ETO STERILISATION

METHODS, REQUIREMENTS & TESTING

By

BUSINESS MANAGEMENT CONSULTANTS INT’L

in collaboration with
Tti Testing Laboratories Lahore

WWW.BMCI.PK info@bmci.pk
SHAUKAT ALI Cell. 0333-8612798
Regulatory and Management Consultant
Introduction

 Sterilization
 Process used to transform product free from
viable microorganisms

 Microorganisms
 Bacteria
 Viruses
 Fungi
Introduction

 Why sterilization is needed?

 Medical device is
assembled in controlled
t ll d
environment,
but may contain
microorganisms
Introduction

 Why sterilization is needed?

 Microorganisms may cause infection

 Invasive devices enter normally sterile body tissue
Introduction

 Sterilization purpose

 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 conditions
Sterlity ?

The absence of microorganisms cannot be proven

A sterility assurance level (SAL) is used to define

the sterility
Sterlity
 Sterility Assurance Level (SAL)

 Probability of a
viable organism
being present
on a product unit
after sterilization
 SAL of 10-6 is required
by the FDA for
invasive medical
device
Sterlization Methods
Sterilization Methods

Steam Sterilization (Moist Heat)

Eto Sterilization
Gamma Radiation Sterilization
ETO Sterlization

 Ethylene oxide (ETO)

 Colorless flammable gas

 Chemically reactive

 Irritating, carcinogenic, mutagenic gas

 Alkylation reaction cause damage to DNA

and proteins of microorganisms
ETO Sterlization
 ETO processing steps

1. Preconditioning/conditioning
 Exposure to relative humidity and temperature
 Ensure uniformity of conditions

2. Sterilization cycle
 Exposure to ETO gas

3. Aeration
 Dissipation of remaining gases
ETO Sterlization
 Process parameters

1. Gas quantity
 >400mg/L

2. Temperature
 ~45ºC

3.Relative humidity
 ~35 – 80%

4. Exposure time
 ~90 – 360 minutes
ETO Sterlization

 Advantages
 Most product and packaging are compatible materials
 Relatively low temperature process

 Disadvantages
 Penetration sometimes difficult
 Residuals
 Long process and release time
ETO Sterlization Process Map (Courtesy MSS)
Gamma Radiation Sterlization
 Gamma radiation

 Electromagnetic radiation of short wavelength

 High-energy photons are emitted from an isotope

(Cobalt 60)) source producing
so rce prod cing ionization throughout
ioni ation thro gho t a
product

 Cause damage to DNA and cellular structures of

microorganisms

 Radiation dose is measured in kGy values

Gamma Radiation Sterlization

 Gamma radiation effects on materials

 Brittle
 Color
 Odor
 Stiffness
 Softens
 Toxicity
 Chemical
 inertness
 Melt temperature
Gamma Radiation Sterlization

 Advantages
 Deep penetration power
 No residuals
 Only one process parameter – time
 Low temperature process
 Release immediately after sterilization

 Disadvantage
 Not all product and packaging materials compatible
Sterilization validation

 Documented procedure for obtaining, recording 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

 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 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 - Installation 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
ETO sterilization validation
validation

 Product definition

 Product families
 Product configuration
 Product and packaging materials
 Density
Manufacturing 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

 PQ – Physical
 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:

1. Cycle calculation approach

Cycle
C l parameters t that
th deliver
t d li minimally
i i ll 12 log
l reduction
d ti
shall be calculated

2. 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

a. Fractional cycle

b. 3 x Half cycles

c. 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 l
Ampoule
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

 One full cycle is required

 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:

1. Irritation
2. Mutagenicity
3. Carcinogenicity
 ETO residual quantity is effected by product,
ETO residual
packaging quantity
and processis characteristics
effected by product
 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
ETO sterilization validation

 Product definition

 Product families

 Bioburden
 Size of product
 No. of components
 Complexity of product
 Manufacturing environment
ETO 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

Maintaining process effectiveness

 Routine monitoring of product bioburden

bioburden

 Maintenance of the sterilization equipment

 Instrumentation used to monitor and control

process parameters should be calibrated
Sterilization validation

 Assessment of change

1. A change to equipment, product, packaging, or loading pattern

2. Effect on effectiveness of the sterilization process

3. Effect on IQ, OQ or PQ validations

4. Documented rationale for decisions reached

ISO Standards for ETO Sterilization

ISO 11135-1:2007
Sterilization of health care products -- Ethylene oxide -- Part 1: Requirements for
development, validation and routine control of a sterilization process for medical devices

ISO/TS 11135-2:2008
Sterilization of health care products -- Ethylene oxide -- Part 2: Guidance on the application
of ISO 11135-1

ISO 10012:2003
Measurement management systems -- Requirements for measurement processes and
measuring equipment

ISO 11138-1:2006
Sterilization of health care products -- Biological indicators -- Part 1: General requirements

ISO 11138-2:2006
Sterilization of health care products -- Biological indicators -- Part 2: Biological indicators
for ethylene oxide sterilization processes

ISO 11140-1:2005
Sterilization of health care products -- Chemical indicators -- Part 1: General requirements
 ISO Standards for ETO Sterilization
2006
Sterilization of medical devices -- Microbiological methods -- Part 1: Determination of a population
of microorganisms on products

ISO 11737-2:2009
Sterilization of medical devices -- Microbiological methods -- Part 2: Tests of sterility performed in
the definition, validation and maintenance of a sterilization process

ISO 14161:2009
Sterilization of health care products -- Biological indicators -- Guidance for the selection, use and
interpretation of results

ISO 14937:2009
Sterilization of health care products -- General requirements for characterization of a sterilizing
agent and the development, validation and routine control of a sterilization process for medical
devices

ISO 11607-1:2006
Packaging for terminally sterilized medical devices -- Part 1: Requirements for materials, sterile
barrier systems and packaging systems

ISO 11607-2:2006
Packaging for terminally sterilized medical devices -- Part 2: Validation requirements for forming,
sealing and assembly processes
Summary

1. Sterilization process is crucial for patient safety

2. Validation is required to establish that a process will

consistently yield SAL of 10-6

3. process effectiveness must be maintained

4. Any change to product design or packaging shall be

assessed

5. ETO Residue Test as per ISO 10993-7 should be performed

for establishing safety of product /Medical Device.
Any questions?

Questions?