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

Personnel Validated processes Procedures
Raw Materials
Equipment
Packing Materials Premises
Environment
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Defining The Environment

What is the optimal manufacturing environment ?
How does the manufacturing environment affect quality, contamination and cross-contamination ? How do we arrive at an optimal environment ?
Cleanroom concept
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Design Considerations
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Systems
To support pharmaceutical production activities, state-of-the-art factories include systems, which have to be conceived according to GEP and cGMP. Some of these systems have a direct impact on product quality, some an indirect impact. Systems with direct impact must be identified and documented in a more exhaustive way, and evaluated in relation to critical GMP parameters. QA, Production and Engineering must agree beforehand on the scope of qualification activities, ideally right at project start.
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Good Engineering Practice

Good Engineering Practice (GEP) is defined as those established engineering methods and standards that are applied throughout the lifecycle to deliver appropriate and cost effective solutions. Generally the term is used to describe an engineering management system that is being applied in the engineering profession for delivering, operating and maintaining capital assets. While GEP is expected in a pharmaceutical enterprise, it is not mandated by GMP regulations.
Good HVAC installation: GEP + cGMP

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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.).
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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.
No GMP Direct Impact

Heating systems Potable water Fire systems Effluent treatment General HVAC Lighting Cooling water 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
Japan GMP
EU 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
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Qualification Success
GEP GEP GEP
+ GMP + GMP + GMP
= Qualification = Qualification = Qualification
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HVAC Design Requirements

The complexity resulting from the different requirements for air quality in the various cleanliness zones, makes it recommendable to define up-front the following criteria:
Critical room parameters which affect product or materials (i.e. humidity)
Process operations presenting a potential for contamination.

Process or operations not affected by room conditions (e.g. closed systems). Potential sources of room contamination (process equipment / operation, HVAC components, HVAC operation type, personnel, failure of HVAC functions...). Equipment failure modes (fans, room / zone fail safe modes, interlocks, user action in the event of failure).
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HVAC
100 % fresh air versus air re-circulation Local extraction systems Turbulent or uni-directional flows Position end-filters Low-wall returns Targeted hygiene class
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Definition Of Conditions
As built
air
At rest
air
In operation
air
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HVAC And GMP

In pharmaceutical primary as well as in secondary manufacturing, HVAC systems are a major factor for the observance of cleanliness and product purity, and thus for GMP compliance. Qualification activities of HVAC systems with their measurement and control and computerized units are cost intensive and necessitate a great deal of time. The key issues to keep HVAC qualification in quality, time, and costs are the understanding of interfaces beween product purity / characteristics, process, cleanliness zones, HVAC functions and clean rooms requirements. the structured identification of critical functions and operations, the objective evaluation, and the definition of appropriate measures (design, qualification, calibration, and validation activities) in a documented way.
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HVAC Design Requirements And Process
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HVAC Design Requirements And Process
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To Start With
HVAC: Heating, Ventilation and Air Conditionning
HVAC System or Ventilation System ?

HVAC System: Includes sub-systems (chilled water, brine, steam, etc.). Ventilation system: Air treatment components (AHU, ducts, flow controllers, etc.).
BMS: Building Management System

BMS:
Building Management System (BMS) is a computer based control system installed in buildings that controls and monitors the buildings mechanical and electrical equipment such as air handling and cooling plant systems, lighting, power systems, fire systems, and security systems
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Key Qualification Aspects

A HVAC system serving a production area must be considered as direct impact system
Such a system consists of sub-systems
As a consequence, it is necessary to identify sub-systems which also could have a direct impact. Within these sub-systems, critical components and instruments have to be identified as well.
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HVAC Qualification
For example, for a typical HVAC system in an aseptic area, critical components would be: Terminal HEPA filters. Unidirectional airflow units.
The monitoring of the critical GMP parameters indicates whether the system operates within the pre-established criteria.
A breakdown in a fan would for instance have as consequence a drop in differential pressures, as well as changes in temperature and humidity. The monitoring system in itself is thus critical as well.
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HVAC Qualification
IQ Tests Installation (Static verifications) Installation of components OQ Tests Installation (Dynamic verifications) Individual tests components (fans, coils, etc.) Functional tests sub-systems Verification control system
These tests confirm that the installation is working as a whole and must be done before the room qualification
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HVAC Key Qualification Aspects

Facility qualification tests
Air changes Differential pressure cascade Flow patterns (turbulent and uni-directional) Room classification (ISO norms) Temperature and humidity Integrity tests HEPA filters Exactness of readings of GMP critical parameters Uni-directional airspeed Laminarity at point of use
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In establishing design criteria for critical parameters, consideration should be given to operating ranges which will assist in the definition of the tightness of control range of these parameters.
Process limits Process limits Process tolerance Action limit Alert limit
Continuous ringing of alarms to be avoided !!
Process range
Range of measurement and control unit
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Physical / Technical OQ And PQ Tests

In addition to the general tests (e.g. power failure and recovery tests, verification of functions and sequences, verification of alarms and interlocks...) specific tests have to be performed.
Test: Differential pressure on filters Room differential pressure Airflow velocity / uniformity Airflow volume / rate Parallelism Unidirectional airflow / LAF: 1 N/A 2, 3 2 2 Turbulent / mixed airflow: 1 2, 3 Optional 2 N/A
Air flow patterns

Filter leak test / challenge test Recovery
Optional
2 N/A
Optional
2 2
Room classification (airborne particle)

Particle fall out Temperature, humidity
2
Optional N/A
2
Optional 2, 3
1 := As built (ideally used to perform IQ); 2:= At rest (ideally used to perform OQ); 3:= Operational (ideally used to perform PQ)
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Determination of differential pressure on filters
to detect initial defects of filters, to verify the pressure differential (for a defined flow) meets the value specified by the vendor, to set the correct value of the alarm as indicated by the vendor for triggering a filter replacement.
Differential pressure between rooms

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

The purpose of this test is to demonstrate the capability of the clean room (HVAC system with (de)humidification units) to maintain air humidity levels within the specified limits and over a certain period of time. The result of these tests can also be used to support qualification of the location of fixed installed humidity monitoring devices.
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Summary
The key factors for a successful HVAC qualification are

the understanding of interfaces beween product purity / characteristic, process, cleanliness zones, HVAC functions and clean rooms requirements, the knowledge concerning general and HVAC specific tests, the structured identification of critical functions and operations, the objective evaluation, and the definition of appropriate measures (design, qualification, calibration, and validation activities) in a documented way.
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Classification And Monitoring
EU Guidelines Annex 1 Revision 2008

Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected. Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.
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Monitoring
Monitoring in critical areas ( Room Class B and LF area = class A )
Particles Measurement Microbial Monitoring Environmental control: tC, r.H., p
Air flow Speed ( conditions different for EU and WHO)
Reference point for pressure
LF
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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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Differential Pressure Indicators
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Particle Counters
Probe Measuring device Computer, printer
Transfer of particles
Transfer of data
Manifold system
INTEGRATED SYSTEM
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REMOTE SENSORS
Particle Counters (1 Ft3/Min)
Lighthouse Climet
Met One
PMS
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AIR MONITORING FOR PARTICLES

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

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

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

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HVAC

Technical and Qualification Issues

GMP Manufacturing Environments

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors,

Nanjing, November 2009

Factors Contributing To Quality Products

Packing Materials Premises

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

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

Equipment shall be suitable, correct material, calibrated, Basis for qualification

Quality risk management can be used to determine the extent of qualification

ISPE Commissioning and Qualification Baseline Guide

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors,

Nanjing, November 2009

GEP GEP GEP

+ GMP + GMP + GMP

= Qualification = Qualification = Qualification

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors,

Nanjing, November 2009

HVAC Design Requirements

Process operations presenting a potential for contamination.

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