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Guidelines

VIEWS: 4 PAGES: 65

  • pg 1
									                                              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.


     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
2|   Nanjing, November 2009
Factors Contributing To Quality Products

                                                 Personnel
                   Validated processes
                                                                  Procedures


             Raw Materials

                                                                       Equipment



                Packing Materials
                                                            Premises
                                  Environment



      Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
 3|   Nanjing, November 2009
                  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


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
  4|   Nanjing, November 2009
                     Design Considerations




     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
5|   Nanjing, November 2009
                                          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.


     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
6|   Nanjing, November 2009
              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

     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
7|   Nanjing, November 2009
              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.).



     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
8|   Nanjing, November 2009
                              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 !




     Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
9|   Nanjing, November 2009
                                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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
10 |   Nanjing, November 2009
                                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.



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
11 |   Nanjing, November 2009
                         Examples Of Systems

         GMP Direct Impact                                         No GMP Direct Impact
       Purified water                                          Heating systems
       WFI                                                     Potable water
       HVAC to clean rooms                                     Fire systems
       Compressed air and                                      Effluent treatment
       gasses for production                                   General HVAC
       CIP/SIP                                                 Lighting
       Environmental monitoring                                Cooling water
       Etc.                                                    Etc.




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
12 |    Nanjing, November 2009
                                          Examples
                                                                   AHU system
                                                                     (direct)

                                              AHU
                                                                                          Critical component
                                                                                                 (direct)

                                                                                       HEPA

              Chilled water system
                    (indirect)
                                                                                Aseptic
                                                                                 area

       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
13 |   Nanjing, November 2009
                          Extent Of Qualification

                    US GMP                          Japan GMP                             EU GMP




       Equipment shall be
                                                                                    Quality risk management
       suitable, correct material,
                                                       ICH Q9                       can be used to determine
       calibrated, …
                                                                                    the extent of qualification
       Basis for qualification




                                   ISPE Commissioning and Qualification
                                            Baseline Guide




          Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
14 |      Nanjing, November 2009
                         Qualification Success


GEP                     + GMP                                 = Qualification

GEP                    + GMP                                 = Qualification

GEP                    + GMP                                 = Qualification


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
15 |   Nanjing, November 2009
                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).




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
16 |   Nanjing, November 2009
                HVAC Design Requirements


                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



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
17 |   Nanjing, November 2009
                 HVAC Design Requirements




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
18 |   Nanjing, November 2009
                      Definition Of Conditions

       As built                                    At rest                              In operation

          air                                           air                                 air




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
19 |    Nanjing, November 2009
                                 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.



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
20 |   Nanjing, November 2009
HVAC Design Requirements And Process




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
21 |   Nanjing, November 2009
HVAC Design Requirements And Process




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
22 |   Nanjing, November 2009
                                   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 building’s mechanical and electrical equipment such as air handling and cooling
           plant systems, lighting, power systems, fire systems, and security systems




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
23 |   Nanjing, November 2009
                   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.


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
24 |   Nanjing, November 2009
                            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,
25 |   Nanjing, November 2009
                            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


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
26 |   Nanjing, November 2009
           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



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
27 |   Nanjing, November 2009
                HVAC Design Requirements

 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
                                                                                  tolerance




                                                              Process limits




                                                                                               Process limits
                                                                                                                Action limit


 Continuous ringing of                                                                                         Alert limit


  alarms to be avoided !!
                                                                               Process range




                                                           Range of measurement and control unit



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
28 |   Nanjing, November 2009
    Physical / Technical OQ And PQ Tests

 In addition to the
                                                                                                    Unidirectional            Turbulent /
  general tests (e.g.                                                                    Test:
                                                                                                    airflow / LAF:           mixed airflow:
  power failure and                                        Differential pressure on filters                           1                        1
  recovery tests,                                              Room differential pressure                          N/A                      2, 3

  verification of                                             Airflow velocity / uniformity                         2, 3              Optional

  functions and                                                       Airflow volume / rate                           2                        2

  sequences, verifi-                                                              Parallelism                         2                     N/A

                                                                           Air flow patterns                 Optional                 Optional
  cation of alarms
                                                           Filter leak test / challenge test                          2                        2
  and interlocks...)
                                                                                    Recovery                       N/A                         2
  specific tests have
                                                Room classification (airborne particle)                               2                        2
  to be                                                                      Particle fall out               Optional                 Optional
  performed.                                                        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)


         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
  29 |   Nanjing, November 2009
  Physical / Technical OQ And PQ Tests
 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.

         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
30 |     Nanjing, November 2009
 Physical / Technical OQ And PQ Tests

 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.




         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
31 |     Nanjing, November 2009
   Physical / Technical OQ And PQ Tests

 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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
32 |   Nanjing, November 2009
  Physical / Technical OQ And PQ Tests


 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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
33 |   Nanjing, November 2009
  Physical / Technical OQ And PQ Tests
  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.


         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
34 |     Nanjing, November 2009
  Physical / Technical OQ And PQ Tests

 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.




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
35 |   Nanjing, November 2009
  Physical / Technical OQ And PQ Tests


 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.




         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
36 |     Nanjing, November 2009
  Physical / Technical OQ And PQ Tests

 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.



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
37 |   Nanjing, November 2009
  Physical / Technical OQ And PQ Tests
 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.



         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
38 |     Nanjing, November 2009
                                              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.




           Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
39 |       Nanjing, November 2009
              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.




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
40 |    Nanjing, November 2009
                                         Monitoring

 Monitoring in critical areas ( Room Class B and LF area = class A )

                                                Environmental control: t°C, r.H., p
             Particles
           Measurement
        Microbial Monitoring


                                                                                        Reference point
        Air flow
                                                                                           for pressure
         Speed
( conditions different
   for EU and WHO)
                                                         LF




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
 41 |   Nanjing, November 2009
                                         Monitoring

                 Monitoring in non-critical areas (C, D and other classes)
                                                Environmental control: t°C, r.H., p




                                                                                        Reference point
                                                                                           for pressure

            Particles
          Measurement
       Microbial Monitoring




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
42 |    Nanjing, November 2009
                                      Balinometers

Air changes measurement




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
 43 |   Nanjing, November 2009
            Differential Pressure Indicators




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
44 |   Nanjing, November 2009
                                Particle Counters
            Probe                               Measuring device                      Computer, printer



                        Transfer of particles                      Transfer of data




                                                                                                          REMOTE SENSORS
                                          Manifold system




                                                                                      INTEGRATED SYSTEM

       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
45 |   Nanjing, November 2009
                        Particle Counters (1 Ft3/Min)




                                                                                       Lighthouse
 Climet




        Met One                                                                            PMS




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
46 |   Nanjing, November 2009
                AIR MONITORING FOR PARTICLES
                                 HARDWARE - LAYOUT




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
47 |   Nanjing, November 2009
                     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.




         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
  48 |   Nanjing, November 2009
               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. 




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
49 |   Nanjing, November 2009
                         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


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
50 |   Nanjing, November 2009
                                Particle Counters


                                                                                          REMOTE
                                                                                       Transfer of data
           INTEGRATED

                                                               Metone




                                                      PMS                               Lighthouse
 Climet
       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
51 |   Nanjing, November 2009
                 Particle Counters (Remote)




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
52 |   Nanjing, November 2009
                                Particle Counters




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
53 |   Nanjing, November 2009
                            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.


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
54 |   Nanjing, November 2009
           Docking Through „Wall Plates“

                                                                Reinraum mit
                                                                 C/D-Zonen                           isokinetische
                                                                                                     Probenahmestelle




                                                                                            Mobiler Partikelzähler
                                                                                            CLIMET CI-500 mit
                                                                                            Docking-Position-
                                                                                            Modul




                                                                 Pos. 1

                                                                          Pos. 2




                                                                                            Pos. 4


                                                                                                       Pos. 5


                                                                                                                Pos. 6


                                                                                                                         Pos. 7
                                                                                   Pos. 3
                                                                                   BUS-Controller
                                                                                                                                        PC-System
                                                                                                                                  mit SCADA Applikation


       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
55 |   Nanjing, November 2009
                               Filter Integrity Test

                                               HEPA

                                    Sampling                      Sampling
                                                                                   Supply aerosol
                                    clean air                    unfiltered air




                                                       Dilution system

                                                                                        Aerosol generator




                  Particle counter clean air     Particle counter unfiltered air



       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
56 |   Nanjing, November 2009
                             Filter Integrity Test
                                (Leak Testing)




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
57 |   Nanjing, November 2009
                                    Anemometers




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
58 |   Nanjing, November 2009
                                Air Speed Monitoring




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
59 |   Nanjing, November 2009
       INTEGRATED MONITORING SYSTEM




        Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
60 |    Nanjing, November 2009
                                  Microbial Monitoring
                                  Active Air Sampling




+ passive air sampling
    with settle plates



         Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
  61 |   Nanjing, November 2009
                          Airflow Visualisation




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
62 |   Nanjing, November 2009
               Light Intensity Measurement




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
63 |   Nanjing, November 2009
           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).

             Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
   64 |      Nanjing, November 2009
                        Questions, please…. ?




       Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors,
65 |   Nanjing, November 2009

								
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