Department of Quality Assurance
Maliba Pharmacy College
Validation of HVAC
Validation master plan
Heating Ventilation and Air Conditioning
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
Temperature, relative humidity control where appropriate
Supplement to basic GMP
It is "the undesired introduction of impurities (chemical/
microbial/ foreign matter) into or on to starting material or
intermediate – during sampling, production, packaging or
Contaminants are :-
Products or substances other than the product being
Endotoxins (degraded micro-organisms)
“Contamination of a starting material, intermediate product,
or finished product with another starting material or product
Cross-contamination originates from:-
Poorly designed air handling systems and dust extraction
Poorly operated and maintained air handling systems and
dust extraction systems
Inadequate procedures for personnel and equipment
Insufficiently cleaned equipment
Use of closed production systems
Adequate, validated cleaning procedures
Appropriate levels of protection of product
Correct air pressure cascade
Dehumidifier / Heater
Filters (Pre & HEPA)
Ducting (For delivery of controlled air)
Humidity / Temperature / Pressure sensors
Heating / Cooling Coils
Area 2 I
Impure air Pure air U
Area 3 R
Area 4 I
Exhaust Air Grille
Silencer Flow rate controller Fan Filter
Weather louvre Control damper
Prefilter Terminal filter
Cooling Secondary Filter Production Room
Precursor to qualification
Includes setting up, balancing, adjustment and testing
of entire HVAC system to ensure it meets requirements
Acceptable tolerances for parameters
Training of personnel
Records and data maintained include:-
Installation records – documented evidence of measure
capacities of the system
Data: design and measurement for, e.g. air flow, system
O&M manuals, schematic drawings, protocols, reports
To ensure that equipment is designed as per requirement,
Action of proving that any equipment works correctly and
leads to the expected results.
Validation Master Plan
User Requirement Specification
Manufacturers should qualify HVAC systems using a risk-
The qualification of the HVAC system should be described
in a validation master plan (VMP).
The validation master plan should define the nature and
extent of testing and the test procedures and protocols to be
A change control procedure should be followed
Risk analysis to determine critical and non-critical parameters,
components, subsystems and controls
Critical parameters should be included
Non-critical systems and components are subjected to Good
Engineering Practices (GEP)
Acceptance criteria and limits defined in design stage
Design conditions, normal operating ranges, operating ranges,
alert and action limits
This document should contain :
Organizational structure of validation activities
Summary of facilities, systems, equipment and processes to be
Documentation format to be used for protocols and reports
Planning and scheduling
References to documents
Typical parameters to be included in qualification:
Supply, return and exhaust air quantities
Room air change rates
Room pressures (pressure differentials)
Room clean-up rate
Particulate matter, microbial matter (viable and non-
HEPA filter penetration test
Time intervals and procedure to be defined by the
Influenced by the type of facility and level of
Requalification, and change control Tests performed
according to protocols and procedures for the tests
Results recorded and presented in report
Test procedure Maximum time Objective Test Parameter
and key aspects interval
Particle count test 6 months or 12 Verifies Particle count
Readings and months cleanliness
positions depending on
Measure pressure 12 months Absence of Air pressure
difference cross- difference
Measure supply and 12 months Verify air Airflow volume
return air, calculate change rates
air change rate
Velocity 12 months Verify Airflow velocity
airflow and or
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.
Compliance with GMPs and other regulatory
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-
4. Details materials of construction.
5. Details safety requirements.
6. Full details of the intended construction prior to
7. Details all equipment that must be ordered.
IQ Should include:-
Instrumentation checked against current engineering
drawings and specifications
Properly served by the required utilities
Verification of materials of construction
Installation of equipment and with piping
Calibration of measuring instruments
Operation manuals and spare parts lists to assure the proper
and continuous operation of the system
Components are installed at specified location
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
All equipment documentation and maintenance
requirements would be documented.
Completed calibration of measuring instruments.
To provide a list of critical instrumentation and control panel
and to document that they have been identified and
calibrated in accordance with the approved procedure
SOP verification :
To verify that required SOPs exist in either draft or final
form and must be current and approved for use.
Utilities Connection Verification:
Utilities supported to HVAC need to be verified to assure
that they are installed properly.
Change Parts and Replacement Parts Verification
Maintenance Procedures Verification
Critical Systems Change Request Procedure verification
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.
Scope of OQ is to test the individual components of the
system such as AHU, blowers and others.
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
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.
Testing Equipment Calibration Verification
Instrumentation Calibration verification
Operation Qualification tests
OQ protocols to be written and approved prior to
completion. It includes following:
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 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)
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 the critical parameters, as defined in the
DQ are being achieved.
PQ Should include -
Test to include a condition or set of conditions
encompassing upper and lower operating limits.
Tests should be conducted under “in use”, condition either
or simulated as close as possible to the actual process
PQ is used to demonstrate consistent achievement of
critical parameters over time. ( under manufacturing
PQ and OQ tests are sometimes performed in conjunction
with one another.
Any changes to the HVAC system should be revalidated
before proceeding to the PQ phase.
Air flow measurement
Room air changes per hour.
Filter Integrity Testing (HEPA Leak test)
Particulate count measurement
Temperature and Relative Humidity
Air Flow Pattern
Microbial Count 35
A. PHYSICAL TESTS
A1. NON-VIABLE PARTICLE COUNTS
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
1 cubic ft
GMP compliance:- Quarterly
Sch M - 6 Monthly
1. Critical environments: The particle concentration under the
dynamic condition should not more than 100 particle of 0.5µm
and larger per cubic meter (for class 100 area)
A2. PRESSURE DIFFERENTIALS
● 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.
Electronic manometer (portable and easy to use),
o Sample location
Between adjacent areas connected either by a door or grille.
o Frequency of sampling
Continuously by gauges / manometer & recorded daily.
> 10 Pa between classified area & adjacent area of lower
> 15 Pa between classified area & unclassified area
HEPA filter blockage
Increase fan speed
Increase air flow to specific area by altering dampers
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 %
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.
Deviation indicates the blockade of filter
Solution : Alteration of fan speed or HEPA filter
A4. HEPA filter integrity test (DOP test)
To confirm that no damage to filter, seals and no leakage of
1. Aerosol generator
Scan at 1 inch from filter surface.
Make separate passes at peripheries.
An unacceptable leak is defined as a penetration of 0.03% or
more of particle, 0.3µm and larger than the reference
calibration curve for 99.97% efficient filter
A5. Temperature and 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
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.
Temperature : NMT 27 degree centigrade
Humidity : NMT 55 %
Frequency : Daily
A6.Air change rate:
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.
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
A7. MICROBIOLOGICAL TESTS
Solid growth media (e.g. settle and contact plates) Soybean
Casein Digest Agar medium can be used for both Bacteria &
The recommended size of solid media is 90 mm in diameter
(for settle plates)
55 mm for contact plates.
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 of samples, inverted, at 20 – 25o C for at least 5
days is suitable for the growth of mould and fungi.
Incubation of samples, inverted, at 30 - 350C for at least 2
days is suitable for the growth of bacteria.
Acceptance criteria for Airborne Bioburden test:
Critical Environment: no more than 1 CFU/m3, or
0.03 CFU/ft3(USP monograph)
Acceptance criteria for Surface Bioburden test:
Critical Environment: no more than 1 CFU/12.9cm2,
or 2 in2 (FDA Aseptic Processing Guidelines)
Supplementary guidelines on good manufacturing
practices for HVAC systems for non-sterile
pharmaceutical dosage forms. (WHO Technical Report-
Series, No. 937), Annex 2.(2006)
Validation of pharmaceutical process, sterile product
2ndEdition, edited by Fredrick J. Carleton, James P.
Agalloco, page no.240-256.