Technical and Qualification Issues: Alain Kupferman

HVAC
Technical and Qualification Issues

Alain Kupferman
Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors,
Nanjing, November 2009
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The primary objective of manufacturing in an ideal GMP
environment is that this should lead to a high quality
product being produced.
Manufacturing in an ideal environment not only leads to
better quality products but should also result in :
Improved production rates.
Operator comfort, satisfaction and safety.
GMP Manufacturing Environments
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Factors Contributing To Quality Products
Raw Materials
Personnel
Procedures
Validated processes
Equipment
Premises
Environment
Packing Materials
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Defining The Environment
What is the optimal manufacturing environment ?
How does the manufacturing environment affect
quality, contamination and cross-contamination ?
How do we arrive at an optimal environment ?

Cleanroom concept

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Design Considerations
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Systems
To support pharmaceutical production activities, state-of-the-art
factories include systems, which have to be conceived according to
GEP and cGMP.
Some of these systems have a direct impact on product quality,
some an indirect impact.
Systems with direct impact must be identified and documented in a
more exhaustive way, and evaluated in relation to critical GMP
parameters.
QA, Production and Engineering must agree beforehand on the scope
of qualification activities, ideally right at project start.
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Good Engineering Practice
Good Engineering Practice (GEP) is defined as those established
engineering methods and standards that are applied throughout the
lifecycle to deliver appropriate and cost effective solutions.
Generally the term is used to describe an engineering management
system that is being applied in the engineering profession for
delivering, operating and maintaining capital assets.
While GEP is expected in a pharmaceutical enterprise, it is not
mandated by GMP regulations.

Good HVAC installation: GEP + cGMP
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A HVAC system conceived, installed and commissioned
according to GEP should be:
Fit for the intended purpose, reliable and economic to run.
Conceived and installed taking into account GMP norms, as
well as norms for safety, ecology, ergonomy, operation,
maintenance and local industry rules and country regulations.
Conceived, constructed, installed and commissioned by
professionnal and competent people.
Supported by appropriate documentation (conceptual
documents, diagrams, as-built drawings, test reports, manuals,
etc.).

Good Engineering Practice
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Some Definitions
Direct impact system
System which could have a direct impact on product quality
These systems are generally to be documented more
in-depth (qualification).
Normally contain critical components.
These systems normally depend on other systems, with indirect
impact.
Interface important !
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Some Definitions
Indirect impact system
A system which does not have a direct impact on product
quality !
Can affect the performance of direct impact systems and thus
indirectly affects product quality.
Needs less detailed documentation (no qualification).
Must be constructed, tested and commissioned according to
GEP.
By definition, do not contain critical components.
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More Definitions
Critical GMP parameter
A GMP criteria, influencing product quality (differential
pressure, airflow pattern, etc.).
Critical component
A component which maintains a GMP critical within pre-
determined limits (filter HEPA, dehumidifier, etc.).
Critical instrument
Instrument measuring a critical GMP parameter.
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Examples Of Systems
Purified water
WFI
HVAC to clean rooms
Compressed air and
gasses for production
CIP/SIP
Environmental monitoring
Etc.
Heating systems
Potable water
Fire systems
Effluent treatment
General HVAC
Lighting
Cooling water
Etc.
GMP Direct Impact No GMP Direct Impact
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Examples
AHU
Aseptic
area
HEPA
Chilled water system
(indirect)
AHU system
(direct)
Critical component
(direct)
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Extent Of Qualification

Japan GMP US GMP

EU GMP

ICH Q9
ISPE Commissioning and Qualification
Baseline Guide
Equipment shall be
suitable, correct material,
calibrated,
Basis for qualification
Quality risk management
can be used to determine
the extent of qualification
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Qualification Success
GEP + GMP = Qualification



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HVAC Design Requirements
The complexity resulting from the different requirements for air quality
in the various cleanliness zones, makes it recommendable to define
up-front the following criteria:
Critical room parameters which affect product or materials (i.e. humidity)
Process operations presenting a potential for contamination.
Process or operations not affected by room conditions (e.g. closed systems).
Potential sources of room contamination (process equipment / operation, HVAC
components, HVAC operation type, personnel, failure of HVAC functions...).
Equipment failure modes (fans, room / zone fail safe modes, interlocks, user
action in the event of failure).
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HVAC
100 % fresh air versus air re-circulation
Local extraction systems
Turbulent or uni-directional flows
Position end-filters
Low-wall returns

Targeted hygiene class
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Definition Of Conditions
air
As built
air
air
At rest In operation
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HVAC And GMP
In pharmaceutical primary as well as in secondary manufacturing, HVAC
systems are a major factor for the observance of cleanliness and product purity,
and thus for GMP compliance.

Qualification activities of HVAC systems with their measurement and control and
computerized units are cost intensive and necessitate a great deal of time.

The key issues to keep HVAC qualification in quality, time, and costs are

the understanding of interfaces beween product purity / characteristics,
process, cleanliness zones, HVAC functions and clean rooms requirements.
the structured identification of critical functions and operations, the objective
evaluation, and the definition of appropriate measures (design, qualification,
calibration, and validation activities) in a documented way.

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HVAC Design Requirements And Process
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HVAC Design Requirements And Process
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To Start With
HVAC: Heating, Ventilation and Air Conditionning
HVAC System or Ventilation System ?
HVAC System: Includes sub-systems (chilled water, brine, steam, etc.).
Ventilation system: Air treatment components (AHU, ducts, flow controllers, etc.).
BMS: Building Management System
BMS: Building Management System (BMS) is a computer based control system installed in buildings that
controls and monitors the buildings mechanical and electrical equipment such as air handling and cooling
plant systems, lighting, power systems, fire systems, and security systems
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Key Qualification Aspects
A HVAC system serving a production area must be
considered as direct impact system
Such a system consists of sub-systems
As a consequence, it is necessary to identify sub-systems
which also could have a direct impact.
Within these sub-systems, critical components and
instruments have to be identified as well.
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HVAC Qualification
For example, for a typical HVAC system in an aseptic area, critical
components would be:
Terminal HEPA filters.
Unidirectional airflow units.
The monitoring of the critical GMP parameters indicates whether
the system operates within the pre-established criteria.
A breakdown in a fan would for instance have as consequence a
drop in differential pressures, as well as changes in temperature
and humidity.
The monitoring system in itself is thus critical as well.
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HVAC Qualification
IQ Tests Installation (Static verifications)
Installation of components

OQ Tests Installation (Dynamic verifications)
Individual tests components (fans, coils, etc.)
Functional tests sub-systems
Verification control system

These tests confirm that the installation is working as a
whole and must be done before the room qualification

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HVAC Key Qualification Aspects
Facility qualification tests
Air changes
Differential pressure cascade
Flow patterns (turbulent and uni-directional)
Room classification (ISO norms)
Temperature and humidity
Integrity tests HEPA filters
Exactness of readings of GMP critical parameters
Uni-directional airspeed
Laminarity at point of use
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In establishing design criteria for critical parameters,
consideration should be given to operating ranges which
will assist in the definition of the tightness of control range
of these parameters.
Continuous ringing of
alarms to be avoided !!

Action limit
Alert limit
Range of measurement and control unit
Process range
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Process
tolerance
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Physical / Technical OQ And PQ Tests
In addition to the
general tests (e.g.
power failure and
recovery tests,
verification of
functions and
sequences, verifi-
cation of alarms
and interlocks...)
specific tests have
to be
performed.
Test:
Differential pressure on filters
Turbulent /
mixed airflow:
Unidirectional
airflow / LAF:
Room differential pressure
Airflow velocity / uniformity
Airflow volume / rate
Parallelism
Air flow patterns
Filter leak test / challenge test
Recovery
Room classification (airborne particle)
Particle fall out
1 1
N/A 2, 3
2, 3 Optional
2 2
2 N/A
Optional Optional
2 2
N/A 2
2 2
Optional Optional
Temperature, humidity 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)
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Determination of differential pressure on filters
to detect initial defects of filters,
to verify the pressure differential (for a defined flow) meets the value specified
by the vendor,
to set the correct value of the alarm as indicated by the vendor for triggering a
filter replacement.
Differential pressure between rooms
This measurement consists in measuring with a calibrated manometer the
differential pressure existing between the inside of a clean room and the
surrounding areas as defined in the specifications.
This determination should be made under various operational conditions such
as day mode, night mode, opening of doors, etc. to identify also situations
when the pressure differential cannot be met and as a consequence the
product may be at risk.
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Determination of air flow velocity
This verification is used to determine average airflow velocity and uniformity of
velocity within a clean room, clean zone or unidirectional flow work zone.
This method is not recommended for non-unidirectional airflow cleanliness
zones; in that case the measurement of airflow volumes should be performed
instead.
The airflow velocity is measured at a distance of 15--30 cm from the supply
source using an anemometer (WHO), at the working station (EU).
The uniformity of air flow velocity is defined as being the relative standard
deviation of the velocity, expressed as a percentage of the mean as follows:
Uniformity = standard deviation / average velocity * 100.
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Measurement of air volume and uniformity air exchange rate
This procedure / verification is used to determine average airflow volume
and uniformity of volume wihin a clean room, clean zone or unidirectional
flow work zone.
The airflow volume is measured from each terminal filter or supply diffuser
by using an electronic microanemometer with an appropriate airflow hood in
a manner that includes all of the air issuing from each single source.
The uniformity should not exceed 15 %, except where otherwise specified.
Total air volume will, in turn, be used to determine the air exchange rate
(room air volume per hour) for the clean room, as defined:
Air exchange rate = total airflow volume / volume of the room.
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Airflow parallelism test
The purpose of the test is to verify the parallelism of air flow throuout the
work zone of a unidirectional airflow and whether the clean room is capable
of limiting the dispersion of internally generated contamination.
The measurement is made using a isokinetic smoke generator and defining
the offset distance between the smoke streamline and the theoretical
straight line coming from the smoke outlet and parallel to the specified
unidirectional airflow.
To be valid, such tests must be documented using video techniques.
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Determination of airflow patterns
This verification is above all valuable for demonstrating the interactions of
airflow and equipment during the OQ phase, and for demonstrating the
effectiviness of aerodynamic barriers.
This test is particularly recommended for the initial qualification of cleanliness
zones (HVAC or clean rooms) where aerodynamic barriers are employed
instead of physical barriers (A/B areas) and where therefore acceptable
differential pressures cannot be achieved.
The test consists of a visualisation of the air flow patterns, using a smoke or
other visible aerosol and is designed to show evidence that all air flows are as
expected.
In addition it is also recommended for the initial qualification in the at rest
mode of all types of clean room to demonstrate absence of non desirable
dead zones, backflows, leaks or turbulances which may contaminate a critical
part of a clean zone. To be valid, such tests must be documented using video
techniques.
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Filter installation leak test (challenge test)
These verifications are performed to confirm that
HEPA and ULPA filters are properly installed by verifying
there is no by-pass leakage in the installation (frame, gasket seal, and
filter bank framework) and
the filters are free of defects and small leaks in the filter medium and
frame seal.
These tests are required for unidirectional airflows, but have only limited
value for non-unidirectional airflow systems.
Tests are performed by introducing an aerosol challenge upstream of the
filters and scanning immediatly downstream of the filters and support frame
or sampling in a downstream duct.
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Determination of the recovery time
This test is not recommended for unidirectional airflows.
It is performed to determine whether the clean room or clean zone is capable
of returning to its specified cleanliness class within a finite time, after being
expoused to a source of airborne particulate challenge in form of smoke or
aerosol.
The result of this test is an important information for correct operation of the
system, because it defines also the minimum hold time which should be
taken into account after power failure, start (recovery), mode change, use of
changing rooms, etc.
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Determination of room classification (airborne particle count mapping)
This test is performed to determine that the completed clean room can meet the
cleanliness class specified.
The test consists in measuring the concentration of particles of a well defined size
in the clean room in order to prove with a defined confidence limit, that the clean
room complies with the cleanliness class.
In case of unidirectional airflows, the sample points should include test points
located immediately upstream of the work activity level.
All sample points must comply with the class limit.
In the case of class A, this test must be repeated to take into account generation
of particles by operator, equipment or process. The main purpose is then to
identify worst case locations which should also be taken into account when
installing probes for continuous particle monitoring.
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Temperature level and uniformity test
The purpose is to demonstrate the capability of the clean room / HVAC
system to maintain air temperature wihin the specified limits and over a certain
period of time.
The result of this test can also be used to support qualification of the location
of fixed installed temperature monitoring devices.
Humidity level and uniformity test
The purpose of this test is to demonstrate the capability of the
clean room (HVAC system with (de)humidification units) to
maintain air humidity levels within the specified limits and
over a certain period of time.
The result of these tests can also be used to support
qualification of the location of fixed installed humidity monitoring
devices.

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Summary
The key factors for a successful HVAC qualification are

the understanding of interfaces beween product purity / characteristic, process,
cleanliness zones, HVAC functions and clean rooms requirements,
the knowledge concerning general and HVAC specific tests,
the structured identification of critical functions and operations, the objective
evaluation, and the definition of appropriate measures (design, qualification,
calibration, and validation activities) in a documented way.

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Classification And Monitoring
EU Guidelines Annex 1 Revision 2008

Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1.
Classification should be clearly differentiated from operational process environmental monitoring
For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample
locations and the sample size based on the class limit of the largest considered particle size and the method
of evaluation of the data collected.

Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations
based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean
air devices.

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Monitoring in critical areas ( Room Class B and LF area = class A )
L F
Environmental control: tC, r.H., p
Particles
Measurement
Microbial Monitoring
Air flow
Speed
( conditions different
for EU and WHO)
Reference point
for pressure
Monitoring
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Monitoring in non-critical areas (C, D and other classes)
Environmental control: tC, r.H., p
Particles
Measurement
Reference point
for pressure
Monitoring
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Balinometers
Air changes measurement
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Differential Pressure Indicators
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Particle Counters
Probe Measuring device
Computer, printer
Transfer of particles
Transfer of data
Manifold system
R
E
M
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E

S
E
N
S
O
R
S

INTEGRATED SYSTEM
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Particle Counters (1 Ft
3
/Min)
Met One
Climet
PMS
Lighthouse
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AIR MONITORING FOR PARTICLES
HARDWARE - LAYOUT
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The particle counter is taken from one
sampling point to another, according
to a fixed sampling plan (SOP)
Only one sampler is needed
to monitor sequentially the sampling
points.

Mobile Particle Monitoring
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The particle counter is installed in a fixed
position and is permanently connected to its
sampling probe.
The sampling is continuous, without
interrruptions.
Every sampling point needs ist own sampling
probe/counter
Automatic data transfer
Low personnel requirements.
Stationary On-line Monitoring
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A-Zones -> stationary only
-> continuous measurements are required

B-Zones
-> continuous measurements are recommended

C/D-Zones
-> mobile measurements can and should take place

No fixed rules, but logical deductions from relevant
GMP Guidelines
Stationary Or Mobile ?
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Particle Counters
Climet
PMS
Lighthouse
Metone

REMOTE
Transfer of data
INTEGRATED
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Particle Counters (Remote)
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Particle Counters
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Particle Monitoring

REMOTE
Transfer of particles
Short extensions from the sample point to the sensor are generally acceptable,
assuming that the tubing has a minimum of turns or curves and that the curves have a generous radius.
Due to the statistically low number of particles within a sample under "Class 100" conditions,
it is best to limit the use of tubing, which causes some entrapment or fragmentation of particles.
If the tubing must be longer than 10 feet. then the loss factor for that given tubing must be
determined and a correction factor must be used to adjust the counts obtained during filling procedures.
In general, the use of manifolds for sampling in clean areas Is strongly discouraged by EU/ FDA.
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Docking Through Wall Plates
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7
Mobiler Partikelzhler
CLIMET CI-500 mit
Docking-Position-
Modul

PC-System
mit SCADA Applikation
Reinraum mit
C/D-Zonen
isokinetische
Probenahmestelle

BUS-Controller
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HEPA
Particle counter clean air Particle counter unfiltered air
Aerosol generator
Dilution system
Supply aerosol
Sampling
unfiltered air
Sampling
clean air
Filter Integrity Test
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Filter Integrity Test
(Leak Testing)
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Anemometers
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Air Speed Monitoring
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INTEGRATED MONITORING SYSTEM
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Active Air Sampling
+ passive air sampling
with settle plates
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Airflow Visualisation
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Light Intensity Measurement
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Maintaining continuous compliance
4.2.4 Where the installation is equipped with instrumentation for continuous or frequent monitoring of the airborne particle concentration, and air pressure
difference, where applicable, the maximum time interval as stated in Table 1 may be extended, provided that the results of continuous or frequent
monitoring remain within the specified limit(s).
4.2.5 In those installations that require additional tests, and where the installation is equipped with instrumentation for continuous or frequent monitoring
of the test parameter applicable, the maximum time interval(s) as stated in Table 2 may be extended, provided that the results of continuous or frequent
monitoring remain within the specified limit(s).
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Questions, please. ?

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Technical and Qualification Issues

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