1. Qualification of
HVAC systems
Case studies
• physical / technical tests
• risk analysis calibration
• risk analysis computerized systems
1

2. Table of Contents
1. Introduction
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
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
2

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.
3

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.
4

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).
5

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 give
a conception for relevant
parameters in conjunction
with cleanliness zones used
in secondary manufacturing.
Process
tolerance
Action limit
Figure: The picture demonstrates
the relation of process, operation
ranges, limits, and tolerances.
Process range
Process limits
Process limits
Alert limit
Range of measurement and control unit
6

7. HVAC design requirements
 Typical parameters and ranges for the design of HVAC systems under
consideration of cleanliness zoning concept (table).
 If cleanliness zoning
requirements are different
Room
Room
relative
to product specific reRoom
Room air
relative
pressure in
Zone:
temperature
changes in
quirements the relevant parahumidity in
Pa:
in °C:
h :
%:
meters with their ranges,
to barometric
reference
tolerances, and limits should
be fixed and documented.
A
N/A (a)
40,0 ± 10,0
(a)
N/A (a)
-1
Example:
Products which are sensitive
to moisture (e.g. effervescence tablets).
In this case the setpoint, tolerances,
and limits of the dehumidification
is the major factor for
the conditioning.
B
22,0 ± 4,0
45,0 ± 15,0
30 - 90
30 - 45
C/1
22,0 ± 4,0
45,0 ± 15,0
20 - 50
20 - 30
D/2
22,0 ± 5,0
45,0 ± 15,0
5 - 30
10 - 15
E/3
20,0 ± 8,0
45,0 ± 15,0
4 – 10 (b)
0
4
Not defined
Not defined
Not defined
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
7

8. HVAC design requirements
 Example layout
effervescents factory
Figure: The picure shows
humidity controlled areas.
Typically, exposed humiditysensitive 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).
8

9. HVAC construction requirements
 In case of humidity sensitiveness a
dehumidification unit has to be
integrated / 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.
9
Figure: Simplified picture of a small
dehumidification unit (cooling coils).

10. HVAC construction requirements
 General structure of a HVAC system
used in sterile manufacturing
of parenterals. Critical process steps
are covered by laminar air flow units.
Figure: In general the HVAC system includes several
basic units such as fresh / exhaust air, and air
conditioning units with their fans, filters, and
measurement and control instrumentation
 10

11. HVAC construction requirements
 Dehumidification method by adsorptive separation
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
 11

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.
 12

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.
Figure: The DQ part of
Sulzers validation
structure matrix for clean
rooms and HVAC
systems
Clean rooms
HVAC
 13

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 documented
evidence that the operational
functions with its specific
parameters, ranges and limits
comply with the functional
requirements and specifications.
Figure: The IQ / OQ part of
Sulzers validation structure matrix
for clean rooms and HVAC
systems
Clean rooms
HVAC
 14

15. Physical / technical OQ and PQ tests for HVAC systems
 In addition to these
general tests (e.g.
power failure and
recovery tests,
verification of
functions and
sequences, verification of alarms
and interlocks...)
typical HVAC specific
tests has to be
performed.
Unidirectional
airflow / LAF:
Test:
Turbulent /
mixed airflow:
Differential pressure on filters
1
1
Room differential pressure
N/A
2, 3
Airflow velocity / uniformity
2, 3
Optional
Airflow volume / rate
2
2
Parallelism
2
N/A
Air flow patterns
Optional
Optional
Filter leak test / challenge test
2
2
Recovery
N/A
2
Room classification (airborne particle)
2
2
Particle fall out
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)
 15

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.
 16

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.
 17

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.
 18

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.
 19

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.
 20

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.
 21

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.
 22

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.
 23

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.
 24

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 support
qualification of the location of fixed installed
humidity monitoring devices.
 The function and sequences of dehumidification
units must be carefully tested (main functions
see slide 12).
Figure: Mobile measurement
device for the acquisition of
humidity data.
 25

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 conditions
in a systematic, documented,
and objective way.
 26

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.
 27

28. Case studies risk analysis
In general, FMEA is the tool
 to prevent
 to confirm and
 to solve problems.
Entstehung von 75 % der Fehler
Behebung von 80 %
der Fehler
60
Fehlerbehebungskurve
55
50
45
Fehlerentstehungkurve
40
35
25
Fehlerquote
30
Failure removal costs
20
15
10
Design
incl.. DQ
Construction:
constructive
changes
...
Qualification:
redesign
new construction
delay of production
...
Production:
costs of delay
costs maintenance
loss of image
loss of market shares
...
5
0
Phases of project
 28
Planung
Konstruktion
Qualifizierung
Produktion
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).
 29

30. Case studies risk analysis
 A potential risk is the hidden, unforeseen
occurrence of a failure with considerable
consequences.
 A potential risk is composed of
several factors:
D
S
 the occurence propability (O) that a
potential failure occur,
 the severity (S) of effects,
 the detection propability (D) that a
failure will be detected.
RPN = f(O, S, D)
O
 A potential risk is described by the risk priority number (RPN) as the
product of O, S, D.
Figure: Several factors of a risk potential.
 30

31. Case studies risk analysis
The FMEA involves four essential steps:
Start
1
 Identification of the potential failure with its
causes and effects.
Identify
2/4
(Re-) Evaluate
 Evaluation of the potential risk with the several
factors O, S, D and calculation of the risk
priority number (RPN).
no
Critical?
yes
3
Define
corrective
actions
 Establishing protective measures.
 Re-evalution of the improved conditions.
 31
Figure: Decision tree of
FMEA
End

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?
 32

33. Case study risk analysis for measurement and control unsits for
HVAC systems
Figure: Relation between normal prozess range, alert
range, and action range
 33

34. Case study risk analysis for measurement and control unsits for
HVAC systems
a ir in
a ir o u t
e q u ip m e n t# 5 2 5 4
3
m e a s u rin g & c o n tro l in s t a lla tio n s P L 3 :
PD SA 6190, PD SA 6265, M SA6187
2
m e a s u rin g & c o n tro l in s t a lla tio n s P L 2 :
T C 6 1 6 3 , T C 6 1 8 5 , M C 6 1 8 6 , P D A 6 1 4 5 , P S A 6 1 6 0 /1 /2 , T C
6 1 6 3 , P D IC 6 1 9 5 , P D A 6 2 6 0
P
f r e s h / e x h a u s t a ir u n it
e q u ip m e n t# .: 5 2 5 4
T
M
1
M
3
2
Figure(s): Evaluated
measurement and control
units of a HVAC unit
P
PDI
T
C le a n r o o m E .2 1 6
C la s s B
1
m e a s u rin g & c o n tro l in s t a lla tio n s P L 3 :
M 6516, S 1528, S 1538, S 1548, S 1566, S 1576
m e a s u rin g & c o n tro l in s t a lla tio n s P L 2 :
TC 6515, TC 6555, PD 6596, PD 6599, PD I 6571, PD I
6 5 7 2 , P D I 6 5 7 3 ...
m e a s u rin g & c o n tro l in s t a lla tio n s P L 1 :
T I 1 5 2 0 , T I 1 5 5 7 , T I1 5 5 8 , T I 1 5 6 7 , T I 1 5 6 8 , T I 1 5 7 7
e q u ip m e n t# 5 2 6 0
S
Q (L K Z )
Q ( P a r t .)
3
0421
0431
0432
2
p ro c e s s
s te p s
p ro c e s s
s te p s
m e a s u rin g & c o n tro l in s t a lla tio n s P L 2 :
n o n e , c le a n r o o m m o n ito r in g
1
m e a s u rin g & c o n tro l in s t a lla tio n s P L 1 :
n o n e , c le a n r o o m m o n ito r in g
P = p r e s s u r e d iffe r e n c e
T = te m p e ra tu re
p ro c e s s
s te p s
M = m o is tu r e
S = a ir v e lo c ity
c r it ic a l ( a s e p t ic ) p r o c e s s s t e p s in E . 2 1 6 ( la m in a r a ir f lo w p r o t e c t e d )
m e a s u rin g & c o n tro l in s t a lla tio n s P L 3 :
c l e a n r o o m m o n i t o r i n g s y s t e m ( o b je c t # 5 2 6 1 ) i n c l u d e s
Q ( L K Z ) 6 4 2 0 , Q (P a r t.) 6 4 1 0 , Q (P a r t.) 6 4 1 1 , Q ( L K Z ) 6 4 2 1 ,
Q ( P a rt.)6 4 1 2 , Q ( P a rt.)6 4 1 3 , Q ( P a rt.)6 4 1 4 , P D 6 4 0 1 ,
PD 6402, PD 6403, PD 6000, T6409
Q ( P a r t. ) = p a r tic le c o u n t in th e a ir
Q ( L K Z ) = c o u n t o f m ic r o o r g a n is m s in th e a ir
 34
distance to cleanroom class B
e q u ip m e n t# 5 2 5 1
T
s u b u n it# 0 5 1 0
level of protection (redundance, calibration period...)
a ir c o n d it io n in g u n it
e q u ip m e n t # 5 2 5 1
P
m e a s u rin g & c o n tro l in s t a lla tio n s P L 1 :
PD I 6121, PD SA 6155, TS 6175, TC 6225, PD I 6261, TI
1110, TI 1126, TI 1152, TI 1153, TI 1161, TI 1167, TI 1168,
P I 1 2 2 9 , P I 1 2 3 1 , P I 1 2 3 3 , P D S A 6 1 3 5 , P D I, 6 1 4 6 , P D S A
6 1 5 5 , P D S A 6 1 7 0 , T S 6 1 7 5 , ...

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.
 35

36. Case study risk analysis computerized systems validation for
HVAC systems
 Approach:
Figure: Level of process
steps and level of
computerized function
B
D
E
P
(U roze
ni ß
t O fu
pe nkt
ra ion
tio e
ns n
)
C
C6
C1
B. Geis, xxxBRG_CSVEbenen_1_0
 36
C2
C4
C5
F
te un
r i s kt
ie ion
r te
sS
y
st
C3
em
A
co
m
pu
 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.

37. Figure: FMEA form used for CSV risk
analysis of clean room monitoring system
Case study risk analysis computerized systems validation for
HVAC systems
confidential
confidential
 37

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.
 38