Bio-decontamination with H2O2 - Vapor
Bio-Decontamination with H2O2 – Vapor
in Pharmaceutical Industry
Dr. Johannes Rauschnabel,
Robert Bosch GmbH
SBM Expert’s Congress 13th-14th of September, 2007
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Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
Î
“VHP” for Isolators
Î
Results
Î
More Applications
Î
Summary
Packaging Technology
2
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1
Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
z
Chemistry /
Biocidal Effect
z
Challenges
z
Regulatory
Î
“VHP” for Isolators
Î
Results
Î
More Applications
Î
Summary
Packaging Technology
3
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Bio-decontamination with H2O2 - Vapor
Introduction
Î
Hydrogen Peroxide is an old sterilant – well established in food industry,
where liquid H2O2 is applied for disinfection of packaging material and
plastic bottles.
Î
H2O2 has a broad antimicrobial activity spectrum and shows low toxicity.
Î
Residues of hydrogen peroxide decompose into neutral species, which
underlines the environmental friendliness of this agent:
2 H2O2 ' 2 H2O + O2
Î
But: hydrogen peroxide can decompose with fast kinetics – under some
circumstances it can explode at high concentrations.
Î
For complex geometries disinfection with liquid peroxide has limits. For
this case H2O2 in the vapor state is widely used.
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Bio-decontamination with H2O2 - Vapor
Chemistry / Biocidal Effect
Î
The hydrogen peroxide molecule has a
unique geometry with a high energy angle,
which makes splitting of O-O-bond easy:
H2O2 ' 2 HO●
2 HO● ' H-O-H + ½O2
Î
The decomposition can be catalyzed by
metallic surfaces (Cu, Pb, Mg…) – which
can be used to decompose after use.
On the other side this makes the need for
noble surfaces in the equipment to be
disinfected.
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Bio-decontamination with H2O2 - Vapor
Chemistry / Biocidal Effect
Î
The biocidal effect of hydrogen peroxide
comes from the oxygen atom/radical,
which is released under influence of the
enzyme catalase at the microbiotic surface.
The oxidative power of oxygen radicals
cause irreversible damage to enzymic
systems and DNA.
Î
A minimum of humditiy at the surface
to be treated helps to promote this metabolismism – especially bacterial spores
need a basic humidity to show any biochemical activity.
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Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
z
Chemistry /
Biocidal Effect
z
Challenges
z
Regulatory
Î
“VHP” for Isolators
Î
Results
Î
More Applications
Î
Summary
Packaging Technology
7
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Bio-decontamination with H2O2 - Vapor
Challenges
Î
Vaporized Hydrogen Peroxide is used
to disinfect bottles and pharmaceutical
equipment interior, such as isolators
(mini-cleanrooms on top of machinery).
Î
Pioneer in that technique was AMSCO,
later bought by Steris Co., with their
VHP® technology back in the 80 ies.
Î
T [°C]
Disadvantage of vaporizing H2O2 are the
two physical states present in the system,
when using diluted H2O2 for evaporation.
This results in different concentrations and
thereby in different inactivation efficacy.
Gas + liquid
Gas state
25
liquid state
2
35
79
Conc. H2O2 [%]
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Bio-decontamination with H2O2 - Vapor
Challenges
Î
Slow evaporation of e.g. 35%
H2O2 separates the both components
(”destillation”) during transition into
vapor. Condensation on the surfaces
makes the next separation
(“concentration change”).
Î
Sterilisation means absence of viable
microbiotics. In complex geometries
this is a challenge, because homogeneous inactivation is required. This can be
questioned with vapor/liquid mixtures.
Î
H202 vapor is known as bio-decontaminating, not sterilizing surfaces –
though 6 log inactivation can be achieved/proven.
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distribution, as well as in the event of applications for industrial property rights.
Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
z
Chemistry /
Biocidal Effect
z
Challenges
z
Regulatory
Î
“VHP” for Isolators
Î
Results
Î
More Applications
Î
Summary
Packaging Technology
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5
Bio-decontamination with H2O2 - Vapor
Regulatory
Î
In “Guidance for Industry: Sterile Drug
Products Produced by Aseptic
Processing — Current Good Manufacturing Practice” published by FDA
in September 2004, within Appendix 1:
Aseptic Processing Isolators the need
for decontaminated surfaces is explained:
“1. Surface Exposure
Decontamination procedures should ensure full exposure of all isolator
surfaces to the chemical agent. The capability of a decontaminant to
penetrate obstructed or covered surfaces is limited….”
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Bio-decontamination with H2O2 - Vapor
Regulatory
Î
Continuation “Aseptic Guidance”:
“2. Efficacy
The decontamination method should render the inner surfaces of the isolator free
of viable microorganisms. Multiple available vaporized agents are suitable for
achieving decontamination…. Cycles should be developed with an appropriate
margin of extra kill to provide confidence in robustness of the decontamination
processes. Normally, a four- to six-log reduction can be justified depending on the
application.”
“E. Filling Line Sterilization
…Where decontamination methods are used to render certain product contact
surfaces free of viable organisms, a minimum of a six-log reduction should be
demonstrated using a suitable biological indicator.”
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Bio-decontamination with H2O2 - Vapor
Regulatory
Î
Continuation “Aseptic Guidance”:
“E. Filling Line Sterilization
…Where decontamination methods are used to render certain product contact
surfaces free of viable organisms, a minimum of a six-log reduction should be
demonstrated using a suitable biological indicator.”
Î
In EC GUIDE to Good Manufacturing Practice, Annex 1 a list of
sterilization techniques (heat, moist heat, radiation, ethylene oxide…)
does not include hydrogen peroxide. The description of
sterilization/decontamination of isolators does not specifically discuss
issues coming from bio-decontamination instead sterilization.
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Bio-decontamination with H2O2 - Vapor
Regulatory
Î
In EC GUIDE to Good Manufacturing
Practice, Annex 1 a list of sterilization
techniques (heat, moist heat, radiation,
ethylene oxide…) does not include
hydrogen peroxide. The description of
sterilization/decontamination of isolators
does not specifically discuss issues
coming from bio-decontamination
instead “sterilization”.
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Bio-decontamination with H2O2 - Vapor
Regulatory
Î
PIC/S Recommendation “Isolators used for Aseptic Processing and
Sterility Testing”; Chapter “An expansion of the detailed points to be
considered for the implementation of the principles to isolators subjected
to a sporicidal process” collects 14 points for the sporicidal process. Point
9.4.1 mentions H2O2 bio-decontamination:
“…The agent selected for gas generation
should be sporicidal. The agent used for
gas generation or other means of application
should be capable of rapidly killing bacterial
endospores, fungal spores and vegetative
microorganisms.
… Peracetic acid, hydrogen peroxide and
formaldehyde are used. …”
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Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
Î
“VHP” for Isolators
Î
Results
Î
More Applications
Î
Summary
Packaging Technology
16
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Î
Vaporized hydrogen peroxide is
widely used to decontaminate the
inside of pharmaceutical isolators.
The good old pioneering days
applied a mixture of steam and
H2O2 to be on the safe side,
but validation was a nightmare.
Î
Nowadays several H2O2 gas generators are on the market –
different philosophy, but more or
less reliable technology.
Î
Cycle development and validation
has become a routine job.
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Î
Isolator design principle
Air Management
System (HVAC)
Unidirectional Air
Flow Unit
Aseptic Processing
Chamber
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Example (isolated vial/bottle fill line in Austria)
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Î
Liquid H2O2 is dropped on a heated
plate inside the filter level of an isolator. Recirculation and continous
injection of peroxide goes to saturation
of atmosphere including strong visible
condensation
Î
H2O2
Closed loop system:
Heat plate
Filter
Open loop system:
Liquid hydrogen peroxide is evaporated
outside of the isolator in a gas generator;
which carries the vapor with air into the
Isolator
Dry air
H2O2
isolator, where it is recirculated.
Some o-l-systems perform “flash evaporation”.
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Î
Î
H2O2
Closed loop system:
Ò
Simple air management
Ò
Vapor passes filters first
Ô
Incomplete evaporation
Ô
Limited injection rate
Ô
Saturation/condensation soon
Open loop system:
Ò
Complete (“flash”) evaporation
Ò
Controlled atmosphere
Ò
Capability for high gas conc.
Ô
Air management more complex
Ô
More sophisticated generator
H2O2
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Preparation (Phase I)
- Expanding gloves, load monitoring goods
Conditioning (Phase II)
- Injection of H2O2 with a high rate to
achieve a high gas concentration
H2O2-conc.
- Preparation of isolator atmosphere
- Preheating of peroxide duct work
I+ II
Biodecontamination (Phase III)
- Injection with a lower rate to replace
III
IV
Process time
inactivated peroxide and keep level
Aeration (Phase IV)
- Removal of H2O2 from injection system
Idealized process cycle
- Removal of peroxide from all isolator surfaces including filters.
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Î
Bosch SafeVAP (open loop system)
Features:
z
Venturi transport
z
3-step evaporation
z
Inj.rates up to 80g / min
z
Controlled atmosphere
SafeVAP = Safe Vacuum Assisted Peroxide Evaporation
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Î
Description
Compressed air
HVAC
Particle filter
Blower
Evaporator
Filter
Venturi
Peroxide
source
(35%)
Scale
Air to
isolator
Isolator
Exhaust air
Peroxide duct
HEPA H14
Aseptic Processing Chamber
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Isolator vol. 8 m³
Description
Cycle time 22 min
Aeration 1,5
hours
Peroxide: 310 g
Inj. rate I: 25 g/min
Inj. rate II: 9 g/min
800
H2O2 concentration [ppm]
700
600
500
25000
20000
15000
400
10000
300
200
5000
100
0
H2O concentration [ppm]
Î
0
-100
5:
:0
15
06
-5000
1:
:1
15
04
:1
15
7:
02
:
15
1
:0
23
8:
:2
15
59
4:
:3
15
58
:
15
6
:5
40
:
15
4
:5
46
1
3
:5
52
5:
Time
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Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Î
Cycle Development for H2O2 biodecontamination include
z
OQ-studies
z
tests with chemical indicators (CI’s)
z
Î
Tests with bio indicators (BI’s),
which are stainless steel coupons
inoculated with 6 log of the most
resistant viable (spores of
Geobacillus stearothermophilus).
To ease handling (and to put an extra
challenge on the biological test
system), BI’s wrapped in Tyvek became
industrial standard.
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13
Bio-decontamination with H2O2 - Vapor
“VHP” for Isolators
Air
flow
study
Worst location CIs
for H2O2
concentration
Air
velocity
mapping
D-value
determination
Evaluate
aeration
time
Worst location
BIs 3 times
Safety
Evaluation
Worst location with
triplicate BIs
Critical
design
area
Testing
Complete
Biological
Verification
Temperature
mapping
Physical
System
Evaluation
Chemical
System
Evaluation
Biological
System
Characterization
and Optimization
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distribution, as well as in the event of applications for industrial property rights.
Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
Î
“VHP” for Isolators
Î
Results
z
Recent Studies
z
Results
Î
More Applications
Î
Summary
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14
Bio-decontamination with H2O2 - Vapor
Recent Studies
Î
Many studies were performed at
Bosch during the last 3 years
(PhD thesis). Basis for these
studies was a reference isolator
equipped with the SafeVAP system
and placed in the Bosch PharmaLab.
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Bio-decontamination with H2O2 - Vapor
Recent Studies
st
an
da
r
d
co
nt
ro
(E ls
S
(E -1)
SF
( E G)
SE
(E P )
(E S-G
S)
(E 443
S 5
( A - 43 )
lu 01
m
in )
iu
m
(P )
O
(E M)
PD
(P M)
VD
F
(F )
P
( H M)
( P YP
A- A )
12
(P G F
VC )
(C -T
G R
( P - TI )
VC SS
-S )
C
H
)
(P ( P
EE C
K- )
N
(P at)
ET
(
P
( P PVC )
EE -U
K
(P - P )
E- VX
U
H )
M
W
(V )
M
(T Q )
R
FX
)
D-Value in min
5
4,5
4
3,5
3
2,5
2
1,5
1
0,5
0
Material
av
er
ag
e
Goal of this study was to learn
the influence of different surfaces
(material, finish) on inactivation
efficacy of bioburden.
Prestudy
Mainstudy
Poststudy
Humidity Study
Influence of relative humidity
at different H2O2 gas concentration levels was studied
and compared with dew point
analysis.
2100
20000
1900
1700
15000
1500
1300
10000
1100
900
5000
700
Water concentration [ppm]
Î
D-Values of tested Materials in Pre-, Main- and Poststudy
Material of Construction Study:
Hydrogen peroxide concentration [ppm]
Î
500
300
00:00
00:02
00:05
00:08
00:11
00:14
0
00:17
Duration of bio-decontamination phase [hh:mm]
W ater concentration (humidity level
W ater concentration (humidity level
W ater concentration (humidity level
W ater concentration (humidity level
Hydrogen peroxide concentration
4)
3)
2)
1)
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15
Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
Î
“VHP” for Isolators
Î
Results
z
Recent Studies
z
Results
Î
More Applications
Î
Summary
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31
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distribution, as well as in the event of applications for industrial property rights.
Bio-decontamination with H2O2 - Vapor
Results
Objective of material study:
z
z
z
Examine influence of different
construction material surfaces
on inactivation of spores
Determine variable kill kinetics
(D-Value)
Test organism: spores of Geobacillus stearothermophilus
ATCC 12980 with population
of > 1*106 spores per BI.
Exposure
time [min]
0
5
10
15
20
25
Results
+
+
+
-
-
-
+
+
-
-
-
-
+
+
-
-
-
-
Survival
Fractio
nal
Killing
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16
Bio-decontamination with H2O2 - Vapor
Results
Results on some materials (50 different surfaces tested)
5
4,5
4
3,5
3
2,5
2
1,5
1
0,5
0
st
a
nd
ar
d
co
nt
ro
(E ls
S
(E -1)
SF
(E G)
SE
(E P )
(E S-G
S)
(E 443
S- 5 )
4
(A
l u 301
m
in )
iu
m
(P )
O
M
(E )
PD
(P M)
VD
F
(F )
P
(H M)
(P YP
A- A )
1
(P 2G F
VC )
(C -T
G R
( P - TI )
VC SS
-S )
C
H
)
(P (P
EE C
K- )
N
(P at)
ET
(
P
(P PVC )
EE -U
K
(P -P )
E- VX
U
H )
M
W
(V )
M
(T Q)
R
FX
)
D-Value in min
D-Values of tested Materials in Pre-, Main- and Poststudy
av
er
ag
e
Material
Prestudy
Mainstudy
Poststudy
*
No reliable kill
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Bio-decontamination with H2O2 - Vapor
Results
Results on standard control (commercial Bio indicator made from SSL)
1,2
1100
1,0
1000
0,8
900
0,6
800
0,4
700
0,2
600
0,0
Average
Concentration
of H2O2 in ppm
D-Value of
Standard
Contorls in min
D-Values of Standard Controls and average Hydrogen Peroxide
Concentration during the Cycles
500
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Number of Cycle for Material Study
D-Value Standard Controls
Concentration of Hydrogen Peroxide
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Bio-decontamination with H2O2 - Vapor
Results
Summary of the study:
z
z
z
z
z
Most materials tested show good inactivation properties.
Plastic/elastomeric materials have generally higher D-values
compared with stainless steel and glass.
Standard commercial available BI’s show a certain spread of D-values
(0,2 min to 0,9 min – late positives included in the calculation), which
represents microbiobolgical accuracy.
A correlation between wetting properties, surface roughness and the
entire D-values can be recognized.
Critical materials of construction should either be replaced or need
prolonging of the cycle time.
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Bio-decontamination with H2O2 - Vapor
Results
The results were recently published:
PDA journal, Vol. 61, No. 4, July-August 2007
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18
Bio-decontamination with H2O2 - Vapor
Results
Procedure for Humidity study:
z
z
z
z
Separate evaporation of water
and hydrogen peroxide (35%)
Control of humidity level with
NIR probe, dew point sensor
and standard humidity sensor
D - value determination of
commercial BI’s (SSL)
Investigation on inactivation
in hindered surfaces with
high aspect ratio
35% liq. H2O2
H2O
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Bio-decontamination with H2O2 - Vapor
Results
2100
20000
1900
1700
15000
1500
1300
10000
1100
900
5000
700
Water concentration [ppm]
Hydrogen peroxide concentration [ppm]
Details:
500
300
00:00
00:02
00:05
00:08
00:11
00:14
0
00:17
Duration of bio-decontamination phase [hh:mm]
Water concentration (humidity level 4)
Water concentration (humidity level 3)
Water concentration (humidity level 2)
Water concentration (humidity level 1)
Hydrogen peroxide concentration
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Bio-decontamination with H2O2 - Vapor
Results
400 ppm:
Water concentration [ppm]
25000
20000
15000
10000
5000
0
0
2
4
6
8
10
12
14
16
18
20
14
16
18
20
D-value [min]
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Bio-decontamination with H2O2 - Vapor
Results
600 ppm
Water concentration [ppm]
25000
20000
15000
10000
5000
0
0
2
4
6
8
10
12
D-value [min]
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Bio-decontamination with H2O2 - Vapor
Results
800 ppm:
25000
Water concentration [ppm]
20000
15000
10000
5000
0
0,0
0,5
1,0
1,5
2,0
2,5
3,0
3,5
D-value [min]
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distribution, as well as in the event of applications for industrial property rights.
Bio-decontamination with H2O2 - Vapor
Results
Comparison
Wrapped vs.
Nude BI’s :
3,0
D-value [min]
2,5
2,0
1,5
1,0
0,5
0,0
Humidity
level 1
Humidity
level 2
Humidity
level 3
Humidity
level 4
Humidity level
BIs wrapped in Tyvek
unpacked BIs
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distribution, as well as in the event of applications for industrial property rights.
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Bio-decontamination with H2O2 - Vapor
Results
Correlation of injected H2O2-amount during Cond.phase with D
values (mean average)
Mittelwert 800ppm 1. FL
Mittelwert 800ppm 2. FL
Mittelwert 800ppm 3. FL
Mittelwert 800ppm 4.FL
Mittelwert 600ppm 1. FL
Mittelwert 600ppm 2. FL
Mittelwert 600ppm 3. FL
Mittelwert 600ppm 4. FL
Mittelwert 400ppm 1. FL
Mittelwert 400ppm 2. FL
Mittelwert 400ppm 3. FL
Mittelwert 400ppm 4. FL
14,00
D-Wert [min]
12,00
10,00
8,00
6,00
4,00
2,00
0,00
0
100
200
300
400
500
600
700
Injected H2O2 amount [g]
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Bio-decontamination with H2O2 - Vapor
Results
Summary:
z
z
z
z
The higher the cgas phase concentration, the more independent is the
inactivation effect from the humidity level.
At lower concentrations the same kill as at higher concentration can be
achieved with higher humidity (condensation)
The faster the concentration rises during conditioning phase (flash
evaporation), the less peroxide is needed to achieve a good kill.
(Nano/micro) condensation occurs at all humidity levels. Visible
concentration is not needed to get short inactivation times.
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22
Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
Î
“VHP” for Isolators
Î
Results
Î
More Applications
Î
Summary
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distribution, as well as in the event of applications for industrial property rights.
Bio-decontamination with H2O2 - Vapor
More Applications
Î
Vaporized H2O2 is applied with all kinds
of isolators: fill/finish isolators, sterility
testing isolators, hospital isolators…
Î
A new trend is fumigation of cleanrooms
and animal testing facilities with hydrogen
peroxide vapor.
Î
H2O2 in vapor state could potentially replace
alcoholic spray&pray procedures in material
transfer chambers and material locks for
thermolabile products.
Î
Bio-decontamination of tubs with presterilized,
nested syringes can also be performed with H2O2.
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PA-PH/EPP | 10/09/2007 | © Robert Bosch GmbH 2007. All rights reserved, also regarding any disposal, exploitation, reproduction, editing,
distribution, as well as in the event of applications for industrial property rights.
23
Bio-decontamination with H2O2 - Vapor
Structure
Î
Introduction
Î
“VHP” for Isolators
Î
Results
Î
More Applications
Î
Summary
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PA-PH/EPP | 10/09/2007 | © Robert Bosch GmbH 2007. All rights reserved, also regarding any disposal, exploitation, reproduction, editing,
distribution, as well as in the event of applications for industrial property rights.
Bio-decontamination with H2O2 - Vapor
Summary
Î
Hydrogen peroxide vapor is widely used in pharmaceutical industry. One
major application is disinfection of isolator interior.
Î
Closed and open loop systems are established in the market, which are
technically robust and validatable.
Î
Inactivation effect on bioburden differs depending on the material of
construction (material and finish).
Î
Gas concentration and humidity effect dominate the kill efficacy: high gas
concentrations through flash evaporation help to achieve efficient
processes.
Î
New applications of H2O2 vapor include cleanroom fumigation and
decontamination of thermolabile materials in transfer chambers,
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Bio-decontamination with H2O2 - Vapor
Thank you for your attention !
johannes.rauschnabel@de.bosch.com
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distribution, as well as in the event of applications for industrial property rights.
25