HVAC Qualification/Validation

Heating, Ventilation and

Air- Conditioning
(HVAC)
WHO Technical Report Series,
No. 1010. Annex 8 2018

Prof.Dr.Yasir Mehmood
President
Pakistan Pharma Technical Alliance
 HVAC Qualification Flow Chart

PQ Docs
URS PERFORMANCE
All PQ tests
What HVAC must QUALIFICATION
PQ Report
do……Acceptance criteria Can we make the product?

OQ Docs
DATA SHEET OPERATIONAL
HEPA tests
How it is works… QUALIFICATION
Airflow
Do the systems work?
Air Changes
Recovery

DESIGN INSTALLATION IQ Docs

QUALIFICATION QUALIFICATION Verify Installation
How to make or install... Is it all there? Calibration
Loop checks

IMPLEMENTATION
FAT & SAT
(Buy & Build)
 DESIGN QUALIFICATION

OBJECTIVE
SYSTEM DESCRIPTION
a. Air Circulation System - Supply Blower Return Blower
b. Air Conditioning & Heating System - Cooling Coil
Heating Coil
c. Air Distribution System - Air Distribution Network
d. Air Filtration System - Fresh Air Filters
Terminal HEPA Filters
e. Dehumidification System - Dehumidifier
f. HFC System - HFC Unit (Hydroflurocarbons)
g. Control System - Instrumentation and Control System
h. Safety System - Safety precautions
3. BASIC DESIGN CONCEPT
4. ACCEPTANCE CRITERIA
METHODOLOGY
Summary and Conclusion
Design Qualification Approval
 INSTALLATION QUALIFICATION

1. Pre-Approval Inspection Checklist

2. Overview Installation Qualification
Purpose Major component Verification
Responsibility Levelling and Alignment
Re-qualification Verification of Utilities
System Description Verification of Installation
System Distribution Check List for Duct Network
Drawings
3. Equipment Specification
Documents
4. Equipment Identification SOP Verification
5. Equipment Location Deficiency (if any) and CAPA
6. Installation Qualification 7. Acceptance Criteria
Procedure 8. Summary
Pre Requisite for IQ Test 9. Conclusion
Test Equipment 10. Post-Approval
Qualification of
Execution Team
 OPERATIONAL QUALIFICATION

1. Pre-Approval
2. Overview
Purpose
Responsibility 4. Acceptance Criteria
Re-qualification 5. Summary
System Description 6. Conclusion
System Distribution 7. Post-Approval
3. Operational Qualification Procedure
Pre Requisite for OQ Test
Test Equipments
Qualification of Execution Team
Inspection Checklist
Operational Qualification
Instrument Calibration
Key Functionality
Operational Checks
Safety Features
SOP verification
Deficiency / Corrective Action
Report
5
 PERFORMANCE QUALIFICATION

1. Pre-Approval
2. Overview
Purpose
Responsibility
Re-qualification
System Description
System Distribution
3. Performance Qualification Procedure
Validation Re-qualification Frequency
Validation Test Procedure
Qualification of Execution team
Test Instrument Calibration Record
3.1 Pressure Drop across the HEPA and Fine filters of Air Handling Unit
3.2 Air Velocity Measurement and Calculation of Air Changes
3.3 Integrity test of HEPA filters
3.4 Differential Pressure Test
3.5 Temperature and Relative Humidity Test
3.6 Air Flow Direction Test
3.7 Cleanliness Class Verification
Particle Count) (Non viable
3.8 Sound level Test
3.9 Light Level Test
3.10 Air Borne Viable Particle Monitoring
3.11 Recovery test
 Re-qualification

Scheduled Qualification
Scheduled qualifications as per validation plan shall be carried out.

Unscheduled Qualification shall be carried out incase of

Substitution of existing HVAC system with a new system.
Replacement of existing HEPA-Filter or critical component.
Any major modification to the existing HVAC system since purchase or after
the last performance qualification.
Frequent surpassing of the alert or action limits of routine environmental monitoring
parameters
Inspecting the air handling plant
1. Verification of design documentation, including
description of installation and functions
specification of the requirements
2. Operating procedures
3. Maintenance instructions
4. Maintenance records
5. Training logs
6. Environmental records
7. Discussion on actions if OOS values
8. Walking around the plant
Documentation requirements
1. Description of installation and functions
2. Specification of the requirements
3. Operating procedures
4. Instructions for performance control
5. Maintenance instructions and records
6. Maintenance records
7. Training of personnel (program and records)
 HVAC Main sub-systems

Exhaust air treatment

Fresh air treatment

(make-up air) Terminal air treatment
+
at production room level

Production Room
Central air handling unit
 HVAC
Components
Components in HVAC may include, depending on need:
 Filters
 Fans
 no fan failure; including supply air fans, return air fans, exhaust air fan, dust
extract system fans
 Driers
 Drying of air with chemical driers, e.g. rotating desiccant wheel
 Frost coils for preheating air
 HVAC
General
 Pharmaceutical products should be manufactured in
areas of appropriate cleanliness
 Prevent contamination and cross-contamination
 Design of HVAC dependent on various factors e.g.
 Outside air quality
 Recirculation of air (or not)
 Products and range of products
 Risk assessment to determine clean room conditions.
 HVAC
General
 Two basic concepts of air delivery

a re-circulation system, and

a full fresh air system (100% outside air supply).
 Recirculation – determine the amount of fresh air based on criteria:

to compensate for leakage and loss

to comply with national building regulations; and
for odour control.
 HVAC
General
 Validated automated monitoring systems (e.g. Building
management systems (BMS), building automation system
(BAS) or system control and data acquisition (SCADA)
system) - capable of indicating any out-of-specification
condition without delay e.g. by means of an alarm
 Also helps with preventive maintenance and trend logging
 Critical alarms easily identifiable, visible and/or audible
 Fan interlock failure matrix
 Fan failures can cause a system imbalance, resulting in a
pressure cascade malfunction with a resultant airflow
reversal.
 HVAC
Air distribution
 Positioning of supply and extract grilles to provide effective
room flushing.
 Low-level return or exhaust air grilles preferred.
 If not possible, a higher air change rate may be needed to
achieve a specified clean area condition, e.g. where
ceiling return air grilles are used.
 There may be alternative locations for return air
HVAC
 HVAC

Air types

+ Exhaust
Fresh air Supply air
(make-up air) air

Production Room
Return air
(recirculated)
 HVAC
Recirculation systems
 Increased risk of contamination and cross-contamination.
 Need HEPA filters (EN1822 classification of H13)
 HEPA filters may not be required:
 a single product facility and there is evidence that cross-
contamination would not be possible.
 No dust generated e.g. secondary packing
 HEPA filters installed in the air-handling unit or terminally
placed
 If terminally mounted - not with flexible ducting
 If highly toxic processes – never recirculate
 HVAC
Ventilation with recirculated air + make-up air

Exhaust Unit

Central Air-Handling Unit

Return air
 HVAC
Full fresh-air systems
 100% fresh air normally used in a facility dealing with toxic
products or solvents, where recirculation of air with
contaminants should be avoided
 Degree of filtration of the exhaust air depends on the
exhaust air contaminants and local environmental
regulations
 HEPA filters in the exhaust system normally when handling
hazardous materials
 HVAC

Ventilation with 100% fresh air (no air recirculation)

Washer (optional)
Exhaust Unit

Central Air-Handling Unit

Production Rooms
Definition of Conditions

as built at rest in operation

air air air
 Air flow patterns (4)
Workbench (vertical) Cabin/ booth Ceiling
 Air flow patterns (1)
Turbulent Uni-directional / laminar
dilution of dirty air displacement of dirty air

0,30 m/s
Air flow patterns (3) Prefilter

AHU

Main filter

1 2 3

Turbulent Uni-directional Turbulent

 Positioning of filters (1)

AHU mounted final filter Filter in terminal position

HEPA Filter

Production Room Production Room

HEPA Filter
 Positioning of filters (2)
Prefilter

AHU

Main filter
Ceiling
exhausts

1 2 3

Low level exhausts

 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

 Weather louvre  To prevent insects, leaves, dirt and

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

Components
 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
 Ducts microorganisms
 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

HEPA or tertiary filter

Primary panel filter

Secondary filter
 HVAC

3
4

1 Filter
Swirl Type air diffusors with
2 Tightening frameterminal filters
3 Register outlet
4 Screw fixation for register
 HVAC
Problems with components
 Flow rate controller  Blocked
 Control damper  Poorly adjusted, bad pressure
differential system
 Humidifier  Bad water/steam quality/
poor drainage
 Cooling battery  No elimination of condensed water/
poor drainage
 Filters  Incorrect retention
rate/damaged/badly installed
 Ducts  Inappropriate material/internal
insulator leaking
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
 Cleanroom monitoring program (1)

Cleanrooms should be monitored for micro-organisms

and particles air

Sampling point
Cleanroom monitoring program

Routine monitoring program as part of quality

assurance
Additional monitoring and triggers
1. Shutdown
2. Replacement of filter elements
3. Maintenance of air handling systems
4. Exceeding of established limits
 Cleanroom maintenance program
Schedule of Tests to Demonstrate Continuing Compliance

Test Parameter Class Maximum Time Test Procedure

Interval
Particle Count Test A, B 6 Months ISO 14644 -1 Annex A
<= ISO 5
C, D 12 Months ISO 14644 -1 Annex A
> ISO 5
Air Pressure Difference All Classes 12 Months ISO 14644 -1 Annex B5

Air Flow All Classes 12 Months ISO 14644 -1 Annex B4

 Cleanroom maintenance program
Schedule of Additional Optional Tests

Test Parameter Class Maximum Time Test Procedure

Interval
Installed Filter Leakage All Classes 24 Months ISO 14644-1 Annex B6

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

 Examples of aspects to consider in qualification
(OQ, PQ)
Uni-
Turbulent /
Test directional
mixed airflow
Description
airflow / LAF
Differential pressure on
2 2
filters
Room differential 1 := As built (ideally used to
N/A 2, 3
pressure perform IQ)
Airflow velocity /
2, 3 Optional 2 = At rest (ideally used to
uniformity
perform OQ)
Airflow volume / rate 2 2
3 = Operational (ideally used to
Microbial checks 2,3 2,3 perform PQ)

Airflow pattern 2 3

Recovery time N/A 2

Room classification
2 2,3
(airborne particle)
Temperature, humidity N/A 2,3
42
Pressure Drop across the HEPA and Fine filters of Air Handling Unit

Objective:
The purpose of this test is to check the Clogged or clean condition
of the across HEPA filters, Fine Filter and Pre - filter, of the Air
Handling Unit.

Test Equipment:
Differential pressure Transmitter or Manometer

Procedure for HEPA, Fine and Pre Filters:

Manom
Ensure that the differential pressure transmitter is connected to
before the filter and after the filter.
Check the status of the filter whether the filter is in clean condition

eter
or Clogged condition.

Acceptance Criteria:
HEPA, Pre and Fine filters should be in clean condition.
 Air Velocity Measurement and Calculation of Air Changes

Objective:
To demonstrate that the air system is balanced and capable of delivering air velocities and providing
number of air changes per hour in the respective rooms as per requirement.

Test Equipment:
Digital Anemometer / Vane Anemometer.

Procedure:
For compliance of air change rate, velocity to be measured at 5 different locations 2” below the each
Terminal HEPA Filter or Grill (Four Corners and center) with the help of calibrated Anemometer. Anemomet
Calculate the average velocity of the air coming from Supply Grill / Terminal Filter.
Calculate the airflow by multiplying the average velocity with the effective Grill area. er
Air flow = Average Velocity x Face Area of the Air Inlet Grill / Filter
= Ft / Min. x Ft 2
= Ft 3 / Min. or CFM

Calculate the total airflow from all the Supply Grill / Terminal Filter in the room and add values to get
the total airflow in the room (CFM).
Calculate the number of air changes per hour in the room by using the formula :

Total air flow in the room (CFM) x 60 = Air Changes / hour

Room Volume ( Ft 3 )
Acceptance Criteria:
Average velocity and subsequent airflow through supply terminals should meet the design criteria of
air change rate as per requirement.
Air Velocity Measurement and Calculation of Air Changes Cont…

CLASS Number of Air Changes / Hour

CLASS 100 NLT 250

CLASS 10 000 60 + 10 %

CLASS 1 00 000 40 + 10 %

45
 Integrity (Leak) test of HEPA filters

Objective:
To check the installation integrity of the HEPA Filter in Air Handling Units.

Test Equipment:
Aerosol generator
Aerosol Photometer, duly calibrated with national / international traceability.
DOP Liquid (Di Octyl Phthalate) / PAO (Poly Alpha Olefin) Liquid

Procedure: Aerosol
Position the Aerosol generator and introduce Aerosol into the upstream air,
ahead of the HEPA filters, at the concentration of 80-100 g per liter (this can
Generator
be achieved with a compressed air pressure of 25 Psig) of air at the filter’s
designed airflow rating and set the instrument at 100% concentration. Scan
the downstream side of the filter with an appropriate photometer probe at a
sampling rate of at least 1 ft3 / min. The probe should scan the entire filter face
and frame at a position about 1 to 2 inches from the face of the filter. Scanning
shall be done at the rate of maximum 2 feet per minute.

Acceptance Criteria:
During scanning percentage of the PAO/ DOP Liquid penetration shown by
photometer should be less than 0.01% through the filter media and should be
‘zero’ through mounting joints for 99.97 efficiency HEPA Filters and 0.001% for
99.997 Efficiency.
Aerosol
Photometer
 HVAC
Differential Pressure Test

Objective:
To demonstrate the capability of air system and to provide pressure gradient
among different rooms.

Equipment Used:
Differential Pressure Display Unit or BMS System.

Procedure:
To avoid unexpected changes in air pressure and to establish a baseline, all
doors in the facility must be closed and no man movement to be allowed
during the observations. Observe the differential pressure through Display
Unit or BMS System

Acceptance Criteria: Differential Pressure

Pressure differentials should meet the requirement as specified in SYSTEM Gauge
SPECIFICATION.
 Temperature and Relative Humidity Test

Objective:
To demonstrate the ability of the HVAC system to provide temperature and Relative
Humidity within the specified range.
Test Equipment:
Temperature and Relative Humidity Sensor
Display Unit for Temperature and Relative Humidity
Procedure:
Observe the temperature and relative humidity through respective display unit wherever Hygro meter
installed. Use Hygrometer to check the reading of Temperature and RH in other rooms.
Temperature and RH in the area to be checked and recorded in Static as well as
Sensor
Dynamic Condition.
Static Condition:
In static condition all the machines shall be kept switched ‘OFF’. Only restricted man
movement shall take place.
Dynamic Condition:
In dynamic condition machines having maximum loads shall run and restricted man
movement shall take place.

Acceptance Criteria
Temperature and relative humidity should meet the requirement as specified in system
specification. Hygro meter
 Air Flow Direction Test

Objective
To ensure that the HFC system in aseptic area, LAF and Pass box provide unidirectional
airflow up to the working height during rest and operating condition.
To demonstrate that the air pressure is balanced and air is flowing from high-pressure
zone to low pressure zone.
Procedure
Unidirectional Air Flow Area:
Static Condition in Unidirectional Air Flow Area:
Under HFC, no specific operation shall be carried out except Air Flow Pattern Test
Place a torch of Dry Ice / TiCl4 under HFC.
Observe the flow of Dry Ice / TiCl4 smoke at the filter downstream.
Videotape the smoke flow pattern.
Dynamic Condition in Unidirectional Air Flow Area:
During operation place a torch of Dry Ice / TiCl4 under HFC.
Observe the flow of Dry Ice / TiCl4 smoke at the filter downstream.
Videotape the smoke flow pattern.
Non Unidirectional Air Flow Area:
Place the torch of Dry Ice / TiCl4 in between two rooms in door open condition.
Observe the flow of Dry Ice / TiCl4 smoke between the rooms.
Videotape / Photograph the smoke flow pattern.
Acceptance Criteria
Under HFC, Smoke Flow should be unidirectional up to working height
Smoke should flow from the higher-pressure zone to low-pressure zone between the
rooms when the door is open.
 Cleanliness Class Verification (Non viable Particle Count)

Objective:
To verify that the clean rooms are having cleanliness class as specified in
specification sheet.

Test Equipment:
Air borne particulate counter of 1 CFM suction capacity, duly calibrated with
traceability to national / international standard.

Procedure:
Particulate counting shall be carried out at predefined locations.
Particulate Count shall be taken in 3 rounds of Static condition and 3 rounds of
Dynamic condition. Air borne particulate
Static Condition: counter
In static condition all the machines shall be kept switched ‘OFF’. Only restricted man
movement shall take place.
Dynamic Condition:
In dynamic condition the operator shall mock desired operation and restricted man
movement shall take place.

Acceptance Criteria:
Clean room or clean zone shall meet the acceptance criteria for an air borne
particulate as referred in standard ISO 14644-1.
 HVAC
Cleanliness Class Verification (Non viable Particle Count) Cont…. 3.7
ISO 14644-1
> 0.1 m > 0.2 m > 0.3 m > 0.5 m > 1.0 m > 5.0 m
ISO 14644-1 (Particles / (Particles / (Particles / (Particles / (Particles / (Particles /
Mt3) Mt3) Mt3) Mt3) Mt3) Mt3)

ISO 1 1 2 0 0 0 0

ISO 2 100 24 10 4 0 0

ISO 3 1 000 237 102 35 8 0

ISO 4 10 000 2 370 1 020 352 83 0

ISO 5 1 00 000 23 700 10 200 3 520 832 29

ISO 6 10 00 000 2 37 000 1 02 000 35 200 8 320 293

ISO 7 NA NA NA 3 52 000 83 200 2 930

ISO 8 NA NA NA 35 20 000 8 32 000 29 300

ISO 9 NA NA NA 3 52 00 000 83 20 000 2 93 000

51
 HVAC
Cleanliness Class Verification (Non viable Particle Count) Cont…. 3.7
FED STD 209 E CLASS

> 0.1 m > 0.2 m > 0.3 m > 0.5 m > 5.0 m
FED 209 E CLASS
(Particles / Mt3) (Particles / Mt3) (Particles / Mt3) (Particles / Mt3) (Particles / Mt3)

1 35 7.5 3 1 NA

10 350 75 30 10 NA

100 NA 750 300 100 NA

1 000 NA NA NA 1 000 7

10 000 NA NA NA 10 000 70

1 00 000 NA NA NA 1 00 000 700

52
 HVAC
Cleanliness Class Verification (Non viable Particle Count) Cont…. 3.7
EU GGMP

Static (at rest) Dynamic (in operation)

EU GGMP
> 0.5 m > 5.0 m > 0.5 m > 5.0 m
(Particles / Mt3) (Particles / Mt3) (Particles / Mt3) (Particles / Mt3)

GRADE A 3 500 1 3 500 1

GRADE B 3 500 1 3 50 000 2 000

GRADE C 3 50 000 2 000 35 00 000 20 000

GRADE D 35 00 000 20 000 Not defined Not defined

GRADE E Not defined Not defined Not defined Not defined

53
 Cleanliness Class Verification (Non viable Particle Count) Cont….
FED STD 209 E / ISO 14644-1 / EU GGMP
EU GGMP
FED 209 E CLASS ISO 14644-1
(in operation)
CLASS
> 0.5 m > 5.0 m > 0.5 m > 5.0 m > 0.5 m > 5.0 m
(Particles / (Particles / (Particles / (Particles / (Particles / (Particles /
Mt3) Mt3) Mt3) Mt3) Mt3) Mt3)

Class 100 /
ISO 5 / 100 NA 3 520 29 3 500 1
Grade A
Class 10 000
/ ISO 7 / 10 000 70 3 52 000 2 930 35 00 000 20 000
Grade C
Class 100 000 /
Not Not
ISO 8 / 1 00 000 700 35 20 000 29 300
defined defined
Grade D
 Sound level Test

Objective:
To verify that the sound level is in limit in the clean room area.

Test Equipment:
Sound Level Meter, duly calibrated with traceability to national /
international standard.

Procedure:
Take the reading at 5 locations in the room and take the average of the
sound in the unit of decibels.

Sound Level Meter

Acceptance Criteria:
The clean room or clean zone shall meet the acceptance criteria for sound
level as mentioned below.
 Sound level Test Cont….

Sound Level Limit

S.No Cleanliness Class
( db )

1 Class 100 / ISO 5 NMT 60

2 Class 10, 000 / ISO 7 NMT 80

3 Class 1,00, 000 / ISO 8 NMT 80

 HVAC
Light Level Test 3.9

Objective:
To verify that the Light level is in limit in clean room area.

Test Equipment:
Lux Meter, duly calibrated with traceability to national / international standard.

Procedure:
Take the reading at 5 locations in the room and take the average of the light level in
the unit of Lux.

Acceptance Criteria: Lux Meter

The clean room or clean zone shall meet the acceptance criteria for light level as
mentioned below.

57
 Light Level Test Cont….

S.No Cleanliness Class Lighting Level Limit (lux)

1 Class 100 / ISO 5 NLT 400

2 Class 10, 000 / ISO 7 NLT 300

3 Class 1,00, 000 / ISO 8 NLT 300

 Air Borne Viable Particle Monitoring

Objective:
To determine the air borne microbial contamination level in critical area.

Air borne microbial count by settling plate exposure

method:
Pre incubated SCDA Media plates shall be exposed in Locations mentioned for 4 hours
and incubated for 48 hours at 30°C to 35°C followed by next 72 hours at 20°C to
25°C.Record the results in respective format. PDA plates shall be exposed weekly to Petri Dish
monitor the fungal counts. SCDA plates shall be incubated once in fifteen days to monitor
the anaerobic Microorganisms

Air borne microbial count by Active Air Sampling:

To check the Viable Air borne particle count active air sampling is done and incubate the
tested Cassettes for 48 hours at 30°C to 35°C and further for 72hours at 20°C to 25°C and
observations are recorded in the respective format.

Acceptance Criteria:
All the Parameters performed in the area should meet the following requirements.

Air Borne
59
Particle Counter
 Air Borne Viable Particle Monitoring Cont…

Microbial Count

Plate Exposure Air Sampling

Locations
[CFU/plate] [CFU/ 1 m3]

Alert Action Alert Action

Class 100 --- <1 ----- <1

Class 10000 3 5 3 5

Class 100000 20 30 20 30
 Recovery test

Objective:
To establish the recovery time frame for the area to attain the required conditions
after the simulation of particle counts from class A & class B.

Test Equipment:
Non-viable particle counter dually calibrated.

Procedure:
Simulate and ensure to a count equivalent to that of grade C areas at rest by the
following methods as below:
Personnel Movement.
Garments dusting.
Operate the Air borne non – viable particulate counter in the Class A & B areas
Air borne particulate
and continuously operate the non viable particulate counter and note down the counter
time taken after restoration as equivalent to class A & B.

Acceptance Criteria:
During restoration the particle count limits should fall in the class limits (as
referred in standard ISO 14644-1).
Q&A
Than Q