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Alternative Production Methods for WFI and Compendial Challenges
Anthony Bevilacqua, Ph.DMettler-Toledo Thornton
April 5, 2011
Aqua Distillata (Distilled Water)
Aqua distilleteur vasis permundis, donec ejus duo circiter trientes stillaverint. Aquam distillatum in lagena vitrea servato.
“Let water be distilled in very clean vessels until about two thirds have come over, which is to be kept in a glass bottle.”
Printed in USP I (1820) by thePharmacopoeia of the United States of America
USP History of WFI (continued)
Based on data from a user, USP added RO as an acceptable WFI production method in USP XIX (1975)• In spite of allowance, RO not widely adopted• Many early design problems and microbial control issues,
spotty success, validation difficulties
Many advances in last decade - overcome historic problems• Less problematic RO designs• Other emerging technologies and heat-tolerant MOCs• Better scientific understanding of endotoxin removal
approaches• Better scientific understanding of biofilm control
Academic vs. Engineering Argument
Academic - “Distillation is the gold standard, it works by inherently better separation methods”
Engineer – “Don’t tell me how to make it, tell me the specifications you need it to meet”
Water for Injection is the ONLY material in USP where it is prescribed “how to make it”.
EMEA Reflection Paper of WFI
http://www.emea.europa.eu/pdfs/vet/qwp/2827108en.pdf
Response in PDA Letter- Vol XLIV (7) pp 15-16
Multiple responses (100%) reflecting a very negative opinion of specific comments of the EMEA position
But comments were qualitative, not quantitative
Comments indicated more data was needed
USP Pharm Water Perspective
It is documented that there are Highly Purified Water systems in operation today• by definition they do meet WFI requirements for
chemical and microbiological tests
It is “known” that there are Purified Water systems in operation today that meet WFI requirements – but not proven
USP Pharm Water Perspective
It is not the final purification step that determines the water quality…
It is not RO that is good or bad…
…it is the entire water system and related supporting processes that determine the water quality
It is NOT about RO, it is about the system.
What Specifically?
Feedwater and microbial control methods
Pre-treatment system design/sanitization
Purification system design/sanitization
System size, subloops, and distribution
Water criticality relative to product
What Else?
Sanitization methods• Type(s)• Frequency
In-line microbial/endotoxin/purity controls
Hours of operation/days of operation
Usage – intermittent or continuous
Cost – capital and operational
And more
USP Survey
Since it is the water system AND related processes…
Let’s get data from industry to justify whether alternative techniques can produce WFI reliably and consistently
Utilize the ISPE Critical Utilities COP to get the best available data.
USP’s WFI Survey Needs to Reveal Factors Facilitating Reliable WFI Production Using Non-distillation Approaches
Need to understand source water quality and consistency
Need to understand purification & distribution system • Design• Maintenance• Sanitization approaches• Ongoing purification and microbial/endotoxin controls• Excursion restoration approaches• Specifications, Action, Alert and Typical Levels
Need to understand system reliability and consistency
Hoped to see survey responses representing long term system success
WFI Survey probed attributes of these WFI systems
Expected to see a few clusters of successful design configurations and approaches to purification, sanitization, controls – some surprises!
Q1. For non-distillation based endotoxin controlled system, the level of endotoxin/microbial control it achieves is (check all that apply)
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
Intended result ofdesign/maintenance
focused onendotoxin and
microbial control
Unintended result ofdesign/maintenancefocused on microbial
control
Unintended result ofdesign/maintenance
focused onendotoxin control
An unintendedconsequence of
system design andmaintenance
focused on chemicalpurity control.
Consistent attributeincluded in theoriginal water
system validation
Not included in theoriginal validation,
but historicallyproven, and laterincluded in water
system revalidation.
Not included in watersystem validation,but consistently
remained at/below adesired level
80 respondents/88 responses
Q2. The endotoxin levels from this water system meet...
0%
10%
20%
30%
40%
50%
60%
WFI specifications allthe time
WFI specificationsmost of the time withoccasionally higher
levels
Looser entodoxinspecifications than WFI
Tighter endotoxinspecifications than WFI
No endotoxin controlexpectations
63 respondents
The endotoxin levels from this water system meet...
Looser entodoxin specifications than
WFI, 0.00%
Tighter endotoxin specifications than
WFI, 15.87%
WFI specifications most of the time with occasionally higher
levels, 19.05%
WFI specifications all the time, 53.97%
No endotoxin control expectations, 11.11%
63 respondents
Q2a. Indicate your TYPICAL value in EU/mL
0
2
4
6
8
10
12
14
16
18
< Detection limit or"0"
<0.05 0.05-0.10 0.10-0.25 0.25 >0.25
# r
es
po
nd
en
ts
Q2a. Indicate your Endotoxin specification (EU/mL)
0
5
10
15
20
25
30
less than 0.25 0.25 more than 0.25
# r
es
po
nd
en
ts
Q5. What is the typical microbial count in cfu/100mL?
0
2
4
6
8
10
12
14
<1 <2 <5 <10 >10
# r
es
po
nd
en
ts
Q8. If you had to restore endotoxin/microbial control in the distribution system by remedial sanitization, which remedial
approaches were or would be used:
0
2
4
6
8
10
12
14
16
18
20
Neverneeded
Chemicalsanitizer
Hot water Steam Ozone None Other:Describe
# r
es
po
nd
en
ts
Minnicare for GNRs, sanitization does not remove endotoxinJust preventiveOnly preventive maintenanceHydrogen peroxide solution
8a. Are the above remedial distribution system sanitization parameters more extreme than routine sanitization parameters?
No, 22, 76%
Yes, 7, 24%
Q8b. If you had to restore endotoxin/microbial control in the finished water by remedial approaches within the purification part of the system,
indicate which remedial approaches were used.
Never needed, 7, 6%
Remedial bed backwashing, 10, 9%
Remedial bed regeneration, 9, 8%
Remedial chemical cleaning, 9, 8%
Remedial chemical sanitization, 12, 11%
Replace coarse filters, 8, 7%
Replace micro-retentive filters, 10, 9%
Replace RO membranes, 12, 11%
Other: Describe in no more than 50 words, 7, 6%
Replace valves, 3, 3%
Replace piping, 2, 2%
Remove unit operations, 2, 2%
Add unit operations, 2, 2%
Redesign water flow, 0, 0%
Replace unit operations, 0, 0%
Re-bed unit operations, 4, 4%
Remedial hot water sanitization, 17, 15%
Q9. How many years has this water system been operating with this level of endotoxin control and microbial control?
0
1
2
3
4
5
6
7
8
9
10
0-2 years 3-5 years 6-10 years >10 years
# r
es
po
nd
en
ts
Q10. What is this water grade officially called?
0%
5%
10%
15%
20%
25%
WFI WFI, USP WFI,PhEur
WFI, USPand PhEur
PurifiedWater
PurifiedWater,USP
PurifiedWater,PhEur
PurifiedWater,
USP andPhEur
PurifiedWater withEndotoxin
Control
HighlyPurifiedWater,PhEur
Anothername
31 Respondents
Low Endotoxin Purified WaterRO WaterProcess WaterWater for Bulk Sterile Operations/Final Rinse (WBSO/FR)
Q12. What is the source of the feedwater for your water system?
0%
10%
20%
30%
40%
50%
60%
70%
80%
Only from surfacewaters, including
lakes, reservoirs, andrivers
Only from groundwaters, includingwells and springs
From a mixture ofsurface and ground
waters
From the local publicdrinking water
authority
From private sourcesnot available to the
public and not underyour company’s
control
From private sourcesunder control of your
company
37 Respondents
Q15. What is the geographical area where the products made in association with this water are marketed?
US, 14, 22%
North America, 14, 22%
Europe, 20, 32%
Japan, 6, 10%
Other, 9, 14%
What’s Next?
Summary of purification and control points necessary for reliable WFI production
Discussion of survey descriptions of: • Successful purification designs• Successful purification train sanitization approaches• Successful distribution designs• Successful distribution sanitization approaches• Successful distribution in-line controls
Implications for the future of WFI production by non-distillation approaches
Logical WFI Purification and Control PointsFirst, remove endotoxins from source water using
• Size exclusion using RO and/or UF (~10KD cutoff or less)• Deionization removal (endotoxin is very negatively charged)
Then, minimize biofilm colonization within purification train for the sake of• Purification efficiency and operational cost• Avoiding release of additional endotoxins• Can control with sanitization and in-line microbial controls
Finally, control biofilm and endotoxin in the distribution system• Avoid/prevent release into distribution system from purification
train• Avoid/minimize biofilm growth and generation of endotoxins in
loop• Can control with sanitization and in-line microbial controls• Can control with endotoxin polishing in loop (e.g., UF and DI)
Survey responses for Q13 and Q14 reveal system design and control approaches
Presented here at a high level (still revealing)• Purification unit operations used• Purification train configurations used• Purification train sanitization approaches used• Distribution system sanitization approaches used• Distribution system unit operations used• Distribution system micro/endotoxin control approaches
used
Interpretation of what it all says about successful ways of making WFI other than by distillation
Unit Operations Used in Main Purification Train
0
5
10
15
20
25
ChemSani
HWSani
1 PassRO
2 PassRO
DI/EDI DI EDI UF UV 0.1 or0.2 Filt
0.1 Filt 0.2 Filt Ozone
# o
f S
ys
tem
s U
sin
g U
nit
Op
(22 Systems)
Critical Purification Approaches
0
2
4
6
8
10
12
14
16
No
Sa
ni,
DI a
lon
e
No
Sa
ni,
1P
-RO
+ D
I
Ch
em
Sa
ni,
1P
-RO
+D
I/ED
I
Ch
em
Sa
ni,
2P
-RO
+D
I/ED
I
HW
Sa
ni,
1P
-RO
+E
DI
HW
Sa
ni,
2P
-RO
+E
DI
Ch
em
Sa
ni,
1P
-RO
+D
I/ED
I + U
F
Ch
em
Sa
ni,
2P
-RO
+D
I/ED
I + U
F
Ch
em
Sa
ni,
2P
-RO
+U
F
HW
Sa
ni,
1P
-RO
+E
DI +
UF
No
Sa
ni -
Un
it O
ps
HW
Sa
ni -
Un
it O
ps
Ch
em
Sa
ni -
Un
itO
ps
With
UF
in P
ur
or
Lo
op
No
UF
in P
ur
or
Lo
op
# o
f S
ys
tem
s U
sin
g A
pp
roa
ch
(22 Systems)
Critical Purification Unit Op
Purification Train Sanitization
Approach Summary
Utilization of UF
(22 Systems)
(23 Systems)
Sanitization/Control Used in Distribution Loop
0
5
10
15
20
25
Period
ic Che
m S
ani
Period
ic HW
Sani
Contin
uous
HW
San
i
Period
ic Ste
am
Contin
uous
Tan
k O3
Period
ic Ta
nk O
3
Contin
uous
Loo
p O
3
Period
ic Lo
op O
3
Ultrap
ure
Wat
er
Loop
DI/E
DI
Loop
UV
Loop
UF
Loop
Micr
oFilt
(0.1
or 0
.2)
Loop
0.1
Filt
Loop
0.2
Filt
# o
f S
ys
tem
s U
sin
g A
pp
roa
ch
(26 Systems)
Loop Sanitization Approaches
Loop Micro/Endotoxin Polishing
(26 Systems)
Loop Sanitization Combinations
0
1
2
3
4
5
6
7
8
No Loop Sani Noted Chem Only Heat Only Ozone Only Chem + Heat Chem + Ozone Heat + Ozone
# o
f S
ys
tem
s U
sin
g A
pp
roa
ch
(26 Systems)
Loop Micro/Endo Control/Polishing Combinations
0
1
2
3
4
5
6
7
8
9
10
Nothingnoted
UPW / DIOnly
UF only UV Only MicroFiltOnly
UPW / DI+ 1 other
UF + 1other
UV + 1other
MicroFilt+ UV
MicroFilt+ 1 other(incl UV)
UPW / DI+ 2
others
UF + 2others
UV + 2others
MicroFilt+ 2
others
All 4
# o
f S
yste
ms
Usi
ng
Ap
pro
ach
(26 Systems)
Years of Reliable OperationQ9. How many years has this water system been operating with this level of
endotoxin control and microbial control?
0
1
2
3
4
5
6
7
8
9
10
0-2 years 3-5 years 6-10 years >10 years
# re
spo
nd
ents
Non-Distillation WFI Uses
Q11. Please indicate all uses of your endotoxin/microbially controlled water (Original selection categories shown)
0
5
10
15
20
Fre
qu
en
cy
Se
lec
ted
26 Respondents 228 Selections
Q11. Please indicate all uses of your endotoxin/microbially controlled water (Selection category groups shown)
0%
20%
40%
60%
80%
100%H
um
an D
rug
s
Vet
erin
ary
Dru
gs
Dev
ice/
Dia
gn
ost
ics
Ass
oci
ated
R&
D/D
rug
Dev
elo
pm
ent
No
n-P
aren
tera
l Dru
gs
(Op
hth
alm
ics,
To
pic
als,
OT
Cs,
Gen
eric
s)
AP
I, B
ulk
Bio
log
ic, E
xcip
ien
t
Cle
anin
g, D
epyr
og
enat
ion
, Fee
dw
ater
No
n-P
aren
tera
l Ap
plic
atio
ns
(No
n-
Par
ente
ral D
rug
s, D
iag
no
stic
s,A
nal
ytic
al R
eag
ent,
Lab
Wat
er)
ON
LY
No
n-P
aren
tera
l Ap
plic
atio
ns
(No
n-P
aren
tera
l Dru
gs,
Dia
gn
ost
ics,
An
alyt
ical
Rea
gen
t, L
ab W
ater
)
ON
LY
Cle
anin
g, D
epyr
o, F
eed
wat
er,
No
n-P
aren
tera
l Ap
plic
atio
ns
ON
LY
R&
D, C
lean
ing
, Dep
yro
,F
eed
wat
er, N
on
-Par
ente
rals
(N
OT
Co
mD
rug
s &
AP
I/Bu
lkB
io)
ON
LY
AP
I, B
lk B
io, E
xcip
, Cle
anin
g,
Dep
yro
, Fee
dw
ater
, No
n-P
aren
tera
ls(N
OT
Co
m/R
&D
Par
ente
rals
)
Sel
ecti
on
% (
#) b
y 26
Res
po
nd
ents
19
54
19
5
910
1
17
13
79
26 Respondents
Non-Distillation WFI Use Clusters
What Does All This Mean About Suitable Approaches to Generating WFI ?
Some general Unit Op train pattern commonalities• 1 or 2 pass RO + DI or EDI is common, but others also
work• Chem > HW > No RO+EDI sanitization, but all work• With UF ≈ Without UF for last unit op, but both work
Plain DI (no sani) without RO or UF (minority approach) also successful
Bottom Line: Many approaches can work, likely with varying degrees of diligence to maintain control, but control nevertheless
No such thing as fool-proof (even for distillation)!
What Does All This Mean About Suitable Approaches to Generating WFI ?
Concerns essentially no different than with distillation-based WFI, however…• Cost considerations, usually water not already hot, so ambient
control measures more common/creative• Micro/endo control/polishing in loop could be beneficial• Use of high water purity (minority approach) also successful in
controlling growth
Loop sanitization approach commonality• HW > Ozone ≈ Chem sanitization use, but all can work• Multiple approaches >> Single approach >> No loop sani, but
all can work
What Does All This Mean About Suitable Approaches to Generating WFI ?
Ongoing in-line micro control/endo polishing• Combo approaches >> Single approach >> No control unit ops,
but all can work• Most common combo is a UV sanitizer + MicroFiltration (0.1 or
0.2 µm rated)
Bottom Line: Many approaches can work, with the systems having more control options likely needing less diligence in keeping the quality controlled
No such thing as fool-proof!
Thank You!
Dr. Anthony Bevilacqua, Head of R&DMettler-Toledo Thornton
36 Middlesex TurnpikeBedford, MA 01730 USA
+1 781 301 8642anthony.bevilacqua@mt.com
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