PHARMA INDUSTRY HVAC

MAINTENANCE, VALIDATION &

DOCUMENTATION
 Introduction

 Heating, ventilation and air-conditioning (HVAC)

play an important role in ensuring the
manufacture of quality pharmaceutical products.
 The prevention of contamination and cross-
contamination is an essential design consideration
of the HVAC system.
 Temperature, relative humidity and ventilation
should be appropriate and should not adversely
affect the quality of pharmaceutical products
during their manufacture and storage, or the
accurate functioning of equipment.
3 Area 1

I
Area 2 M
P
90% HVAC U
R
IMPURE Area 3 E
AIR PURE AIR
A
I
Area 4 R
10% Returned Air

EXHAUST IMPURE AIR

HVAC Functioning
 Provide a specific set of environment
condition required for the manufacturing
process.

Heating and cooling

Humidifying and dehumidifying
Cleaning the air
Regulate air flow
Pressurization

To prevent contamination
To provide comfortable working
conditions
4 HVAC SYSTEM VALIDATION 19/05/2012
 Introduction
5

 HVAC consists of
 Air conditioner
 AHUs
 Dehumidifiers/Heater
 Filters (Pre/HEPA)
 Dust extractors
 Ducting (for delivery of controlled air)
 Supply fan
 Smoke detector
 Dampers
 Humidity/Temperature/Pressure sensors
 Bag filters
 Heating/Cooling coils
 Protection
Level of Protection
Level Condition Example of area Recommended filtration
Level 1 General Area with normal housekeeping and Primary filters only
maintenance, e.g. warehousing,
secondary packing
Level 2 Protected Area in which steps are taken to protect Production facility operating on 100%
the exposed pharmaceutical starting outside air: primary plus
material or product from secondary filters
contamination or degradation, e.g.
manufacturing, primary packing,
dispensing.
Level 3 Controlled Area in which specific environmental Production facility operating on re
conditions are defined, controlled and circulated plus ambient air,
monitored to prevent contamination or where potential for cross-contamination
degradation of the pharmaceutical exists: Primary plus secondary plus
starting material or product tertiary filters.
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 Air Handling Unit (AHU)

 AHU comprises of air supply,

coarse filtration, heating or
cooling and HEPA filtration.
AHU producing class A, class
B and class C HEPA filters
may be located in the air
handling units. In less clean
rooms they may be located
terminally. There may be
alternative location for return
air i.e low level return air and
ceiling return air.
 HVAC Specifications
11

Temperature 18-23 o C

Relative humidity 45% ± 5%

Dry powder- 30% ± 5%
Moisture sensitive drug- 5% ± 5%
Air velocity 80- 120 ft/min

Air flow Laminar airflow

Pressure gradient 15 Pascal

Particulate count NMT 100 particles of 0.5 µm/ft3

(Critical area)
Air system failure alarm (ASFA)
 Problems With Components

Filters Incorrect retention rate/leaking/badly installed

Fan Low air flow loss of pressure cascade

Flow rate Blocked poor pressure cascade, cross-

controller contamination

Control damper Poorly adjusted, bad pressure differential system

Humidifier Bad water/steam quality/poor drainage/No

elimination of condensed water/poor
drainage/stagnating water
Cooling coil Inappropriate material/internal insulation

Ducts Leaking ducts

 Maintenance
13

 The HVAC system should be subjected to planned preventative

maintenance.
 Maintenance should be done in accordance with written
procedures and records of maintenance should be kept.
 HVAC systems for clean room facilities are normally sophisticated
and maintenance staff should be adequately trained.
 HEPA filters should only be changed by specialists or trained
personnel.
 Where possible, items requiring routine maintenance should be
located outside of the clean zones.
 Any maintenance activity should be critically assessed to
determine any impact on product contamination.
 Prevention of operator contamination should also be addressed at
the design stage, e.g. exhaust air filters that could be
contaminated with harmful products may require safe-change
filter housings.
 HVAC qualification
14

 To ensure that the equipment is designed as per

the requirement, & installed properly
 Action of proving that any equipment works
correctly & leads to the expected result
 HVAC validation
15

Validation Master Plan

User Requirement Specification

Qualification
Design Qualification

Installation Qualification

Operational Qualification

Performance Qualification

Re-Qualification VALIDATION
 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 16
 User Requirement Specification
17

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.
 Design Qualification
18

 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.
 Installation Qualification
19

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.
 Verification of Materials of construction.
 Operational Qualification
20

 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.
Example:
 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)
 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
 Walking around the plant
Finally certification (Sign Off) by Engineering,
User (Production) and QA Heads.
 HVAC 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.
 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
 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
 A. PHYSICAL TESTS

 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 floor and
NMT 1 Ft from work station.)
 A. PHYSICAL TESTS
 Frequency
 Schedule M - 6 Monthly
 GMP compliance - Quarterly
 Acceptance Criteria
AT REST IN OPERATION

Grade Maximum number of permitted particles per cubic metre equal to or

above
0.5 5.0 0.5 5.0
A 3520 29 3500 29
B 35,200 293 3,52,000 2930
C 3,52,000 2,930 35,20,000 29,300
D 35,20,000 29,300 Not defined Not defined
 A. PHYSICAL TESTS
 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.
 Continuously by gauges / manometer & recorded
daily.
 A. PHYSICAL TESTS
Acceptance Criteria
 > 10 Pascal between classified area &
adjacent area of lower classification
 > 15 Pascal between classified area &
unclassified area
Action
 HEPA filter blockage
 Increase fan speed
 Increase air flow to specific area by altering
dampers
 A. PHYSICAL TESTS

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 %

 A. PHYSICAL TESTS

 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
 A. PHYSICAL TESTS

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.
 A. PHYSICAL TESTS
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
and wet bulb depression.
 A. PHYSICAL TESTS

Acceptance Criteria
 Temperature : NMT 27 degree centigrade
 Humidity : NMT 55 %

Frequency
 Daily
 A. PHYSICAL TESTS
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
 A. PHYSICAL TESTS

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
 Schedule M - 6 Monthly
 GMP compliance – Quarterly
 B. MICROBIOLOGICAL TESTS
B.1. Setting Plate Method
 Solid growth media (e.g. settle and contact plates)
Soybean Casein Digest Agar medium can be used for
both Bacteria & Fungi tested.
 Recommended size of solid media is 90 mm in
diameter (for settle plates)
 55 mm (surface area 25 cm²) for contact plates

 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.
 B. MICROBIOLOGICAL TESTS

 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
least 2 days is suitable for the growth of bacteria.

RESULT:
 Counts of over 3 to 5 colonies/cubic meter air are
unsuitable
Recommended Limits For Microbiological
Monitoring Of Clean Areas

Total Viable Count

(Guidelines)
Condition : in operation
Grade EU Schedule – M US

A <1 <1 <1

B <10 <5 <3

C <100 <50 <5

D <200 <100 <100

 B. MICROBIOLOGICAL TESTS

B.2. Slit sampling

 Air sample is to be drawn through the slits and
impinges on a rotating sterile agar plate
 Plates are incubated at 30-350C for 5 days

 No. of colony forming units are counted and

recorded
 List of equipments used
for validation
40
 References
o “Validation in pharmaceutical industry” ;
edited by P.P.Sharma; 1st edition 2007 ; Page169-
192

o “Pharmaceutical Process Validation”;

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

o http://www.qatech.co.in/hvac-validation.html
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