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Technical and Qualification Issues: Alain Kupferman
Technical and Qualification Issues: Alain Kupferman
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Packing Materials
Premises
Environment
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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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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 predetermined limits (filter HEPA, dehumidifier, etc.).
Critical instrument
Instrument measuring a critical GMP parameter.
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Examples Of Systems
GMP Direct Impact
Purified water
WFI
HVAC to clean rooms
Compressed air and
gasses for production
CIP/SIP
Environmental monitoring
.Etc
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Examples
AHU system
(direct)
AHU
Critical component
(direct)
HEPA
Chilled water system
(indirect)
Aseptic
area
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Extent Of Qualification
US GMP
EU GMP
Japan GMP
Equipment shall be
suitable, correct material,
, calibrated
Basis for qualification
ICH Q9
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Qualification Success
GEP
+ GMP
= Qualification
GEP
+ GMP
= Qualification
GEP
+ GMP
= Qualification
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Definition Of Conditions
As built
At rest
In operation
air
air
air
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To Start With
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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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 .
,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors
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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
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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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Process
tolerance
Process limits
Continuous ringing of
alarms to be avoided !!
Process limits
Process range
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Action limit
Alert limit
:Test
Unidirectional
:airflow / LAF
Turbulent / mixed
:airflow
N/A
3 ,2
3 ,2
Optional
Parallelism
N/A
Optional
Optional
Recovery
N/A
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
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Summary
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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
LF
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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
Microbial Monitoring
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Balinometers
Air changes measurement
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Particle Counters
Probe
Measuring device
Transfer of particles
Computer, printer
Transfer of data
Manifold system
INTEGRATED SYSTEM
,Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors
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Lighthouse
Climet
Met One
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PMS
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?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
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Particle Counters
REMOTE
Transfer of data
INTEGRATED
Metone
Climet
PMS
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Lighthouse
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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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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
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Sampling
unfiltered air
Supply aerosol
Dilution system
Aerosol generator
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Anemometers
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Microbial Monitoring
Active Air Sampling
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Airflow Visualisation
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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)
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. ?Questions, please
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