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Tài liệu (Phần 3) | Hệ thống HVAC
1. HVAC | Slide 1 of 28 May 2006
Heating, Ventilation and
Air-Conditioning (HVAC)
Part 3:
Commissioning, Qualification,
and maintenance
Supplementary Training Modules on
Good Manufacturing Practice
2. HVAC | Slide 2 of 28 May 2006
HVAC
Objectives
To understand key issues in
commissioning,
qualification and
maintenance of HVAC systems
8.
3. HVAC | Slide 3 of 28 May 2006
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
Documentation requirements to assist in
commissioning, qualification and maintenance
HVAC
4. HVAC | Slide 4 of 28 May 2006
HVAC
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
8.1.1, 8.1.4, 8.1.5
5. HVAC | Slide 5 of 28 May 2006
HVAC
Commissioning (2)
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
O&M manuals, schematic drawings, protocols, reports
8.1.2, 8.1.3,
8.1.6
6. HVAC | Slide 6 of 28 May 2006
HVAC
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,
2005, Annex 4.
Risk-based approach for HVAC qualification
8.2.1
7. HVAC | Slide 7 of 28 May 2006
HVAC
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, subsystems and controls
8.2.2 - 8.2.5
8. HVAC | Slide 8 of 28 May 2006
HVAC
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 - 8.2.11
9. HVAC | Slide 9 of 28 May 2006
HVAC
Design
conditions
and normal
operating
ranges set to
achievable
limits
OOS results
recorded
8.2.12 – 8.2.15
A C TIO N L IM IT
A L E R T L IM ITA L E R T L IM IT
A C TIO N L IM IT
O p e ra tin g R a n g e - V a lid a te d A c c e p ta n c e C rite ria
N o rm a l O p e ra tin g R a n g e
D e s ig n C o n d itio n
10. HVAC | Slide 10 of 28 May 2006
HVAC
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. HVAC | Slide 11 of 28 May 2006
HVAC
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)
8.2.17
12. HVAC | Slide 12 of 28 May 2006
HVAC
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
8.2.17.
13. HVAC | Slide 13 of 28 May 2006
HVAC
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 14644 for methods of testing
Requalification, and change control
8.2.18 – 8.2.20, 8.2.9
14. HVAC | Slide 14 of 28 May 2006
HVAC
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
15. HVAC | Slide 15 of 28 May 2006
HVAC
Schedule of tests to demonstrate continuing compliance
*Test procedure as per ISO 14644 8. Table 3
Test Parameter Objective Maximum time
interval
Test procedure*
and key aspects
Particle count test Verifies cleanliness 6 months or 12
months depending on
Class
Particle counter.
Readings and
positions
Air pressure
difference
Absence of cross-
contamination
12 months Measure pressure
difference
Airflow volume Verify air change
rates
12 months Measure supply and
return air, calculate
air change rate
Airflow velocity Verify unidirectional
airflow and or
containment condition
12 months Velocity
measurement
16. HVAC | Slide 16 of 28 May 2006
HVAC
Recommended optional strategic tests
*Test procedure as per ISO 14644 8. Table 3
Test Parameter Objective Maximum time
interval
Test procedure*
and key aspects
Filter leakage Verify filter integrity 12 months Filter media and filter
seal integrity
Containment leakage Verify absence of
cross-contamination
12 months Airflow direction and
pressure differential
Recovery (time) Verify clean-up time 12 months Time taken maximum
15 minutes
Airflow visualization Verify required airflow
patterns
12 months Airflow direction,
documented evidence
17. HVAC | Slide 17 of 28 May 2006
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
HVAC
18. HVAC | Slide 18 of 28 May 2006
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
HVAC
See also ISO 14644
19. HVAC | Slide 19 of 28 May 2006
air
Example of a sampling point
Cleanroom monitoring program (3)
Cleanrooms should be monitored for microorganisms and
particles
HVAC
20. HVAC | Slide 20 of 28 May 2006
Definition of Conditions
air
as built
air air
at rest in operation
HVAC
21. HVAC | Slide 21 of 28 May 2006
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 2
N/A 2, 3
2, 3 Optional
2 2
2 N/A
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)
HVAC
22. HVAC | Slide 22 of 28 May 2006
Test
Turbulent /
mixed airflow
Description
Uni-directional
airflow / LAF
Recovery time
Room classification (airborne particle)
Temperature, humidity
N/A 2
2 2,3
N/A 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)
HVAC
Qualification – examples of aspects to consider in
qualification (OQ, PQ)
23. HVAC | Slide 23 of 28 May 2006
HVAC
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
8.3.1 – 8.3.5
24. HVAC | Slide 24 of 28 May 2006
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)
Inspecting the air-handling system
HVAC
25. HVAC | Slide 25 of 28 May 2006
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
Conclusion
HVAC
26. HVAC | Slide 26 of 28 May 2006
This series of explanations will now be followed by:
Group discussion, with a simple exercise
Short test
Further proceedings
HVAC
27. HVAC | Slide 27 of 28 May 2006
Group Session
S e r v i c e R o o m
W a re h o u s e
A/Lock1
AirLock2
A i r S h o w e r
S a m p l i n g
R o o o m S e rv i c e C o rr i d o r
(c o ntain s V a c uum & R O w ater s upply )
W e i g h i n g T a b l e t 1 T a b l e t 2 L i q u i d s M i x S o f t g e l C a p s u l e
P a c k i n g
E m ergenc y
E x it
C l e a n C o rr i d o r
E q u i p m e n t W a s h
A i r L o c k 3
S t e ri l e e y e d ro p s
d i s p e n s i n g
& a c e p t i c f i l l i n g
2 S t a g e
p e r s o n n e l
e n t ry f o r
e y e d ro p s
M a l e
C h a n g e 2
M a l e
C h a n g e 1
F e m a l e
C h a n g e 1
F e m a l e
C h a n g e 2
P a c k e d
G o o d s
Q u a ra n t i n e
A i r L o c k 4
P r i m a ry & S e c o n d a ry
P a c k i n g
HVAC
28. HVAC | Slide 28 of 28 May 2006
Group Session – modified layout
S e c o n d a r y
P a c k i n g
3 0 P a
0 P a
2 0 P a 3 0 P a
0 P a
0 P a
1 0 P a
1 0 P a 1 0 P a
2 0 P a2 0 P a
4 0 P a
5 0 P a
6 0 P a
5 0 P a
4 0 P a
1 5 P a
1 5 P a
P r i m a r y
P a c k i n g
C h a n g e
M A L 3
A i r L o c k
3 0 P a
P o s t
S t a g i n g
3 0 P a
3 0 P a
0 P a
1 5 P a1 5 P a
2 0 P a
2 0 P a
3 0 P a
2 0 P a
0 P a
1 0 P a
S e rv i c e R o o m
A i r L o c k 4
P a c k e d
G o o d s
Q u a ra n t i n e
F e m a l e
C h a n g e 2
F e m a l e
C h a n g e 1
M a l e
C h a n g e 1
M a l e
C h a n g e 2
P A L
S t e ri l e e y e d ro p s
d i s p e n s i n g
& a s c e p t i c f i l l i n g
M A L 4
E q u i p m e n t W a s h
C l e a n C o r ri d o r
E m ergenc y
E x it
S o f t g e l C a p s u l e
P a c k i n gL i q u i d s M i xT a b l e t 2T a b l e t 1
W e i g h
B o o t h
(c on tains V ac uum & R O w ate r s u pply )
S e rv i c e C o rri d o r
S a m p l i n g
R o o o m
A i r S h o w e r
MAL2
MAL1
W a re h o u s e
MAL = Material Air Lock
PAL = Personnel Air Lock
HVAC
Notas do Editor
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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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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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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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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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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.
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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.
8.2.10 Acceptance criteria and limits should be defi ned during the design
stage.
8.2.11 The manufacturer should defi ne design conditions, normal operating
ranges, operating ranges, and alert and action limits.
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8.2.17 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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8.2.18 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.
8.2.19 Periodic requalifi cation of parameters should be done at regular
intervals, e.g. annually.
8.2.20 Requalifi cation should also be done when any change, which could
affect system performance, takes place.
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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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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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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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The diagram, which is given in handout 3-3-26, 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, 3-3-27, giving suggested modifications, should not be distributed until after the group discussion has taken place.)
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This slide indicates the proposed additions, and can be displayed after the group session discussions have taken place. See handout 3-3-27.