STERILIZATION VALIDATION
Presented by:
Efrat Hartog-David
Regulatory Affairs, Qsite
Introduction
Sterilization
Process used to transform product free from viable
microorganisms
Microorganisms
Bacteria
Viruses
Fungi
Introduction
Why
y sterilization is needed?
Medical device is
assembled in
controlled
t ll d
environment,
but mayy contain
microorganisms
Introduction
Why
y sterilization is needed?
Microorganisms may cause infection
Invasive devices enter normally sterile body tissue
Introduction
Sterilization purpose
p p
To inactivate the microorganisms
Transform the medical device into sterile
Introduction
Inactivation of microorganisms
D value:
Time required to
achieve inactivation of
90% of a population of
the microorganism
under specific
f conditions
Sterility
The absence of microorganisms cannot be proven
A sterility assurance level (SAL) is used to define
the sterility
Sterility
Sterility Assurance Level (SAL)
Probability of a
viable organism
being present
on a product unit
after sterilization
SAL of 10-6 is required
byy the FDA for
invasive medical
device
Sterilization methods
Moist heat
Ethylene oxide (ETO)
Gamma radiation
ETO sterilization
Ethylene oxide (ETO)
Colorless flammable gas
Chemicallyy reactive
Irritating,
g, carcinogenic,
g , mutagenic
g g
gas
Alkylation
y reaction cause damage
g to DNA and
proteins of microorganisms
ETO sterilization
ETO processing steps
Preconditioning/conditioning
Exposure
p to relative humidity
y and temperature
p
Ensure uniformity of conditions
Sterilization cycle
Exposure to ETO gas
g
Aeration
Dissipation of remaining gases
ETO sterilization
Process parameters
Gas quantity
>400mg/L
Temperature
p
~45C
Relative humidity
~35 80%
Exposure time
~90 360 minutes
ETO sterilization
Advantages
Most product and packaging materials are compatible
Relatively low temperature process
Disadvantages
Penetration sometimes difficult
Residuals
Long process and release time
Gamma radiation sterilization
Gamma radiation
Electromagnetic radiation of short wavelength
High-energy photons are emitted from an isotope
(Cobalt 60) source
so rce prod
producing
cing ioni
ionization
ation thro
throughout
gho t a
product
Cause damage to DNA and cellular structures of
microorganisms
Radiation dose is measured in kGy values
Gamma radiation sterilization
Gamma radiation effects on materials
Brittle
Color
Odor
Stiffness
Softens
Toxicity
Chemical inertness
Melt temperature
Gamma radiation sterilization
Advantages
Deep penetration power
No residuals
Only one process parameter time
p
Low temperature p
process
Release immediately after sterilization
Disadvantage
Not all product and packaging materials are
compatible
Sterility concerns
Sterilization validation
Documented p procedure for obtaining,g, recording
g and
interpreting the results required to establish that a
process will consistently yield product complying
with predetermined specifications
SAL of 10-6 shall be demonstrated
Sterilization validation
Objectives
j
The sterilization process will consistently achieve sterility
The sterilization process will not have an adverse impact
on the device or its packaging
ETO sterilization validation
Applicable
pp standards
ANSI/AAMI/ISO 11135-1:2007
Sterilization of health care products Ethylene oxide -
Part 1: Requirements for the development, validation and
routine control of a sterilization process for medical
devices
ANSI/AAMI/ISO 11135-2:2008
Sterilization of health care products Ethylene oxide -
Part 2: Guidance on the application of ISO 11135-1
ETO sterilization validation
ETO validation overview
Process and equipment characterization
IQ (Installation Qualification)
OQ (Operational Qualification)
Product definition
PQ (Performance Qualification) Physical
PQ (Performance Qualification) Microbiological
Documentation
Revalidation
ETO sterilization validation
IQ
Q - Installation Q
Qualification
IQ shall demonstrate that the sterilization equipment
have been installed in accordance with their
specification
OQ Operational Qualification
OQ shall demonstrate that the installed equipment is
capable of delivering the specified process within
defined tolerances
ETO sterilization validation
Product definition
Product families
Product configuration
Product and ppackaging
g g materials
Density
Manufacturingg environment
Bioburden
PCD (Product Challenge Device)
ETO sterilization validation
PQ - Performance Qualification
PQ shall use product or PCD to demonstrate that:
Equipment consistently operates in accordance
with predetermined criteria
The process produces product that is sterile
ETO sterilization validation
PQQ Physical
y
Physical PQ shall confirm the predetermined process
parameters throughout the load, for the duration of the
sterilization process
PQ - Microbiological
Microbiological PQ shall confirm the effectiveness of
the defined process in achieving the required SAL, for
product/load combination
ETO sterilization validation
PQ - Physical
The physical PQ can be performed in parallel with the
microbiological PQ
During sterilization process parameters are
monitored:
Temperature
Relative humidity
Pressure
Process parameters are within the required range
ETO sterilization validation
PQ Microbiological
Determination of lethal rate of the sterilization
process, according to one of the approaches:
Cycle calculation approach
C
Cycle
l parameters
t th
thatt deliver
d li minimally
i i ll 12 log
l reduction
d ti
shall be calculated
Half cycle approach
3 half cycles resulting in 6 log reduction shall be
performed
ETO sterilization validation
PQ Microbiological
Bioburden estimation
Validation cycles according to half cycle approach
Fractional cycle
3 x Half cycles
Full cycle
Sterilized samples testing
ETO residual testing
ETO sterilization validation
Bioburden estimation
Population of viable microorganisms on or in the
product
Test non-sterilized samples
Bioburden <100 CFU/product is considered relatively
low
If bioburden > 1000 CFU/product the cleanness level
of the manufacturing environment should be
improved
ETO sterilization validation
Validation Cycles
Fractional cycle
3 x Half cycles
y
Full cycle
ETO sterilization validation
Biological Indicators (BI)
Test system containing 106 viable microorganisms to
ensure SAL of 10-6
BI must be inserted in the most difficult location to
sterilize in the product
Discs and Wires
Paper Strips
Gl
Glass A
Ampoule
l
ETO sterilization validation
Fractional cycle
Products inoculated with BIs Products
BI Sterility Test Product Sterility Test
BI product
X BIs show GROWTH If X>Y Y products show GROWTH
The BI is more resistant to the sterilization
process, compared to the bioburden
ETO sterilization validation
Half cycle
Presents worst case scenario
Samples inoculated with BIs are subjected to half
cycle
Following sterilization, BIs are removed from the
samples and tested for BI sterility
All BIs should show NO GROWTH
ISO 11135: 3 half cycles must be run
ETO sterilization validation
Full cycle
y
O
One
e full
u cyc
cycle
e is
s required
equ ed
Samples inoculated with BIs are subjected to full cycle
All BIs should show NO GROWTH
ETO residual testing
ETO sterilization validation
ETO residual testing
ETO is known to exhibit a number of biological
effects:
Irritation
Mutagenicity
Carcinogenicity
ETO residual quantity is effected by product
product,
packaging and process characteristics
The ETO residuals should meet the acceptance
criteria according to ISO 10993-7
Aeration may be prolonged
ETO sterilization validation
Revalidation
Annually the status of the sterilization validation must be
reviewed
Inspection of:
Bioburden
Product design and packaging
Process equipment and parameters
Revalidation usually consist one half cycle and one full
cycle
Gamma radiation sterilization validation
Applicable standards
ANSI/AAMI/ISO 11137-1:2006
Sterilization of health care products Radiation - Part 1:
Requirements for development,
development validation and routine
control of a sterilization process for medical devices
ANSI/AAMI/ISO 11137-2:2006
Sterilization of health care products Radiation - Part 2:
Establishing the sterilization dose
ANSI/AAMI/ISO 11137-3:2006
11137 3 2006
Sterilization of health care products Radiation - Part 3:
Guidance on dosimetric aspects
p
Gamma radiation sterilization validation
Gamma radiation validation overview
Equipment characterization
IQ (Installation Qualification)
OQ (Operational Qualification)
Product definition
Process definition
PQ (Performance Qualification)
Documentation
Dose audit
Gamma radiation sterilization validation
P d t definition
Product d fi iti
Product
P d t families
f ili
Bioburden
Size of product
No. of components
Complexity of product
Manufacturing environment
Gamma radiation sterilization validation
Process definition
Establishing the sterilization dose, according to one of
the approaches:
The number of the bioburden is obtained and used
t sett the
to th sterilization
t ili ti dosed
A sterilization
t ili ti d dose iis selected
l t d and
d substantiated
b t ti t d
Gamma radiation sterilization validation
PQ
Dose mapping shall be carried out:
Identify the sterilization dose accepted within each
point inside the package
The dose mapping is dependent on:
The dimensions and density of packaged product
The orientation of product within the package
Gamma radiation sterilization validation
VDMAX25 method
Average
A bi b d shall
bioburden h ll b
be 1000
Obtain samples of product
Select at least 10 products from each of 3 batches
Determine average bioburden
Obtain verification dose using Table 9
( SO 11137-2))
(ISO
Gamma radiation sterilization validation
VDMAX25 method (cont.)
Perform verification dose experiment
Select 10 products from a single batch
Irradiate at verification dose (10%)
Product
Prod ct sterilit
sterility test
IInterpretation
t t ti off results
lt
1 non-sterile 25 kGy is substantiated
=22 non-sterile
t il confirmatory
fi t experiment
i t
>2 non-sterile sterilizaion dose shall be
re established
re-established
Gamma radiation sterilization validation
VDMAX25 method confirmatory
y experiment
p
Confirmatory
Co ato y verification
e cat o dose e experiment
pe e t
Select 10 products from a single batch
Irradiate at verification dose (10%)
Product sterility test
Interpretation of results
All sterile 25 kGy is substantiated
>1 non-sterile sterilizaion dose shall be
re established
re-established
Gamma radiation sterilization validation
VDMAX25 method dose audit
Shall be performed quarterly
Obtain samples of product
Select at least 10 p
products from a single
g batch
Determine average
g bioburden
Perform verification dose experiment
p
Select 10 products from a single batch
Irradiate at verification dose (10%)
Product sterility test
Gamma radiation sterilization validation
VDMAX25 method dose audit (cont.)
Interpretation of results
1 non-sterile 25 kGy is substantiated
=2 non-sterile confirmatory experiment
3, 6 non-sterile augmentation of the
sterilization dose
7 non-sterile sterilization dose shall be
re-established
bli h d
Gamma radiation sterilization validation
VDMAX25 method dose audit confirmatory experiment
Confirmatory verification dose experiment
Select 10 products from a single batch
Irradiate at verification dose (10%)
Product sterility test
Interpretation of results
All sterile 25 kGy is substantiated
1,
1 4 non-sterile augmentation of the sterilization
dose
5
5 non
non-sterile
sterile sterilization dose shall be
re-established
Sterilization validation additional tests
Additional tests for sterilized products
The sterilization process will not have an adverse impact
on the device or its packaging:
Product functionality
Packaging integrity
Visual inspection
Peel test
Dye penetration test
Sterilization validation
M i t i i process effectiveness
Maintaining ff ti
Routine monitoring of product bioburden
Maintenance of the sterilization equipment
Instrumentation used to monitor and control process
parameters should be calibrated
Sterilization validation
A
Assessment
t off change
h
A change
h tto equipment,
i t product,
d t packaging,
k i or lloading
di
pattern
Effect on effectiveness of the sterilization process
Effect on IQ, OQ or PQ validations
Documented rationale for decisions reached
Summary
Sterilization process is crucial for patient safety
Validation is required to establish that a process will
consistently yield SAL of 10-6
process effectiveness must be maintained
Any change to product design or packaging shall be
assessed
Any questions?
