GMP Training on HVAC Systems

Supplementary Training Modules on
Good Manufacturing Practice
Heating, Ventilation and Air-

Conditioning (HVAC)
Part 1 (a):
Introduction and overview
WHO Technical Report Series,
No. 937, 2006. Annex 2
HVAC | Slide 1 of 26 May 2006

HVAC
Introduction and Scope
 HVAC systems can have an impact on product quality
 It can provide comfortable conditions for operators
 The impact on premises and prevention of contamination and

cross-contamination to be considered at the design stage
 Temperature, relative humidity control where appropriate
 Supplement to basic GMP text

1, 2

HVAC
The guideline further focuses on three concepts of
the system:
 Product protection
– Contamination
– Cross-contamination
– Environmental conditions
 Personnel protection
– Prevent contact
– Comfort conditions
 Environment protection 2

HVAC
Personnel
Factors contributing to
Validated processes
quality products
Procedures
Starting materials
Equipment
Packing materials
Premises
Environment

HVAC
The manufacturing environment is critical for product
quality. Factors to be considered include:
1. Light
2. Temperature
3. Relative humidity
4. Air movement
5. Microbial contamination
6. Particulate contamination
 Uncontrolled environment can lead to product degradation
 product contamination (including cross-contamination)
 loss of product and profit

HVAC
What is contamination?
It is "the undesired introduction of impurities (chemical/ microbial/

foreign matter into or on to starting material or intermediate –
during sampling, production, packaging or repackaging".
Impurities could include products or substances other than the

product manufactured, foreign products, particulate matter, micro-
organisms, endotoxins (degraded microorganisms), etc.
Glossary

HVAC
What is Cross-contamination?
"Contamination of a starting material, intermediate product, or
finished product with another starting material or product
during production".
Cross-contamination can result from, e.g.
1. Poorly designed, operated or maintained air-handling systems
and dust extraction systems
2. Inadequate procedures for, and movement of personnel,
materials and equipment
3. Insufficiently cleaned equipment Glossary,
4.1.11

HVAC
Cross-Contamination
Contaminant
Contaminant
from
Contamination from
Environment
Equipment
Operators
Product
Product
from Cross
from
Environment Contamination
Equipment
Operators

HVAC
Cross-contamination can be minimized by, e.g.

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

HVAC
The classification should be

achieved in the state as
specified (1):
 "As built"
– Bare room, without equipment or
personnel
4.1.7 - 4.1.8

HVAC

specified (2):
 "At rest"
– Equipment may be operating, but
no operators present
4.1.9

HVAC

specified (3):
 "In operation"
– Normal production process with
equipment and personnel,
– Clean up time validated –

normally in the order of 20
minutes
4.1.10

HVAC
Level of protection and air cleanliness determined
according to:
 Product to be manufactured
 Process to be used
 Product susceptibility to degradation
4.1.16

HVAC
Parameters influencing Levels of Protection
 Number of particles in the air, number of microorganisms in the

air or on surfaces
 Number of air changes for each room
 Air velocity and airflow pattern
 Filters (type, position)
 Air pressure differentials between rooms
 Temperature, relative humidity

HVAC
Tools to help achieve the desired Level of
Protection
Air Handling
System
Production Room
Supply With Outlet
Air Defined Air
Requirements

HVAC
Tools to help achieve the desired Level of Protection (2)
 Air-handling system can be the main tool for reaching required

parameters
 May not be 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

HVAC
Tools to help achieve the desired Level of Protection (2)
Cleanroom Class
defined by
Critical Parameters
Air Handling Additional Measures

System

HVAC
Examples of Levels of Protection
Types of Clean room classes
 WHO, EC, PIC/S: A, B, C, D
 US FDA: Critical and controlled
 ISPE: Level 1, 2 or 3
 ISO: Class 5, 6, 7 or 8


Conditioning (HVAC)
Part 1 (b):
Introduction and overview
WHO Technical Report Series,
No. 937, 2006. Annex 2

HVAC
Air Filtration
 Degree of filtration is important to prevent contamination
 Type of filters to be used dependent on the quality of ambient

air, return air and air change rates
 Manufacturer to determine, select and prove appropriate filters

for use considering level of ambient air contamination, national
requirements, product specific requirements
4.2.1, 4.2.3

HVAC
Airflow patterns
Filtered air entering a production room or covering a
process can be
 turbulent, or
 unidirectional (laminar)
 GMP aspect
 economical aspect
Other technologies: barrier technology/isolator technology.

HVAC
Airflow patterns
Turbulent Unidirectional/laminar
dilution of dirty air displacement of dirty air

HVAC
Airflow patterns Prefilter
AHU
Main filter
1 2 3
Turbulent Unidirectional Turbulent

HVAC
Unidirectional airflow (UDAF):
Provided where needed over product or material to prevent
contamination, or to protect operator
UDAF in weighing areas

 The aim is to provide dust containment
 Airflow velocity should not affect balance
 Position of material, balance, operator determined and
validated – no obstruction of airflow or risk
4.3.1 – 4.3.10

HVAC
Annex 5, 7.

HVAC
Annex 5, 7.

HVAC
Pressure differential concept
 Concept can include high pressure differential, low airflow, and
airlocks in the design
 Sufficient pressure differential required to ensure containment

and prevent flow reversal – but not so high as to create
turbulence
 Consider effect of other items such as equipment and

extraction systems in cubicles
 Operating limits and tolerances

4.5.13 – 4.5.18,
4.5.22

HVAC
Pressure differential concept (2)
 Calibrated monitoring devices, set to alarm system
 Monitoring and recording of results
 Doors open to higher pressure
 Dust extraction system design

– Interlocked with air-handling system
– No airflow between rooms linked to same system
– Room pressure imbalance 4.5.19 – 4.5.26

HVAC
Pressure cascade solids
Protection from cross-contamination
Room 1 Room 2 Room 3
15 Pa 15 Pa 15 Pa
Air Lock Air Lock
Air
Lock
30 Pa E 0 Pa
Passage
15 Pa
Note : Direction of door opening relative to room pressure

HVAC
Temperature and relative humidity (RH)
 Controlled, monitored and recorded where relevant
 Materials and product requirements, operator comfort
 Minimum and maximum limits
 Premises design appropriate, e.g. low humidity areas,

well sealed and airlocks where necessary
 HVAC design – also prevent moisture migration

4.6.1. – 4.6.6

HVAC
Temperature and relative humidity (RH) (2)
 Remove moisture, or add moisture as necessary
 Dehumidification
– Refrigerated dehumidifiers with cooling media
– Chemical dehumidifiers
 Humidifiers should not be sources of contamination
– Use of pure steam or clean steam
– No chemicals added to boiler system if these can have a
detrimental effect on product (e.g. some corrosion
inhibitors/chelating agents)
4.6.7. – 4.6.11

HVAC
Dust Control
 Dust and vapour removed at source
 Point of use extraction – fixed points or movable hood –

plus general directional airflow in room
 Ensure sufficient transfer velocity to prevent dust settling

in ducting
 Risk analysis – airflow direction, hazards, operator
5.1. – 5.7

HVAC
Protection of the environment (Exhaust air dust)
 Exhaust air from equipment and some areas of production
carry heavy loads of dust (e.g. FBD, coating, weighing)
 Filtration needed to prevent ambient contamination
 Not highly potent material
– EN779 F9 filter recommended
 Harmful substances (e.g. hormones)
– EN1822 H12 (HEPA) filter recommended
– In some cases two banks of HEPA filters
– Safe change filter housings ("bag-in bag-out" filters)
6.1.1 – 6.1.5


Conditioning (HVAC)
Part 2:
HVAC systems and components
Section 7

HVAC Main subsystems
Exhaust air treatment
Fresh air treatment

(make-up air) Terminal air treatment
+
at production room level
Production Room
Central air handling unit

HVAC
Overview components
Exhaust Air Grille
Silencer Flow rate controller Fan Filter
Weather louvre Control damper
Heater
+
Humidifier
Prefilter Terminal filter
Cooling coil Production Room

with droplet Secondary Filter
separator
Heating
coil
Recirculated air

HVAC
Components (1)
 Weather louvre  To prevent insects, leaves, dirt and rain

from entering
 Silencer  To reduce noise caused by air
circulation
 Flow rate controller  Automated adjustment of volume of air
(night and day, pressure control)
 Control damper  Fixed adjustment of volume of air

HVAC
Components (2)
 Heating unit  To heat the air to the proper
temperature
 Cooling unit/  To cool the air to the required
dehumidifier temperature or to remove moisture
from the air
 Humidifier  To bring the air to the proper humidity,
if too low
 Filters  To eliminate particles of predetermined
dimensions and/or microorganisms
 Ducts  To transport the air

HVAC
Air-handling unit
Control damper for airflow
Adsorber wheel Dry air

Humid room air
AHU with fan Variable
Speed Controller
Regeneration air Humid room air

Filter Pressure
Air heater Gauges
De-humidification

HVAC
Humidifier Silencer Heating and
cooling units

HVAC
Filter classes Dust filters
Standard Aerosol
Coarse Fine HEPA ULPA

Dp > 10 µ m 10 µ m > Dp > 1 µ m Dp < 1 µ m
G1 - G4 F5 - F9 H 11 - 13 U 14- 17
EN 779 Standard EN 1822 Standard

HVAC
HEPA or tertiary filter
Primary panel filter
Secondary filter

HVAC
Classification of filters according to their efficiency

Average Efficiency Peak Arrestance
Integral Value Local Value
Retention in Penetration Efficiency Penetration
%
F9 85 0.15
H11 95 0.05
-3 -3
H12 99.5 5x10 97.5 25x10
-4 -4
H13 99.95 5x10 99.75 25x10
-5 -5
U14 99.995 5x10 99.975 25x10

HVAC
Positioning of filters (1)
AHU mounted final filter Filter in terminal position

HEPA Filter
Production Room Production Room
HEPA Filter

HVAC
Positioning of filters (2)
Prefilter
AHU
Main filter
Ceiling
exhausts
1 2 3
Low level exhausts

HVAC
Positioning of filters (3) Final filter
AHU
Prefilter
1 2

HVAC
3
4
Swirl Type air diffusors with

1 Filter
2 Tightening frame
terminal filters
3 Register outlet
4 Screw fixation for register

HVAC
High induction Low induction

office type diffusor swirl diffusor
(avoid) (preferred)

HVAC
Regulation of room pressure – pressure differentials concept
Room pressure
gauges
Room pressure indication panel

HVAC
In the next slides
Consider different air types, e.g.:
 Supply air
 Return air (recirculated air)
 Fresh air (make-up air)
 Exhaust air
And: Concepts of air delivery to production areas:

 Recirculation systems
 Full fresh-air systems

HVAC
Air types
+ Exhaust
Fresh air Supply air
(make-up air) air
Production Room
Return air
(recirculated)

HVAC
Recirculation systems
 There should be no risk of contamination and cross-
contamination when air is recirculated
 Normally, HEPA filters (EN1822 H13) needed in supply air

stream
– Not required in single product facility with no risk of cross-contamination
– Not required where no dust generation (e.g. secondary packaging)
 HEPA filters placed in AHU or terminally
 Dust from highly toxic processes should not be recirculated

7.2.1 – 7.2.6

HVAC
Full fresh-air systems
 100% fresh air - normally where toxic products are processed,
and recirculation not recommended
 No contamination from fresh air – sufficient filtration needed
 Degree of filtration on exhaust dependent on exhaust air

contaminants and environment regulations
 Energy-recovery wheels
– Should not be source of contamination
– Relative pressure between supply and exhaust air
7.3.1 – 7.3.3

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Supplementary Training Modules on

Good Manufacturing Practice

Heating, Ventilation and Air-

HVAC | Slide 1 of 26 May 2006

 HVAC systems can have an impact on product quality

 It can provide comfortable conditions for operators

 The impact on premises and prevention of contamination and

 Temperature, relative humidity control where appropriate

 Supplement to basic GMP text

HVAC | Slide 2 of 26 May 2006

HVAC | Slide 3 of 26 May 2006

HVAC | Slide 4 of 26 May 2006

HVAC | Slide 5 of 26 May 2006

It is "the undesired introduction of impurities (chemical/ microbial/

Impurities could include products or substances other than the

HVAC | Slide 6 of 26 May 2006

HVAC | Slide 7 of 26 May 2006

HVAC | Slide 8 of 26 May 2006

Cross-contamination can be minimized by, e.g.

3. Use of closed production systems

4. Adequate, validated cleaning procedures

5. Appropriate levels of protection of product

6. Correct air pressure cascade

HVAC | Slide 9 of 26 May 2006

The classification should be

HVAC | Slide 10 of 26 May 2006

The classification should be

HVAC | Slide 11 of 26 May 2006

The classification should be

– Clean up time validated –

HVAC | Slide 12 of 26 May 2006

 Product susceptibility to degradation

HVAC | Slide 13 of 26 May 2006

 Number of particles in the air, number of microorganisms in the

HVAC | Slide 14 of 26 May 2006

HVAC | Slide 15 of 26 May 2006

 Air-handling system can be the main tool for reaching required

HVAC | Slide 16 of 26 May 2006

Air Handling Additional Measures

HVAC | Slide 17 of 26 May 2006

Types of Clean room classes

 WHO, EC, PIC/S: A, B, C, D

 US FDA: Critical and controlled

HVAC | Slide 18 of 26 May 2006

Heating, Ventilation and Air-

HVAC | Slide 19 of 26 May 2006

 Type of filters to be used dependent on the quality of ambient

 Manufacturer to determine, select and prove appropriate filters

HVAC | Slide 20 of 26 May 2006

Other technologies: barrier technology/isolator technology.

HVAC | Slide 21 of 26 May 2006

HVAC | Slide 22 of 26 May 2006

Airflow patterns Prefilter

Turbulent Unidirectional Turbulent

HVAC | Slide 23 of 26 May 2006

UDAF in weighing areas

HVAC | Slide 24 of 26 May 2006

HVAC | Slide 25 of 26 May 2006

HVAC | Slide 26 of 26 May 2006

 Sufficient pressure differential required to ensure containment

 Consider effect of other items such as equipment and

 Operating limits and tolerances