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
GMP Manufacturing Environments

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.
2|
Factors Contributing To Quality Products

Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Premises
Environment
3|
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
4|
Design Considerations
5|
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.
6|
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
7|
Good Engineering Practice

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.).
8|
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 !
9|
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.
10 |
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 predetermined limits (filter HEPA, dehumidifier, etc.).
Critical instrument
Instrument measuring a critical GMP parameter.
11 |
Examples Of Systems
GMP Direct Impact
Purified water
WFI
HVAC to clean rooms
Compressed air and
gasses for production
CIP/SIP
Environmental monitoring
.Etc
No GMP Direct Impact

Heating systems
Potable water
Fire systems
Effluent treatment
General HVAC
Lighting
Cooling water
.Etc
12 |
Examples
AHU system
(direct)
AHU
Critical component
(direct)
HEPA
Chilled water system
(indirect)
Aseptic
area
13 |
Extent Of Qualification
US GMP
EU GMP
Japan GMP
Equipment shall be
suitable, correct material,
, calibrated
Basis for qualification
ICH Q9
Quality risk management

can be used to determine
the extent of qualification
ISPE Commissioning and Qualification

Baseline Guide
14 |
Qualification Success
GEP
+ GMP
= Qualification
GEP
+ GMP
= Qualification
GEP
+ GMP
= Qualification
15 |
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).
16 |

HVAC
fresh air versus air re-circulation % 100
Local extraction systems
Turbulent or uni-directional flows
Position end-filters
Low-wall returns
Targeted hygiene class
17 |
18 |
Definition Of Conditions
As built
At rest
In operation
air
air
air
19 |
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.
20 |
HVAC Design Requirements And Process
21 |
HVAC Design Requirements And Process
22 |
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
23 |
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.
24 |
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 .
25 |
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
26 |
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
27 |
Process
tolerance
Process limits
Continuous ringing of
alarms to be avoided !!
Process limits
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.
Process range
Range of measurement and control unit
28 |
Action limit
Alert limit
Physical / Technical OQ And PQ Tests

In addition to the
general tests (e.g.
power failure and
recovery tests,
verification of
functions and
sequences, verification of alarms
and interlocks...)
specific tests have
to be
performed.
:Test
Unidirectional
:airflow / LAF
Turbulent / mixed
:airflow
Differential pressure on filters
Room differential pressure
N/A
3 ,2
Airflow velocity / uniformity
3 ,2
Optional
Airflow volume / rate
Parallelism
N/A
Air flow patterns
Optional
Optional
Filter leak test / challenge test
Recovery
N/A
Room classification )airborne particle(
Particle fall out
Optional
Optional
Temperature, humidity
N/A
3 ,2
As built )ideally used to perform IQ(; 2:= At rest )ideally used to perform OQ(; 3:= Operational )ideally used to perform PQ( := 1
29 |

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.
30 |

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.
31 |

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.
32 |

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.
33 |

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.
34 |

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.
35 |

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.
36 |

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.
37 |

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.
38 |
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.
39 |
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
40 |
Monitoring
Monitoring in critical areas ) Room Class B and LF area = class A (
Particles
Measurement
Microbial Monitoring
Air flow
Speed
conditions different )
( for EU and WHO
Environmental control: tC, r.H., p
LF
41 |
Reference point
for pressure
Monitoring
Monitoring in non-critical areas )C, D and other classes(
Environmental control: tC, r.H., p
Reference point
for pressure
Particles
Measurement
42 |
Balinometers
Air changes measurement
43 |
Differential Pressure Indicators
44 |
Particle Counters
Probe
Measuring device
Transfer of particles
Computer, printer
Transfer of data
Manifold system
INTEGRATED SYSTEM
45 |
Particle Counters )1 Ft3/Min(
Lighthouse
Climet
Met One
46 |
PMS
AIR MONITORING FOR PARTICLES

HARDWARE - LAYOUT
47 |
Mobile Particle Monitoring
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
48 |
Stationary On-line Monitoring
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
49 |
?Stationary Or Mobile
No fixed rules, but logical deductions from relevant
GMP Guidelines
A-Zones -> stationary only
-> continuous measurements are required
B-Zones
-> continuous measurements are recommended
C/D-Zones
-> mobile measurements can and should take place
50 |
Particle Counters
REMOTE
Transfer of data
INTEGRATED
Metone
Climet
PMS
51 |
Lighthouse
Particle Counters )Remote(
52 |
Particle Counters
53 |
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
54 |
Docking Through Wall Plates

Reinraum mit
C/D-Zonen
isokinetische
Probenahmestelle
Pos. 7
Pos. 6
Pos. 5
Pos. 4
Pos. 3
Pos. 2
Pos. 1
Mobiler Partikelzhler
CLIMET CI-500 mit
Docking-PositionModul
BUS-Controller
PC-System
mit SCADA Applikation
55 |
Filter Integrity Test

HEPA
Sampling
clean air
Sampling
unfiltered air
Supply aerosol
Dilution system
Aerosol generator
Particle counter clean air
Particle counter unfiltered air
56 |
Filter Integrity Test

)Leak Testing(
57 |
Anemometers
58 |
Air Speed Monitoring
59 |
INTEGRATED MONITORING SYSTEM
60 |
Active Air Sampling
passive air sampling+

with settle plates
61 |
Airflow Visualisation
62 |
Light Intensity Measurement
63 |
Maintaining continuous compliance
Where the installation is equipped with instrumentation for continuous or frequent monitoring of the airborne particle concentration, and air 4.2.4
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)
In those installations that require additional tests, and where the installation is equipped with instrumentation for continuous or frequent monitoring 4.2.5
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)
64 |
. ?Questions, please
65 |

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HVAC

Technical and Qualification Issues

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

GMP Manufacturing Environments

Improved production rates.

Operator comfort, satisfaction and safety.

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

Factors Contributing To Quality Products

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

Defining The Environment

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

Good Engineering Practice

Good HVAC installation: GEP + cGMP

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

Good Engineering Practice

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

No GMP Direct Impact

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

Quality risk management

ISPE Commissioning and Qualification

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

HVAC Design Requirements

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

HVAC Design Requirements

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

HVAC Design Requirements

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

HVAC And GMP

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

HVAC Design Requirements And Process

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

HVAC Design Requirements And Process

,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, November 2009

HVAC: Heating, Ventilation and Air Conditionning