How to do Equipment validation and process

Validation Process

1. Validation Tools in the
Pharmaceutical & Biotech
Industries
By Pamela Hardt-English
PhF Specialists, Inc.
www.phfspec.com

2. Objective
•
T
he objective of validation in the food,
pharmaceutical and biotech industries is
the same….
•
C
onfirm that the equipment or process
performs as designed now and
over time.

3. Getting Started
•
W
hat is the equipment or process?
•
W
hat is the scope?
•
W
hat is the validation strategy?

4. Critical to Quality Tree
Definitions
•
C
TQ –
C
ritical to Quality Tree
•
K
POV-
Key Process Output Variables
•
KPIV –
K
ey Process Input Variables
•
V
OC –
V
oice of the Customer

5. Critical to Quality Tree
(CTQ)
VOC
CTQ
KPOV
KPIV
Good quality product Commercially steril
e

product
Recipe executes a
s

specified (time, temperature, press
u
re)
Recipe executes a
s

specified (time, temperature, press
u
re)
Calibration
Perform
e
d as
specified PM perfor
med as
required
Right Recipe (time, temperature, press
u
re)
Calibration of temperature sensor
s
Preventive Maintenance (PM) performed
No retort bypass
Ot
h
e
r
KP
OV
’
s
:

Water chlorination documented; temperature sen
s
itive tape
changes color
Other pos
s
ible
KPIV’s
:
Chlorinated cooling w
a
ter, temperature
sen
s
itive tape

6. Risk Assessment
Process/Product Failure
Modes and Effects Analysis
(FMEA)
Food products with low water activity and
low pH are considered lower risk than
foods with high pH or high water activity

7. RISK
Food products with low water activity and high pH were thought to be lower risk than
foods with low pH or high water activity,
but …..
without good GMP compliance,
low risk can become high risk.

8. RISK -
B
SE
•
Bovine
Spongiform
Encephalopathy
(
BSE
),
commonly known as
Mad
-
Cow
D
isease
(MCD), is a
fatal, neurodegenerative
disease
in cattle, that causes
a spongy degeneration in the brain and spinal cord and also causes red eyes.
BSE
has a long incubation
period, about 4 years, usually affecting adult cattle at a peak age onset of four to five years, all breeds being equally susceptible. In the United Kingdom, the country worst affected, more than 179,000 cattle have been infected and 4.4 million slaughtered during the eradication ... For Biotech industry using animal products, the risk of BSE getting into one of their products is very low, but the severity, if it does, is unacceptably high.

9. Process/Product Failure Modes and Effects Analysis
(
FMEA)

10. Severity Evaluation
Effe
ct
of
Fai
l
ur
e
Custom
e
r
Effe
ct
Manufa
c
turi
ng/ As
s
e
mbl
y
Effe
ct
Env
i
ronm
ental
Effect
Ran
k
ing
Ha
za
rdou
s
w
i
thout
wa
r
n
i
n
g
Ve
r
y
h
igh
se
ve
r
ity
rank
ing w
hen a
potentia
l fa
ilur
e
mode
e
f
fects

sa
fe
opera
t
ion and
/o
r

in
vo
lve
s
non
co
mp
liance with

go
vern
men
t

r
egu
lation
w
ithout warn
ing
.
O
r

ma
y end
a
nger
opera
t
o
r

(
m
a
c
h
ine o
r

asse
mb
ly)
w
ithout warn
ing
.
Ecos
ys
te
m
s
t
r
u
c
t
u
r
e
and func
tion
are

ad
ve
rse
ly
a
f
fec
t
ed. Impact is
long las
t
ing
.

Pos
s
ib
le
se
ver
e

in
ju
r
ies
o
r
death
to

ind
ividua
ls
, p
opu
lation

is a
t

r
is
k
.
10
Ha
za
rdou
s
wi
t
h

wa
r
n
i
n
g
Ve
r
y
h
igh
se
ve
r
ity
rank
ing w
hen a
potentia
l fa
ilur
e
mode
e
f
fects

sa
fe
opera
t
ion and
/o
r

in
vo
lve
s
non
co
mp
liance with

go
vern
men
t

r
egu
lation
w
ith

wa
rn
ing
.
O
r

ma
y end
a
nger
opera
t
o
r

(
m
a
c
h
ine o
r

assembly)
w
ith
warning.
Ecos
ys
te
m
s
t
r
u
c
t
u
r
e
and func
tion
are

ad
ve
rse
ly
a
f
fec
t
ed. Impact is
long las
t
ing
.

P
o
ssi
bl
e
sev
e
re i
n
ju
rie
s
t
o
in
divi
d
u
a
ls,
popula
t
ion
is
not a
t

r
is
k
.
9
V
e
ry
high
Ite
m
inoperable
(
lo
s
s

of
p
r
ima
r
y
function)
O
r
100% o
f
pr
oduct
ma
y h
a
ve
to
be s
c
r
appe
d, o
r

ite
m
re
wo
rked

off-
line w
ith

r
e
wo
rk
time

gr
eate
r

than one hour.
8
High
Ite
m
ope
rab
le
but at a

redu
ced

lev
e
l of p
e
r
f
o
rma
n
c
e.
Cu
st
om
er
ver
y
dissatisfied.
O
r
p
r
oduct
ma
y ha
ve
to be
so
r
t
ed and a po
rtion
(
le
s
s
than
10
0
%
)

sc
rapped
o
r
ite
m
re
wo
rked

off-
line

w
ith

re
wo
r
k

time
between ha
lf an ho
u
r
and
an hour
.
Ecos
ys
te
m s
t
r
u
c
t
u
r
e

and
function/en
viron
m
ent a
r
e exposed but
impac
t
is
int
e
rmittent.
E
c
os
ys
t
e
m
s
t
ruc
t
ural
and
functional
in
teg
r
ity a
r
e
in
tac
t.
Poss
ib
le

in
ju
r
ies
to ind
ividua
ls
,

popu
la
tion is

not
at
risk.
7
Moder
a
te
Ite
m
ope
rab
le
but
C
o
mfo
r
t/Conven
ience ite
m
(
s
)

inoperab
le
. C
u
s
t
o
m
e
r

dissa
tisfi
e
d.
O
r

a

por
tion
(
less
than
100
%)
o
f
the
p
r
oduc
t
ma
y
ha
ve
to
be scr
apped w
ith
no
so
r
t
ing, o
r

ite
m

r
e
wo
rked
o
ff-
line
w
ith re
wor
k
time
les
s

than
ha
lf
an hour
.
6
Lo
w
Ite
m
ope
rab
le
but
C
o
mfo
r
t/Conven
ience ite
m
(
s
)

operab
le
at a r
educed
le
ve
l
of
pe
rfo
r
mance.
Cu
s
t
o
m
e
r

so
me
what d
issa
tis
f
ied.
O
r
100% o
f
pr
oduct
ma
y h
a
ve
to
be so
r
t
ed and
r
e
wo
rked o
r

repa
ired off-
line
.
Ecos
ys
te
m and
func
tion/en
viron
m
en
t a
r
e

e
x
posed but
impac
t
is
te
mpo
r
a
r
y.
Ecos
ys
te
m s
t
r
u
c
t
u
r
a
l
and func
tiona
l integ
r
ity
a
r
e intac
t

poss
ib
le
mino
r
in
ju
r
ies
to

ind
ividua
ls
, p
opu
lation

is a
t

r
is
k
.
5
V
e
ry
minor
F
it & F
in
ish/Squeak
& Rattle
ite
m

does
not confo
r
m. Defec
t

noticed
by di
scrimin
at
in
g cu
st
om
ers
(le
s
s
than 25%)
O
r

a

por
tion
(
less
than
100
%)
o
f
the
p
r
oduc
t
ma
y
ha
ve
to
be
rew
o
rked
w
ith
no
sc
rap
,
on
-
line but
in-st
a
ti
on.
Ecos
ys
te
m
s
t
r
u
c
t
u
r
e
and func
tion
are
not
e
x
posed
to
str
e
s
s
, o
r
e
x
p
r
es
s
ion o
f
s
t
ress

is

not
measu
r
able
o
r
adve
r
se.
2
None
N
o
d
isce
rn
ib
le
effec
t
.
O
r
s
ligh
t
incon
v
en
ience to
opera
t
ion
o
r

ope
rato
r
,

o
r
no effec
t
.
Ecos
ys
te
m
s
t
r
u
c
t
u
r
e
and func
tion
are
not
e
x
posed.
Individua
ls
and p
opu
lations
a
r
e
not
at
risk.
1

11. Occurrence Evaluation
Guideline
Probabil
ity
o
f
Failure
Pr
ocess
Produ
ct
Ran
k
ing
>
once
per
da
y
>
100
/
100
0 p
ieces
10
once pe
r da
y
50/1000 p
ieces
9
V
e
ry
High: Pe
r
s
i
s
te
nt F
a
il
ur
e
once pe
r
week
20/1000 p
ieces
8
once in
two
w
eeks
10/1000 p
ieces
7
High: Fr
equ
e
nt F
a
ilur
e
s
once pe
r
mon
t
h
5
/
100
0
p
ieces
6
once in
th
ree
mon
t
hs
2
/
100
0
p
ieces
5
once in

s
ix m
onths
1
/
100
0
p
ieces
4
Mo
d
e
ra
te
:
Occasio
n
al
fa
ilu
r
es
once pe
r
year
.5/1000 p
ieces
3
Lo
w
:
Rel
a
tiv
e
ly
fe
w

Fai
l
ures
once in
five
yea
r
s
0
.
1/1000 p
ieces
2
R
e
m
o
te
:
Fa
i
l
u
r
e
is
u
n
like
l
y
once in
ten yea
r
s
<
.
01
/1000 p
ie
c
es
1

12. Detection Evaluation
D
e
tect
io
n
Crit
eri
a
Dete
c
t
ion Method
s
Ran
k
ing
Almo
st impo
s
s
i
bl
e
Abso
lu
te
Ce
r
t
a
in
t
y of non-de
tection
C
annot detect o
r

is
not chec
ked
10
Ve
r
y
R
e
m
o
te
C
ontrols
w
ill
probably not det
ec
t
C
ontro
l is

achie
v
ed
w
ith ind
ir
e
c
t

o
r

r
a
ndo
m check
s

only
9
Re
m
o
t
e
C
ontro
l is

achie
v
ed
w
ith vis
u
a
l
in
spection
on
ly
8
Ve
r
y
L
o
w
C
ontro
ls
have
poor
chance o
f

detec
tion
C
ontro
l is

achie
v
ed
w
ith
doub
le
vis
u
a
l inspec
tion

on
ly
7
Lo
w
C
ontro
l is

achie
v
ed
w
ith ch
a
r
ting
me
thods, I.e.
SPC
6
Moder
a
te
C
ontro
ls
ma
y detec
t
C
ontro
l
is
based on
va
r
iab
le
gau
g
ing
a
fte
r
pa
r
t
s
hav
e

le
f
t
the
s
t
at
io
n
5
Moder
a
te
ly
high
Er
r
o
r
detec
tion

in
subsequ
ent
opera
t
ions
o
r
gauging on
se
t-up and
FAI
4
High
C
ontro
ls
have
a good chan
ce
of
detec
tion
Er
r
o
r
detec
tion

in
s
t
ation
o
r

detec
tion

in
subsequ
ent op
e
r
ations
3
Ve
r
y
H
i
g
h
Abs
o
lu
te
a
lmos
t
c
e
r
t
a
in
to
detec
t
Er
r
o
r
detec
tion

in
s
t
ation
can
not
pass
bad par
t
s
2
Fully
Dete
ctabl
e
C
ontro
ls
ce
r
t
a
in

to detec
t
D
is
c
r
epant pa
r
t
s

can not be

made
because of e
r
r
o
r
p
r
oofing
1

13. FMEA
Curr
e
n
t Pr
oc
e
s
s
C
ontro
ls
PROCE
S

S STEP

Po
tentia
l
Fail
ure
Mode
Po
tentia
l
Eff
e
ct(s) o
f

Fail
ure
SEVERITY
Po
tentia
l
Ca
u
s
e
of

Fail
ure
OCCURRENCE
Prev
ent
De
t
e
ct
DETECTION
RPN
R
e
co
mmend
ed A
c
tion
C
ook time
Time t
o
o
shor
t
U
nder
p
r
ocess
ing
9
Wro
n
g

re
ci
p
e
,
pro
g
ram
ma
lfunc
tion
2
Re
ci
p
e
,

PM, SOP
Re
c
o
r
d

rev
iew
3
5
4
NA. R
P
N
under

control
Co
oli
n
g
Inade
qua
te cooling
U
nder
coo
ling
7
C
o
o
ling
w
a
te
r
too
hot,
time
too shor
t
3
Re
ci
p
e
,

& S
O
P
Ope
r
at
or,
re
c
o
r
d

rev
iew,
in
spect ion
36
3
NA. R
P
N
under

control

14. Who should be on FMEA team? •
V
alidation protocol author/leader
•
T
echnology expert
•
T
echnicians that use system (retort
operator)
•Q
A
•
R
egulatory
•
E
ngineering

15. Validation Strategy
•
W
hat is the process/equipment?
•
W
hat is the scope?
•
H
ow will we validate the
process/equipment?
–
C
ritical to Quality Tree
–
A
cceptance Criteria
•
F
MEA & Control Plan

16. What is the process/equipment?
•
A
BC Batch Water Immersion Retort
•
A
utomatic loading
•
C
omputer control by recipe
•
C
ontainers are aluminum and steel cans
•
P
roducts are low acid vegetables
•
F
low chart of process

17. What is the scope?
•
R
etort processing temperature range: 240-
260
o
F
•
O
verpressure (25-35 psi)
•
C
ontainers: Steel 300x400 to 603x700
–
and Aluminum: 300x400
•
C
ans staggered loaded
•
O
ther restrictions

18. How will we validate the
process/equipment?
•
C
ritical to Quality Tree (CTQ)
•
Acceptance Criteria for IQ, OQ and PQ

19. Critical to Quality Tree
(CTQ)
VOC
CTQ
KPOV
KPIV
Good quality product Commercially steril
e

product
Recipe executes a
s

specified (time, temperature, press
u
re)
Recipe executes a
s

specified (time, temperature, press
u
re)
Calibration
Perform
e
d as
specified PM perfor
med as
required
Right Recipe (time, temperature, press
u
re)
Calibration of temperature sensor
s
Preventive Maintenance (PM) performed
No retort bypass
Ot
h
e
r
KP
OV
’
s
:

Water chlorination documented; temperature sen
s
itive tape
changes color
Other pos
s
ible
KPIV’s
:
Chlorinated cooling w
a
ter, temperature
sen
s
itive tape

20. Acceptance Criteria
•
I
nstallation Qualification (IQ)
•
O
peration Qualification (OQ)
•
P
erformance Qualification (PQ)

21. Installation Qualification
•
W
as the equipment installed as the
manufacturer specified and the user requires?
•
Q
uestions to consider:
–
A
re right utilities in place?
–
D
oes it work when turned on?
–
D
o alarms activate as specified?
–
I
s system in the calibration program?
–
H
as preventive maintenance occurred or is it in
place?
–
S
OP’s in place?
(Note: Empty chamber mapping in Pharm industry)

22. Operation Qualification (OQ)
•
D
oes the equipment operate as expected
when tested at the operational extremes?

23. Heat Sealer
•
S
etting time and temperature extremes:
+/-10%.
Temperature was fine …
3
40, 350, 360
o
F
Time: 5.4, 6.0, 6.6 seconds
•
B
ut, doing an engineering study, we learned
that: 1/8”
makes a 1 second difference in the
residence time.

24. OQ-Heat Sealer

25. Operation Qualification
•
R
efrigerators/ Incubators:
–
O
pen door/recovery test
•
R
etort:
–
P
artial loads

26. Performance Qualification (PQ)
•
D
oes the equipment operate as designed
and specified over time?
For temperature distribution study: •
M
ost conservative conditions for range of
containers and products in duplicate or triplicate.
Acceptance Criterion: •
R
eproducible temperature distribution
results

27. Performance Qualification (PQ)
•
F
or Heat Penetration Studies--
Is the process adequate for the most
conservative conditions of viscosity, headspace, RPM, fill weight, etc.?
Acceptance criteria: 1) Meet Fo minimum by Ball Method 2) Meet quality guidelines

28. Performance Qualification (PQ)
•
F
or equipment such as heat sealer:
Is a quality seal delivered over time, e.g.,
over 2 shifts when operators change?
•
Acceptance criteria:
0 critical defects over 13 hours production in
3 production runs
<1cosmetic defect per 200 pouches over
same time period.

29. Control Plan
•
T
he purpose of validation is to confirm that
the process or equipment is performing as designed and specified and is properly controlled.
•
T
he Control Plan assures that the process
or equipment stays in control.

30. Control Plan
Pr
ocess Step
R
e
fere
nce
Docum
e
nt
s
Pr
ocess
Va
r
i
ab
le
Va
r
i
ab
le

C
l
ass
if
icat
i
on
Control Method
S
e
tpoints / Limits
S
a
mpling Pl
an
Re
s
pon
si-
bilit
y
R
eact
io
n

Pl
an
Fillin
g bottles
SOP 1234
Heads
pace
Major
Check w
e
ighe
r on line a
n
d
1/2 hr checks
0.4 “/ 0.25”,
0.7”
30 min checks
Check w
e
ig
her tech
Adjust check w
e
ig
her,
Hold pr
oduct,
Call su
per-
viser
Retort cook
SOP 1234
Recip
e
(time,
temperature)
Major
Automated time, temperature & pressure control
30 minutes at 250
o
F
/
29’
at
248
o
F
Revie
w
all
process records
Retort operator,QC/ QA
Hold pr
oduct

31. Conclusion
•
W
e all want our processes and equipment to
operate properly and stay in control all of the time.
•
T
horough understanding of the equipment,
processes, risks, restrictions and customer requirements will help us determine how best to validate and operate.
•
T
his presentation hopefully added to your
validation “Tool kit.”

32. Things are not always what they
seem at first glance