VALIDATION OF HVAC SYSTEM

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CONTENTS
➢ Introduction
➢ AHU
➢ HVAC Qualification
➢ Validation parameter

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INTRODUCTION

To understand:

➢ The need and reason for pharmaceutical

air handling systems.
➢ The technical requirements for air handling
systems.
➢ Different types of air handling systems.
➢ Qualification and Validation requirements

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INTRODUCTION

Air handling systems,

➢ Play a major role in the quality of

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

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INTRODUCTION

The manufacturing environment is critical for

product quality.

Environment consists of,

➢ Light
➢ Temperature
➢ Humidity
➢ Air movement
➢ Microbial contamination
➢ Particulate contamination

Uncontrolled environment can lead to product

degradation
➢ product contamination 5
➢ loss of product and profit
INTRODUCTION

HVAC consists of,

1. Air conditioner
2. AHUs
3. Dehumidifier / Heater
4. Filters (Pre & HEPA)
5. Dust Extractors
6. Ducting (For delivery of controlled air)
7. Supply Fans
8. Smoke Detector
9. Humidity / Temperature / Pressure sensors
10. Bag Filters
11. Heating / Cooling Coils
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INTRODUCTION

HVAC (AHU) is

HEART

of Pharmaceutical Industries

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 INTRODUCTION

Area - 1

I
Area - 2 M
9 P
0 U
%Impure Air HVAC R
Pure Air
Area - 3 E

A
I
Area - 4 R

10% Return Air

Impure Air
8
Exhaust
AIR FLOW PATTERNS

Prefilter

AHU

Main filter

1 2 3

Turbulent Uni-directional Turbulent

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AIR FLOW PATTERNS

Workbench (vertical) Cabin/ booth Ceiling

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HVAC QUALIFICATION

➢ To ensure that equipment is designed as per

requirement, installed properly.
➢ Action of proving that any equipment works
correctly and leads to the expected results.

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HVAC QUALIFICATION

N
TIO
ICA
LIF
QU

VALIDATION 12
 THE VALIDATION MASTER PLAN

This document should contain

➢ Validation
• policy
➢ Organizational structure of validation
activities
➢ Summary of facilities, systems, equipment
and processes to be validated
➢ Documentation format to be used for
protocols and reports
➢ Planning and scheduling
➢ Change control
➢ References to documents 13
USER REQUIREMENT SPECIFICATION

It mainly requires:
➢ Room temperatures and relative humidities
➢ Clean room classifications for the areas i.e. B.
C. or D.
➢ Single pass or re-circulated HVAC systems ?
➢ Room pressures / Air flow directions
➢ GMP requirements.

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USER REQUIREMENT SPECIFICATION

Capacity of HVAC depends on,

1.Room Volume.
2.No. of Air Changes Required.
3.Production / Consumption Data
4.Seasonal fluctuation.
5.Air Classification of Rooms.
6.Future Development.
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USER REQUIREMENT SPECIFICATION
Parameters to be defined in Levels of Protection :

Air cleanliness requirements

1. filters type and position,
2. air changes,
3. air flow patterns,
4. pressure differentials,
5. contamination levels by particulate matter
& micro-organisms.

• User Requirement Specification should be

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approved by Production, Engineering and
QA Heads.
 DESIGN QUALIFICATION

Based on the URS supplier designs the

equipment-First step in the qualification of new
HVAC systems.
➢ It documents the design of the system and will
include :

1. Functional Specification.
2. Technical / Performance specification for
equipment.
3. Detailed Air Flow Schematics.
4. Detailed layout drawing of the system. 17
DESIGN QUALIFICATION

➢ Compliance with GMPs and other regulatory

requirements.
➢ Ensures that design,
1. meets the user requirements.
2. details facility airflow and pressure cascade
philosophy.
3. takes into account process and personnel
flow (cross-contamination issues)
4. Details materials of construction.
5. Details safety requirements.
6. Full details of the intended construction prior
to implementation. 18
7. Details all equipment that must be ordered.
INSTALLATION QUALIFICATION

➢ System Description
➢ Equipment Delivery
➢ Utilities / Facility / Environment
➢ Assembly & Installation

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INSTALLATION QUALIFICATION

IQ Should include,

➢ Instrumentation checked against current

engineering drawings and specifications
➢ Verification of materials of construction
➢ Installation of equipment and with piping
➢ Calibration of measuring instruments
requirements
➢ Collection and collation of supplier
operating and working instructions and
maintenance requirements 20
INSTALLATION QUALIFICATION

Practical aspect of IQ (Cont….)

➢ Calibration of measuring instruments.
➢ Calibration of additionally used instruments.
➢ Initial cleaning records.
➢ Basic commissioning checks.
➢ Maintenance requirements.
➢ IQ process checks that the correct components
are installed in
the correct location.
➢ Materials of construction
➢ Spare parts 21

➢ Change controls
INSTALLATION QUALIFICATION

IQ Document should contain,

➢ Instrument name, model, I.D. No., Personnel
responsible for activities and Date.
➢ A fully verified installation that complies with the
documented design. (all deviations will have
been recorded and assessed.)
➢ All equipment documentation and maintenance
requirements would be documented.
➢ Completed calibration of measuring
instruments.
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➢ Verification of Materials of construction.
OPERATION QUALIFICATION

➢ ISPE definition : The purpose of OQ is to

establish, through documented testing, that all
critical components are capable of operating
within established limits and tolerances.

➢ The purpose of OQ is to verify and document

that an HVAC system provides acceptable
operational control under “at-rest” conditions.

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OPERATION QUALIFICATION

Operation Qualification Checks,

➢ Ability to provide air of sufficient quality and

quantity to ensure achievement of specified
clean room conditions.
➢ Ability to maintain temperature, relative
humidity and pressure set points.
➢ Ability to maintain any critical parameters
stated in the DQ consistently.
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OPERATION QUALIFICATION

➢ Includes the tests that have been developed

from knowledge of processes, systems and
equipment.
➢ Tests to include a condition or a set of
conditions encompassing upper and lower
operating limits, sometimes referred to as
‘worst case’ conditions.

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OPERATION QUALIFICATION

➢ IQ reports must be completed and signed off.

➢ OQ protocols to be written and approved prior to completion.
➢ Measurement reports are required to demonstrate achievement of
critical parameters as detailed in DQ.

Eg: * All relevant SOPs should be in place

* Temperature measurement report
* Humidity measurement report
* Differential pressure measurement report
* Air flow direction measurement report
* Room particle count measurement report
* All drawings etc. – done in ‘as-built’ status
* All maintenance/ cleaning instructions available
* All O & M staff to be trained to use and maintain the system.
* Sign off. (Compliance Certificate by Engineering Dept & QA)
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PERFORMANCE QUALIFICATION

➢ The purpose of PQ is to verify and document

that an HVAC system provides acceptable
control under ‘ Full Operational ‘ conditions.
➢ PQ should follow successful completion of IQ
and OQ.
➢ PQ verifies that over time, the critical
parameters, as defined in the DQ are being
achieved.

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PERFORMANCE QUALIFICATION

PQ Should include,
➢ Tests, using production materials, qualified
substitutes or simulated product, that have
been developed from knowledge of the
process and facilities, systems or equipment.
➢ Test to include a condition or set of
conditions encompassing upper and lower
operating limits.
➢ PQ is used to demonstrate consistent
achievement of critical parameters over time. 28
( under manufacturing conditions)
➢ PQ is ongoing.
QUALIFICATION
COMPLETE DOCUMENTATION

➢ Verification of design documentation, including

✓ Description of installation and functions
✓ Specification of the requirements
➢ Instructions for performance control
➢ Operating procedures
➢ Maintenance instructions
➢ Maintenance records
➢ Training of personnel (program and records)
➢ Environmental records
➢ Discussion on actions if OOS values
➢ Walking around the plant
Finally certification (Sign Off) by Engineering, User
(Production) and QA Heads. 29
VALIDATION

➢ Document act of proving that any procedure,

process, system / equipment ACTUALLY leads
to expected results.

➢ To ensure that system provides continuously

required environmental conditions.

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VALIDATION PARAMETERS

1. Air flow measurement

2. Room air changes per hour.
3. Filter Integrity Testing (HEPA Leak test)
4. Pressure Differentials
5. Particulate count measurement
6. Recovery test
7. Temperature and Relative Humidity
8. Air Flow Pattern
9. Microbial Count
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VALIDATION PARAMETERS

A. PHYSICAL TESTS
A1. NON-VIABLE PARTICLE COUNTS
•Equipment
•Optical Particle Counter (Discrete Particle Counter)
•Air sample is drawn into the instrument & passed
through light scattering device. The signal that this
generates is electronically processed to display particle
counts at different size ranges.
•Sample Volume
•1 cubic ft
•Sample Time
•1 Min 32
VALIDATION PARAMETERS
➢ Sample Location (ISO 14644)
➢ No. of sampling location = NLT Sq. Rt.A
Where A = Area of entrance plan in
Sq.Meter
➢ No. of location rounded to nearest higher
integer
➢ Minimum location 3
➢ Evenly distributed within the area under test
and at a position related to the working
activity (typically at bench height 1m from the 33
floor and NMT 1 Ft from work station.).
VALIDATION PARAMETERS
➢ Frequency
✓ Sch M - 6 Monthly
✓ GMP compliance – Quarterly
➢ Acceptance Criteria

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VALIDATION PARAMETERS
A2. PRESSURE DIFFERENTIALS

Introduction
➢ Correct degree of overpressure can be maintained
relative to the adjacent areas of lower classification
to ensure that air moves from clean areas to less
clean areas.
Equipment
➢ Electronic manometer (portable and easy to use),
➢ Incline manometer
Sample Location
➢ Between adjacent areas connected either by a door
or grille.
➢ Frequency of sampling
➢ Continuously by gauges / manometer & recorded
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daily.
VALIDATION PARAMETERS
– Acceptance Criteria
➢ > 10 Pa between classified area &
adjacent area of lower classification
➢ > 15 Pa between classified area &
unclassified area
– Action
➢ HEPA filter blockage
➢ Increase fan speed
➢ Increase air flow to specific area by
altering dampers
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VALIDATION PARAMETERS
A3. AIRFLOW VELOCITY
Equipment :- Anemometer.
➢ Reading should be taken 10cm from the surface of filter.
➢ Record velocity reading from all the four corners and the Centre of
the filter surface.
➢ Repeat twice at each location
➢ For Grade A laminar flow workstations, the air flow rates shall be
0.3 meter per second + 20% (for vertical flows) and 0.45 + 20%
(for Horizontal flows)

➢ * No value may deviate from the mean by more than + 20 %

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 VALIDATION PARAMETERS

➢ Air velocity exceeding the stated value may

cause excessive air movement & affect work
zone protection.
➢ Air velocity below the limit may be insufficient
to maintain critical work zone protection.

Action: Deviation indicates blockage of filter

Solution : Alteration of fan speed
HEPA filter replacement

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VALIDATION PARAMETERS
A4. HEPA FILTER INTEGRITY TEST
(DOP Test)
Purpose : To confirm that there is no damage to
filter, seals and there is no leakage of particles.

Equipment : 1. Aerosol generator (Using

Dioctylphthalate)
2. Photometer
Scan at 1 inch from filter surface. Traverse at
NMT 10Ft. Min. Cover entire range.
Make separate passes at peripheries.
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VALIDATION PARAMETERS
A5. TEMPERATURE & RELATIVE HUMIDITY
➢ Use a sling psycrometer to measure the dry bulb and
wet bulb temperature of the air.
➢ Check the wick of the sling psycrometer, it should be
always in wet conditions in order to record correct wet
bulb temperature.
➢ Sling the psycrometer in air for about a minute’s time
and record the dry bulb and wet bulb temperature.
➢ Check the wet bulb depression i.e. difference between
dry bulb and wet bulb temperature.
➢ Refer the psycrometric chart to check the relative
humidity corresponding to the dry bulb temperature
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and wet bulb depression.
VALIDATION PARAMETERS
ACCEPTANCE CRITERIA

➢Temperature : NMT 27 degree

centigrade
➢Humidity : NMT 55 %

➢FREQUENCY :Daily

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VALIDATION PARAMETERS
A6. AIR CHANGE RATE (ACR)
Introduction
➢ Conventional clean rooms operate on the principle that the air
supplied to the room is of sufficient quantity to dilute or remove
the contamination generated within the room.
➢ Measurement of the air supply volume and determination of
the air change rate (ACR) is a measure of the frequency of air
turnover in the clean room.
➢ This gives some idea as to how quickly contamination may be
removed from the clean room provided there is acceptable
mixing of air in the room.
➢ The ACR can be determined by measuring the mean air
velocity at the supply HEPAs or grilles and calculating the air
change rate based on the mean air supply volume or by using
a flow measuring hood which collects all of the air from the
supply and gives an air supply volume directly. 42
VALIDATION PARAMETERS

Equipment
➢ Anemometer
Sample locations
➢ At least four positions are tested across
the filter or grille face to obtain the mean
supply air velocity.
Frequency of sampling
➢ Sch M - 6 Monthly
➢ GMP compliance – Quarterly 43
VALIDATION PARAMETERS
Results and interpretation of results

➢ The ACR (per hour) can be calculated using the

following formula: ACR = Air supply volume (m³/s)
x 3600/ Room volume (m³)
Air Volume = Sum ( Avg. Velocity x Filter
area)
➢ Where there is more than one supply HEPA in a
room the air supply volume for each filter should be
determined and the volumes summed (to give a
total air supply volume) before multiplying by 3600
and dividing by the room volume.

➢ To achieve the level of cleanliness in an aseptic 44

room and a clean support room the ACR should be
greater than 20 air changes per hour.
VALIDATION PARAMETERS

Requirement : Class B = 60, C & D = 20 ACPH

Action
• Change the filter
• ACR to be rebalanced

B. MICROBIOLOGICAL TESTS

➢ Solid growth media (e.g. settle and contact

plates) Soybean Casein Digest Agar medium
can be used for both Bacteria & Fungi tested.
➢ The recommended size of solid media is 90 mm
in diameter (for settle plates) 45
➢ 55 mm (surface area 25 cm²) for contact plates.
 VALIDATION PARAMETERS
• Sampling conditions
➢ Sampling in the at rest condition may be continued at
an agreed frequency to monitor baseline
contamination levels.

➢ The operational conditions and the activities being

performed at the time of testing should be recorded.

• Incubation conditions
➢ Incubation of samples, inverted, at 20 - 25C for at
least 5 days is suitable for the growth of mould and
fungi.

➢ Incubation of samples, inverted, at 30 - 35C for at 46

least 2 days is suitable for the growth of bacteria.
VALIDATION PARAMETERS
Recommended Limits for microbiological
monitoring of clean areas
Total Viable Count
(Guidelines)
Conditions : In operation
Grade EU US Air Sampling
(90mm / 4 Hrs) (90mm / 2 Hrs) (90mm / 4 Hrs)
(1000cc)
A <1 <1 <1
B <10 <5 <3
C <100 <50 <5
D <200 <100 <100

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REFERENCES

1. “Validation in pharmaceutical industry” ; edited by

P.P. sharma ;first edition 2007 ; 169-192

2. “Pharmaceutical Process Validation”; An

international 3rd edition; edited by R. A. Nash and A. H.
Wachter; 413-432

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