Supplementary Training Modules on

Good Manufacturing Practice

Heating, Ventilation and AirConditioning (HVAC)

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

HVAC

Slide 1 of 26

May 2006

HVAC
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)
Commissioning, qualification and maintenance (Part 3)
HVAC

Slide 2 of 26

May 2006

1, 2

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

HVAC

Slide 3 of 26

May 2006

1, 2

HVAC
Factors contributing to
quality products

Personnel
Validated processes
Procedures

Starting materials
Equipment

Packing materials
Premises
Environment

HVAC

Slide 4 of 26

May 2006

HVAC
The manufacturing environment is critical for product
:quality. Factors to be considered include
2.

Light
Temperature

3.

Relative humidity

4.

Air movement

5.

Microbial contamination

6.

Particulate contamination

Uncontrolled environment can lead to product degradation

1.

product contamination (including cross-contamination)

loss of product and profit
HVAC

Slide 5 of 26

May 2006

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, microorganisms, endotoxins (degraded microorganisms), etc.

Glossary

HVAC

Slide 6 of 26

May 2006

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
HVAC

Slide 7 of 26

May 2006

Glossary,
4.1.11

HVAC
Cross-Contamination

HVAC

Contaminant
from
Environment
Operators

Contamination

Contaminant
from
Equipment

Product
from
Environment
Operators

Cross
Contamination

Product
from
Equipment

Slide 8 of 26

May 2006

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

Slide 9 of 26

May 2006

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
HVAC

Slide 10 of 26

May 2006

HVAC
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
HVAC

Slide 11 of 26

May 2006

HVAC
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
HVAC

Slide 12 of 26

May 2006

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

Slide 13 of 26

May 2006

HVAC
The classification should be
achieved in the state as
specified (2):

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

4.1.9

HVAC

Slide 14 of 26

May 2006

HVAC
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

HVAC

Slide 15 of 26

May 2006

HVAC
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

HVAC

Slide 16 of 26

May 2006

HVAC

Cleanroom Class A / B
Cleanroom Class C
Cleanrm. Class D

May 2006
Slide 17 of 26
|
HVAC

Others

Manufacturing Environment
requirements

Therapeutic risks

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

Slide 18 of 26

May 2006

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

Slide 19 of 26

May 2006

HVAC
Tools to help achieve the desired Level of Protection

Air Handling
System

Production Room
With
Defined
Requirements

Supply
Air

HVAC

Slide 20 of 26

May 2006

Outlet
Air

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

Slide 21 of 26

May 2006

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

Air Handling
System
HVAC

Slide 22 of 26

May 2006

Additional Measures

HVAC
Examples of Levels of Protection
Types of Clean room classes

HVAC

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

Slide 23 of 26

May 2006

HVAC
Comparing International Cleanroom Classifications
Particles / m3

0.5m
1
3,5
10
35
100
353
1.000
3.530

US 209D
nonmetric

1
10
100

US 209E
1992
metric

M1
M 1.5
M2
M 2.5
M3
M 3.5

EC cGMP
Annex I
1997

A, B

Germany
VDI 2083
1990

UK
BS 5295
1989

Japan
ISO 14644JIS B 9920
1
1989

E or F

G or H

A= unidirectional
B= turbulent

10.000
35.300
100.000
353.000
1.000.000
3.530.000
10.000.000
HVAC

Slide 24 of 26

1.000
10.000
100.000

M4
M 4.5
M5
M 5.5
M6
M 6.5
M7
May 2006

HVAC
Examples of levels of protection
4.1.16

Level

HVAC

Condition

Example of area

Level 1 General

Area with normal housekeeping, e.g.

warehouse

Level 2 Protected

Area where steps are taken to protect

exposed material/product, e.g. dispensing

Level 3 Controlled

Area with defined, controlled, monitored

environmental conditions to prevent
contamination and degradation

Slide 25 of 26

May 2006

HVAC
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

Washing of containers

Preparation of solution for terminal sterilisation

Preparation of solutions for aseptic filling

Depyrogenisation of containers

Filling for terminal sterilisation

Filling for aseptic process
etc.

HVAC

Slide 26 of 26

May 2006

X
X