risk assessment of hvac

A Risk Assessment Approach:Qualification of HVAC System inAseptic Processing Area Using BuildingManagement System

Anil K. Shukla1,*, Ashutosh Katole2, Nilesh Jain1, C. Karthikeyan1, Farhad Mehta1 andPiyush Trivedi1

1School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, MadhyaPradesh, India2Ranbaxy Laboratories Limited, Industrial Area 3, Dewas, Madhya Pradesh, IndiaQ1

Abstract

In thepharmaceutical industry qualificationofHVAC systems is donebyusinga riskbasedapproach. FMEAQ2 concept was used for risk assessment in HVAC system to determinescope andextent of qualification and validation in this presentwork. The level of riskwasassessed, based on the impact and severity on the aseptic practice in sterilemanufacturing because the HVAC system is the “direct impactQ3 ” system in the asepticpractice expected to have a direct impact on product quality and regulatory compliance.On completion of the risk assessment, existing controls, measures and recommendedaction were identified required for the better cGMP and upgradation of the system.Q4

After completion of the risk assessment the recommended actions were extended andverified against the qualification stages of the HVAC system. Finally, the HVAC systemwas subjected to PQQ5 study. All of the tests were performed and a report was generated.Onevaluation of the data collectedduring PQ, itwas found that theHVAC systemmet allthe specified design criteria and complied with the entire cGMP requirement. Hence thesystem stands validated for PQ. Copyright © 2011 John Wiley & Sons, Ltd.

Key Words: HVAC; UAF; PQ; ICH; FMEAQ6

Introduction

Quality risk management is an important part ofscience based decision making which is essential

for quality management of pharmaceuticalmanufacturing. The ICH Q9 guideline, qualityrisk management and other literature provideguidance on the principal of quality risk manage-ment. The FMEA model can be used to facilitaterisk assessment for any system in the asepticprocessing area of sterile products. It provides a

*Correspondence to: Anil Shukla, School of Pharmaceu-ticalSciences,RajivGandhiProudyogikiVishwavidyalaya,Bhopal,MadhyaPradesh,India.E-mail:[email protected]

Copyright © 2011 John Wiley & Sons, Ltd.Qual Assur J (2011)

DOI: 10.1002/qaj

Journal Code Article ID Dispatch: 11.09.11 CE:Q A J 4 8 5 No. of Pages: 9 ME:

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tool to assess and evaluate different activities andconditions. Risk in sterile product manufacturingand aseptic processing is relatively high whencompared to other pharmaceutical process,making risk assessment particularly important.

The European Union GMP requirementsplace specific obligations on manufacturers ofmedicinal products to implement risk basedqualification, validation and change controlprograms. In pharmaceutical manufacturing,validation is an important part of QA and is arequirement of cGMP and other guidelines.

In the air handling system, special attentionmust be made to keep the environment clean andprevent product contamination. From a techni-cal perspective, the role of the HVAC system isparamount in achieving and maintaining anacceptable manufacturing environment. TableT1 1Q8

Experimental

Risk assessment (FMEA model)

Evaluate the overall risk of the qualification andvalidation steps by combining individual riskvalues. For the most of the direct impact system,the severity will always be high. The RPRQ9 thenbecomes a combination of an occurrence anddetection. If the level of risk is not acceptable, arecommendation must be made to modify thequalification and validation step to reduce the riskto an acceptable level or enhance the method ofdetection to reduce the risk to an acceptable level.Preference should be given to reducing theoccurrence rather than increasing the level ofdetection. After completion of the risk assessment,the recommended action of unacceptable risk

extended to qualification stages of HVAC systemto have a high level of assurance and if the testresult are not acceptable, carry out correctiveaction that may include modification in theexisting controls and the system. Table T22 Q11

Performance Qualification for HVACand Q12UAF System

Air Velocity and Air Changes

Velocityat the inletairgrillswasmeasuredat5points inaplane parallel to filter face plane and at a distance ofabout 6 inches (~ 150mm) from the filter/opening face.Thevelocitywasmeasuredforat least 10 seconds fromeach point. It is performed by thermal anemometerand vane type anemometer and calculated byformula where, D is no. of air changes, B is airsupply volume (CFM), R is volume of the room(ft3), 60 is factor (for air change per hour).

D ¼P

B� 60R

Differential Pressure Test

Measure and record the pressure differencebetween the room to be tested and anysurrounding ancillary environment.

HEPA Filter Leakage TestPosition the aerosol generator to introduce anaerosol challenge upstream of the HEPA filter to aconcentration of 20-100mg/m³ (20–100 mg/lit.) ofair by opening appropriate number of nozzles.Measure upstream concentration of aerosol byusing upstream port. Adjust the photometer’s gain

Table 1. Risk ranking system Q7

Qualitativeranking

Risk factor

Severity Occurrence Detection

High Impact of unwanted event issevere

Occurrence isoften

The process failure will almost certainlyescape detection

Medium Impact of unwanted event ismoderate

Occurrence isperiodic

Control may detect the existence of aprocess failure

Low Impact of unwanted event islow

Occurrence isseldom

The process failure is obvious andreadily detected

A. K. Shukla et al.2

Copyright © 2011 John Wiley & Sons, Ltd. Qual Assur J (2011)DOI: 10.1002/qaj

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/ span control for a full-scale deflection on 100%range. Scan the downstream side of the HEPAfilter. The photometer probe should be about 1inch from the surface and at a transverse rate notmore than 10ft/minute with a sample flow rate of1cft/min � 10%.

AirFlowVisualization (Non-unidirectionalflow)

Generate the tracer particles by WFI foggerQ13 .Position the tracer at the appropriate place,such as at the downstream of supply air and thereturn air risers as well as at the doors openingand check for the indication of the airflowdirection. Record the airflow pattern usingphotography/videography.

Airborne Particle Count

Derive the number of sampling point locationsby using the equation where, NL is the minimumnumber of sampling locations and √A is Area ofthe room in square meter.

NL ¼ √AVolume of sample (for grade A at rest and

operation,gradeBatrest)-1m3equivalentto35.3ft3

Volume of sample (for grade B at operationand other grades at both conditions) -1 ft3

Recovery/decontamination rate testTake the particle count in the area before aerosolgeneration at rest condition. The sampling rateshould be 1CFM.Artificially generateDOP/PAOaerosol in the classified area and check the count(1000 times more than classified area “at rest”).Record the particle count and time. Stop theaerosol generator. The time at which the aerosolgenerator is stopped should be the starting timefor establishing the recovery rate. Start theparticle counting at the specified location at asampling rate of 1 CFM. Establish the timerequired for attaining the “at rest” condition.

Environmental Conditions -Temperature and Relative Humidity

It was performed by digital hygrometers andSling hygrometer and performed the test for 5consecutive days for category A1 AHUs and for3 consecutive days for AHUs of other catego-ries. Readings should be for minimum 16hours/day at 2 hour interval.

Q10

Table 2. Determination of RPR

Risk related to probability of detection

Low Medium High

Occurrence High This is likely to occur, butwhenit does, it will be detected. Ifwe are certain it will bedetected, it is Low Risk, but ifwe are not certain then itshould be a Medium Risk.

This is likely to occur and thedetection is not certain. It is aHigh Risk.

This is likely to occur andthe detection is not certain.It is a High Risk.

Medium This could occur but if it did, itwould be detected.Depending on the frequencyof occurrence and theconfidence in the detection, itis a Low or a Medium Risk.

This could occur and it couldbe detected. Depending onour confidence in thedetection, its risk would beMedium or High Risk.

This may occur and it willnot be detected The Risk isHigh.

Low This is not likely to occur andif it does occur it will bedetected. This is a Low Risk.

The cause is not likely to occurand if it did, it may be detected.Depending on the frequency ofoccurrence and the confidencein detection method, it wouldbe a Low orMedium Risk.

The cause is not likely tooccur but if it did occur, itprobably would not bedetected. The Risk isMedium.

Qualification of HVAC System in Aseptic Processing Area 3


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Table

3.Riskassessmen

tforHVACsystem

Recommen

ded

action

Useran

dsupplie

rspecificationsan

ddrawingsareev

aluated

fortheir

complia

nce

totheintended

use

and

cGMPduringDQ.

Ductleak

ageshou

ldbe

checke

dthroug

hsm

oke

testan

dreports

addressed

intheIQ.

Schem

atic,P&

ID,GA

drawingsshould

be

verified

inIQ

.

Iden

tify

andve

rify

theSO

PduringOQ.

DPsw

itches

areprovide

dacross

HEP

Afilter

formonitoringthe

chockingof

thefilter

and

feed

back

givento

DDCwhich

gene

ratesan

alarm.

Riskaccepted?

(yes/no)

No

No

No

No

No

Riskpriority

rank

High

Med

ium

High

High

High

Riskrelatedto

Probab

ility

of

detection

High

High

High

High

High

Ifan

ymismatch

observed

betwee

nuseran

dsupplie

rspecification.

Ifthereisnoch

eck

doneto

verify

theduct

leak

age.

Ifdrawingsarenot

available.

Iftheoperatingan

dmaintenan

cepersonarenot

trained

withrespectto

the

relatedSO

P.

Ifthesensors

arefailto

gen

eratealarms.

Like

lihoodof

occurren

ce(probab

ility

andfreq

uen

cy)

Low

Low

Low

Med

ium

Low

URSan

dve

ndorDQ

arein

place.

Shee

tsarelock

form

ing

quality.

Ven

dorinstalled

componen

tas

per

approve

ddrawing.

Instrumen

tisruningas

per

approve

dSO

Pwithco

ntrol

param

eter.

Differential

pressure

monitoringsw

itch

esare

placedacross

thefilter.

lock.Insulation

thermoco

le.

Prefilter

arein

place.

Cladding-aluminum.

Impact

(sev

erity)

High

Med

ium

High

High

High

Descriptionof

iden

tified

risk

(unwan

ted

even

ts)

New

equipmen

tfacilityorsystem

oran

y“majorch

angein

the

existingeq

uipmen

t”may

affect

theproduct

requirem

entsafety

feature

anden

vironmen

t.

Air/energylosses

may

occurduringair

distributionthrough

ducts.

Installationof

componen

tat

inap

propriateplaces

lead

ingto

inad

equate

perform

ance

of

AHU.

Inap

propriateoperationof

AHU

may

lead

tonon-

complia

nce

withrespectto

perform

ance

requirem

ent

andfreq

uen

tmaintenan

ce.

Chockingofthefilter

affected

thedifferential

pressure

leve

lan

dmay

lead

toco

ntaminationin

area

athigher

clea

nlin

essclass.

Contaminationdueto

airleak

agewhen

AHU

isshutdown.(neg

ative

pressure

may

lead

toco

ntamination)

Riskno.

12

34

5

(Con

tinu

es)



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Instrumen

t/componen

tshould

becalib

rated

(tem

p.,RH,D

P)an

dreportad

dressed

inthe

OQ.

Allalarmsshould

be

checke

d,verifiedan

dset

theparam

etersrelatedto

safety

ofproduct/person/

environmen

tduringOQ.

Theairv

elocity

andACPH

should

bechecke

dbyan

emometer

toen

sure

that

adeq

uateam

ounto

fairissupplie

din

theroom

and

reportad

dressed

inthePQ

.

DPshould

bech

ecke

dthrough

mag

neh

elic

gau

geto

verify

the

capab

ility

ofco

mplete

installation

tomaintain

thespecifiedpressure

difference

andreport

addressed

inPQ

.

Theintegrity

should

be

checke

dthrough

DOPtest

and

report

addressed

inthePQ

.

Nonunidirectional

air

flow

should

bech

ecke

dthroughWFI

fogger

and

report

addressed

inthe

PQ.

No

No

No

No

No

No

High

High

High

High

High

High

High

High

High

High

High

High

Iftheinstrumen

tare

notcalib

ratedas

per

freq

uen

cy.

Ifthealarmsarenot

gen

erated

duringthe

excu

rsionin

temp./R

H/DP

bey

ondthesetlim

it.

Ifthereisnoch

eckdoneto

verify

theairve

locity

air

chan

ges

per

hour(A

CPH

).

Ifdifferential

pressure

valueless

than

alarm

limitan

dgreater

than

specifiedtimebetwee

nsimila

ran

dnonsimila

rclasses.

Ifthereisno

checkdoneto

verify

the

integrity

offilter.

Ifdifferential

pressure

valueless

than

alarm

limitan

dgreater

than

specifiedtimebetwee

nsimila

ran

dnonsimila

rclasses.

Med

ium

Med

ium

Med

ium

Low

Low

Low

Instrumen

t/co

mponen

tare

iden

tified

for

calib

rationwithtag

no.

List

ofallalarmsare

verified

andclassified

incritical/n

oncritical

onthe

basisofim

pacton

product

quality/purity.

Supply

andreturn

airvo

lume

(CFM

)ofAHU

areas

per

requirem

entofarea

and

occupan

cy.

DPgau

geco

ntinuousmonitorthe

pressure

difference

betwee

ndifferentclassroom

(oneforea

chroom

separately).

Thechan

gein

HEP

Afilter

atregularinterval

andas

required

.

Roomsaredesigned

from

positive

lyto

neg

atively

pressurize

dzo

ne.

TheHEP

Afilter

installedbythe

certified

supplie

r.

Dam

persmaintain

the

desired

differential

pressure

intheroom.

High

High

High

High

High

High

Uncalib

rated

instrumen

taffected

themonitoringan

dco

ntrollingthedesired

product

environmen

tco

ndition.

Failu

reofAudio/visual

indicationofalarmsmay

nota

lertthepersonnelan

dwill

continueto

operatein

non-complyingconditions.

Airve

locity

andairch

anges

may

affect

theclea

nlin

ess

class,hea

tload

andreco

very

from

contamination.

Differential

pressure

iscritical

for

maintainingclea

nlin

essclassan

dcross

contamination.

Thevalid

ation

statuswith

respectto

the

filter

integrity

may

beaffected

.

Airflow

pattern

may

affect

theeffective

clea

nlin

essofthearea

.

67

89

1011

Table

3.(Continued

)

(Con

tinu

es)



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Unidirectional

airflow

should

be

checke

dthroughWFI

fogger

ensure

that

airflow

should

hav

ea

swee

pingactionove

ran

daw

ayfrom

theproduct

under

dyn

amic

conditionan

dreport

addressed

inthePQ

.

Airborneparticleco

unt

should

bech

ecke

dthrough

particleco

unterto

Determinetheclea

nlin

ess

leve

las

per

ISO

stan

dards.

Recove

ry/decontamination

rate

test

should

bech

ecke

dthroughDOPtest

inclassified

area

andreco

very

report

addressed

inthePQ

.

Temperature

should

bech

ecke

dthroughcalib

rated

instrumen

tan

dreport

addressed

inthePQ

.

RH

should

be

checke

dthrough

calib

rated

hyg

rometer

and

report

addressed

inthePQ

.

Viable

countshould

be

monitoredthrough

settle

plate,air

samplin

g,sw

absamplin

gan

dreport

addressed

inthePQ

.

No

No

No

No

No

No

High

High

High

High

High

High

High

High

High

High

High

High

Iftheturbulence

foundin

theair

flow

pattern.

Ifthereisnoch

eckdoneto

verify

theintegrity

offilters.

Ifthereisnoch

eckdoneto

verify

theintegrity

offilters

andairve

locity.

Excu

rsionoftemp.

bey

ondthesetlim

itdueto

different

operation.

Excu

rsionofRH

bey

ondtheset

limitdueto

CIP/

SIPoperation.

CriticalforGradeA

environmen

t.

Low

Low

Med

ium

Low

Low

Med

ium

TheUAFunitisinstalled.

Final

filtrationofsupply

air

intheroom

through

term

inal

mountedHEP

Afilter

(H-13)

efficien

cy99

.97%

downto

0.3micron

particles.

Environmen

talmonitoring

dev

ices

arein

place

(FMS).

Temperature

sensors

arelocated

inea

chroom

and

commonreturn

air

duct.

RH

sensors

are

provided

for

commonreturn

airduct.

Alert

andactionlim

its

aredetermined

by

tren

dsan

alysis.

Thearea

under

theunitshould

comply

withclassA.

Final

filtrationofsupply

air

intheroom

through

term

inal

mountedHEP

Afilter.

Deh

umidifierisin

place.

High

High

High

High

High

High

Comply

GradeA

environmen

tAirclea

nlin

essin

clea

nroomsmay

affect

the

contaminationsensitive

activities.

Airborneparticle

concentrationmay

affect

thespecificationofair

clea

nlin

essin

clea

nrooms.

Temperature

may

lead

toproduct

instab

ility,

personnel

disco

mfort

and

microbialgrowth.

Relativehumidity

may

affect

the

moisture

sensitive

activity.

Microbialcontamination

lead

sto

loss

ofsterility.

1213

1415

1617

Table

3.(Continued

)



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Viable Count Monitoring - Settle Plateand Air SamplingSettled plates should be of 90mm diameter andshould be exposed for duration of 4 hours. Platesshould be exposed at a height above 1 meter from

thefloor andalso atwork level for better exposure.For air sampling, 1m3 of air from specifiedlocations should be sampled using SoybeanCaseinDigest Agar. Incubate settle plate at 20 - 250C forTFC and at 30 - 350C for TBC. Table T33 T4T5–5 Q14

Table 4. Performance Qualification of HVAC and UAF System

S. No Test performed Acceptance criteria Results

1 Air velocity and CFM �20% of the avg. face velocity 4106 CFM2 No. of air changes per hour NLT 40 66.313 Differential pressure test NLT 05 Pa 8 to 10 Pa4 HEPA filter leakage test less than 0.01% Max. 0.0004%

Min. 0.0002%5 Air flow visualization (non-unidirectional flow) from +ve to –ve pressurized zone. Meets the

acceptancecriteria for flowpattern

6 Airborne particle count condition Class area 0.5 mm 5 mmat rest condition With in class B 191 6at operational condition With in class B 500 15

7 Recovery/decontamination rate test Within 10 min 4 min.8 Environmental conditions -Temperature 22 � 3�C Max. 23�C9 Environmental conditions - Relative humidity NMT 20% Max. 1410 Viable count monitoring Sampling Class area TBC TFC

active air sampling With in class B 9 <1settle plate method With in class B 4 <1

Table 5. Performance Qualification of UAF System

S.No Test performed Acceptance criteria Results

1 Air velocity 90�20 FPM at 6 inch. From filterface

Complies

2 Differential pressure test NLT 10mm of WC 14 to 16mm ofWC

3 HEPA filter integrity test Less than 0.01% of upstream conc. Max. 0.002 %4 Air flow visualization (unidirectional flow) Flow should be unidirectional Meeting the

acceptancecriteria underdynamiccondition

5 Airborne particle count condition Class area 0.5 mm 5 mmat rest condition With in class A 0 0at operationalcondition

With in class A 247 0

6 Viable countmonitoring

Sampling Class area TBC TFCactive air sampling With in class A <1 <1swab sampling method With in class A <1 <1



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Failure Mode Effect Analysis (FMEA)

Results

Conclusion

Qualification and validation is appearing to bethe beginning of a continuous developmentprocess in pharmaceutical QA. Risk assessmentis an essential tool for qualification of HVACsystem in aseptic processes. It is not just a toolfor cGMP compliance, its offers real benefits tothe validation process by identifying risks andensuring that critical risks are controlled. Byfocusing managing risks to the patient, phar-maceutical manufacturers can ensure that theright resources are applied at the right placeand at the right time improving patient safetywhile eliminating unnecessary qualification andvalidation efforts.

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trolled Environments, Part-2: Specifications for

Testing and Monitoring to Prove Continued Com-

pliance with ISO 14644–1, 2000(E), 1–4.


trolled Environments, Part 3: Metrology & Test

Methods, 2005(E), 1–3.

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Specialist Interest Group. Guideline On Test Meth-

ods For Environmental Monitoring For Aseptic

Dispensing Facilities, 2nd ed. February 2004, 3–6.

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