hvac manpreet singh naroo
TRANSCRIPT
1
Qualification ofQualification ofHVAC systemsHVAC systems
Case studies
• physical / technical tests
• risk analysis calibration
• risk analysis computerized systems
2
Table of Contents
1. Introduction
2. HVAC design requirements
3. HVAC construction requirements
4. General HVAC qualification activities (DQ, IQ, OQ, PQ)
5. Physical / technical OQ and PQ tests for HVAC systems
6. Case study risk analysis for measurement and control unsits for HVAC systems
7. Case study risk analysis computerized systems validation for HVAC systems
8. Summary
Figure slide 1: Silica gel and structure of zeolite used as adsorbent for dehumification of clean rooms to protect products which are sensitive against moisture exposion
3
Introduction
In pharmaceutical primary as well as in secondary manufacturing HVAC systems are a major factor for the observance of cleanliness and product purity.
No wonder that the qualification activities of HVAC systems with their measurement and control and computerized units are cost intensive and 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 / characteristic, 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.
4
Introduction
These key issues are the reason for the following seminar topics listed below.
Design and construction requirements of HVAC systems with their functions and units.
General HVAC qualification steps to ensure a sufficient scope and structered approach,
Specific physical and technical tests such as filter leak tests, measurement of room difference pressures, temperature and humidity, capability study of dehumification function.
Method and practice of risk analysis to cover potential risks and to define the scope and approach of calibration and computerized systems validation in relation to HVAC systems.
5
HVAC design requirements
The complexity resulting from the different requirements for air quality in the various cleanliness zones, make it recommendable to define up-front the following process criteria:
Critical room parameters which affect product or materials (i.e. humidity) and the corresponding acceptance limit.
Which process operations present a reasonable potential for contamination.
Which process or operations are not affected by room conditions (e.g. closed systems).
Potential sources of room contamination (outdoor air, process equipment / operation, HVAC components, failure of HVAC functions...).
Equipment failure modes (fans, room / zone fail safe modes, interlocks, user action in the event of failure).
6
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.
The following tables will givea conception for relevantparameters in conjunctionwith cleanliness zones usedin secondary manufacturing.
Action limit
Alert limit
Range of measurement and control unit
Process range
Pro
cess
lim
its
Pro
cess
lim
its
Process tolerance
Figure: The picture demonstrates the relation of process, operation ranges, limits, and tolerances.
7
HVAC design requirements
Typical parameters and ranges for the design of HVAC systems under consideration of cleanliness zoning concept (table).
If cleanliness zoningrequirements are differentto product specific re-quirements the relevant para-meters with their ranges,tolerances, and limits shouldbe fixed and documented.
Example:
Products which are sensitiveto moisture (e.g. effervescence tablets).In this case the setpoint, tolerances,and limits of the dehumidificationis the major factor for the conditioning.
Zone:
N/A (a)
B
C / 1
D / 2
E / 3
4
Room temperature
in °C:
Room relative
humidity in %:
Room air changes in
h-1:
Room relative
pressure in Pa:
to barometric reference
A
22,0 4,0
22,0 4,0
22,0 5,0
20,0 8,0
Not defined
40,0 10,0
45,0 15,0
45,0 15,0
45,0 15,0
45,0 15,0
Not defined
(a)
30 - 90
20 - 50
5 - 30
4 – 10 (b)
Not defined
N/A (a)
30 - 45
20 - 30
10 - 15
0
Not defined
(a) The driving factor in zone A is the laminar air speed of 0,45 ms-1 0,09 ms-1 (b) Optional
8
HVAC design requirements
Example layouteffervescents factory
Figure: The picure shows humidity controlled areas. Typically, exposed humidity-sensitive products require humidity control to 30,0 to 50,0 %, but different values are not uncommen (e.g. effervescence products). Process range can also range to 10,0 % to 20,0 % rel. humidity depending on process and mixture of components (acid / alkaline gradient).
9
HVAC construction requirements
In case of humidity sensitiveness adehumidification unit has to beintegrated / installed.
Such a unit selected should not adversely contaminate the product. Cooling coils generate large quantities of condensate which must drained properly to avoid microbial contamination. Provisions should also be made that no condensate droplets can be entrained into the air stream passing throug the cooling coils.
Liquid and dry type desiccant systems should be evaluated for potential carry-over of dessicant into the supply air stream and the effect of such carry-over on the exposed product.
Figure: Simplified picture of a small dehumidification unit (cooling coils).
10
HVAC construction requirements
Figure: In general the HVAC system includes severalbasic units such as fresh / exhaust air, and air conditioning units with their fans, filters, and measurement and control instrumentation
General structure of a HVAC system used in sterile manufacturingof parenterals. Critical process stepsare covered by laminar air flow units.
11
HVAC construction requirements
Figures: The exchange of humidity happens in the slow rotating adsorption-rotor (charched with silica gel).The humidity load will be desorbed by a countercurrent heated air flow. The loaded air can be exhaust. There are different types available (heat recovery unit or with integrated condenser). The adsorption process is frequently reversal and continuous. Pictures authorized by Munters GmbH
Dehumidification method by adsorptive separation
12
HVAC construction requirements
Dehumidification by adsorption:
Continuous working dehumidification (adsorbed layer / adsorbent made of silica or zeolites). Simultaneous adsorption and regeneration.
Supply with dry air flow ranges from 50 m3h-1 to 80.000 m3h-1.
Adsorption as well as desorption results are a function of
temperature of air to dehumidification unit,
stable pressure conditions inside dehumidification unit,
humidity load of inlet air (fresh air / recirculated air rate),
angle velocity / revolutions per minute (adsorbed layer / rotor)
and contact time with adsorbent as a function of air flow rate.
Additional requirements are the proper insulation of the conditioned rooms, and measures to eliminate electrostatic differential potential.
13
General HVAC qualification activities (DQ, IQ, OQ, PQ)
General acceptance criteria DQ: The design and its documentation comply with user and GMP requirements. Chronology and trace ability are covered. The main contents of the concept, basic, and detail engineering are documented.
Clean rooms
HVAC
Figure: The DQ part of Sulzers validation structure matrix for clean rooms and HVAC systems
14
General HVAC qualification activities (DQ, IQ, OQ, PQ)
The IQ will bring the documented evidence that the as it is on site to be installed system with its components, measurement and control units and instrumentation, hardware / software(modules) complies with the specification.
The OQ will bring the documentedevidence that the operationalfunctions with its specificparameters, ranges and limitscomply with the functionalrequirements and specifications.
Clean rooms
HVAC
Figure: The IQ / OQ part of Sulzers validation structure matrix for clean rooms and HVAC systems
15
Physical / technical OQ and PQ tests for HVAC systems
In addition to these general tests (e.g. power failure and recovery tests, verification offunctions andsequences, verifi-cation of alarmsand interlocks...)typical HVAC specifictests has 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)
16
Physical / technical OQ and PQ tests for HVAC systems
Determination of differential pressure on filters This preliminary test is performed to detect initial defects of filters, and to verify the pressure differential (for a defined flow) meets the value
specified by the vendor, and finally, where applicable, 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 can not be met and as a consequence the product may be at risk.
17
Physical / technical OQ and PQ tests for HVAC systems
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 30 cm from the supply source using an anemometer (therma / vane-type). The number of individual measurements should be at least equal to 3 per m2. The duration of each measurement should not less than 15 s.
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.
The relative standard deviation (or uniformity) should not exceed 15 %, except where otherwise specified.
18
Physical / technical OQ and PQ tests for HVAC systems
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.
19
Physical / technical OQ and PQ tests for HVAC systems
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 wether 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.
The number of individual measurements should be equal to 1 / 10 m2. The angle of the offset should not exceed 14°. To be valid, such tests must be documented using video techniques.
20
Physical / technical OQ and PQ tests for HVAC systems
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 should be considered as an alternative to differential pressure between rooms (slide 16) and is particularly recommended for the initial qualification of cleanliness zones (HVAC or clean rooms) where aerodynamic barriers are employed instead of physical barriers and where therefore acceptable differential pressures can not 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.
21
Physical / technical OQ and PQ tests for HVAC systems
Filter installation leak test (challange test) These verifications are performed to confirm that HEPA and ULPA filters are
properly installed by verifying the absence of by-pass leakage in the installation (frame, gasket seal, and filter bank framework) and that 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 challange upstream of the filters and scanning immediatly downstream of the filters and support frame or sampling in a downstream duct.
In rooms with turbulent airflow, the filter installation leak test can be substituted by in-situ vergification of the integral particle penetration value through the filter. See VDI 2083, Blatt3 for further information.
22
Physical / technical OQ and PQ tests for HVAC systems
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 challange 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. See VDI 2083, Blatt 3 for further infomation.
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.
23
Physical / technical OQ and PQ tests for HVAC systems
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. Fore more and detailed information refer US Fed. Std 209E / ISO 14644-1. If not performed in the operational mode, in the case of cleanliness zones
belonging to class A and B, 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.
24
Physical / technical OQ and PQ tests for HVAC systems
Particle fallout test These tests are done by allowing a small test surface to collect natural particles
that settle out in the clean room area. The particles on the plate are counted with a surface particle detection instrument and a particle-deposition rate is determined.
These verification could also be used in multipurpose / multi-product facilities to support a demonstration of absence of croos contamination.
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.
25
Physical / technical OQ and PQ tests for HVAC systems
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 supportqualification of the location of fixed installedhumidity monitoring devices.
The function and sequences of dehumidificationunits must be carefully tested (main functionssee slide 12).
Figure: Mobile measurement device for the acquisition of humidity data.
26
Case studies risk analysis
The FMEA is a tool for Quality Management that combines the technology and experience of specialists in identifying failure modes.
In the Pharmaceutical Industry the regulatories of Good Manufacturing Practice (GMP) demand a high level on quality assurance system and documentation.
Therefore the main intention of the FMEA is to identify evaluate and cover
GMP critical functions and process conditionsin a systematic, documented,and objective way.
27
Case studies risk analysis
Typical applications in the Pharmaceutical Industry are qualification of technical equipment, calibration of measurement and control installations, validation of processes and computerized systems.
In conjunction with an increasing uncertainty what, when, and how
to qualify, calibrate and maintain.
28
Case studies risk analysis
In general, FMEA is the tool to prevent to confirm and to solve problems.
Behebung von 80 %der Fehler
Entstehung von 75 % der Fehler
5
0
10
15
20
25
30
35
40
45
50
55
60
Planung Konstruktion Qualifizierung Produktion
Fe
hle
rqu
ote
Fehler-entstehungkurve
Fehler-behebungskurve
Design incl.. DQ
Construction:constructive
changes...
Qualification:redesign
new constructiondelay of production
...
Production:costs of delay
costs maintenanceloss of image
loss of market shares...
Phases of project
Fai
lure
rem
oval
cos
ts
Figures: Most of the failures come into being in a early project phase (design and construction) and must be repaired cost intensive in a late project phase. The FMEA is a usefull tool to identify, evaluate and cover potential failures.
29
Case studies risk analysis
A guide for a successfull FMEA used in Pharmaceutical Industry
Systematic way of identification
Objective way of evaluation Define criteria for evaluation. Form a team with speacialist‘s competence and the courage to make decisions. Set a trigger (yes/no) for decision of recommended actions.
Define appropriate protective measures.
Set a high level of documentation (create forms for FMEA-documentation and recommended actions).
30
Case studies risk analysis
A potential risk is the hidden, unforeseenoccurrence of a failure with considerableconsequences.
A potential risk is composed ofseveral factors: the occurence propability (O) that a
potential failure occur, the severity (S) of effects, the detection propability (D) that a
failure will be detected.
A potential risk is described by the risk priority number (RPN) as the product of O, S, D.
O
S
D
RPN = f(O, S, D)
Figure: Several factors of a risk potential.
31
Case studies risk analysis
The FMEA involves four essential steps:
Identification of the potential failure with itscauses and effects.
Evaluation of the potential risk with the severalfactors O, S, D and calculation of the riskpriority number (RPN).
Establishing protective measures.
Re-evalution of the improved conditions.
1Identify
Critical?
2 / 4(Re-) Evaluate
3Define
corrective actions
yes
Start
End
no
Figure: Decision tree of FMEA
32
Case study risk analysis for measurement and control unsits for HVAC systems
Objective 1: Reducing monitoring activities / costs and cover safty and availability.
Objective 2: Understanding interfaces between HVAC, clean room monitoring. Find a logical / conclusive approach for calibration of HVAC / monitoring instrumentation.
Approach:
The process parameter is leaving the normal prozess range in which the product quantity and quality is covered into alert range. What is the occurance propability and the consequences / sefirity for product quality? How can the detection propability evaluated (e.g. respond other measurement and control unsits?
The process parameter is crossing the limit to the action range. What is the occurance propability and the consequences / sefirity for product quality? How can the detection propability evaluated (e.g. respond other measurement and control unsits?
33
Case study risk analysis for measurement and control unsits for HVAC systems
Figure: Relation between normal prozess range, alert range, and action range
34
Case study risk analysis for measurement and control unsits for HVAC systems
Cleanroom E.216Class B
fresh / exhaust a ir un itequ ipm ent# .: 5254
a ir cond ition ing un itequ ipm ent# 5251
subunit# 0510
0421
processsteps
0431
processsteps
0432
processsteps
P
T
M
P
T
M
S
Q(LKZ)
Q(Part.)
T
P
critica l (asep tic ) p rocess s teps in E .216 (lam ina r a ir flow p ro tec ted )
P = pressure d ifference
T = temperature
M = moisture
S = a ir velocity
Q (LKZ) = count of microorganisms in the a ir
Q (Part.) = partic le count in the a ir
PDI
air in air out
m easuring & contro l installations PL 1:PDI 6121, PDSA 6155, TS 6175, TC 6225, PDI 6261, T I1110, T I 1126, T I 1152, T I 1153, T I 1161, T I 1167, T I 1168,PI 1229, P I 1231, PI 1233, PDSA 6135, PDI, 6146, PDSA6155, PDSA 6170, TS 6175, ...
m easuring & contro l installations PL 2:TC 6163, TC 6185, M C 6186, PDA 6145, PSA 6160/1/2, TC6163, PDIC 6195, PDA 6260
m easuring & contro l installations PL 3:PDSA 6190, PDSA 6265, M SA6187
equipment# 5254
m easuring & contro l installations PL 3:cleanroom monitoring system (object# 5261) includesQ (LKZ)6420, Q (Part.)6410, Q (Part.)6411, Q (LKZ)6421,Q (Part.)6412, Q (Part.)6413, Q (Part.)6414, PD6401,PD6402, PD6403, PD6000, T6409
equipment# 5260
m easuring & contro l installations PL 1:TI 1520, T I 1557, T I1558, T I 1567, T I 1568, T I 1577
m easuring & contro l installations PL 2:TC 6515, TC 6555, PD 6596, PD 6599, PDI 6571, PDI6572, PDI 6573...
m easuring & contro l installations PL 3: M 6516, S 1528, S 1538, S 1548, S 1566, S 1576
equipment# 5251
m easuring & contro l installations PL 2:none, clean room monitoring
m easuring & contro l installations PL 1:none, cleanroom monitoring
dist
ance
to
clea
nroo
m c
lass
B
level of prote
ction (re
dunda
nce, calib
ration p
eriod...)
3
2
1
1
2
3
3
2
1
Figure(s): Evaluated measurement and control units of a HVAC unit
35
Case study risk analysis for measurement and control unsits for HVAC systems
Result of FMEA case study: Out of nearly 60 Measurement and control units 44 % have only to be adjusted. No calibration activities are required. 26 % have to be adjusted and initial calibrated. No periodic calibration activities
are required. 30 % (because of redundant design of clean room monitoring system) have to
be adjusted, initial and periodic calibrated.
Reduction in costs: nearly 10.000,00 DM only because of reduced initial calibration.
36
Case study risk analysis computerized systems validation for HVAC systems
Approach:
Each essential process step (e.g. A...E) will divided in the functions of the computerized system. Derive from reverse function it is possible to identify potential failures in a systematic way.
Because of that the CSV risk analysis will cover the unit operations as well as the computerized system.
Proze
ßfunk
tione
n
(Uni
t Ope
ratio
ns)
Funkt
ion
com
pute
risier
tes S
yste
m
A B D E
C
C1 C2
C3
C4 C5
C6
B. Geis, xxxBRG_CSVEbenen_1_0Figure: Level of process steps and level of computerized function
37
Case study risk analysis computerized systems validation for HVAC systems
confidentialconfidential
Fig
ure
: F
ME
A f
orm
use
d f
or
CS
V r
isk
an
aly
sis
of
cle
an
ro
om
mo
nito
ring
sys
tem
38
Summary
The key for a successful HVAC qualification are
the understanding of interfaces beween product purity / characteristic, cleanliness zones, HVAC functions and clean rooms requirements,
the knowledge concerning general and HVAC specific tests, and 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.