Hvac manpreet singh naroo

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Qualification ofQualification ofHVAC systemsHVAC systems

Case studies

• physical / technical tests

• risk analysis calibration

• risk analysis computerized systems

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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

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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.

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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.

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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).

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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.

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.

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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

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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).

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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).

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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.

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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

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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.

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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

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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

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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)

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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.

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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 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.

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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 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.

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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 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.

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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.

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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 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.

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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.

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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.

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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.

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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.

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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.

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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.

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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).

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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.

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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

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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?

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Figure: Relation between normal prozess range, alert range, and action range

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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

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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.

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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

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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

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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.

Hvac manpreet singh naroo

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