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 1 of 27

WHO - EDM

Air Handling Systems

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

Module 3, Part 3: Design, qualification and maintenance

Slide 2 of 27

WHO - EDM

Air Handling Systems

Air flow patterns (1)
Turbulent

Uni-directional / laminar

dilution of dirty air

displacement of dirty air

0,30 m/s

Annex 1, 17.3
Module 3, Part 3: Design, qualification and maintenance

Slide 3 of 27

WHO - EDM

Air Handling Systems

Air flow patterns (2)
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
Module 3, Part 3: Design, qualification and maintenance

Slide 4 of 27

WHO - EDM

Air Handling Systems

Air flow patterns (3)

Prefilter
Annex 1, 17.3

AHU

Main filter

Turbulent

Uni-directional

Module 3, Part 3: Design, qualification and maintenance

Slide 5 of 27

Turbulent

WHO - EDM

Air Handling Systems

Air flow patterns (4)
Workbench (vertical)

Cabin/ booth

Module 3, Part 3: Design, qualification and maintenance

Slide 6 of 27

Ceiling

WHO - EDM

Air Handling Systems

Positioning of filters (1)

AHU mounted final filter

Filter in terminal position

HEPA Filter

Production Room

Production Room

HEPA Filter

Module 3, Part 3: Design, qualification and maintenance

Slide 7 of 27

WHO - EDM

Air Handling Systems

Positioning of filters (2)

Prefilter

AHU

Main filter
Ceiling
exhausts
2

Low level exhausts

Module 3, Part 3: Design, qualification and maintenance

Slide 8 of 27

WHO - EDM

Air Handling Systems

Positioning of filters (3)

Final filter

AHU
Prefilter

Module 3, Part 3: Design, qualification and maintenance

Slide 9 of 27

WHO - EDM

Air Handling Systems

Air re-circulation
The filtered air entering a production room can be

100% exhausted or
a proportion re-circulated
GMP aspect
economical reasons
Annex 1, 15.10, 17.24

Module 3, Part 3: Design, qualification and maintenance

Slide 10 of 27

WHO - EDM

Air Handling Systems

Ventilation with 100% fresh air (no air re-circulation)
Washer (optional)

Exhaust Unit
W

Central Air Handling Unit

Production Rooms
Annex 1, 17.24
Module 3, Part 3: Design, qualification and maintenance

Slide 11 of 27

WHO - EDM

Air Handling Systems

Ventilation with re-circulated air + make-up air
Exhaust Unit

Central Air Handling Unit

Return air
Module 3, Part 3: Design, qualification and maintenance

Slide 12 of 27

WHO - EDM

Air Handling Systems

Definition of Conditions
as built

at rest

in operation

air

air

air

Module 3, Part 3: Design, qualification and maintenance

Slide 13 of 27

WHO - EDM

Air Handling Systems

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 re-qualification

Adequate documentation

Module 3, Part 3: Design, qualification and maintenance

Slide 14 of 27

WHO - EDM

Air Handling Systems

Qualification (OQ, PQ) (1)
Uni-directional
airflow / LAF

Test

Turbulent / mixed
airflow

Differential pressure on filters

Room differential pressure

N/A

2, 3

Airflow velocity / uniformity

2, 3

Optional

Airflow volume / rate

Parallelism

N/A

Air flow pattern

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

Module 3, Part 3: Design, qualification and maintenance

Slide 15 of 27

WHO - EDM

Air Handling Systems

Qualification (OQ, PQ) (2)

Uni-directional
airflow / LAF

Test

Turbulent / mixed
airflow

Description

Recovery time

N/A

1 := As built (ideally used to perform IQ)

Room classification (airborne particle)

2,3

2 = At rest (ideally used to perform OQ)

Temperature, humidity

N/A

2,3

3 = Operational (ideally used to perform PQ)

Annex 1, 17. 4

IQ tests are not mentioned on this slide

Module 3, Part 3: Design, qualification and maintenance

Slide 16 of 27

WHO - EDM

Air Handling Systems

Microbiological validation
1.

Definition of alert / action limits as a function of

cleanliness zone
Identification and marking of sampling points

2.

Definition of transport, storage, and incubation conditions

1.

ACTION LIMIT

Ask the question:

What are the alert
and action Limits and
what procedures are
followed if these
points are exceeded?

ACTION LIMIT
ALERT LIMIT

ALERT LIMIT

Design Condition

Normal Operating Range

Operating Range - Validated Acceptance Criteria

Module 3, Part 3: Design, qualification and maintenance

Slide 17 of 27

WHO - EDM

Air Handling Systems

Cleanroom monitoring program (1)
Cleanrooms should be monitored for micro-organisms
and particles
air

Sampling point

Module 3, Part 3: Design, qualification and maintenance

Slide 18 of 27

WHO - EDM

Air Handling Systems

Cleanroom monitoring program (2)
Routine monitoring program as part of quality assurance
Additional monitoring and triggers
1.
2.
3.
4.

Shutdown
Replacement of filter elements
Maintenance of air handling systems
Exceeding of established limits
Annex 1, 17.37

Module 3, Part 3: Design, qualification and maintenance

Slide 19 of 27

WHO - EDM

Air Handling Systems

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

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

Module 3, Part 3: Design, qualification and maintenance

Test Procedure

Slide 20 of 27

WHO - EDM

Air Handling Systems

Cleanroom maintenance program (2)
Schedule of Additional Optional Tests

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

ISO 14644-1 Annex B13

Air Flow Visualisation

All Classes

24 Months

ISO 14644-1 Annex B7

Test Parameter

Class

Module 3, Part 3: Design, qualification and maintenance

Test Procedure
ISO 14644-1 Annex B6

Slide 21 of 27

WHO - EDM

Air Handling Systems

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)

Module 3, Part 3: Design, qualification and maintenance

Slide 22 of 27

WHO - EDM

Air Handling Systems

Inspecting the air handling plant
1.

Verification of design documentation, including

description of installation and functions
specification of the requirements

2.

3.
4.
5.
6.
7.
8.

Operating procedures
Maintenance instructions
Maintenance records
Training logs
Environmental records
Discussion on actions if OOS values
Walking around the plant

Module 3, Part 3: Design, qualification and maintenance

Slide 23 of 27

WHO - EDM

Air Handling Systems

Conclusion
Air handling systems:
1.
2.
3.

Play a major role in the quality of pharmaceuticals

Must be designed properly, by professionals
Must be treated as a critical system

Module 3, Part 3: Design, qualification and maintenance

Slide 24 of 27

WHO - EDM

Air Handling Systems

Further proceedings
This series of explanations will now be followed by:

Group discussion, with a simple exercise

Short test

Module 3, Part 3: Design, qualification and maintenance

Slide 25 of 27

WHO - EDM

Air Handling Systems

Group Session
Sampling
Rooom

Service Corridor
(contains Vacuum & RO water supply)

Air Shower

A/ Lock1

Air Lock2

Warehouse

Weighing

Tablet 1

Tablet 2

Liquids Mix

Softgel Capsule
Packing

Clean Corridor
Emergency
Exit

Air Lock 3

Equipment Wash

Sterile eyedrops
dispensing
& aceptic filling

2 Stage
personnel
entry for
eyedrops

Male
Change 2

Female
Change 2
Packed
Goods
Quarantine

Male
Change 1

Module 3, Part 3: Design, qualification and maintenance

Female
Change 1

Air Lock 4

Slide 26 of 27

Primary & Secondary

Packing

Service Room

WHO - EDM

Air Handling Systems

Group Session modified layout
Sampling
Rooom

20Pa

0Pa

Service Corridor
(contains Vacuum & RO water supply)

30Pa

Air Shower
20Pa
10Pa

MAL 2

Warehouse

0Pa

Weigh
Booth
20Pa

30Pa

Post
Staging
Tablet 1

30Pa

Tablet 2

15Pa

Softgel Capsule
Packing

Liquids Mix

15Pa

30Pa

MAL1

Air Lock
15Pa

30Pa

Clean Corridor
Emergency
Exit

PAL
40Pa

MAL 3
40Pa

Sterile eyedrops
dispensing
& asceptic filling

20Pa

20Pa

Male
Change 2

Female
Change 2

10Pa
60Pa
15Pa

Equipment Wash

MAL 4
50Pa

Change
50Pa

10Pa

Male
Change 1

Female
Change 1

10Pa

Packed
Goods
Quarantine

Air Lock 4
0Pa

MAL = Material Air Lock

Secondary
Packing

20Pa

30Pa

Service Room

0Pa

PAL = Personnel Air Lock

Module 3, Part 3: Design, qualification and maintenance

Slide 27 of 27

Primary
Packing

WHO - EDM

0Pa