HVAC Technical and Qualification Issues Alain Kupferman Manufacture of sterile medicines –...

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 EnvironmentsGMP 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 EnvironmentDefining 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 ConsiderationsDesign Considerations

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SystemsSystems

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

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 Good Engineering Practice

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Some DefinitionsSome 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 DefinitionsSome 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 DefinitionsMore 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 SystemsExamples Of Systems

Purified water WFIHVAC to clean roomsCompressed air and gasses for productionCIP/SIPEnvironmental monitoringEtc.

Heating systemsPotable waterFire systemsEffluent treatmentGeneral HVACLightingCooling waterEtc.

GMP Direct Impact No GMP Direct Impact

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ExamplesExamples

AHU

Aseptic area

HEPA

Chilled water system(indirect)

AHU system(direct)

Critical component(direct)

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Extent Of QualificationExtent Of Qualification

Japan GMPUS GMP EU GMP

ICH Q9

ISPE Commissioning and QualificationBaseline Guide

Equipment shall be suitable, correct material,

calibrated… ,Basis for qualification

Quality risk management can be used to determinethe extent of qualification

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Qualification SuccessQualification Success

GEP + GMP = Qualification



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HVAC Design RequirementsHVAC 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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HVAC100 % fresh air versus air re-circulation

Local extraction systemsTurbulent or uni-directional flowsPosition end-filtersLow-wall returns

Targeted hygiene class

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HVAC Design Requirements

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Definition Of ConditionsDefinition Of Conditions

air

As built

air air

At rest In operation

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HVAC And GMPHVAC 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…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

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Key Qualification AspectsKey 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 QualificationHVAC 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 QualificationHVAC 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 AspectsHVAC 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 ofalarms to be avoided !!

Action limit

Alert limit

Range of measurement and control unit

Process range

Pro

cess

lim

its

Pro

cess

lim

its

Process tolerance

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Physical / Technical OQ And PQ TestsPhysical / Technical OQ And PQ Tests

In addition to the general tests (e.g. power failure and recovery tests, verification offunctions andsequences, verifi-cation of alarmsand interlocks...)specific tests have to beperformed.

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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Physical / Technical OQ And PQ Tests 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.

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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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SummarySummary

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 MonitoringClassification 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: t°C, r.H., pParticles

MeasurementMicrobial Monitoring

Air flowSpeed

(conditions different for EU and WHO )

Reference pointfor pressure

Monitoring

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Monitoring in non-critical areas )C, D and other classes(

Environmental control: t°C, r.H., p

Particles Measurement

Microbial Monitoring

Reference pointfor pressure

Monitoring

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Balinometers

Air changes measurement

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Differential Pressure Indicators

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Particle CountersParticle Counters

Probe Measuring device Computer, printer

Transfer of particles Transfer of data

Manifold system

INTEGRATED SYSTEM

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Particle Counters )1 Ft3/Min(Particle Counters )1 Ft3/Min(

Met One

Climet

PMS

Lighthouse

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AIR MONITORING FOR PARTICLESHARDWARE - 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 neededto 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 transferLow 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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Climet PMS Lighthouse

Metone

REMOTETransfer of data

INTEGRATED

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Particle Counters )Remote(Particle Counters )Remote(

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Particle MonitoringParticle Monitoring

REMOTETransfer 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“Docking Through „Wall Plates“

Pos

. 1

Pos

. 2

Pos

. 3

Pos

. 4

Pos

. 5

Pos

. 6

Pos

. 7

Mobiler PartikelzählerCLIMET CI-500 mitDocking-Position-Modul

PC-Systemmit SCADA Applikation

Reinraum mitC/D-Zonen isokinetische

Probenahmestelle

BUS-Controller

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HEPAHEPA

Particle counter clean air Particle counter unfiltered air

Aerosol generator

Dilution system

Supply aerosolSampling

unfiltered airSamplingclean air

Filter Integrity TestFilter Integrity Test

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Filter Integrity Test)Leak Testing(

Filter Integrity Test)Leak Testing(

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Anemometers

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Air Speed MonitoringAir Speed Monitoring

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INTEGRATED MONITORING SYSTEMINTEGRATED MONITORING SYSTEM

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Microbial MonitoringActive Air Sampling

+passive air samplingwith 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? .…Questions, please? .…

HVAC Technical and Qualification Issues Alain Kupferman Manufacture of sterile medicines –...

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