1. World Health Organization
24 April, 2019
Supplementary Training Modules on Good Manufacturing Practice
Heating, Ventilation and Air- Conditioning (HVAC)
Part 4:
Commissioning, qualification and maintenance
WHO Technical Report Series, No. 961, Annex 5
Part 4:
Commissioning, qualification and maintenance
Section 8

2. World Health Organization
HVAC
24 April, 2019
Objectives
To understand key issues in
commissioning,
qualification and
maintenance of HVAC systems 8.

3. World Health Organization
24 April, 2019
HVAC
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
programme and records

4. World Health Organization
HVAC
24 April, 2019
Commissioning
Commissioning (is integrated in qualification) and includes:
Setting up, balancing, adjustment and testing of entire HVAC system
It helps to ensure it meets URS and capacity
Acceptable tolerances for parameters set before commissioning
Precursor to qualification
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 specified in the user requirement specification (URS), and capacities as specified by the designer or developer. The commissioning plan should start at the early stages of a project so that it can be integrated with qualification and verification procedures.
   
8.1.4 Acceptable tolerances for all system parameters should be specified prior to commencing the physical installation.   
8.1.6 Commissioning should be a precursor to system qualification and process validation.
8.1.1, 8.1.4, 8.1.6

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HVAC
24 April, 2019
Commissioning (2)
Records and data include:
Installation records – documented evidence of measured capacities of the system
Acceptance criteria set for system parameters
Training of personnel (e.g. operation and maintenance)
O&M manuals, schematic drawings, protocols, reports
8.1.2 The installation records of the system should provide documented evidence of all measured capacities of the system.
8.1.3 Acceptance criteria should be set for all system parameters. The measured data should fall within the acceptance criteria.
8.1.5 Training should be provided to personnel after installation of the system, and should include operation and maintenance.
8.1.2, 8.1.3, 8.1.5

6. World Health Organization
HVAC
24 April, 2019
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
See also full guidelines on "Validation" in WHO TRS No 937, 2005, Annex 4.
8.2 Qualification
8.2.1 Validation is a many-faceted and extensive activity and is beyond
the scope of these guidelines. Qualification and validation guidelines are
included in: Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization, 2005
(WHO Technical Report Series, No. 937), Annex 4 (see also Fig. 28)
Companies should do risk assessment exercises to determine what the scope and extent of qualification.
8.2.1

7. World Health Organization
HVAC
24 April, 2019
Qualification
Described in a Validation Master Plan (VMP)
Reflects the nature and extent, test procedures, and protocols
DQ, IQ, OQ, and PQ
Risk analysis to determine critical and non-critical parameters, components, subsystems 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.

8. World Health Organization
HVAC
24 April, 2019
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
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 qualification 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 qualified. The heat transfer system, chemical drier or
steam humidifier, which is producing the humidity controlled air, is further
removed from the product and may not require operational qualification.
A room cleanliness classification is a critical parameter and, therefore,
the room air change rates and HEPA filters should be critical parameters
and require qualification. Items such as the fan generating the airflow
and the primary and secondary filters are non-critical parameters, and
may not require operational qualification.
8.2.8 Non-critical systems and components should be subject to GEP and
may not necessarily require qualification.
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 defined during the design
stage.
The manufacturer should define design conditions, normal operating
ranges, operating ranges, and alert and action limits.

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Design conditions and normal operating ranges set to achievable limits
OOL results recorded and investigated
The design condition, normal operating ranges, operating range and alert and action limits should be defined and be realistic.
Out-of-limit results (e.g. action limit deviations) should be recorded and their impact should be investigated.
The relationships between design conditions, normal operating range and validated acceptance criteria (also known as proven acceptable range) –

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HVAC
24 April, 2019
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

11. World Health Organization
HVAC
24 April, 2019
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)
For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualified 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 airflow patterns
— unidirectional flow velocities
— containment system velocities
— HEPA filter 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.
8.2.13

12. World Health Organization
HVAC
24 April, 2019
Qualification
Typical parameters to be included in qualification (based on risk assessment) (2):
Room air flow patterns
Room clean-up rate
Particulate matter, microbial matter (viable and non-viable)
HEPA filter penetration tests
Containment system velocity
Warning/alarm systems
For a pharmaceutical facility, based on a risk assessment, some of the typical HVAC system parameters that should be qualified 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 airflow patterns
— unidirectional flow velocities
— containment system velocities
— HEPA filter 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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Conduct of the tests:
Time intervals and procedure to be defined by the manufacturer - based on risk assessment (influenced by the type of facility and level of protection)
See also ISO for procedures
Requalification, and change control
Documents: system airflow schematics, room pressure cascade drawings, zone concept drawings, air-handling system allocation drawings, particle count mapping drawings
The maximum time interval between tests should be defined by the
manufacturer. The type of facility under test and the product level of protection should be considered. No
Requalification should also be done when any change, which could affect system performance, takes place.
Clean-up or recovery times normally relate to the time it takes to “clean up” the room from one condition to another, e.g. the relationship between “at-rest” and “operational” conditions in the clean area may be used as the criteria for clean-up tests. Therefore, the clean-up time can be expressed as the time taken to change from an “operational” condition to an “at rest” condition.
If energy-saving procedures such as reducing the airflow during non-production hours are used, precautionary measures should be in place to ensure that the systems are not operated outside the defined relevant environmental conditions.
These precautionary measures should be based on a risk assessment to ensure that there is no negative impact on the quality of the product.
Documents that should be included in the qualification manuals should include system airflow schematics, room pressure cascade drawings, zone concept drawings, air-handling system allocation drawings, particle count mapping drawings, etc. –

14. World Health Organization
HVAC
World Health Organization
24 April, 2019
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 (7)
Tests should be done by following appropriate protocols and procedures. Normally, procedures should be as described in ISO 14644
All results should be recorded and presented in report (source data should be kept as these will be verified against the report by inspectors).
For the tests and results – there should be sufficient traceability, e.g. devices and standards used, their calibration records; and conditions under which the tests were done should be specified

15. World Health Organization
HVAC
24 April, 2019
Schedule of tests to demonstrate continuing compliance
*Test procedure as per ISO 14644
Test procedure* and key aspects
Considerations
Objective
Test Parameter
Particle counter. Readings and positions
Number of readings and positions
Verifies cleanliness
Particle count test
Measure pressure difference
Continuous. Defined limits
Absence of cross- contamination
Air pressure difference
Measure supply and return air, calculate air change rate
See ISO 14644
Verify air change rates
Airflow volume
Velocity measurement
Velocity and containment
Verify unidirectional airflow and or containment condition
Airflow velocity
8. Table 3

16. World Health Organization
HVAC
24 April, 2019
Recommended optional strategic tests
*Test procedure as per ISO 14644
Test procedure* and key aspects
Considerations
Objective
Test Parameter
Filter media and filter seal integrity
For HEPA filters
Verify filter integrity
Filter leakage
Airflow direction and pressure differential
Containment, smoke and air pressure
Verify absence of cross-contamination
Containment leakage
Time taken maximum 20 minutes
Certain classes
Verify clean-up time
Recovery (time)
Airflow direction, documented evidence
Clean to dirty area, uniformly. Video
Verify required airflow patterns
Airflow visualization
8. Table 3

17. Cleanroom monitoring program (1)
World Health Organization
24 April, 2019
HVAC
Cleanroom monitoring program (1)
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

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24 April, 2019
HVAC
Cleanroom monitoring programme (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
See also ISO 14644

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HVAC
Cleanrooms should be monitored for microorganisms and particles
Example of a sampling points

20. World Health Organization
24 April, 2019
HVAC
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
Airflow 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.

21. World Health Organization
HVAC
24 April, 2019
Maintenance
Procedure, programme and records for planned, preventative maintenance
e.g. cleaning of filters, calibration of devices
Keep O&M manuals, drawings etc.
Appropriate training for personnel
Change of HEPA filters by suitably trained persons
Impact of maintenance on:
Product quality and 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 Operating and maintenance (O&M) manuals, schematic drawings, protocols and reports should be maintained as reference documents for any future changes and upgrades to the system. These documents should be kept up to date, containing any system revisions made.
8.3.3 Maintenance personnel should receive appropriate training.
8.3.4 HEPA filters should be changed either by a specialist or a trained person, and then followed by installed filter leakage testing.
8.3.5 Any maintenance activity should be assessed critically to determine any impact on product quality including possible contamination.
8.3.6 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 requalification of an area as a result of an interruption of the service.
8.3.1 – 8.3.6

22. World Health Organization
HVAC
24 April, 2019
Premises may influence HVAC design / performance. Therefore consider:
Adequate airlocks, change rooms, passages
Required pressure cascades
Detailed diagrams available with pressure cascades, air flow directions and flow routes for personnel and materials should be prepared and maintained;
Change room classification
As the efficient operation of the air-handling system and cleanliness levels attained are reliant on the correct building layout and building finishes, the following items should be considered:
adequate airlocks, such as personnel airlocks (PAL) and/or material airlocks (MAL), change rooms and passages should be provided to protect passage between different cleanliness conditions . These should have supply and extract air systems as appropriate;
areas such as airlocks, change rooms and passages, should be designed so that the required pressure cascades can be achieved;
detailed diagrams depicting pressure cascades, air flow directions and flow routes for personnel and materials should be prepared and maintained;
where possible, personnel and materials should not move from a higher cleanliness zone to a lower cleanliness zone and back to a higher cleanliness zone; (if moving from a lower cleanliness zone to a higher cleanliness zone, changing /decontamination procedures should be followed); and
the final stage of the changing room should, in the "at rest" state, be the same GMP classification grade as the area into which it leads. 9

23. World Health Organization
24 April, 2019
HVAC
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)

24. World Health Organization
24 April, 2019
HVAC
Take home message. What is essential?
Appropriate design of AHUs and HVAC system
Correct components, and MOC
Ensuring appropriate cleanliness of air, environmental conditions (e.g. temperature and RH), and area classification to prevent contamination and cross-contamination
Qualification data to support claims
Regular calibration, maintenance and cleaning
What is essential in HVAC?
As there are many variable in terms of what is required for appropriate production and control environments, the essential aspects to consider are (but not limited to) the following:
Appropriate design of AHUs and HVAC system to provide sufficiently cleaned air, environmental conditions, and containment. All components should be of appropriate MOC and correctly placed
Air should be free from contaminants and provide suitable and appropriate environmental conditions (e.g. temperature and RH), and pressure cascades where required to ensure containment.
Areas classified should be maintained within their classification.

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HVAC
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

26. World Health Organization
24 April, 2019
HVAC
Group Session
The diagram, which is given in handout , shows a layout of a small pharmaceutical plant for non-sterile tablets, liquids and soft-gel capsules, as well as aseptically filled eye-drops.
The group session participants should indicate on the diagram the required cleanroom classes, room pressures (in Pa), as well as any architectural changes which they think necessary.
(This layout is not ideal, but as many different types of operations have been incorporated in the facility as possible, so that different concepts can be addressed.)
(Note to trainer: The next handout, , giving suggested modifications, should not be distributed until after the group discussion has taken place.)

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HVAC
Group Session – modified layout
MAL = Material Air Lock
PAL = Personnel Air Lock
This slide indicates the proposed additions, and can be displayed after the group session discussions have taken place. See handout