossary
Cross-Contamination ( 3 )
Contaminant
from
Environment
Operators
Contamination
Contaminant
from
Equipment
Product
from
Environment
Operators
Cross
Contamination
Product
from
Equipment
Cross Contamination
Definition of Cross-Contamination:
According to WHO, cross-contamination is Contamination of a
starting material, intermediate product, or finished product with
another starting material or product during production. WHO Expert
Committee on Specifications for Pharmaceutical Preparations.
Thirty-second Report. Geneva, World Health Organization, 1992
(WHO Technical Report Series, No. 823). Annex 1: Good
manufacturing practices for pharmaceutical products.
In other words, cross-contamination is the presence in a particular
product of small, traceable quantities of other pharmaceutical
products manufactured
at the same time in the same premises

previously on the same equipment or in the same premises
Cross Contamination
Cross-Contamination is thus only concerned with the
presence of traces of products manufactured in-house !
Adequate analytical detection is important to detect
traces of contamination.
Validated analytical methods, especially developed for
detection purposes, may be necessary to detect crosscontamination.
An absence of cross-contamination being detected may
just mean the absence of adequate analytical
procedures.
From where does Cross-Contamination
originate?
1. Poorly designed air handling systems
and dust extraction systems
2. Poorly operated and maintained air
handling systems and dust extraction
systems
3. Inadequate procedures for personnel
and equipment
4. Insufficiently cleaned equipment
insufficient control over

1.Design of premises and systems quality
2.Air handling and dust extraction systems
3.Operation and maintenance of air handling
and dust extraction systems
4.Procedures for cleaning of equipment and
for restriction of movement of personnel
5.Procedures for cleaning of premises
Sources of cross-contamination
cross-contamination can be either airborne or physically
transferred:
by bringing traces of a product through ventilation

systems
by transfer of contaminants
from one room to another due to poor pressure

cascade
through clothing into another product

through badly cleaned equipment retaining traces of a
product and
contaminating another product.
Cross-contamination can be minimized
by:
1. Personnel procedures
2. Adequate premises
3. Use of closed production systems
4. Adequate, validated cleaning
procedures
5. Appropriate levels of protection of
product
6. Correct air pressure cascade
There are different ways to prevent or reduce the effect

of cross-contamination.
Personnel procedures: Clean clothing, and for clean

rooms (C, B, A) to be washed in special laundries;
Personal hygiene on entering a pharmaceutical area.
Adequate premises: Minimisation of possibility of

accumulation of dust;
Premises with good
ventilation and dedusting system.
Closed production systems: Closed

systems, in which product is transferred
from
one piece of equipment to another one, without
being exposed to the
atmosphere.
Validated cleaning procedures: Manual

cleaning procedures may not be
reproducible.
Level of Protection concept 2: A good hygiene, or Level

of Protection concept, specifying requirements for
environmental conditions; entry procedures for
personnel and material is fundamental for keeping
cross-contamination under
control.
Maintaining the correct air pressure differential

between rooms helps
prevent crosscontamination.
The module on HVAC deals precisely with the last of

these ways, namely a good air handling system.
Level of Protection Concept

1. Defines environmental
requirements
2. Helps prevent contamination and
cross-contamination
3. Allows production under optimal
hygiene conditions
4. Takes into account
product sensitivity to contamination
therapeutic risk
Cleanroom Class A / B
Cleanroom Class C
Cleanrm. Class D
Others
Manufacturing Environment
requirements
Therapeutic risks
Levels of Protection
Parameters to be defined:
1. Air cleanliness requirements (filters
type and position, air changes, air
flow patterns, pressure differentials,
contamination levels by particulate
matter and micro-organisms)
2. Personnel and material transfer
methods
3. Permitted operations
Annex 1, 17.3, 17.4
4. Building design and finishes
Types of Cleanroom Classes
International
WHO
A, B, C, D
National
EC, PIC/S, TGA, etc. : A, B, C, D

US FDA :
critical and controlled
ISPE:
level 1, 2 or 3 or
cleanroom class
Companies :
various others
Annex 1, 17.3, 17.4
Therapeutic Goods
Administration (TGA). TGA is Australia's
regulatory agency for medical drugs and
devices.
Pharmaceutical Inspection Convention
and Pharmaceutical Inspection Cooperation Scheme (jointly referred to
as PIC/S)
Washing of containers
Preparation of solution for terminal sterilisation
Preparation of solutions for aseptic filling
Depyrogenisation of containers
Filling for terminal sterilisation

Class
Filling for aseptic Cleanroom
process
X
X
etc.
Annex 1, 17.3, 17.4,

17.5
Based on the cleanroom class requirements,
various Levels of Protection have to be
created, including:
Correlation between process operations
and cleanroom classes
Type of operation permitted in each Level
of Protection
Definition of cleanroom class

(parameters, building materials,
room requirements, HVAC systems)
Requirements for personnel and

material in the different classes
(clothing, training, type of materials,
etc.)
Requirements on entry conditions for

personnel and material
( change procedures )
Air Handling
System
Supply
Air
Production Room
With
Defined
Requirements
Outlet
Air
Annex 1, 17.4
Parameters influencing Levels of

Protection (2)
1 Number of particles in the air
2 Number of micro-organisms in the
air or on surfaces
3 Number of air changes for each
room
4 Air velocity
5 Air flow pattern
6 Filters ( type, position )
7 Air pressure differentials between
rooms
8 Temperature, humidity
Parameters influencing Levels of Protection (3)
Cleanroom Class
defined by
Critical Parameters
Air Handling
System
Additional Measures
Air handling systems:

Are the main tool for reaching
required parameters
But are not sufficient as such
Need for additional measures such as

appropriate gowning (type of clothing, proper
changing rooms)
validated sanitation
adequate transfer procedures for materials and
personnel
Annex 1, 17.10 to 17.16
Zone
Grade
Process
Particles
Limit(> 0.5
micron /M3
Air
change/hr
Filter
Aseptic filling in
final container
Class 100
40
HEPA
Background of
Zone A
Class 100
20
HEPA
Sterile solution
preparation
Class 10,000
20
HEPA
Dispensing of
starting materials
for products
terminally
sterilized.
Class 100,000
20
HEPA
Production and
packing of non
sterile products.
Class 100,000
Secondary
packaging
Optically
Clean
Warehousing, QC
Labs, General Area.
General Area
Depends
on heat
load
AHU must be located outside the

space they are controlling!
Air Handling
System
Supply
Air
Production Room
With
Defined
Requirements
Outlet
Air
Main subsystems
Exhaust air treatment
Fresh air treatment

(make-up air)
Terminal air treatment

at production room level
Production Room
Central air handling unit
4 sub-systems
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).
Overview components
Exhaust Air Grille
Silencer
Weather louvre
Flow rate controller
Fan
Filter
Control damper
Heater
+
Prefilter
Humidifier
Cooling
coil
with
Heating droplet
coil
separator
Secondary Filter
Terminal filter
Production Room
Re-circulated air
Components
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
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 predetermined dimensions and/or
micro-organisms
To transport the air
Problems with components
Flow rate
controller
Blocked
Control damper
Poorly adjusted, bad pressure

differential system
Humidifier
Bad water/steam quality/poor drainage
Cooling battery
Filters
No elimination of condensed water/poor

drainage
Ducts
Incorrect retention rate/damaged/badly

installed
Inappropriate material/internal insulator
leaking
Air types
Fresh air
(make-up air)
Supply
air
Exhaust
air
Production Room
Return air
(re-circulated)
Function of AHU
Heating
Cooling
Humidification
Dehumidification
Filtration
Measurement of Humidity
Air
Dry Air
Moist Air
Saturated Air
Unsaturated Air
Humidity Control
Various Terms
Dry air
Air which is free from water
Moist air
The mixture of dry air and water
Saturated air
When air contains maximum amount of moisture
Unsaturated air Air which is not saturated

Absolute
humidity
Weight of water per pound of dry air.

Unit: grains/ lb. dry air
Relative
humidity
Ratio of actual amount of water & maximum

amount of water
Dew point
Temperature at which condensation will just begin

with the existing moisture.
Determination of Volume of Air

1. Length, height and width of tablet process room
are 12 ft, 8 ft and 10 ft respectively. Determine
the Volume of air of that room.
Ans.:
Volume of air = Volume of Room
= Length, x height x width
= 12 x 8 x 10
= 840 ft3.
Determination of weight of Air

2. Length, height and width of tablet process room are 12
ft, 8 ft and 10 ft respectively. Determine the weight of dry
air of that room.
Ans.:
= 12 x 8 x 10
= 840 ft3.
Weight of air = Volume x Density
= 840 ft3 x 0.0807 lb/ ft3.
= 67.788 lb.
Determination of Maximum amount of

moisture in Air
Moisture content capacity of air depends on temperature.
Higher temperature air can contain more moisture.
Air temperature
( 0F)
Maximum amount of moisture

(Grains/ lb. dry air.)
54
62
60
78
67
99
81
161
85
185
Maximum amount of moisture in Air

3. Length, height and width of tablet process room are 12 ft, 8 ft and 10
ft respectively. Calculate the maximum amount of moisture at 600F.
air of that room.
Ans.:
= 12 x 8 x 10
= 840 ft3.
Weight of air = Volume x Density
= 840 ft3 x 0.0807 lb/ ft3.
= 67.788 lb.
Maximum Amount of moisture= 67.788 lb x 78 Grains/ lb. dry air
= 5287.464 grains
= 0.755 lb
Determination of AH , % RH
4. Capsule process room contains 67.788 lb. dry
air and 4000 grains moisture. Calculate the AH.
Answer:
AH (Absolute Humidity)
= Wt. of moisture per lb. of dry air.
= Wt of moisture / Wt of dry air
= 4000/67.788
= 59 grains/ lb. dry air
5. Liquid process room contains 100.5 lb. moist air
and 0.5 lb. moisture. Calculate the AH.
Answer:
= (0.5 x 7000 grains) / (100.5-0.5)
= 3500 / 100
6. Capsule process room contains 100.5 lb. moist
air and 0.5 lb. moisture at 600F. Calculate the
AH & %RH.
Answer:
= (0.5 x 7000 grains) / (100.5-0.5)
= 3500 / 100
%RH = (Actual amount of moisture / amount

of moisture in saturation) x 100
= 35/78*100
=44.87 %
3. % RH of a room is 80%. The air of the room
contains 0.25 lb. moisture. Calculate the amount
of moisture at saturated condition.
Answer:
%RH = (Actual amount of moisture / amount of
moisture in saturation) x 100
Amount of moisture in saturation = (Actual amount
of moisture / RH) x 100
= (0.25 / 80) x100
= 0.3125 lb.
Instruments
Hygrometer: It is an instrument containing dry
bulb temperature and wet bulb thermometer.
Dry bulb thermometer: Temperature recorded
by a dry bulb thermometer
Wet bulb thermometer: Temperature recorded
by a wet bulb thermometer
Observe the dry bulb temperature & wet bulb
temperature. Determine the difference. Now
various parameters can be determined by using
either psychometric table or psychometric chart
Hygrometer
Psychometric Table
Definition
A Psychometric table is a representation
of various thermodynamic parameters of
moist air.
Psychometric Table
Determination of Relative humidity:
1. Observe the dry bulb temperature & wet
bulb temperature.
2. Determine the difference.
3. Now cross point of dry bulb temperature
and depression of temperature in the
Psychometric Table indicates the Relative
Humidity
DEPRESSION OF WET BULB 0C
Dry Bulb
Tem.
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
21
95
91
86
82
78
73
69
65
61
57
53
49
45
42
22
95
91
87
82
78
74
70
66
62
58
54
50
47
43
23
96
91
87
83
79
75
71
67
63
59
55
52
48
45
24
96
91
87
83
79
75
71
68
64
60
57
53
49
46
25
96
92
88
84
80
76
72
68
65
61
58
54
51
47
26
96
92
88
84
80
76
73
69
66
62
59
55
52
49
27
96
92
88
84
81
77
73
70
66
63
59
56
53
50
28
96
92
88
85
81
77
74
70
67
64
60
57
54
51
29
96
92
89
85
81
78
74
71
68
64
61
58
55
52
30
96
93
89
85
82
78
75
72
68
65
62
59
56
53
32
96
93
89
86
82
79
76
73
70
67
64
61
58
55
34
96
93
89
86
83
80
77
74
71
68
65
62
59
56
36
96
93
90
87
84
81
78
75
72
69
66
63
61
58
Psychometric chart
Definition
A Psychometric chart is a graphical
representation of various thermodynamic
parameters of moist air.
Psychometric chart
Various Lines
Dry bulb temperature
lines
These are the straight and vertical lines drawn

parallel to the ordinate.
Wet bulb temperature

lines
These are the straight but inclined lines which

extend diagonally as shown on the chart
Absolute humidity
lines
These are the straight and Horizontal lines

drawn parallel to the abscissa.
Relative humidity lines These are the curved lines. The saturation
lines show 100% Relative humidity
AH & RH from psychometric chart

Determine the dry bulb temperature and wet
bulb temperature from the hygrometer. Then
determine the cross point in the Psychometric
chart.
Now absolute humidity line passing though the
cross point indicates the Absolute Humidity.
Relative humidity line passing though the cross
point indicates the Relative Humidity.
Dew point can be find out from the cross point of
Absolute Humidity line and saturation humidity
line.
REQUIREMENT
Humidity
(% RH)
Area
Aseptic filling
30-45
Weighing, Processing (Aseptic)& Filtration of Sterile product
45-55
Weighing, Processing of Sterile product with terminally sterilization.
45-55
Ophthalmic ointment
30-40
Weighing, processing and packing of non-sterile product.
45-75
a. Capsule
40-50
b. Hygroscopic Tablet
40-50
c. Dry Syrup
40-50
d. Liquid
45-75
Secondary Packing
45-75
a. Cool store
45-75
b. Controlled store
45-75
c. Normal store
45-75
Dehumidifier
Dehumidifier
Desiccant
Refrigeration
Desiccant type Dehumidifier:

Desiccant type Dehumidifier:
Desiccants are used in a desiccant type dehumidifier.
Desiccant can adsorb moisture from air. As a result the
quantity of moisture in air will decrease. By passing the
air through the desiccant again and again, we will get
moisture free air. Desiccant type dehumidifier acts on
this principle.
When the unit is started, the fan begins to pass
moisture-laden air through the desiccant, which adsorbs
moisture from the air making the air moisture free.
Desiccant becomes inactive due to adsorption of
moisture. Desiccant can be again reactivated by passing
hot air through it.
Adsorber wheel
Dry
air
Humid room air
Regeneration
air
AHU with fan
Variable Speed
Controller
Air heater
Filter Pressure
Gauges
De-humidification
Refrigeration type Dehumidifier

Components:
Refrigerants: Substances that are circulated in a closed
refrigeration system to transfer heat.
Examples:
Trichloro Monofluro Methane Dichloro Difluro Methane
Monochloro Trifluro Methane
Compressor: Circulates refrigerants through a closed
system.
Condenser: It receives hot, high-pressure refrigerants
from the compressor and converts it into liquid
refrigerants.
Evaporator: liquid refrigerant is vaporized at lower
pressure in evaporator.
Evaporating Coil
Condensed Coil

Principle:
The content ability of air is temperature
dependent. Hot air can contain more
moisture than cool air. Refrigeration type
dehumidifier can decrease the
temperature of air. As a result air will be
first saturated and then excess water will
be separated from air. Refrigeration type
dehumidifier acts on this principle.

Principle:
Refrigerants are used in refrigerants type
dehumidifier. These refrigerants are evaporated
in the evaporator. Heat is taken by the
refrigerants as a latent heat for this conversion.
As a result the evaporation coils become very
cool. In contact with the evaporating coil, air also
becomes very cool. As cool air can contain less
moisture, the excess water will be separated
from the air.

When the unit is started, the fan begins to
pull moisture-laden air across the
evaporating coils making the cool and
moisture free. Then the moisture free air is
passed through the condenser where the
air becomes hot due to the latent heat of
condensation of refrigerants in the
condenser.
Temperature Control
Air Cooler
Air Heater
Air Cooler
Components:
Refrigerants: Substances that are circulated in a closed
refrigeration system to transfer heat.
Examples:
Trichloro Monofluro Methane Dichloro Difluro Methane
Monochloro Trifluro Methane
Compressor: Circulates refrigerants through a closed
system.
Condenser: It receives hot, high-pressure refrigerants
from the compressor and converts it into liquid
refrigerants.
Evaporator: liquid refrigerant is vaporized at lower
pressure in evaporator.
Refrigerants
Numerical designation Chemical name
11
12
13
Chemical
Formula
Trichloro Monofluro Methane CCl3F

CCl2F2
Dichloro Difluro Methane
Monochloro Trifluro Methane CClF3
Principle of Air Cooler

Refrigerants are used in air cooler. These
refrigerants are evaporated in the
evaporator. Heat is taken by the
refrigerants as a latent heat for this
conversion. As a result the evaporation
coils become very cool. In contact with the
evaporating coil, air also becomes very
cool. This cool air is distributed in the
room.

Condenser receives hot, highpressure refrigerants from the
compressor and converts it into liquid
refrigerants. Heat is released from the
refrigerant at this conversion. Air from
out site the room is passed across the
condenser to transfer heat.

When the unit is started, the fan begins to
pull hot air of the room across the
evaporating coils making the cool and this
cool air is distributed in the room. At the
same time fan passes the out site air
across the condenser and keep it cool by
removing heat from the condenser.
Temperature Control
Hot Water Coil

Ideal for a wide variety of
basic, custom, and
heavy-duty industrial
applications, hot water
coils are designed to
meet a variety of heating
applications. Applications
include booster heat,
reheat, waste heat
reclamation, pre-heat,
fluid process heat &
more.
Chilled water coil

For applications
including comfort
cooling,
dehumidification,
process cooling, and
more.
Filter classes
Dust filters
Standard
Aerosol
Coarse
Fine
Dp > 10 m
10 m > Dp > 1 m
G1 - G4
F5 - F9
EN 779 Standard
HEPA
ULPA
Dp < 1 m
H 11 - 13
U 14- 17
EN 1822 Standard
ULPA (Ultra Low Penetration Air)

filter.
a filter with a higher efficiency than a HEPA filter
was offered. It had a DOP efficiency of 99.999%
and the 12 in. (304.8 mm.) deep version had a
clean pressure drop of 273.6 Pa when operating
at a face velocity of 250 fpm (1.27 m/s). This
filter has helped meet the requirement for
cleaner air in facilities needed for the
manufacture of microelectronics. It is identified
by the generic name ULPA (Ultra Low
Penetration Air) filter.
HEPA filters
The first HEPA filters were developed in
the 1940's by the USA Atomic Energy
Commission to fulfill a top-secret need for
an efficient, effective way to filter
radioactive particulate contaminants. They
were needed as part of the Manhattan
Project, which was the development of the
atomic bomb. The first HEPA air filters
were very bulky compared to the HEPA air
filters that are produced today.
Filter
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).
Filter
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).
Filter
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.
Classification of filters according to their efficiency
F9
Average Efficiency
Integral Value
Retention in Penetration
%
85
0.15
Peak Arrestance
Local Value
Efficiency Penetration
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
HEPA or tertiaary filter
Primary panel
filter
Secondary
filter
Humidifier
Heating and
cooling units
Silencer
Control damper for air flow

Adsorber wheel
Humid room air
Regeneration air
Dry
air
AHU with fan

Variable Speed
Controller
Humid room air

Filter Pressure
Gauges
Air heater
De-humidification
Air handling unit
1
2
3
4
1
2
3
4
Swirl Type air diffusors

Filter
with
Tightening frame
Register outlet
terminal
filters
Screw fixation for register
High induction
office type diffusor
(avoid)
Low induction
swirl diffusor
(preferred)
Regulation of room pressure pressure

differentials concept
Room pressure
gauges
Room pressure indication panel
Annex 1, 17.26
Pressure cascade injectables

Protection from micro-organisms and
particles
Annex 1, 17.24,
17.25
Pressure cascade solids

Protection from cross-contamination
Supplementary Training
Modules on GMP
Air Handling Systems
Heating
Ventilation and
Air Conditioning (HVAC)
Part 3: Design, qualification
and maintenance
Module 3, Part 3: Qualification and maintenance
Slide 130 ofWHO

27 EDM
Characteristics of air handling

systems
In the following slides, we will study alternatives in
air handling systems
Turbulent or uni-directional airflows

Filter position
Air re-circulation vs fresh air
Return air systems (positions)
Overpressure requirements
Air flow patterns (1)

Turbulent
Uni-directional / laminar
dilution of dirty air
displacement of dirty air
0,30 m/s
Annex 1, 17.3

There are 2 ways to supply air to a room or a
piece of equipment:
Turbulent air flow
Uni-directional flow, often called laminar flow
The air speed in the uni-directional flow is

defined by the WHO at:
0,45 m/s for horizontal units

0,30 m/s for vertical units (most commonly
used)

It is important to know that the WHO definition(*) for the air speed
differs from those of other guidelines.
For the air exhaust, in case of a vertical unit, a low return is more
favourable, as the air is better distributed in the room.
Objects in the room can significantly disturb the flow of air, and even
block it, so that there might be pockets without air circulation.
During the qualification phase, the air flow is visualized if possible,
and air samples are taken in different points, to make sure that there
are no such pockets, in which case adjustments to the layout or to
the air handling systems must be made.
(*)
WHO Expert Committee on Specifications for Pharmaceutical

Preparations. Thirty-second Report. Geneva, World Health
Organization, 1992: 59-60 (Technical Report Series, No. 823).
Annex 1, 17.3.

Filtered air entering a production room or
covering a process can be
turbulent
uni-directional (laminar)
GMP aspect
economical aspect
New technologies: barrier technology/isolator

technology.
Annex 1, 17.3, 17.4

As seen in the previous slide, filtered air entering a
production room or covering a process can be
Turbulent
Uni-directional (laminar)
Two aspects have to be considered:
GMP aspect: uni-directional air (laminar)

installations give a better protection, because of the
displacement effect rather than the dilution effect.
Economical aspect: turbulent air installations are

cheaper, as less air has to
be treated.

For certain operations, namely in class A, a laminar
flow must be used.
It should be said here that such installations can give a
false impression of security, and that the purpose of
such installations is that there should be, whenever
possible, no human interventions under them during the
process.
If interventions have to occur, they should be performed
in a well-documented way, and recorded and evaluated
for possible damage to the products.
The use of barrier technology systems (isolator
technology) is highly recommended in cases of
operations in class A, or for sterility testing operations.
Prefilter
AHU
Annex 1, 17.3
Main filter
Turbulent
Uni-directional
Turbulent

This slide shows an HVAC installation feeding 3 rooms, each one
with terminal filters, all terminal filters protected by a remote prefilter.
Room 1 has a turbulent air flow, with low level exhaust.
Room 2 has a uni-directional air flow, over the largest part of the
surface, hence the large number of filters, with low level air returns.
Due to the high cost of the ventilation in class A areas, the tendency
is to keep these areas as small as possible.
Room 3 has a turbulent air flow, with ceiling exhaust.
Good design practices recommend that cleanrooms A, B and C (ISO
Class 5, 6 & 7) should have low level air returns.

Workbench (vertical)
Cabin/ booth
Ceiling
Uni-directional (laminar) flow units exist mostly as vertical, but also as

horizontal, units.
Often, we are just dealing with LF workbenches (mainly used in sterility

testing) or LF cabins/booths, routinely used in production, for instance on
top of a filling machine.
In some cases, the units can be integrated into the ceiling of a room and
also connected to the central air conditioning system.
Due to the high air velocity, it is important to have objects with good
aerodynamical properties under the laminar flow. If not, turbulences and,
therefore, particles are unavoidable.
Laminar flow units are comparatively expensive. Surfaces covered by them

should be reduced to a minimum.
Only the product in a critical production phase, and not the personnel,
should be under laminar flow (aseptic filling, sterile blending, etc.). Manual
interventions should be restricted to a minimum, and should be recorded
and evaluated for possible consequences.
Positioning of filters
(1)
AHU mounted final filter
Filter in terminal position

HEPA
Filter
Production Room
Production Room
HEPA Filter
In some of the previous slides, we have seen filters both
in the central air handling units ( AHU ) and terminally
mounted at the production rooms.
The filtered air entering a production room can be
coming from:
an air-handling unit, equipped with pre-filtration and

the main (HEPA) filter, but at some distance from that
room (left drawing);
an air-handling unit, equipped with pre-filtration in

the AHU, and an additional
filter (HEPA) situated
immediately on the air outlet (right drawing).
In many cases, there are only filters in the AHU. However, for injectables
and sterile forms, it is recommended that they be placed in terminal
position, though there is a growing tendency to have terminal filters in all
rooms where open products are handled. It is recommended that classes A
& B (ISO 4, 5 & 6) have terminal HEPA filters. (Refer to: WHO Export
Committee on Specifications for Pharmaceutical Preparations. Thirtysecond Report. Geneva, World Health Organization, 1992:59-60
(Technical Report Series, No. 823). Annex 1, 17.3.)
If we look at the advantages and disadvantages of terminal or non-terminal

filters, we can say that generally speaking, the terminal positioning
is more expensive;
provides a better protection (any problem arising from the ducts is
eliminated);
is the preferred method in cleanroom classes with high requirements.
(2)
Prefilter
AHU
Main filter
Ceiling
exhausts
2
Low level exhausts
Filters can be in different positions, when one considers
the central AHU and the rooms.
This slide shows an HVAC installation feeding 3 rooms,
each one with terminal filters, all filters protected by a
remote pre-filter.
Room 1 has a turbulent air flow, with low level exhaust.
Room 2 has a uni-directional (laminar) air flow over the
largest part of the surface, hence the large number of
filters.
Positioning of filters (3)
Final filter
AHU
Prefilter
This slide shows an HVAC installation feeding two
rooms, each one without terminal filters, but with remote
final filters protected by a pre-filter.
Room 1 has a turbulentair flow, with low level exhaust.
If there is no filter in terminal position, it should be
ascertained that there are no elements between the
main filter and the air outlets which could add
contamination. No elements such as fans,
heating/cooling batteries, should be situated downstream
of the final filter.
Air re-circulation
100% exhausted or
a proportion re-circulated
GMP aspect
economical reasons
Annex 1, 15.10, 17.24
Air re-circulation

eliminated at 100% (exhaust air)
a proportion re-circulated
Re-circulated air must be filtered, at an efficiency rate which is such that

cross-contamination can be excluded.
In case of re-circulation, every possible measure of protection must be

taken to ensure that the air coming from a production unit and loaded with
product particles does not flow to other production units, thereby
contaminating them.
It makes sense to re-circulate the air for reasons of energy conservation,

but there can be a contradiction between pharmaceutical requirements and
energy conservation.
There are also cases, in which air re-circulation is prohibited, for example if
solvents are used or cytotoxic products are manufactured.
Ventilation with 100% fresh air (no air recirculation)

Washer (optional)
Exhaust Unit
W
Central Air Handling Unit

Production Rooms
Annex 1, 17.24
Ventilation with 100% fresh air

(no air re-circulation
This slide illustrates a typical 100% fresh air
setup, where a central unit distributes the fresh,
treated air to different production rooms.
The exhaust air is collected in a central duct,
treated (filtered or washed) and eliminated. The
degree of exhaust air filtration will depend on
contaminants in the exhaust air and also on
environmental regulations.
Ventilation with re-circulated air + make-up air

Exhaust Unit
Central Air Handling Unit
Return air
Ventilation with re-circulated air

+ make-up air
This slide illustrates a typical re-circulated air
setup, where a central unit distributes a mixture
of fresh and re-circulated air to different
production rooms.
A part of the exhaust air is collected in a central
duct, treated (filtered) and exhausted. The rest
is re-circulated (dotted line).
With control dampers, the proportions of fresh
and re-circulated air can be adjusted.
Definition of Conditions
as built
at rest
in operation
air
air
air
Qualification / Validation
issues
A good design is essential, but it has to

be complemented by:
Qualification of air handling
systems
Process validation
Maintenance and periodic requalification
Adequate documentation
We have now seen why air handling plants are

necessary, what their components are and what
the alternatives are in their design.
However, we also have to remember that, once
a ventilation system is installed, it is necessary
to see how well it performs in comparison to its
planned purpose, which is to provide a quality
environment of specified parameters for the
product.
.
We are now going to see how it is possible to

achieve
demonstrate
document
the required purity in practice by:
systems qualification and
process validation (media fill, for instance)
Additionally, good maintenance is essential.
The whole process is of course supported by
adequate documentation
Qualification (OQ, PQ)

(1)
Test
Uni-directional
airflow / LAF
Turbulent /
mixed airflow
Differential pressure on filters
Room differential pressure
N/A
2, 3
2 = At rest (ideally used to perform OQ)
Airflow velocity / uniformity
2, 3
Optional
Airflow volume / rate
3 = Operational (ideally used to perform

PQ)
Parallelism
N/A
Air flow pattern
Description
1 := As built (ideally used to perform IQ)
Annex 1, 17. 4
IQ tests are not mentioned on this slide
Ask the question: What are the alert and

action Limits and what procedures are
followed if these points are exceeded?
Qualification (OQ, PQ) (2)

Uni-directional
airflow / LAF
Test
Recovery time
Room classification (airborne
particle)
Temperature, humidity
Turbulent /
mixed airflow
N/A
2,3
N/A
2,3
Description
1 := As built (ideally used to perform IQ)
2 = At rest (ideally used to perform OQ)
3 = Operational (ideally used to perform
PQ)
Annex 1, 17. 4
IQ tests are not mentioned on this slide

Microbiological validation
1. Definition of alert / action limits as a
function of
cleanliness zone
1. Identification and marking of sampling
points
2. Definition of transport, storage, and
incubation conditions
Cleanroom monitoring program

(1)
Cleanrooms should be monitored for micro-organisms
and particles
air
Sampling point
Cleanroom monitoring program (2)
Routine monitoring program as part of

quality assurance
Additional monitoring and triggers
1.
2.
3.
Shutdown
Replacement of filter elements
Maintenance of air handling
systems
4. Exceeding of established limits
Annex 1, 17.37
Cleanroom maintenance program (1)

Schedule of Tests to Demonstrate Continuing Compliance
Test Parameter
Class
Air Pressure Difference
A, B
<= ISO 5
C, D
> ISO 5
All Classes
Air Flow
All Classes
Particle Count Test
Test Procedure
Maximum Time
Interval
6 Months
ISO 14644 -1 Annex A
12 Months
ISO 14644 -1 Annex A
12 Months
ISO 14644 -1 Annex B5
12 Months
ISO 14644 -1 Annex B4
Cleanroom maintenance program (2)

Schedule of Additional Optional Tests
Test Procedure
Installed Filter Leakage
All Classes
Maximum Time
Interval
24 Months
Containment Leakage
All Classes
24 Months
ISO 14644-1 Annex B4
Recovery
All Classes
24 Months
Air Flow Visualisation
All Classes
24 Months
Test Parameter
Class
Documentation requirements
1.
2.
3.
4.
5.
6.
7.
Description of installation and functions

Specification of the requirements
Operating procedures
Instructions for performance control
Maintenance instructions and records
Maintenance records
Training of personnel (program and records)
Inspecting the air handling plant

1.
Verification of design documentation, including
2.
Operating procedures
Maintenance instructions
Maintenance records
Training logs
Environmental records
Discussion on actions if OOS values
Walking around the plant
3.
4.
5.
6.
7.
8.
description of installation and functions

specification of the requirements
Conclusion
Air handling systems:
Play a major role in the quality of pharmaceuticals

Must be designed properly, by professionals
Must be treated as a critical system
Further proceedings
This series of explanations will now be followed by:
Group discussion, with a simple exercise

Short test
Group
Session
Group Session modified layout
MAL = Material Air Lock

PAL = Personnel Air Lock

HVAC Overview

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HVAC

Harmful Effects Examples

Quantity Harmful Effects

Microbial contamination, Antacid &

Quantity Harmful Effects Examples

Harmful Effects of Air

Factors that contribute to quality

Starting materials and packaging materials

Environmental factors have a direct

Environmental factors have a direct

These factors, if not properly controlled, can lead

- product degradation (Physical-Chemical

- sensitization or allergic reactions.

- loss of product and profit

Cross contamination In the case of highly potent

Harmful effects of temperature

Thermal degradation of Drugs:

Harmful effects of temperature

Harmful effects of temperature

Harmful effects of temperature

Dust Particle Control

Harmful effects of dust particle:

1. Microbial contamination can lead to the

Harmful Effects of Moisture

Hydrolysis of drugs: Hydrolysis is considered

Harmful Effects of Moisture

Oxidation of drugs: Moisture can

Harmful Effects of Moisture

Harmful Effects of Moisture

Harmful Effects of Moisture

Agglomeration of powder: Fine powder may

Moisture regain: Materials may regain

due to the absorption of moisture from air.

Harmful Effects of Moisture

Microbial Growth: Microbial growth is

What are contaminants ?

at the same time in the same premises

insufficient control over

by bringing traces of a product through ventilation

from one room to another due to poor pressure

through clothing into another product

There are different ways to prevent or reduce the effect

Personnel procedures: Clean clothing, and for clean

Adequate premises: Minimisation of possibility of

Closed production systems: Closed

Validated cleaning procedures: Manual

Level of Protection concept 2: A good hygiene, or Level

Maintaining the correct air pressure differential

The module on HVAC deals precisely with the last of

Level of Protection Concept

EC, PIC/S, TGA, etc. : A, B, C, D

Preparation of solution for terminal sterilisation

Preparation of solutions for aseptic filling

Filling for terminal sterilisation

Annex 1, 17.3, 17.4,

Definition of cleanroom class

Requirements for personnel and

Requirements on entry conditions for

Parameters influencing Levels of

Parameters influencing Levels of Protection (3)

Air handling systems:

But are not sufficient as such

Need for additional measures such as

AHU must be located outside the