Heating, Ventilation and

Air-Conditioning (HVAC)

Qualification and Validation

Dr JP Khurana – Director Quality

Ranbaxy Laboratories Limited Mohali
 Objectives

To understand key step in

Commissioning,
Qualification and
Validation of HVAC systems
Regulatory requirement / expectations

• Building and facilities used in manufacturing of

drug substances / products should be located,
designed and constructed to facilitate cleaning
and maintenance of operations as appropriate to
the type of product.
• Facilities should also be designed to minimize
potential contamination and mix-up.
• Where required facilities should be designed to
limit exposure to objectionable microbiological
contamination as appropriate.
 Documentation requirements for commissioning,
qualification and maintenance

• Description of design, installation and functions

• Specifications, requirements
• Manuals
• Operating procedures
• Instructions for performance control, monitoring and records
• Maintenance instructions and records
• Training of personnel
• programme and records
 HVAC system

• Designed and constructed to minimize risk of

contamination and cross contamination
• Adequate as per requirement of product
• Design to consider equipment for control of air-
pressure, microorganism, dust, humidity and
temperature as appropriate
• Design based on risk assessment
• Drains should be of adequate size and provided with
air-break
• Dedicated areas for handling Beta-Lactam products,
steroids, cytotoxic substances or anti-cancer agents
 Design – Risk based evaluation

• Man / material flow

• Processing equipment design (manual
operation/ automation)
• Packing and labeling
• Potential causes of contamination
• Appropriate design and adequate size
• Suitably located for intended use,
maintenance and cleaning
 Commissioning

• Precursor to qualification
• Includes setting up, balancing, adjustment
and testing of entire HVAC system to
ensure it meets requirements in URS and
capacity
• Acceptable tolerances for parameters
• Training of personnel
 Commissioning
Records and data maintained include:
• Installation records – documented
evidence of measure capacities of the
system
• Data: Design and measurement for, e.g.
airflow, system pressures
• Operation &Maintenance manuals,
schematic drawings, protocols, reports
 Qualification

• Validation is an extensive exercise

• Qualification of the HVAC system is one
component in the overall approach that
covers premises, systems/utilities,
equipment, processes, etc.
• Risk-based approach for HVAC
qualification
 Qualification
• Described in a Validation Master Plan
(VMP) Master
• VMP to include the nature and extent of
tests, and protocols
• DQ, IQ, OQ, and PQ
• Risk analysis to determine critical and non-
critical parameters, components,
subsystems and controls
 Qualification
• Direct impact components and 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
 Qualification
Design conditions and normal operating ranges set to achievable
limits
 Qualification
• DQ – Design of the system, URS
• (e.g. components, type of air treatment
needed, materials of construction)
• IQ – Verify installation
• e.g. relevant components, ducting, filters,
controls, monitors, sensors, etc.
• includes calibration where relevant
 Qualification
Typical parameters to be included in
qualification (based on risk assessment):
• Temperature
• Relative humidity
• Supply, return and exhaust air quantities
• Room air change rates
• Room pressures (pressure differentials)
 Qualification
Typical parameters to be included in
qualification (based on risk assessment):
• Room clean-up rate
• Particulate matter, microbial matter (viable and
non-viable)
• HEPA filter penetration tests
• Containment system velocity
• Warning/alarm systems
 Qualification
Conduct of the tests:
• Time intervals and procedure to be defined
by the manufacturer
• Influenced by the type of facility and level
of protection
• See also ISO 14644 for methods of testing
• Requalification, and change control
 Qualification
• Tests performed according to protocols
and procedures for the tests
• Results recorded and presented in report
(source data kept)
• Traceability, e.g. devices and standards
used, calibration records; and conditions
specified
 Qualification
Schedule of tests to demonstrate continuing compliance

Test Objective Maximum Time Test Procedure

Parameter Interval and key aspects

Particle count Verifies cleanliness 6 months or 12 Particle counter.

test months Readings and
depending on positions
Class
Air pressure Absence of cross- 12 months Measure
difference contamination pressure
difference
Airflow Verify air change 12 months Measure supply
volume rates and return air,
calculate air
change rate
Airflow Verify unidirectional 12 months Velocity
velocity airflow and or measurement
containment
condition
 Qualification
Recommended optional strategic tests

Test Parameter Objective Maximum Time Test Procedure and

Interval Key aspect

Filter leakage Verify filter 12 months Filter media and

integrity filter seal integrity

Containment Verify absence of 12 months Airflow direction

leakage cross- and pressure
contamination differential
Recovery (time) Verify clean-up 12 months Time taken
time maximum 15
minutes
Airflow Verify required 12 months Airflow direction,
visualization airflow patterns documented
evidence
 Clean room Monitoring
• Routine monitoring program as part of
quality assurance
• Additional monitoring and triggers, e.g.
1. Shutdown
2. Replacement of filter elements
3. Maintenance of air-handling systems
4. Exceeding of established limits
 Clean room Monitoring
• Number of points/locations for monitoring
determined, specified, documented in procedure and
or protocol
• Sufficient time for exposure, and suitable sample size
• Identification and marking of sampling points
• Definition of transport, storage, and incubation
conditions
• Results to reflect the procedure/protocol followed
• Define alert and action limits as a function of
cleanliness zone/class
 Clean room Monitoring
Clean rooms should be monitored for microorganisms and
particles
air

Example of sampling Point

 Type of Conditions
Various Conditions in a Clean room

as built at rest in operation

air air air
 Maintenance
•Procedure, programme and records for planned,
preventative maintenance
e.g. cleaning of filters, calibration of devices
•Appropriate training for personnel
•Change of HEPA filters by suitably trained persons
•Impact of maintenance on:
Product quality
Qualification
 Maintenance
• Verification of design documentation, including
• description of installation and functions
• specification of the requirements
• Operating procedures
• Maintenance instructions
• Maintenance records
• Training logs
• Environmental records
• Discussion on actions if OOS values
• On site verification (walking around the site)
 Utilities

All utilities that could impact product quality e.g.

steam, gases, compressed air, heating, ventilation
and air conditioning should be
• Qualified
• Appropriately monitored
• Actions should be taken when limits are exceeded
• Drawing for these utilities should be available
• Schedule and procedure for preventive and shut
down maintenance
 Qualification and validation

• Part of VMP & approach to validation

• Peron responsible for design, qualification/
validation
• Schedule for revalidation
 Rules for validation

• Cover all critical activities in VMP e.g. Equipment,

process, HVAC, water system, method validation,
computer system validation, scope for revalidation
• Specify frequency of revalidation based on risk
assessment to ensure system are in state of
validation thru out their lifecycle
• Detailed info on validation team e.g. name,
designation and their responsibilities
 Critical Validation activities

• Drafting of validation protocol

• Approval of protocol
• Experimentation & observations as per protocol
• Recording of results
• Interpretation of results
• Comparison of results with acceptance criteria
• Remarks
• Validation report (summary, recommendations
and certification and approval by all team
members
 Drafting of protocol – most common
deficiencies
• Protocol not relevant to instrument/ supplier and intended
purpose
• Does not cover critical features of design / operation /
performance
• Acceptance criteria not defined
• Statistical analysis provision not defined
• Validation report not made and closed
• Instruction / format for recording of data not provided
• Revalidation not specified
• No details for labeling equipment for due date of
revalidation
• No details on data archival
 PQ

• Focus on identification of sampling points to

cover diffusers, risers, exhaust points, processing
area and corners
• Specify type of physical and microbial tests to be
conducted at identified locations
• Test may include e.g. temperature, humidity,
particle count, air velocity, differential air
pressure, microbial count, air changes filter
integrity
• Conditions – static and dynamic
Validation team – People
• Validation is not routine and need to be
performed by skilled and trained persons

Common deficiencies
• Unskilled / causal person operate machine
• Fresh analyst draw & test samples
• Results recording by inexperienced staff
 Ensure
• Staff well trained on system under validation
• Capable to detecting errors
• Trained on recording of results
• Sincere, hard working and team player
• Know do and don’ts
 Check list for URS
• Prepare DQ with user team and proposed vendor
• Involve skilled operators who has to operate
machine
• Consider environment within and surrounding
factory / installation
• Evaluate Safety aspects
• Any product specific requirement
• Risk assessment
Documents / information required
• Operation manual
• Cleaning, maintenance and calibration procedure
• Schematic diagram
• Calibration certificates
• Material of construction and welding certificates
• Electrical wiring diagrams
• Discuss with vendor, he knows more than us
• Prefer to visit manufacturing site and seek
references
 Operational Qualification
• Equipment details
– Name of equipment
– S No
– Make
– Model
– Installation Location
– Fixed / portable
• Service area and room number etc defined,
layout and area sq ft
 Design - Revisit
• Temperature
• Humidity
• Differential pressure
• Classification
• Return risers e.g. EU 6 and HEPA
• Blower capacity
• Dampers – manual / motorized
• Manual / digital control for temp, humidity
and differential pressure
• Manual / digital control for recycle / fresh air
• Manual / digital record for various parameters e.g.
centralized building automatic control system
 Pre-requisite for OQ
• Machine installation check list
– Machine installed properly
– SOPs – identified, signed and implemented
– Utility identification and connected
– Control penal charged
 Calibration check and verification
• Measuring instruments e.g. voltmeter, RPM
(tachometer), air flow (anemometer), current
(ammeter)
• Record – make, model, calibration status and
certificate
- Specification, acceptance limit, set point,
observed values
 Check status for following wrt % opening, specs, acceptance
criteria, recording instrument number, calibration status and
observation and acceptable status

• Chilled water motorized valve

• Hot water motorized valve
• Exhaust air motorized damper
• Exhaust air motorized damper
• Mixing air motorized damper
• Return air motorized damper
• Room wise air motorized dampers
No Load trial check – about 2 hrs
• Vibration
• Wear and tear
• Noise

Key functionality check point

• Return air blower should trip is supply air
blower trips
• Open AHU blower section door AHU should
stop
 Alarm checks & verifications
• Return air filter fan trips
• Supply air fan trips
• Room temp high/ low
• Room humidity High/ low
• RH high/ low
• Supply air pre-filter dirty
• Low differential pressure
 SOPs
• Operation and controls
• Preventive maintenance
• Cleaning of filters
• Disposal of dust
 Performance Qualification
Reason for validation
• New installation
• Scheduled qualification
• Any other
 Pre conditions for completion
• DQ
• IQ
• OQ
• SOP on HVAC
• SOP on environmental monitoring
 Classification of clean rooms and
application
Category
A Aseptic processing area
B Non sterile dosage with terminal HEPA
filters
C Non sterile dosage with HEPA filters in
plenum
D Non sterile dosage without HEPA filters
E Ventilation with HEPA on exhaust
F Others
 Check list on factors to be monitored
• Air velocity
• Number of air changes
• Differential pressure gradient
• HEPA filter leakage test
• Air flow visualization (non unidirectional)
• Air born particles count
• Environmental monitoring temperature
• Environmental monitoring relative humidity
• Viable particulate matter count
 Air velocity and air changes
• Instrument Anemometer
• Acceptance criteria +/- 20% of average
face velocity of
concerned filter
• Fresh air % Class B NLT 40 ACH
Air velocity to be measured min 5 points (corners
and centre) of room at distance of about 6 inches
from filter / opening face for at least 10 sec
/point
 Differential pressure
• Instrument Inclined / digital
manometer /
magnehelic gauge
• Acceptance criteria 12.5 Pascal
Don not change dampers after setting after
balancing
 HEPA filter leakage test
Mostly valid for terminal filters, use poly
disperse aerosol e.g. Di octyl phthalate (DOP),
Poly Alfa olefin (PAO)
• Instrument Aerosol photometer
(detector/scanner)
• Acceptance criteria Leakage down stream
of HEPA filter Less
than 0.01% of up stream
 Air flow visualization
(non-unidirectional flow)
• Instrument Tracer particle
generator and still
photography / video
camera
• Acceptance criteria should be logical from
fresh air inlet to return
air duct
Air flow pattern at door should be from +
pressure to –ve pressure zone
 Air flow visualization (unidirectional
flow)
• Instrument Tracer particle
generator and still
photography / video
camera
• Acceptance criteria Air flow direction
under critical
operation should be
unidirectional
Sweeping action away
from product
 Air born particle count
To comply requirement as specified for 0.5 and 5.0 microns
particles
Class Max particles/m3 (at rest) Max particles/m3
(operation)
0.5 mic 5.0 mic 0.5 mic 5.0 mic
A 3500 20 3500 20
B 3500 20 350,000 2000
C 350,000 2000 3500,000 20,000
D 3500,000 20,000 NS NS
Number of sampling points is normally
sq root Area m2
Position probe facing upward at working height
/ 1 meter from floor
 Environmental condition –
Temperature & Humidity
Temperature
• Normally 22+/- 3 degC
• Position Near air riser/ near door/ near
equipment
Humidity
• Normally NMT 55%
• Position Near air riser/ near door/ near
equipment
 Viable count monitoring
Use settle plate / air sampling
Grade Air sample Settle plate
(cfu/m3) (90 mm & 4 hrs)
A <1 <1
B 10 5
C 100 50
D 200 100
 Report
• Review and conclusion
• Any deviation and CAPA
• Approval
• Requalification frequency
 Conclusion
Air Handling systems:
 Play a major role in assuring the quality of
pharmaceuticals
 Should be designed properly, by professionals
 Should be treated as a critical system
Thanks