Jour

Journa
nall Code
Code Ar
Arti
ticl
clee ID Di
Disp
spat
atch
ch:: 11
11.0
.09.
9.11
11 CE:
CE:
Q A J 4 8 5 No. of Pages: 9 ME:

1 62
2 63
3 64
4
5
A Risk Assessment Approach: 65
66
6
7 Quali󿬁cation of HVAC System in 67
68
8 69
9 Aseptic Processing Area Using Building 70
10 71
11
12 Management System 72
73
13 74
14 75
15 Anil K. Shukla1,*, Ashutosh Katole2, Nilesh Jain1, C. Karthikeyan1, Farhad Mehta1 and 76
16 Piyush Trivedi1 77
17 78
1
18 School of Pharmaceutical Sciences, Rajiv Gandhi Proudyogiki Vishwavidyalaya, Bhopal, Madhya 79
19 Pradesh, India 80
2
20 Q1 Ranbaxy Laboratories Limited, Industrial Area 3, Dewas, Madhya Pradesh, India 81
21 82
22 83
23 84
24 Abstract 85
25 86
26 87
27 88
In the pharmace
pharmaceutic
utical
al industry
industry quali
quali󿬁cati
cation
on of HV
HVACAC sysyst
stem
emss is done
done by us usin
ing
g a ri
risk
sk base
based d
28 89
29
Q2 approach. FMEA conc conceptept was used for risk assessme
assessment nt in HVAC syst system
em to determin
determine e 90
30 sc
scop
opee and
and ex
exte
tent
nt of qual
qualii󿬁cati
cation
on and
and vali
valida
dati
tion
on in th
this
is pr
pres
esen
entt work
work.. Th
Thee leve
levell of ri
risk
sk wa
wass 91
31 as
asse
sess
ssed
ed,, base
basedd on th the
e impa
impactct an
and
d seseve
veri
rity
ty on th the
e as asep
epti
ticc pr
prac
acti
tice
ce in st ster
eriile 92
32 Q3 manufacturing because the HVAC system is the “direct impact” system in the aseptic 93
33 pr
prac
acti
tice
ce ex
expe
pect
cted
ed to have
have a didire
rect
ct im
impa
pact
ct on prod
producuctt qual
qualitity
y and
and re
regugula
lato
toryry comp
compli lian
ance
ce.. 94
34 On completion of the risk assessment, existing controls, measures and recommended 95
35 Q4 action were identi󿬁ed required for the better cGMP and upgradation of the system. 96
36 After completion of the risk assessment the recommended actions were extended and 97
37 veri󿬁ed against the quali󿬁cation stages of the HVAC system. Finally, the HVAC system 98
38 Q5 was subjected to PQ study. All of the tests were performed and a report was generated. 99
39 100
40 On
41
theev
eval
alua
spe uati
speci
ci󿬁tion
ondesi
ed ofsign
de th
the
gnecrit
data
da
cr ta
iter coll
coand
eria
ia llec
anecte
dted
dmpli
du
duri
comp
co ring
ngwith
lied
ed PQ,
PQth
wi , itth
was
wa
the s fo
foun
e enti
en und
re dcGMP
tire th
that
cG at th
MP the
ree
requHVAC
HV
quir ACent.
irem sy
syst
emen stem
t. em me
met
Hence tth
Hence all
alel
the 101
102
42 system stands validated for PQ. Copyright © 2011 John Wiley & Sons, Ltd. 103
43 104
44 Q6 Key Words:
Words: HVAC; UAF; PQ; ICH; FMEA 105
45 106
46 107
Introduction fo
forr qual
qualit
ity
y mana
manage gemen
mentt of pharpharma
mace
ceut
utic
ical
al
47 108
48 Qualit
Qual ity
y ri
risk
sk manag
managem
emen
entt is an impor
importa
tant
nt pa
part
rt of manufacturing. The ICH Q9 guideline, quality 109
49 science based decision making which is essential risk manageme
management nt and other
other literatu
literature
re provide
provide 110
50 guida
gui dance
nce on the
the pr
princ
incip
ipal
al of quality
quality ris
risk
k manag
manage-
e- 111
51 *Corresponden
*Correspo ndence
ce to: Ani
Anill Shu
Shukla,
kla, Scho
School
ol of Phar
Pharmace
maceu-u- ment. The FMEA model can be used to facilitate 112
52 ticalSciences,RajivGandhiProudyogikiVishwavid
ticalSciences,RajivGandhiProudyo gikiVishwavidyalaya,
yalaya, risk
risk as
asse
sess
ssmen
mentt for
for an
anyy sy
syst
stem
em in thethe as
asep
eptic
tic 113
53 Bhopal,MadhyaPradesh,India.E-mail:aksqargpv@gmail. 114
com
processing area of sterile products. It provides a
54 115
55 116
56 117
57 118
58 Qual Assur J (2011) 119
59 Copyright © 2011 John Wiley & Sons, Ltd. DOI: 10.1002/q
10.1002/qaj
aj 120
60 121
61 122
 2 A. K. Shukla et al.

1 Table 1. Risk ranking

ranking system
system Q7
62
2 63
3 Qualitative Risk factor 64
4 ranking 65
Severity Occurrence Detection
5 66
6 High Impact of unwanted event is Occurrence is The process failure will almost certainly 67
7 severe often escape detection 68
8 Medi
Medium
um Im
Impa
pact
ct of un
unwa
want
nted
ed ev
even
entt is Occurrence is Control may detect the existence of a 69
9 moderate periodic process failure 70
Low Impact of unwanted event is Occurrence is The process failure is obvious
obvious and
10 low seldom readily detected 71
11 72
12 73
13 74
14 tool to assess
assess and evaluat
evaluatee dif
differe
ferent
nt activit
activities
ies and extended to quali󿬁cation stages of HVAC system 75
15 76
conditi
conditions.
ons. Risk in ste
sterile
rile product
product manufact
manufacturinuring g to have a high level of assurance and if the test
16 77
17
and aseptic
aseptic proces
processing
sing is relative
relatively
ly high
high when result
result are not accept
acceptabl
able,
e, carry
carry out correc
correctiv
tivee 78
18 compa
compare red
d to other
other pharm
pharmac aceu
eutic
tical
al proc
process
ess,, acti
action
on that
that may
may incl
includ
udee modi
modi󿬁ca
cati
tion
on in the
the 79
19 making risk assessment
assessment particularly important. existing controls and the system. Table 2 T2 Q11 80
20 Thee Eu
Th Euro
rope
pean
an Unio
Union n GMP
GMP requrequirirem
emenents
ts 81
21 place speci󿬁c obligations on manufacturers of 82
22
Performance Quali󿬁cation for HVAC 83
medicin
med icinal
al produc
productsts to impleme
implementnt risk
risk based
based and UAF System Q12
23 84
24 quali󿬁cat
cation
ion,, valida
validatio
tionn and change
change contro
controll 85
25 programs. In pharmaceutic
programs. pharmaceuticalal manufacturi
manufacturing,
ng, Air Velocity and Air Changes 86
26 validation is an important part of QA and is a 87
27 requirement of cGMP and other guidelines. 88
28 Veloc
elocitity
y at
atth
thee inle
inlett ai
airr gr
gril
ills
lswa
wass me
meas
asur
ured
edat
at5
5 po
poin
ints
tsin
inaa 89
In the air handling system, special attention
29 plane parallel to 󿬁lter face plane and at a distance of 90
must
mu st be made
made to ke
keep
ep th
thee en
envi
viro
ronm
nment
ent clea
clean
n and
and
30 about
abo ut 6 inches
inches (~ 150mm)
150mm) from the 󿬁lter/opening face. 91
31 prevent
preve nt product
product contamination
contamination.. From a techni-
techni- 92
Th
Thee ve
veloloci
citywas
tywasme meas asururedfor
edforat at least 10 seconds from
32 cal perspective, the role of the HVAC system is 93
each
each poin
point. t. It is perf
perfor orme
med d by ther
therma
mall an
anem
emom
ometeter
er
33 paramou
par amount nt in achievi
achieving
ng and maintai
maintaining
ning an 94
34
and
and va vane
ne ty type
pe an anem emomometeter
er an
andd ca
calc
lcul
ulat
ated
ed by 95
Q8 T1 acceptable manufacturing environment. Table 1
35 formula where, D is no. of air changes, B is air 96
36 supply volume (CFM), R is volume of the room 97
37 Experimental (ftt3), 60 is factor (for air change per hour).
(f 98
38 99
39 100
PB 
40 Risk assessment (FMEA model) D¼ 60 101
R
41 102
Evaluate the overall risk of the quali 󿬁cation and
42 103
validati
validation
on steps
steps by combining
combining individu
individual
al risk Differential Pressure Test
43 104
44 values. For the most of the direct impact system, 105
Measuree and record
Measur record the pressu
pressure
re differ
differenc
encee
45 Q9 the severity will always be high. The RPR then 106
between the room to be tested and any
46 becomes
beco mes a combina
combinationtion of an occur
occurren
rence
ce and 107
47 surrounding ancillary environment. 108
detection. If the level of risk is not acceptable, a
48 109
recomm
recommendendati
ation
on must
must be mademade to modify
modify the
49 110
quali󿬁ca
cati
tion
on an
and
d va
vali
lida
datition
on st
step
ep to redu
reduce
ce th
thee risk
risk HEPA Filter Leakage Test
50 111
51 to an acceptable level or enhance the method of Position
Position the ae aeros
rosol
ol ge
gener
nerato
atorr to int
intro
roduc
ducee an 112
52 detection to reduce the risk to an acceptable level. aeros
aerosol
ol challe
challeng
ngee upstr
upstream
eam of the HEPA
HEPA 󿬁lter to a 113
53 Pref
Prefer
eren
ence
ce shshou
ould
ld be give given
n to redu
reduci
cing
ng th thee concentration
concentra tion of 20-100mg/m³ (20–100 m g/lit.) of 114
54 115
55 occurrenc
occurr encee ra
rathe
therr than
than increa
increasin
sing
g the lev
level
el of air by
Measure
Mea opening
open
sure ing appropria
apprconcent
upstream
upstream opriate
conc teration
entratinumber
numb er of
on of nozzles.
nozz
sol les.
aerosol
aero by
116
56 detect
detection
ion.. After
After comple
completio
tion
n of the ris
risk
k assess
assessmen
ment,
t, 117
57 the recomme
recommende ndedd action
action of unacce
unaccepta
ptable
ble risk using
using upstr
upstream
eam port.
port. Adjus
Adjustt the
the photom
photomete
eterr’s ga
gain
in 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qajaj
61 122
 Q10 Quali󿬁cation of HVAC System in Aseptic Processing Area 3

1 Table 2. Determinat
Determination
ion of RPR 62
2 63
3 Risk related to probability of detection 64
4 65
Low Medium High
5 66
6 Occurrenc
Occurrence
e High Thi
Thiss is likely
likely to occ
occur,but
ur,but wh whenen This is likely to occur and the This is likely to occur and 67
7 it does, it will be detected. If detection is not certain. It is a the detection is not certain. 68
8 we are certain it will be High Risk.
Risk. It is a High Risk.
Risk. 69
9 detected, it is Low Risk,
Risk, but if 70
we are not certain then it
10 should be a Medium Risk. Risk. 71
11 72
Medium This could occur bu butt if it did, it This could occur and it could This may occur and it will
12 would be detected. be detected. Depending on not be detected The Risk is 73
13 Depending on the frequency our confidence in the High..
High 74
14 of occurrence and the detection, its risk would be 75
15 confidence in the detection, it Medium or High Risk.
Risk. 76
16 is a Low or a Medium Risk. Risk. 77
17 Low This is not likely to occur and The cause is not likely to occur The cause is not likely to 78
18 if it does occur it will be an
andd if it did,
did, it may
may be dete
detectcted
ed.. occur but if it did occur, it 79
19 detected. This is a Low Risk. Risk. Depending
Dependin g on the frequen
frequencycy of probably would not be 80
occurrence and the confidence detected. The Risk is
20 81
in detection method, it would Medium..
Medium
21 82
be a Low or Medium Risk. Risk.
22 83
23 84
24 85
25 full-scalee de󿬂ection on 100%
/ span control for a full-scal Volume of sample (for grade B at operation 86
26 range.
rang e. Scan the downstr
downstreameam side of the HEPA
HEPA and other grades at both conditions) -1 ft3 87
27 88
󿬁lter. The photometer probe should be about 1
28 89
29 inch from the surface and at a transverse rate not 90
30 more than 10ft/minute with a sample 󿬂 ow rate of Recovery/decontamination rate test 91
31 1cft/min  10%. Take the particle count in the area before aerosol 92
32 generation at rest condition. The sampling rate 93
33 shou
should
ld be 1 CFM.
CFM. ArArti
ti󿬁cial
cially
ly generate
generate DOP/PAO
DOP/PAO 94
34 Air Flow
FlowVisu
Visualiz
alizatio
ation
n (Non-u
(Non-unidi
nidirect
rectiona
ionall aerosol in the classi󿬁ed area and check the count 95
35 󿬂ow) 96
36 (1000 times more than classi󿬁ed area “at rest”). 97
37 Q13 Generate
Genera te the tracer
tracer partic
particles
les by WFI fogger
fogger. Recor
Rec ordd the
the partic
particle
le count
count anandd time.
time. St
Stop
op the
the 98
38 Positio
Position
n the tracer
tracer at the approp
appropriat
riatee place,
place, aerosol generator. The time at which the aerosol 99
39 generator is stopped should be the starting time 100
40 such asair
at the downstream of the
supply airopening
and the for
for es
esta
tabli
blish
shing
ing the re reco
cover
veryy ra
rate
te.. St
Star
artt the
the 101
41
return risers as well as at doors 102
an
andd ch
chec
eckk fo
forr th
thee indi
indica
cati
tion
on of th
thee air
air󿬂ow particle counting at the speci 󿬁ed location at a 103
42
43 dire
direct
ctio
ion.
n. Reco
Recordrd th
thee air󿬂ow papatt
tter
ern
n usin
using
g samp
sampliling
ng ra
rate
te of 1 CFM.
CFM. Es Esta
tabl
blis
ish
h the
the time
time 104
44 photography/videography. required for attaining the “at rest” condition. 105
45 106
46 107
47 Airborne Particle Count 108
Environmental Conditions -
48 109
49 Derive the number of sampling point locations Temperature and Relative Humidity 110
50 by us
using
ing th
thee eq
equa
uatio
tion
n wher
where,
e, NL is th
thee minim
minimum
um 111
51 number of sampling locations and √ A is Area of It was perfor
performed
med by digita
digitall hygrom
hygromete
eters
rs and 112
52 the room in square meter. Sling hygrometer and performed the test for 5 113
53 consecutive days for category A1 AHUs and for 114
54 ¼
115
55 NL √A 3 consecutive days for AHUs of other catego- 116
56 Volume
olume of sa
sampl
mplee (f
(for
or grad
gradee A at rest
rest and
and ries
ries.. Re
Read
adin
ings
gs sh
shou
ould
ld be for
for mini
minimu
mum
m 16 117
57 operation,gradeBatrest)-1m equivalentto35.3ft3
3
hours/day at 2 hour interval. 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qajaj
61 122
 4 A. K. Shukla et al.

ss e t
1 o h ch d a 62
t a
cr g
i
h l e
l a
2 a e .s ) 63
d in r
d
n w o
t a
r r. . r
ita y e
r s s
3 e a C li tle a a e
ce n a 64
d tio r D a re s if tle m cl
vi n e D . f e la if e
r in u
ssu
4 tli h d ss 65
o r o f to rm e
r s. ct e p e ffe n n
e itn
5 p m e la a m re i h
t in h i a ito n 66
e r r h e
n a sr r p w s ss t d l
e a li n
6 a fo t vi n a
l l e
r f e v in n o 67
e
s r f
o g a so a ita g ro a o h
t e
l a
e C
7 h tlie k s n e irn c r g m
cl ( 68
ct g c te es t n a
tle in d e
r ta
8 i f in a
b ra e
a
r re tio d if k tce u n e
r 69
w s A ck d e h h h e
w ffi
e n ce h c ss o h
9
P P
E o e n o
e ig ig t e
n o la e
r g
i h
o ffe er
c g i
70
h e f o o
10 D H c f g N H H I g L D m p P H C a p t h 5 71
11 72
t l .
12 P o e r o f o e 73
n h e o t t c
13 SO e t p tr n ct
n
e n 74
r s n - a
14 e
h a to a co ito n e
p m n 75
t d n tc g a o s e e
t
n h r n e ir
15 yf a sro e in ti e r u n
i 76
ir
g e sp n w p to h q a
16 e
v n
it p re ru P
o
d ti e
r m 77
e . is te a w
ce
t
h SO n
17 d . a c P le 78
n Q r n ti t r. ia
r e
c n e
18 a O
e
p a
n w SO n
e e
d te p y
a n a u
q 79
yf o e d d m m v e o
r a il m e
19 it g t e u m r fr 80
in e
in in
e
t i u
d r ro m p p fo
20 n
e r o
h
ig
h
ig
h
t a a a
l e ts p ra h
g
i
p
a
U
H m r d 81
u p a o e n
21 d
I d N H H fI m tr e
r M In a p H In A c p a 4 82
22 83
A s
23 G e t . e
c 84
b o r g a
, d n d e i n l
24 ID l e p p f 85
u . r le s w f t o
25 &P ho Q
I a
s la
ts a
t a
rd o ta e
ti
a e e
c 86
26 ci, s
s in g . in e
n d ito
n n
e r to
t
a
n
a 87
t g ni e
l p
27 a
in
d
e w b r
o
n
o ve lla
n
o or g u
q mr 88
m if h a
a
li d p ro p p in e o .
28 e w
a ir h r
a w n m p h ta m p d d fr U 89
ch r e o ig ig d v o e p g
i s a a a e H
29 S d v N H H fI a L V co a H In o
c ni le n
i p A 3 90
30 91
e ct g U e
31 e
b k u in . y
a
ot H itv o
92
o d h t
32 d
l m . ck e rm m
u m g
u
e
u
A a
g d 93
u s IQ e h fo in s o d n e a
33 o h e ch
t e ir r e e ) 94
h
s g tsr h yf k c n m ss a h n h (n l n
34 e u
o o t o ir lo ito . lu lo g t o
it w . y
a o
it 95
r p in n e a n n
g e la l y in a e a
35 ak
h
t e r d si v . re u
s o
c
-
g gr u
r o
it n
i g
a
w
o
m ni
96
e a e
36 a
el
d
e d
n ss m er to e
g ts yt. In o in m e d u
b . m k
a
d
t r
u m 97
iu il d iu n r ir a
37 ct
k
ce a
ts
er d h e h e
n k
a
w e
e a k
. m
r d d /e u ts tcs n
t e
l h
u ss at 98
d e ig t a c e la e ir cc s e n
u h e d o o o h u h i u o ir r o
38 D c t a N M H fI d le L S q lo t C M A o d d C a is p c 2 99
39 100
40 d
n d
n .ce tm ct
m 101
te a
s ir
e
a
la
e
e ty
41
yss n h
t
es
u p yss e ff fe 102
oit r r h a a
s
42 d d e in r t t. 103
C a fo e il o y t
ci d e
re in a n n
43
A f d n vr p tiy e e 104
V ci te e e p a li e m
m m
44 e a t s su Q c g
n t e n 105
H
”
p s lu in b
o d D fa a n ir o r
45 r . 106
e
r a e
h Q n r t hc
e u vi
fo ch
li v t a o n m q n
46
p e D t r . d e r p e
r e
107
47 t p e
r to g a es n n m jo u
i
tc d 108
n u s a e
c irn msi u it o ve ip
a q u n
48 e s n u n u m e d a 109
d g a d m e ca d q g o e
ssm
“
n in li e n e y n r r
49 a p P y ic󿬁 a n it p u 110
r w h h n w w S
h w a s t
50 e ss e s a
r m M o ig ig a e
t e o R
g
i e r xi e a 111
U d co cG N H H fI b sp L U H N o e h
t ef 1
51 a 112
k
is
52 ) 113
d ? o f y f k
e d t f c
53 R d et y d
o o y n o is
r
114
. n p itr e y d e ti e n d
54 3 e e t ilt n o c li u ) o
i d et
115
m c )o io
r la ib ito o e
rrn a
b erq tc ty
ir tp e n )s o.
55
le m n a /n p e
r a c ih
l b f a e
ir it󿬁 a t n
116
56 b o
c io k s k k k b et e u o d p v c
s n w n
e k 117
a e tc is e is n
a is o
r e k
i
c
c rp n e e e n v is
57 T R a R (y R r R P d L o ( a Im (s D d
i (u e R 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qajaj
61 122
 Quali󿬁cation of HVAC System in Aseptic Processing Area 5

d d m .
1
e n e n r o yl a
62
a
ir k a h
r t re a
n e
e ali fr e h
e . y e )
2
l c
e e n ssu
m
r h d vi t l m a e a
r s 63
t w m t o e
3 a h g i a
l r t si e a . in ait o m itv 64
n c g ed re a e e n g e
ta
r n
e
h
u
4 oi e o
f ss p n t b n isg e n e
n e r c t itn
ffe
65
ct b IF e l a a
e e o
n e n o
z in r h
t
e
tt f
5 e d r ita h
t r itm d to
a e ff a e o n 66
ir l
u Wd n ss g
n
d er yl
d
e m i n
i p e ss o
d d sr d
6 i o h a re e d
n d a .s a e irz e
r w h
t
e
n C
67
n h s g tr fe
l a ife r s vi e d o il (
7 u u o h h fi e ti ic a
il ess m ti ssu p e
ri u
ss h f
l tc n 68
n w or p .Q lu w o s m s ffe a
8 o lfo o ig ig d m e m a o o re a e er i ir
g e 1 69
9 N h
t e
r P N H H fI va il sp si cl Lo R p p D d p H A a cl 1 70
10 h de .re . r . 71
g ss tl l d e d
11 u d to if in t a e tle h
t n e y tce
72
yt
ir
or n e
r o
n f a rv ir if y o
it h itr
12 h a d . e
n o e r te u b h t
g ffe 73
g e t ts d Q is e g e
tli in
q A .r a ti o
13 e b d a P o h tiy n er P d d d
il t te a 74
n
t
i d
l e e
t tr e re d t
yf r a
h f r
la s E
H
ell e
if ile a w
s ct in b
e
ck e ck a
14 g c A a it v e r 75
u P o h
t o h h h ir u p h tu y
15 e
h o e O p ig ig t e
e te w e
o h
P
E g d
n
e
h st r p g
i e
h ta
ps tlie a 0 76
T h
s ch D e
r n
i N H H fI ch v in L T H re a T ni e
c us H T s er f m 1
16 77
17 n e r in ss n d
n e
h
h c r 78
o it u d a a t a of d
18 e ss h n 79
g
h h
t a ll e
e
ss le t
a
r r
o r
e
a
l a
r e r li n ss
19 u
fiy a p e
r e
t it e f o ci 80
or r
ts
d lu a mis n e ti lca
cr
20 n d a o e 81
h
t e i e d v e r w n
v if a n m t ss
21 d e re g e o is 82
e to e
t ci tr
d
e
e s
u b (
e
e .
l e o ssu r iln n
ck
22 83
e p p s p a
n wt s. o
u
e
c m
o . u ss n o
it
23 e g m e
r re ti e sse itn n ro y)l a 84
ch u
a o e p b e
r e e r lce a
n
24 e g c h
t d
n l mil e lca n e
f
ss t p i 85
f a o a a
25 b cile o n
it ae itn m m
it ilra ce fid ltc ra la
it g
n
i m
a
t
d
l yt a r 86
c p n
26 u h il n n re a l e
d g e
r n e n in o 87
o e i i e ffe a if ism u
re
s e ta c
h n b a r
ci
a ssu e
r
in ss
ffe . ffe
27 s g a m h h i n g m h ff 88
a p d a e n w P e o a
P i Q o ig ig o r i g
i i o
28 D m ca ot d P N H H fI h
t sp n o
L D p d ro H D m cr 9 89
29 90
d
l f
30 o e yr 91
u to t d s
31 o r n n
a . to m e e 92
hs te
u Q e ). lu r g ss v
32 H e o m P n ir H vo e d n e o
c 93
P m o e o a P p n a a iln e
33 C m
o
a
e
o r h
t d yt C ir s a ch n
r . 94
A m t e k ci (A a a e
r ir a d n
o
34
n
d e a
u h
t in c
e lo r rn e
r a a lce n
a it 95
n d e u a
35 a a q
e n
i e h c v o tu a f d e d in 96
yt y d ss
ir
h e r U to n
a h a
36 ci b a d
e e o
n a r H n t ol m 97
ol d t
a
il d
r
is
e
p d A e yc. yt tc t ta
37 e
v k
e h
t
p
p d e
h s a
n f m n ci ffe
a
e n 98
a t o o o
38 ir
ce e
r
u s tr re yf
e
g
m
iu
yl ) ire a
p e
l a h
,s
c 99
a h e p v
e c u
s is o h h h
t ir a
n d p FM q
u ccu
h y s m
39 h e n ir p g g
o i i e h e
u e
g
i ir a al o
r
100
40 T b e a er N H H fI v c M S ( re
C o H A m c f 8 101
P d in .s
41 t o / . in h n n 102
e t n Q /D t . ya a te
42 s d osr O t e H . d n tiy a
l l
e a ito 103
d e
t o h
t R
/. it e r eif lo r u m n r i
e n a e g s s e d
43 b a l
e p/ in
n g p ilm a
s
is a
s ic
n
o /p
u vi/ m n
o p n
o
104
d
l d r ct r re irn m lc tir
a r sr o c
44 u ife sr u u a e t m tc tiy o i la e to
105
o ir e d d
t s u t se a
l
r c a l
a
d
f
a p g
in
45 h t o n d in e d n p u e e 106
s
s
e
v e p
r e rm d h a
ll n o m u
q A o h u
n ly
46 , m f la e n t a n i f n t it p 107
m d a o m a t iso d m a d l/ f tc o ito tr m
r e ar n a f e o e e n o
47 a
l k yt o e r r n iu o if ca u r a l o c- 108
c p irv e o iss d ic a c
cxu u
a e h h h d ir it h li lli
e t n y ts t n
48 ll e f n o ig ig e e e
iL e i a ro g
i a d o o
109
49 A h c h
t a s e N H H fI g e b M v rc b p H F in n w n 7 110
t e d
50 n r e t 111
) e
n d
h
t re e g d d irs n
e
d a p
51 e
u
o
p te n
d n
i t s
a
t tce n
a d
e m
112
a a d n a h n
52 itn m b
r ) ess e d
er ti ffe g
n e o 113
n o
c/ il P m e a r
w d a ir h
t ivr
,D fo
53 o a e t . /t 114
C
( t c d
r rtu a
r yc n
t
n n e
t t
n
o
ti g n .
54 . n e H d s e e d o a e in e n 115
55 3 em b R
,p. a
tr n
ie b
ia
l ne m m o
n e
ift ita rb
il m n
o lo tcu o
iit 116
le u ld c u iu u p r a u m tr
56 b
a trs u
o m o .
p Q
h h h
t t eq d trs m n
e
b
il . h c trs e n
d
o n
d 117
T e o ig ig o r e o g
i n r
57 nI h
s t( e r O N H H fI n f M In co d
i a
c n H U in h
t o
c p o
c 6 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qajaj
61 122
 6 A. K. Shukla et al.

n .
1 e ito yti
tis
62
b .
tr a lir
2 ld h o P
Q A ilm y in e
63
u g p e b t
3 o u e e d n . ms 64
h
s or ir b
a
r h
t ra ito d
e iss
a
t o f
t.
4 h a d n s 65
t , c in
n t ws n in G n a yl o
c s
5 u d te , a d r
o e
d rm a
n l o l
66
o e la g g e f m ia o
6 c o
r p n
il iln ss l n mn a te a
s b t
67
el ti e a o iu t e o
7 b n lte p p r h h itc ivr d r d d
n h r d s 68
ai o t m m d
d o ig ig ir n e le re e g
i ic a 7
8
V m e
s as a
s a N H H C e MA a rt H Me l 1
69
9 70
10 h d /P siin tiy ite
v
d 71
g n e
ss H t I . rn d e is
11
e u a R es C re r r i h
72
b or r e
r f n a tu e m t n
12 o e to ito sr fo e if u e 73
d
l
h
t d e
t d
d
. h
t
r i h ct s
13 te e Q n e ra so d n tc. d
i e e 74
u
o e
d
a m tr
a P iso d u e n de o e
itv
ff r y.t
h r o e r n d p
se iv u m . a tu vii
ck
14 m u e 75
s
e b
il r
g o h
t h h u
cx yo
ti o
m d h c h la y is
15 H y p o ig ig e m IP
w
H ro ir e a
l g
i e a o ct 6 76
R ch a
c h e
r in N H H E b il S Lo R p co a D p H R m m a 1
16 77
17 ti 78
d d in .
p m d ir y .
18 e te d il t te d
n
a a h
t 79
ck a
r d e
ss te
m
e
t
e
n ca a rn m ct d w
19 e n lo u n 80
e
r ch
b
il a e
r f s e
r
re m tu e
r d a o
r
t o e ff o re o g
20 u
t e
a
c n d
d n h
t i
.
n tu re ro
u
t r y, e
l tr
l
81
a
r b h e a . d o ra a n a
r p itl n o
f ia
21 iso d it sr o i
82
e ld g m tr Q n to e ch e ot b n m b
22 p u u P r ra p so a m . p o o o 83
m u
o o
r trs o
p e
h h u
o ig ig c yo e e wm n e m ct h
i m
g a
d tas
sr cs r
ic 5
e h h e h x e u p o e o u e e i
se
23 n 84
T s t i r t N H H E b d o L T in c d H T el in p d m1
24 85
25 n
o d
e ye r .Q o
t se r g )S. a ri .s 86
26 it ck v P e tl
if irn yl A ct m 87
a o e n e
n
e c h o tio F(M p P ff ir o
27 i ch e r t d f
o p h E a a o r 88
m e in in k yt n ce su g H
y f n
28 a t b ts d c o f u d a o a 89
n d e ir la ro te lce
29 n
o d
l te a e
ss h c g yt. l
m p o
h n it m
ito
n e
cl 90
c u a e ci ta n t n
30 e o P e r e
r o t in oit
u
o r
a o a n i 91
d h O n in lo n m it ifc
s a d e re a m p ss
31 y/r ts
D
d d is e e
v m a rt o l e a
tr
ic e 92
h e a h mn s li ro a n n
32 e
v et g if
is tr re yf
t
a
ir
iu ro e f e in .r r n
e
e
p il 93
o u o h h h e d i icv l h h o c s n
c e o
r s ir d e v
a t m e br n e a
33
e t a p o ig ig t e n n e n iF r tl g
if iH iA e 4
94
34 R a r h
t cl e
r N H H fI v a ME d in te o
c h
t cl 1 95
sr.
35 96
h to ir n
36 g ss s. e e a rco 97
u e dr tl ly A i
t o n a n if P e
37 n r li o f p E yc m n e itv 98
u h
t n d d p h a is
38 o a n k o
su g H n .3 lce h
t 99
c d to e ta c yt u d ice 0 n
39 e
l e
k r c
l s e ir f
o ro e
t i o in ct e
s 100
h t e
40 citr ce tn e
e h O
SI co g
e n h
t u
n fe n s fa n 101
a ch t r
t ito o ) w e ito
41 p u e
o e n in a m m 3 o iln y a 102
e e c ni p is e tlr
o l 1 - d s. n
a
in
.s
42 n b s h ro a a m e 103
r d
l le m r a re t if
in (H %e l lce s m it
43 o u itc e l h h e yf
ir l h
e r 7 cit h m ta vii 104
b r et e h wn a t m tle 9
. a r n
44 ir o
h a v o ig ig t e o i
r
e if 9 g
i ir o
o o ct 3 105
A s p D le N H H fI v L F in t 9 p H A r c a 1
45 106
a in ir
46 e
b e y ic a
107
47 v a m d e d
l t
d
l r h a a e
ss u
108
e w n h
t o n
48 u a y e e 109
o
h
g d
g lu d d d
r in . sh m
49 s o o n r d d ti n 110
f h a e a d ll e n o
50 w IF s r d tr n
u u ivr 111
o
lf e n tsa .
51 ) Ww v
o u o fo e
h
A n
e 112
d ir h lfo tc p in t ss
52 e
u a g r n u e
r ce is r a A 113
itn l u ia oi d d n . ti e cl e
53 n
a
n o r t ct o
r n le
u rn n n
d
h d
a
114
o oit h a a p a b e u u ti r
54 C
( t h g n r t w G 115
55 3. ce
ir d
e te r n
pi e
h
t o
iti .Q u
t ta p FA a
e
r yl ylp 116
le d
i ck u e
e m d P h h h e
w
U a p h m
56 b n e sn o n e o ig ig t we e m g 117
57 T
a
U ch e ws fr o
c h
t N H H fI lfo o h
L T
h
T co
i o
H C
2
1 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qajaj
61 122
 Quali󿬁cation of HVAC System in Aseptic Processing Area 7

1 Table 4. Performanc
Performance
e Quali󿬁cation of HVAC and UAF System 62
2 63
3 S. No Test performed Acceptance criteria Results 64
4 65
1 Air velo
loccity and CFM 20% of th
the
e avg.
avg. fa
face
ce velo
veloci
city
ty 410
41066 CF
CFMM
5 2 No. of air changes per hour NLT 40 66.31 66
6 3 Differential pressure test NLT 05 Pa 8 to 10 Pa 67
7 4 HEPA filter leakage test less than 0.01% Max. 0.0004% 68
8 Min. 0.0002% 69
9 5 Air
Air fl
flow
ow vi
visu
sual
aliz
izat
atio
ion
n (n
(non
on-u
-uni
nidi
dire
rect
ctio
iona
nall flow
flow)) from
from +v
+ve
e to –ve pre
pressu
ssuriz
rized
ed zon
zone.
e. Mee
Meetsts the 70
10 acceptance 71
11 criteria for flow 72
12 pattern 73
6 Ai
Airb
rbo
orne
rne par
arti
ticl
cle
e co
cou
unt condition Class area 0.5 mm 5 mm
13 74
at rest condition With in class B 191 6
14 75
at operational condition With in class B 500 15
15 7 Recovery/decontamination rate test Within 10 min 4 min. 76
16 8 Environmental conditions -Temperature 22  3  C Max. 23 C 77
17 9 Environmental conditions - Relative humidity NMT 20% Max. 14 78
18 10 Viab
Viable
le coun
countt mo
moni
nito
tori
ring
ng Sampling Class area TBC TFC 79
19 active air sampling With in class B 9 <1 80
20 settle plate method With in class B 4 <1 81
21 82
22 83
23 84
24 85
25 86
26 87
27
Table 5. Performanc
Performance e Quali󿬁cation of UAF System 88
28 S. No Test performed Acceptance criteria Results 89
29 90
30 1 Air velocity 9020 FPM at 6 inch. From filter Complies 91
face
31 92
2 Differential pressure test NLT 10mm of WC 14 to 16mm of
32 93
WC
33 3 HEPA filter integrity test Less than 0.01% of upstream conc. Max. 0.002 % 94
34 4 Air fl
flo
ow vis
isua
uali
liza
zati
tio
on (un
unid
idir
irec
ecttio
ion
nal flo
low
w) Flo
low
w shou
should
ld be uni
nid
dir
irec
ecti
tio
onal Me
Meetetin
ingg the 95
35 acceptance 96
36 criteria under 97
37 dynamic 98
38 condition 99
39 5 Airb
Airbor
orne
ne part
partic
icle
le coun
countt condition Class area 0.5 mm 5 mm 100
40 at rest condition With in class A 0 0 101
at operational With in class A 247 0
41 102
condition
42 103
6 Viable count Sampling Class area TBC TFC
43 monitoring active air sampling With in class A <1 <1
104
44 swab sampling method With in class A <1 <1
105
45 106
46 107
47 108
48 109
49 Viable Count Monitoring - Settle Plate the 󿬂oor
oorand
andals
alsoo at work
work lev
level
el for
for bette
betterr exposu
exposure. re. 110
50 3 111
and Air Sampling Fo
Forr ai
airr sa
samp
mpli
ling
ng,, 1m of ai airr fr
from
om sp spececii󿬁ed
51 Settled plates should be of 90mm diameter and 112
locati
loc ations
ons sh
shoul
ouldd be sample
sampled d us
using
ing Soybea
Soybean n Casein
Casein
52 113
53
should be exposed for duration of 4 hours. Plates Digest Agar. Incubate settle plate at 20 - 25 0C for 114
54 shou
shouldld be ex
expo
pose
sedd at a he
heig
ight
ht abov
abovee 1 mete
meterr from
from TFC and at 30 - 350C for TBC. Table 3–5 T3 T4T5115
Q14

55 116
56 117
57 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qaj aj
61 122
 8 A. K. Shukla et al.

1 62
3. FDA. Guidanc
Guidance
e for Indu
Industry
stry.. Sterile
Sterile Drug Produ
Products
cts
2 63
Produc
Produced
ed by Ase
Asepti
pticc Pro
Proces
cessin
sing,
g, Cur
Curren
rentt Good
Good
3 64
4 Manufactu
Manufacturing
ring Practice, Food and Drug Adminis- 65
5 tration.
tration. Rockville
Rockville,, MD, 2004, 4–6. 66
6 4. Nash Rob
Robert Wachterr Alfred H. Quali󿬁cation of
ert A, Wachte 67
7 water and air handl
handling
ing syst
systems.
ems. Pharm
Pharmaceut
aceutical
ical 68
8 69
Process Validation, 3rd ed. vol. 129
129.. Marcel Dekker,
9 70
–
10 22 24. 71
11 5. WHO. Supplem
Supplementa
entary
ry Training Modul
Modules
es on Good 72
12 Manufactu
Manufacturing
ring Pract
Practice,
ice, Heatin
Heating
g Venti
Ventilatio
lation
n and 73
13 Air Cond
Condition
itioning
ing (HVAC) Part 1 (a). Introdu
Introduction
ction 74
14 75
and Ove
Overvi
rview
ew Tec
Techni
hnical
cal Rep
Report
ort Ser
Series
ies,, no.
no. 937,
15 76
2006, 1–26.
16 77
17 6. Swarb
Swarbrick
rick J. Encyc
Encyclope
lopedia
dia of Pharm
Pharmaceut
aceutical
ical Tech- 78
18 nology, 3rd ed. vol. 1. USA: Informa health care, 79
Failure Mode Effect Analysis (FMEA)
19 127–128. 80
20 7. Annex
Annex 1. EU Gui
Guidel
deline
iness to Goo
Good
d Man
Manufa
ufactu
cturin
ring
g 81
21 82
Practice, Medicinal Products for Human and Veter-
22 Results 83
23 inar
inary
y Use.
Use. Ma
Manu
nufa
fact
ctur
ure
e of St
Ster
erile
ile Me
Medi
dici
cina
nall 84
24 Products, vol. 4
4.. March 2009, 2–9. 85
25 8. Agallo
Agalloco
co JP, Car
Carlet
leton
on FJ. Val
Valida
idatio
tion
n of Ase
Asepti
pticc 86
26 Pharmaceutical Process. 2nd ed. New York: Marcel 87
27 Conclusion 88
Dekker, Inc., 2–3.
28 89
9. WHO.
WHO. Su
Supp
pple
leme
ment
ntar
ary
y Gu
Guid
idel
elin
ines
es on Go
Good
od
29 Quali󿬁cation and validation is appearing to be 90
30 Manufactu
Manufacturing
ring Pract
Practices
ices (GMP)
(GMP):: Valid
Validatio
ation,
n, June 91
the beginn
beginning
ing of a contin
continuou
uouss develo
developmen
pmentt
31 2004, 7–15. 92
process in pharmaceutical QA. Risk assessment
32 10. ICH Q9. Quality Ris
Risk
k Managem
Management.
ent. Curr
Current
ent Step 4 93
33
is an essential tool for quali󿬁cation of HVAC 94
Version, November 2005.
34 system in aseptic processes. It is not just a tool 95
11. Anne
Annex
x 20. EU Guidelin
Guidelines
es to Good Manu
Manufact
facturing
uring
35 for cGMP compliance, its offers real bene󿬁ts to 96
Prac
Practi
tice
ce,, Me
Medi
dici
cina
nall Prod
Produc
ucts
ts for
for Hu
Huma
man
n and
and
36 the validation process by identifying risks and 97
37 Veterinary Use. Quality Risk Management, vol. 4, 98
ensuri
ens uring
ng that
that cri
critic
tical
al risks
risks are contro
controlle
lled.
d. By
38 March 2008. 99
focusi
foc using
ng managi
managingng risks
risks to the patien
patient,
t, phar-
phar-
39 12. PDA
PDA.. Tec
Techni
hnical
cal Repor
Reportt No. 44: Qua
Qualit
lity
y Risk
Risk Man
Man-- 100
40 maceutical
maceut ical manufacturers
manufacturers can ensure
ensure that the agement for Aseptic Processes. Supplement to the
101
41 right
right resour
resources
ces are applied
applied at the right place
place 102
PDA Journal of Pharmaceutical Science and Tech-
42 and at the right time improving patient safety 103
43 nology, vol. 62,
62 , 2008, 6–14. 104
while eliminating unnecessary quali 󿬁cation and
44 13. McDer
McDermott
mott RE, Mikulak RJ, Beauregar
Beauregard
d MR. The 105
validation efforts.
45 Basics of FMEA. Portland: Productivity, Inc; 1995, 106
46 3–44. 107
47 108
14
14.. An
Anne
nex
x 15.
15. EU Gu
Guid
ide
e to Good
Good Ma
Manu
nufa
fact
ctur
urin
ing
g
48 109
49 Q15 References Practice. Quali󿬁cation and validation, 2001, 3 –7. 110
50 15. ISPE Baselin
Baseline
e Guide. Commis
Commissioning and Quali󿬁ca-
sioning 111
51 1. WH
WHO.
O. An
Anne
nex
x 4, Su
Supp
pplem
lemen
enta
tary
ry Gu
Guid
ideli
eline
ness on tion, vol. 5
5,, 2001. 112
52 Good Manuf
Manufactur
acturing
ing Pract
Practices:
ices: Valida
Validation
tion,, World 16. Potdar AM. Pharmaceutical Quality Assurance, 2nd 113
53 114
Health Organization. Technical Report Series, No. ed. Pune: Nirali Prakashan, 2007, 8.6
54 115
55 937, 2006, 116–121. 17
17.. ISO 14644–1. Cleanr
ISO 14644 Cleanroom
oomss and AssAssoci
ociate
ated
d Con
Con-- 116
56 2. Sug
Sugarm
arman
an Sam
Samuel
uel C. HVA
HVAC
C Fun
Fundam
dament
entals
als.. The trolled
trolled Envir
Environme
onments,
nts, Part-
Part-1: Classii󿬁cation of Air
1: Class 117
57 Fairmont press, Inc; 2005, 1–3. Cleanliness, 1999(E), 1–4. 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qajaj
61 122
 Quali󿬁cation of HVAC System in Aseptic Processing Area 9

1 62
18
18.. IS
ISO
O 14
1464
644
4–2. Cleanr
Cleanroo
ooms
ms and Ass
Associ
ociate
ated
d Con
Con-- the Pharmaceutical Sciences, vol. 164.
164. USA: Infor-
2 63
trolled
trolled Envir
Environme
onments,
nts, Part-2: Speci󿬁cation
Part-2: cationss for ma Health Care; 206–210.
3 64
4 Testing and Monitoring to Prove Continued Com- 33. McDow
McDowall
all R. Fund
Fundamen
amentals
tals of HVAC Systems
Systems,, inch 65
5 pliance with ISO 14644–1, 2000(E), 1–4. edition. USA: American society of heating, refrig- 66
6 19
19.. IS
ISO
O 14
1464
644
4–3. Cleanr
Cleanroo
ooms
ms and Ass
Associ
ociate
ated
d Con
Con-- erating and air-conditioning Engineer’s Inc.; 2006, 67
7 tro
trolle
lled
d Env
Enviro
ironme
nments
nts,, Par
Partt 3: Met
Metrol
rology
ogy & Tes
Testt 2–6. 68
8 69
Methods, 2005(E), 1–3. 34. ISO 1464
14644
4–4. Cleanr
Cleanroo
ooms
ms and Ass
Associ
ociate
ated
d Con
Con--
9 70
10 20. A working group of the Scottish Quality Assurance trolled Environments-Part 4: Design, Construction 71
11 Specialist Interest Group. Guideline On Test Meth- and Startup, 2–4. 72
12 ods For Env
Enviro
ironme
nment
ntal
al Mon
Monito
itorin
ring
g For Ase
Asepti
pticc 35. WHO. Gui
Guide
de To Goo
Good
d Man
Manuf
ufact
acturi
uring
ng Pra
Practi
ctice
ce 73
13 Dispensing Facilities, 2nd ed. February 2004, 3 –6. (GMP) Requirements,
Requirements, Part 2: Valid
Validation
ation.. Geneva
Geneva:: 74
14 75
21. Health Canada, Process Validation
Validation.. Aseptic Pr
Process-
ocess- World Health Organization; 1997, 24–32.
15 76
es for Pharmaceuticals, Health Products and Food 36. PIC/S. Guide to Good Manu
Manufactu
facturing
ring Practic
Practice
e for
16 77
17 Branch Inspectorate, Guide, June 2003, 10–12. Medicin
Medicinal
al Pro
Produc
ducts.
ts. Pha
Pharma
rmaceu
ceutic
tical
al Inspec
Inspectio
tion
n 78
18 22. ICH Q10. Pharm
Pharmaceut
aceutical
ical Quality System, Curre
Current
nt Convention, Pharmaceutical Inspection Co-Opera- 79
19 Step 4 Version, June 2008. tion Scheme, PE 009–5, August 2006, 6–12. 80
20 23. Garvey W. Essentials of validation p
project
roject manage- 37. WHO. Annex 6, Good Manufact
Manufacturin
uring
g Practices for 81
21 82
ment part-I. Pharm Technol 2005: 1–6. Ste
Steril
rile
e Pha
Pharm
rmace
aceut
utical
ical Pro
Produ
ducts
cts,, Wor
World
ld Hea
Health
lth
22 83
23 24. Akers JE, Ag
Agalloco JP.. The simpli󿬁ed Akers–Agallo-
alloco JP Organi
Organizat
zation
ion.. Tec
Techni
hnical
cal Rep
Report
ort Series
Series,, No. 902
902,, 84
24 co met
method
hod for ase
asepti
pticc pro
proces
cessin
sing
g ris
risk
k ana
analys
lysis.
is. 2002. 85
25 Pharm Technol 2006: 1–8. 38. FDA
FDA.. Pha
Pharma
rmaceu
ceutic
tical
al cGM
cGMP
P for The Twe
Twenty
nty Fir
First
st 86
26 25
25.. La
Land
nder
er V. 21 CF
CFR
R pa
part
rt 11 an
and
d risk
risk asse
assess
ssme
ment
nt:: Century: A Risk Based Approach. Food and Drug 87
27 88
adapting fundamental methodologies to a current Administration, Rockville, MD, September 2004.
28 89
rule. Pharm Technol Eur 2004: 1–3. 39. PDA. Technic
Technical
al Report No. 22: Proce
Process
ss Simulat
Simulation
ion
29 90
30 26. Draku
Drakulich
lich A. Risk managem
management:
ent: practic
practical
al appli
applica-
ca- Testing for Aseptically Filled Products. Supplement 91
31 tions and value. EPT--The Electronic Newsletter of to The PDA Journal of Pharmaceutical Science and 92
32 Pharmaceutical Technology 2007, 1–2. Technology, vol. 50, 1996. 93
33 27. Del Val
Valle
le MA. Kee
Keepin
ping
g clean
clean roo
rooms
ms com
compli
pliant
ant.. 40. Akers
Akers J, Ag
Agal
allo
loco
co JP
JP.. Risk
Risk anal
analys
ysis
is fo
forr asep
asepti
ticc 94
34 95
Pharm Technol Eur 2006;
2006;18
18(11):1
(11):1–4. processing: the Akers- Agalloco method. Pharma-
35 96
36 28. Str
Straker
aker M. Clea
Clean
n roo
rooms
ms and air handli
handling
ng system
systems:
s: ceutical Technology 2005, 3–5. 97
37 design for compliance. Pharm Technol Eur 2005:1–3. 41. ISPE Basel
Baseline
ine Guide
Guide.. Pharm
Pharmaceut
aceutical
ical Engin
Engineerin
eering
g 98
38 29. Tidsw
Tidswell
ell EC, McGar
McGarvey
vey B. Quantita
Quantitative
tive risk model- Guides for New and Renovated Facility, 1st ed., vol. 99
39 ing in ase
asepti
pticc man
manufa
ufactu
cture.
re. PD
PDA
A J Ph
Phar
arm
m Sc
Scii 3. Sterile Manufacturing Facility, January 1999. 100
40 101
Technol September 2006;60
2006;60:267
:267–269. 42. FDA
FDA.. Gui
Guidan
dance
ce for Ind
Indus
ustry
try,, Pro
Proces
cesss Val
Valida
idatio
tion:
n:
41 102
30. Li J, Poulton G. Dynami
Dynamicc zone modeli
modeling
ng for HVAC Gener
General
al Pri
Princ
ncip
iples
les an
and
d Pract
Practic
ices
es.. Food
Food an
and
d
42 103
43 system
system cont
control.
rol. Int J Mod
Model
el Ident
Ident Contr
Control
ol April Drug Administration, Rockville, MD, November 104
44 2010;9
2010; 9:5–14. 2008. 105
45 31. PIC doc
docume
ument
nt PE 009–1. Guide to Good Manufac- 43. GAMP
GAMP 4. Gu
Guid
ide
e for
for Vali
Valida
dati
tion
on of Auto
Automa
mate
ted
d 106
46 turing Practice for Medicinal Products, September Systems, 2003. 107
47 108
2003, 2–7. 44. FDA
FDA.. Dra
Draft
ft Gui
Guidan
dance
ce for Ind
Indust
ustry,
ry, Pro
ProcessValida
cessValidatio
tion:
n:
48 109
49 32. Dixon AM. Envir
Environme
onmental
ntal Monitor
Monitoring
ing for Clean General
General Princi
Principles
ples and Prac
Practice
tices.
s. Foo
Food
d and Dru
Drug
g 110
50 Roomss and Cont
Room Controlle
rolled
d Envir
Environm
onments,
ents, Drug
Drugss and Administration, Rockville, MD, 2008. 111
51 112
52 113
53 114
54 115
55 116
56 117
57 118
58 119
59 120
60 Copyright © 2011 John Wiley & Sons, Ltd. Qual Assu
Assurr J (2011) 121
DOI: 10.1002/q
10.1002/qajaj
61 122