1. Qualification of HVAC systems
Tony Gould

2. WHO reference WHO Technical Report Series, No. 937, 2006 - Annex 2
"Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms"
Comprehensive guide
May also be applied to other dosage forms
Not intended to be prescriptive – risk principles apply

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Objectives
To understand key issues in
commissioning,
qualification and
maintenance of HVAC systems 8.

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Documentation requirements to assist in 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
program and records

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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
8. Commissioning, qualification and maintenance
8.1 Commissioning
8.1.1 Commissioning should include the setting up, balancing, adjustment
and testing of the entire HVAC system, to ensure that it meets all the
requirements, as specifi ed in the user requirement specifi cation (URS), and
capacities as specifi ed by the designer or developer.
8.1.2 The installation records of the system should provide documented
evidence of all measured capacities of the system.
8.1.3 The data should include items such as the design and measurement
fi gures for airfl ows, water fl ows, system pressures and electrical amperages.
These should be contained in the operating and maintenance manuals
(O & M manuals).
8.1.4 Acceptable tolerances for all system parameters should be specifi ed
prior to commencing the physical installation.
8.1.5 Training should be provided to personnel after installation of the
system, and should include operation and maintenance.

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Commissioning (2)
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 pressures
O&M manuals, schematic drawings, protocols, reports
8.1.3 The data should include items such as the design and measurement
fi gures for airfl ows, water fl ows, system pressures and electrical amperages.
These should be contained in the operating and maintenance manuals
(O & M manuals).
8.1.4 Acceptable tolerances for all system parameters should be specifi ed
prior to commencing the physical installation.
8.1.5 Training should be provided to personnel after installation of the
system, and should include operation and maintenance.
8.1.6 O & M manuals, schematic drawings, protocols and reports should
be maintained as reference documents for any future changes and upgrades
to the system.

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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.
See also full guidelines on "Validation" in WHO TRS No 937, 2006, Annex 4.
Risk based approach for HVAC qualification
8.2 Qualifi cation
8.2.1 Validation is a many-faceted and extensive activity and is beyond
the scope of these guidelines. Qualifi cation and validation guidelines are
included in: Expert Committee on Specifi cations for Pharmaceutical Preparations.
Fortieth report. Geneva, World Health Organization, 2005 (WHO
Technical Report Series, No. 937), Annex 4 (see also Fig. 28).

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Qualification (2)
Described in a Validation Master Plan (VMP)
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, sub-systems and controls
8.2.2 The qualifi cation of the HVAC system should be described in a validation
master plan (VMP).
8.2.3 It should defi ne the nature and extent of testing and the test procedures
and protocols to be followed.
8.2.4 Stages of the qualifi cation of the HVAC system should include DQ,
IQ, OQ and PQ.
8.2.5 Critical and non-critical parameters should be determined by means
of a risk analysis for all HVAC installation components, subsystems and
controls.

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Qualification (3)
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
8.2.5 Critical and non-critical parameters should be determined by means
of a risk analysis for all HVAC installation components, subsystems and
controls.
8.2.6 Any parameter that may affect the quality of the pharmaceutical
product, or a direct impact component, should be considered a critical
parameter.
8.2.7 All critical parameters should be included in the qualifi cation process.
Note: A realistic approach to differentiating between critical and noncritical
parameters is required, to avoid making the validation process
unnecessarily complex.
Example:
• The humidity of the room where the product is exposed should be considered
a critical parameter when a humidity-sensitive product is being
manufactured. The humidity sensors and the humidity monitoring system
should, therefore, be qualifi ed. The heat transfer system, chemical drier or
steam humidifi er, which is producing the humidity controlled air, is further
removed from the product and may not require operational qualifi cation.
Figure 28
Qualifi cation is a part of validation
Equip 1 Equip 2 Equip 3 Equip 4 Equip 5 Equip 6
QUALIFICATION
VALIDATION
Equip 7
System 2 System 1
Process
Equip, equipment. 80
Figure 29
System operating ranges
• A room cleanliness classifi cation is a critical parameter and, therefore,
the room air change rates and HEPA fi lters should be critical parameters
and require qualifi cation. Items such as the fan generating the airfl ow
and the primary and secondary fi lters are non-critical parameters, and
may not require operational qualifi cation.
8.2.8 Non-critical systems and components should be subject to GEP and
may not necessarily require qualifi cation.
8.2.9 A change control procedure should be followed when changes are
planned to the direct impact HVAC system, its components and controls
that may affect critical parameters.
Acceptance criteria and limits should be defi ned during the design
stage.
The manufacturer should defi ne design conditions, normal operating
ranges, operating ranges, and alert and action limits.

10. HVAC
Design conditions and normal operating ranges set to achievable limits
OOS results recorded

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Qualification – examples of aspects to consider
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

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Qualification (7)
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

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Qualification (6)
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 for methods of testing
Re-qualification, and change control
The maximum time interval between tests should be defi ned by the
manufacturer. The type of facility under test and the product level of protection
should be considered.
Note: Table 3 gives intervals for reference purposes only. The actual test periods
may be more frequent or less frequent, depending on the product and process.
Periodic requalifi cation of parameters should be done at regular
intervals, e.g. annually.
Requalifi cation should also be done when any change, which could
affect system performance, takes place.

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Qualification (4)
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)
For a pharmaceutical facility, based on a risk assessment, some of
the typical HVAC system parameters that should be qualifi ed may include:
— temperature
— relative humidity
— supply air quantities for all diffusers
— return air or exhaust air quantities
— room air change rates
— room pressures (pressure differentials)
— room airfl ow patterns
— unidirectional fl ow velocities
— containment system velocities
— HEPA fi lter penetration tests
— room particle counts
— room clean-up rates
— microbiological air and surface counts where appropriate
— operation of de-dusting
— warning/alarm systems where applicable.

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Qualification (5)
Typical parameters to be included in qualification (based on risk assessment) (2):
Room clean up rate
Particulate matter, microbial matter (viable and non-viable)
HEPA filter penetration tests
Containment system velocity
Warning/alarm systems

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Schedule of tests to demonstrate continuing compliance
*Test procedure as per ISO 14644
Test procedure* and key aspects
Maximum time interval
Objective
Test Parameter
Particle counter. Readings and positions
6 months or 12 months depending on Class
Verifies cleanliness
Particle count test
Measure pressure difference
12 months
Absence of cross- contamination
Air pressure difference
Measure supply and return air, calculate air change rate
Verify air change rates
Airflow volume
Velocity measurement
Verify unidirectional airflow and or containment condition
Airflow velocity

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Recommended optional strategic tests
*Test procedure as per ISO 14644
Test procedure* and key aspects
Maximum time interval
Objective
Test Parameter
Filter media and filter seal integrity
12 months
Verify filter integrity
Filter leakage
Airflow direction and pressure differential
Verify absence of cross-contamination
Containment leakage
Time taken maximum 15 minutes
Verify clean-up time
Recovery (time)
Airflow direction, documented evidence
Verify required airflow patterns
Airflow visualization

18. Cleanroom monitoring program (1)
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Cleanroom monitoring program (1)
Routine monitoring program as part of quality assurance
Additional monitoring and triggers e.g.
Shutdown
Replacement of filter elements
Maintenance of air handling systems
Exceeding of established limits

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Cleanroom monitoring program (2) Particles and Microbiological contaminants
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

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Cleanroom monitoring program (3)
Cleanrooms should be monitored for micro-organisms and particles
air
Example of a sampling point

21. Definition of Conditions
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Definition of Conditions
air
as built
at rest
in operation

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Qualification – examples of aspects to consider in qualification (OQ, PQ)
Test
Differential pressure on filters
Turbulent / mixed airflow
Description
Uni-directional airflow / LAF
Room differential pressure
Airflow velocity / uniformity
Airflow volume / rate
Parallelism
Air flow pattern 2
N/A
2, 3
Optional 3
1 := As built (ideally used to perform IQ)
2 = At rest (ideally used to perform OQ)
3 = Operational (ideally used to perform PQ)
This slide shows a series of tests to be carried out during qualification.
There are different tests for the turbulent and for the uni-directional air flows.
The differential pressure on filters is an indication of the clogging of the filters: with the charging of dust on the filters, the differential pressure will increase.
In order to keep the volume of air constant, the fan speed may increase, with the following consequences:
Damage to filters, and passage of unfiltered air
Particles and micro-organismes will be “pushed” through the filter units.
(Inspectors should check whether pressure differential manometers are installed on the AHUs. Without this means of monitoring the filters, the system could go out of control causing contamination problems.)
Airflow patterns are interesting to visualize (smoke tests), as zones without proper flushing can be easily identified.
It is also important to monitor air flow velocities for each HEPA filter according to a program of established intervals because significant reductions in velocity can increase the possibility of contamination, and changes in velocity can affect the laminarity of the airflow.
Airflow patterns should be tested for turbulence, as these can interfere with the flushing action of the air.

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Qualification – examples of aspects to consider in qualification (OQ, PQ)
Test
Turbulent / mixed airflow
Description
Uni-directional airflow / LAF
Recovery time
Room classification (airborne particle)
Temperature, humidity
N/A 2
2,3
1 := As built (ideally used to perform IQ)
2 = At rest (ideally used to perform OQ)
3 = Operational (ideally used to perform PQ)
The recovery time (clean-up time) is also an important parameter to be determined. Once doors have been opened and people have been entering a room, the original conditions have been disturbed and, for a short while, before recovering, the room does not always correspond to the laid down parameters. It is important to know how long this period is. There are no regulations laid down as to how long this clean-up time should be. However, the generally accepted time to clean-up from one cleanroom classification to the next higher classification, should be less than 15 minutes.
It should also be remembered that a room is to be qualified “in operation” when it has a certain number of people in it. After qualification, the number of people in that room, as challenged during qualification, cannot be exceeded.
Temperature and humidity can also be important (comfort in clean areas, stability of effervescent products, etc.)

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Maintenance
Procedure, program 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
8.3 Maintenance
8.3.1 There should be a planned preventive maintenance programme,
procedures and records for the HVAC system. Records should be kept.
8.3.2 Maintenance personnel should receive appropriate training. 82
8.3.3 HEPA fi lters should be changed either by a specialist or a trained
person.
8.3.4 Any maintenance activity should be assessed critically to determine
any impact on product quality including possible contamination.
8.3.5 Maintenance activities should normally be scheduled to take place
outside production hours, and any system stoppage should be assessed with
a view to the possible need for requalifi cation of an area as a result of an
interruption of the service.

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Inspecting the air handling system
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)

26. HVAC and Quality Risk Management
What about risk assessment/risk management in HAVC systems?
Recommended risk assessment prior to qualification
Design requirements
Qualification (GMP) vs GEP
Ongoing performance
Ongoing maintenance

27. HVAC and Quality Risk Management
Type of products and materials
Product range
Campaign
Cleaning
Design, age, changes
Monitoring results (OOLs)

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Conclusion
Air handling systems:
Play a major role in the quality of pharmaceuticals
Should be designed properly, by professionals
Should be treated as a critical system