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

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Objectives
To understand:
 The need for HVAC systems (Part 1a)
 The role of HVAC in protection:
– Product
– Personnel
– Environment

 The role of HVAC in dust control (Part 1b)

 HVAC system design and its components (Part 2) 1, 2

 Commissioning, qualification and maintenance (Part 3)

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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

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Personnel
Factors contributing to
Validated processes
quality products
Procedures

Starting materials

Equipment

Packing materials
Premises

Environment

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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

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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

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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
Glossary,
3. Insufficiently cleaned equipment 4.1.11

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Cross-Contamination

Contaminant
Contaminant
from
Contamination from
Environment
Equipment
Operators

Product
Product
from Cross
from
Environment Contamination
Equipment
Operators

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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

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The guideline further focuses on three concepts of
the system:
 Product protection
– Contamination
– Cross-contamination
– Environmental conditions

 Personnel protection
– Prevent contact
– Comfort conditions
2
 Environment protection

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Protection: Product and personnel
 Areas where materials and products are exposed, should be
classified as "clean areas"
 Achievement of clean area classification depends on factors such
as:
– Building finishes and structure
– Air filtration
– Air change rate
– Room pressure
– Temperature
– Relative humidity
– Material and personnel flow
– Outside environment 4.1.1 - 4.1.3

– Occupancy and type of product

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 Air filtration and air change rate should ensure attainment of
classification

 Air change rate is dependent on factors, e.g.

– Level of protection required
– Quality and filtration of supply air
– Particulates generated
– Room configuration
– Containment effect
– Room heat load
– Room pressure 4.1.4 - 4.1.6

 Air change rate normally varies between 6 – 20 air changes

per hour
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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

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The classification should be

achieved in the state as
specified (2):

 "At rest"
– Equipment may be operating, but
no operators present

4.1.9

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The classification should be

achieved in the state as
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

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Control of contaminants

 External contaminants removed through effective filtration

 Internal contaminants controlled through dilution and flushing,

or displacement airflow

 Airborne particulates and level of filtration considered critical

4.1.12 - 4.1.15

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 Cleanroom Class A / B
Cleanroom Class C Therapeutic risks
Cleanrm. Class D
HVAC

Others

May 2006
Slide 17 of 26
Manufacturing Environment
requirements

|
HVAC
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Level of protection and air cleanliness determined
according to:
 Product to be manufactured

 Process to be used

 Product susceptibility to degradation

4.1.16

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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

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Tools to help achieve the desired Level of Protection

Air Handling
System

Production Room
Supply With Outlet
Air Defined Air
Requirements

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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

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Tools to help achieve the desired Level of Protection (2)

Cleanroom Class
defined by
Critical Parameters

Air Handling Additional Measures

System

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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

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Comparing International Cleanroom Classifications
Particles / m3 US 209D US 209E EC cGMP Germany UK Japan ISO 14644-
 0.5µm non- 1992 Annex I VDI 2083 BS 5295 JIS B 9920 1
metric metric 1997 1990 1989 1989
1
3,5 0 2 2
10 M1
35 1 M 1.5 1 3 3
100 M2
353 10 M 2.5 2 4 4
1.000 M3
3.530 100 M 3.5 A, B 3 E or F 5 5
A= unidirectional
B= turbulent
10.000 M4
35.300 1.000 M 4.5 4 G or H 6 6
100.000 M5
353.000 10.000 M 5.5 C 5 J 7 7
1.000.000 M6
3.530.000 100.000 M 6.5 D 6 K 8 8
10.000.000 M7

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Examples of levels of protection
4.1.16

Example of area Condition Level

Area with normal housekeeping, e.g. General Level 1
warehouse
Area where steps are taken to protect Protected Level 2
exposed material/product, e.g. dispensing
Area with defined, controlled, monitored Controlled Level 3
environmental conditions to prevent
contamination and degradation

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All operations within a pharmaceutical facilility should be
correlated to well-defined clean room classes, and can be
included in a hygiene concept.
Example:

Cleanroom Class A B C D

Washing of containers X
Preparation of solution for terminal sterilisation X

Preparation of solutions for aseptic filling X X X

Depyrogenisation of containers X

Filling for terminal sterilisation X

Filling for aseptic process X
etc.

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