Department of Quality Assurance
Maliba Pharmacy College
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Introduction
Validation of HVAC
HVAC Qualification
Validation master plan
Design Qualification(DQ)
Installation Qualification(IQ)
Operational Qualification(OQ)
Performance Qualification(PQ)
Validation parameter
References
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Heating Ventilation and Air Conditioning
system(HVAC)
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
stage
 Temperature, relative humidity control where appropriate
 Supplement to basic GMP
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It is "the undesired introduction of impurities (chemical/
microbial/ foreign matter) into or on to starting material or
intermediate – during sampling, production, packaging or
repackaging“.
Contaminants are :
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Products or substances other than the product being
manufactured
Foreign matter
Particulate matter
Micro-organisms
Endotoxins (degraded micro-organisms)
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“Contamination of a starting material, intermediate product,
or finished product with another starting material or product
during production”.
Cross-contamination originates from:
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Poorly designed air handling systems and dust extraction
systems
Poorly operated and maintained air handling systems and
dust extraction systems
Inadequate procedures for personnel and equipment
Insufficiently cleaned equipment
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Personnel procedures
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Adequate premises
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Use of closed production systems
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Adequate, validated cleaning procedures
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Appropriate levels of protection of product
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Correct air pressure cascade
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Air conditioner
AHUs
Dehumidifier / Heater
Filters (Pre & HEPA)
Dust Extractors
Ducting (For delivery of controlled air)
Supply Fans
Smoke Detector
Dampers
Humidity / Temperature / Pressure sensors
Bag Filters
Heating / Cooling Coils
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Area 1
Area 2
HVAC
Impure air
Pure air
Area 3
Area 4
I
M
P
U
R
E
A
I
R
10% Return
Air
Exhaust
air
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HVAC
components
Exhaust Air Grille
Silencer
Weather louvre
Flow rate controller
Fan
Filter
Control damper
Heater
+
Prefilter
Humidifier
Cooling
coil
Heating
with
coil
droplet
separator
Secondary Filter
Terminal filter
Production Room
Recirculated air
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It includes:
Commissioning
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Qualification
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Maintenance
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Precursor to qualification
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Includes setting up, balancing, adjustment and testing
of entire HVAC system to ensure it meets requirements
in URS.
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Acceptable tolerances for parameters
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Training of personnel
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Records and data maintained include:
Installation records – documented evidence of measure
capacities of the system
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Data: design and measurement for, e.g. air flow, system
pressures
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O&M manuals, schematic drawings, protocols, reports
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To ensure that equipment is designed as per requirement,
installed properly.
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Action of proving that any equipment works correctly and
leads to the expected results.
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Validation Master Plan
QUALIFICATION
User Requirement Specification
Design Qualification
Installation Qualification
Operation Qualification
Performance Qualification
Re- Qualification.
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Manufacturers should qualify HVAC systems using a riskbased approach.
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The qualification of the HVAC system should be described
in a validation master plan (VMP).
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The validation master plan should define the nature and
extent of testing and the test procedures and protocols to be
followed.
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A change control procedure should be followed
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Risk analysis to determine critical and non-critical parameters,
components, subsystems and controls
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Critical parameters should be included
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Non-critical systems and components are subjected to Good
Engineering Practices (GEP)
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Acceptance criteria and limits defined in design stage
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Design conditions, normal operating ranges, operating ranges,
alert and action limits
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This document should contain :
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Validation policy
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Organizational structure of validation activities
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Summary of facilities, systems, equipment and processes to be
validated
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Documentation format to be used for protocols and reports
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Planning and scheduling
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Change control
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References to documents
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Typical parameters to be included in qualification:
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Temperature
Relative humidity
Supply, return and exhaust air quantities
Room air change rates
Room pressures (pressure differentials)
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Room clean-up rate
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Particulate matter, microbial matter (viable and nonviable)
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HEPA filter penetration test
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Time intervals and procedure to be defined by the
manufacturer
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Influenced by the type of facility and level of
protection
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Requalification, and change control Tests performed
according to protocols and procedures for the tests
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Results recorded and presented in report
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Test procedure
and key aspects
Maximum time
interval
Objective
Test Parameter
Particle count test
Readings and
positions
6 months or 12
months
depending on
Class
Verifies
cleanliness
Particle count
Measure pressure
difference
12 months
Absence of
crosscontaminatio
n
Air pressure
difference
Measure supply and
return air, calculate
air change rate
12 months
Verify air
change rates
Airflow volume
Velocity
measurement
12 months
Verify
Airflow velocity
unidirectional
airflow and or
containment
condition
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First step in the qualification of new HVAC systems.
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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.
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Compliance with GMPs and other regulatory
requirements.
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Ensures that design 1. Meets the user requirements.
2. Details facility airflow and pressure cascade philosophy.
3. Takes into account process and personnel flow (crosscontamination issues)
4. Details materials of construction.
5. Details safety requirements.
6. Full details of the intended construction prior to
implementation.
7. Details all equipment that must be ordered.
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IQ Should include:
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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
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IQ Document should contain
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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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Calibration verification:
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.
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Change Parts and Replacement Parts Verification
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Maintenance Procedures Verification
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Critical Systems Change Request Procedure verification
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Lubricants Verification
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The purpose of OQ is to establish, through documented
testing, that all critical components are capable of operating
within established limits and tolerances.
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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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Scope of OQ is to test the individual components of the
system such as AHU, blowers and others.
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Operation Qualification Checks 
Ability to provide air of sufficient quality and quantity to
ensure achievement of specified clean room conditions.
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Ability to maintain temperature, relative humidity and
pressure set points.
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Ability to maintain any critical parameters stated in the DQ
consistently.
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Includes the tests that have been developed from
knowledge of processes, systems and equipment.
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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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Testing Equipment Calibration Verification
Instrumentation Calibration verification
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SOP Verification
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Operation Qualification tests
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OQ protocols to be written and approved prior to
completion. It includes following:
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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)
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The purpose of PQ is to verify and document that an
HVAC system provides acceptable control under ‘ Full
Operational ‘ conditions.
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PQ should follow successful completion of IQ and OQ.
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PQ verifies that the critical parameters, as defined in the
DQ are being achieved.
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PQ Should include 
Test to include a condition or set of conditions
encompassing upper and lower operating limits.
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Tests should be conducted under “in use”, condition either
or simulated as close as possible to the actual process
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PQ is used to demonstrate consistent achievement of
critical parameters over time. ( under manufacturing
conditions)
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PQ and OQ tests are sometimes performed in conjunction
with one another.
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Any changes to the HVAC system should be revalidated
before proceeding to the PQ phase.
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Air flow measurement
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Room air changes per hour.
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Filter Integrity Testing (HEPA Leak test)
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Pressure Differentials
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Particulate count measurement
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Recovery test
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Temperature and Relative Humidity
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Air Flow Pattern
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Microbial Count
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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
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Frequency:
GMP compliance:- Quarterly
Sch M - 6 Monthly
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Acceptance criteria:
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)
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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
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Sample location
 Between adjacent areas connected either by a door or grille.
o Frequency of sampling
Continuously by gauges / manometer & recorded daily.
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oAcceptance Criteria
 > 10 Pa between classified area & adjacent area of lower
classification
 > 15 Pa between classified area & unclassified area
oAction
 HEPA filter blockage
 Increase fan speed
 Increase air flow to specific area by altering dampers
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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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Air velocity exceeding the stated value may cause
excessive air movement & affect work zone protection.
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Air velocity below the limit may be insufficient to
maintain critical work zone protection.
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Deviation indicates the blockade of filter
Solution : Alteration of fan speed or HEPA filter
replacement
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A4. HEPA filter integrity test (DOP test)
 Purpose :
To confirm that no damage to filter, seals and no leakage of
particles.
 Equipment :
1. Aerosol generator
2. Photometer
 Scan at 1 inch from filter surface.
 Make separate passes at peripheries.
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Acceptance criteria:
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
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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
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.
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Acceptance criteria:
Temperature : NMT 27 degree centigrade
Humidity
: NMT 55 %
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Frequency : Daily
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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.
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Equipment: Anemometer
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Sample locations
At least four positions are tested across the filter or
grille face to obtain the mean supply air velocity.
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Frequency of sampling
Sch M - 6 Monthly
GMP compliance – Quarterly
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A7. 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)
55 mm for contact plates.
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Sampling condition:
 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
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Incubation condition:
 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.
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Acceptance criteria for Airborne Bioburden test:
Critical Environment: no more than 1 CFU/m3, or
0.03 CFU/ft3(USP monograph)
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Acceptance criteria for Surface Bioburden test:
Critical Environment: no more than 1 CFU/12.9cm2,
or 2 in2 (FDA Aseptic Processing Guidelines)
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Supplementary guidelines on good manufacturing
practices for HVAC systems
for non-sterile
pharmaceutical dosage forms. (WHO Technical ReportSeries, No. 937), Annex 2.(2006)
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Validation of pharmaceutical process, sterile product
2ndEdition, edited by Fredrick J. Carleton, James P.
Agalloco, page no.240-256.
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