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

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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)

HVAC | Slide 2 of 26 May 2006

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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
3. Insufficiently cleaned equipment Glossary,
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

Environment protection 2

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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-
0.5m 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

Level Condition Example of area

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