STERILIZATION

An overview

Presented by:
Pacific BioLabs
Hercules, CA
 Sterilization
 What is it?
 For what products is it required?

 How is it accomplished?

 Who does it?

 How is it regulated?

 What standards apply?

 What is sterilization?

Definitions
 Sterile: Free from any living
organisms
 Sterilization: Process of killing or
removing microorganisms from a
product to insure that it is sterile
 Who needs to sterilize?
Anyone who supplies a product on which the
presence of microorganisms could present a
health risk.
Manufacturers of any product that enters the
body, except by ingestion:
 Medical Device Manufacturers
 Pharmaceutical Manufacturers
(both human & veterinary)
Hospitals, Dentists, other health care facilities
Some specialty food product manufacturers
 Some Products Requiring
Medical DevicesSterility
 exam and surgical gloves, cleanroom garments
 specimen cups, wound care products, sutures
 needles, syringes, catheters, drain bags, IV bags
 implants, surgical tools, surgery supplies
Pharmaceuticals
 injectable and inhalation drugs
 nasal, ophthalmic and some topical products

In vitro Diagnostics–for heath care related testing

Prepared Media – for microbiology testing
How is sterilization accomplished?
Filtration
 Many liquids can be sterilized by passing through
0.45 micron or smaller membrane filters.
Aseptic Processing
 Products are filled or assembled using sterile
components maintained under sterile conditions.
 Filtration is often used in aseptic processing.
 Aseptic processing is used for drug products that
are adversely affected by terminal sterilization
processes.
 Aseptic processing is performed in cleanrooms or
in isolators (closed environments without humans).
 How is sterilization
accomplished?
Terminal Sterilization
 Finished products are exposed to a validated
process to kill any living microorganisms.
Terminal Sterilization Processes:
 Ethylene Oxide Gas
 Radiation – gamma and electron beam
 Steam (moist heat)
 Dry heat, chemicals, plasma hydrogen peroxide
(Steris Sterrad), UV light, pulsed bright light, other
technologies
 Selection of a Sterilization
Process – How do you decide?
FDA requires terminal sterilization unless the product
would be adversely effected. The vast majority of
medical devices requiring sterility are sterilized by one
of the following three methods:
Radiation – a method preferred for many types of
single use medical devices.
Ethylene oxide – a method widely used for medical
device kits, particularly those packaged with drugs or
any other component not compatible with radiation.
Steam - the preferred method for many liquid products
and reusable medical devices intended for sterilization
in hospitals.
Sterilization Process Selection
Advantages and Disadvantages
Gamma Radiation – Advantages
 Simple process: The only parameter to control is
exposure time which in turn controls the radiation
dose delivered to the product.
 Excellent penetration: Gamma rays readily
penetrate dense or complex products.
 Dose Uniformity: The dose distribution ratio within
the product does not typically exceed 1.5:1.
 Dosimetric release: No product quarantine is
required after dose validation.
Sterilization Process Selection
Gamma Radiation – Disadvantages
 Limited applicability to kits: It cannot be used for
kits or complex products containing any
component that is incompatible with or not
approved for radiation sterilization (such as a drug
products).
 Material degradation: A few materials degrade
after terminal sterilization radiation dosing.
Sterilization Process Selection
Electron Beam Radiation – Advantages
 Fast process – can sometimes be done as end of
the production process.
 Less material degradation: Some radiation
sensitive materials degrade less with E-beam than
if gamma sterilized
 Dosimetric release: After successful dosimetry
studies and microbiological validation of the dose,
no product quarantine is required after
sterilization.
Sterilization Process Selection
E-Beam Radiation – Disadvantages
 Limited penetration: It is often not appropriate for
dense or complex products.
 Sensitive to product configuration: Various
densities in a product can affect dose distribution.
Extensive dose mapping is often required.
 Dose Uniformity: There is potential for higher
variation within the product.
 Product configuration changes require new dose
mapping studies.
Sterilization Process Selection
Ethylene Oxide – Advantages:
 Well characterized process: Appropriate for a wide
variety of materials and products.
 Good for kits: EO does not penetrate ampules of
drug products, a common kit component.
 Parametric Release: Improving EO equipment control
technology is facilitating parametric release validation
for some products (no end process microbiological
testing and product quarantine pending results).
 Many good contract service providers throughout
U.S.A.
Sterilization Process Selection
Ethylene Oxide – Disadvantages
 Comparatively complex process: Four factors are
required to achieve a successful sterilization cycle:
time, temperature, humidity and EO gas
concentration/distribution.
 Penetration Limitations: EO does not easily
penetrate some sealed areas of devices or some
sealed packages (ie. foil pouches).
 EO & ECH Residuals: Some materials retain
residuals. Product release must be delayed until
residuals dissipate to acceptable levels.
Sterilization Process Selection
Steam – Advantages
 Simple process: The only two parameters to
control are time and temperature. Highly reliable
and easily controlled.
 Widespread capability: All hospitals and many
other heath care facilities have steam sterilizers.
 Excellent process for reusable medical devices
that are not adversely affected by temperatures
>121C (up to 135 C).
 Excellent process for liquids that are not heat
sensitive.
Sterilization Process Selection
Steam – Disadvantages
 Comparatively high temperature required: Many
products and packaging materials cannot tolerate
temperatures of >121C.
 Generally not appropriate for most single use
disposable medical devices produced in high
volumes and sold as sterile.
Sterilization – Who performs it?
Product Manufacturers – especially with
filtration, aseptic processes.
Hospitals – daily use of steam sterilization for
a wide variety of in-house needs.
Laboratories – daily use of steam sterilization
to support microbiology testing.
 At PBL, steam is also frequently used for client
reusable medical device steam sterilization
validations.
Sterilization – Who performs it?
Contract Sterilizers
 Provide terminal sterilization services to
medical device manufacturers.
 Have extensive capacity in EO and
radiation sterilization in many facilities
widely distributed throughout the U.S.
 Sterilize a significant percentage of all
single use disposable medical devices
manufactured.
 Sterilization – How is it
regulated?
FDA
 CDER – Center for Drug Evaluation and
Research (pharmaceuticals)
 CBER – Center for Biologic Evaluation and
Research (vaccines, biopharmaceuticals)
 CDRH – Center for Devices and
Radiological Health (medical devices)
International Regulatory Agencies
 Sterilization – How is it
regulated?
CGMP regulations in 21 CFR
 Part 210: Current Good Manufacturing Practice in
Manufacturing, Processing, Packing or Holding of
Drugs; General (1978)
 Part 211: Current Good Manufacturing Practice for
Finished Pharmaceuticals (1996)
 210 & 211 available at: www.fda.gov/cder/dmpq/
 Parts 808, 812 & 820: Medical Device - CGMP
Final Rule; Quality System Regulation (1996)
 Available at www.fda.gov/cdrh/humfac/frqsr.html
 A written agreement with contract sterilizer is required.
Sterilization - What standards
apply?
USP 25 – applies to drug products.
 Chapter <1211> Sterilization and Sterility
Assurance of Compendial Articles
(contains brief sections on steam, dry heat, gas,
radiation, filtration and aseptic processing)
PDA Technical Reports (guidance documents)
 No. 1 – Validation of Steam Sterilization Cycles (1978)
 No. 3 – Validation of Dry Heat Processes (1981)
 No. 17 – Current Practices in the Validation of
Aseptic Processes (1993)
 Sterilization - What standards
apply?
ANSI/AAMI/ISO standards apply to
sterilization of medical devices – both in U.S. and
internationally.
 AAMI = Association for the Advancement of Medical
Instrumentation
 ISO = International Standards Organization

 ANSI = American National Standards Institute

Most AAMI/ANSI standards are FDA

recognized.
 AAMI TIRs are cited by FDA as relevant guidance
documents, but are not recognized standards.
 ANSI/AAMI/ISO Standards
Ethylene Oxide Sterilization
Medical Devices – Validation and routine control
of EO sterilization (ANSI/AAMI/ISO 11135: 1994)
Contract Sterilization for EO (AAMI TIR 14:1997)
Process development and performance
qualification for ethylene oxide sterilization
-microbiological aspects (AAMI TIR 16:2000)
Parametric release for EO sterilization (TIR 20)
Biological Evaluation of Medical Devices-Part 7:
EO sterilization residuals (10993-7)
 ANSI/AAMI/ISO Standards
Radiation Sterilization
Sterilization of health care products -
Requirements for validation & routine control
– Radiation sterilization (ISO 11137:1995)
 Method 1 (for large & frequent production batches)
 Method 2 (for radiation sensitive & problematic
bioburden products)
 Selection of a sterilization dose for single
production batch (AAMI/ISO TIR 15844:1998)
 Substantiation of 25 kGy as a sterilization dose –
Method VD-max (AAMI TIR 27:2001)
 ANSI/AAMI/ISO Standards
Radiation Sterilization
Radiation sterilization material qualification
(AAMI TIR 17:1997)
Sterilization of health care products –
Radiation sterilization – Product families and
sampling plans for verification dose
experiments and sterilization dose audits and
frequency of sterilization dose audits (ANSI/
AAMI/ISO TIR 15843:2000)
 ANSI/AAMI/ISO Standards
Industrial Steam Sterilization
Principles of moist heat sterilization (AAMI
TIR 13:1997)
Sterilization of health care products –
Requirements for validation and routine
control – Industrial moist heat sterilization
(ANSI/AAMI/ISO 11134:1993)
An industrial dry heat sterilization proposed
standard is in the development process.
AAMI/ISO/ANSI Standards
Sterilization in Health Care
Facilities
 Designing, testing and labeling reusable medical
devices for reprocessing in health care facilities: A
guide for device manufacturers (AAMI TIR
12:1994)
 Good hospital practice: Steam sterilization and
sterility assurance in health care facilities
(ANSI/AAMI ST46:2002)
 Guidelines for the selection and use of reusable
rigid container systems for EO and steam
sterilization in health care facilities (ANSI/AAMI
ST33:1996)
ANSI/AAMI/ISO Standards
Sterilization in Health Care
Facilities
Additional standards on:
 Steam, dry heat & EO table top sterilizers
 Safe handling & biological decontamination
of reusable medical devices (ANSI/AAMI ST35)
 Chemical sterilants & disinfectants

 Flash sterilization (steam at 132C)

 Processing of reusable surgical textiles

ANSI/AAMI/ISO Standards
Laboratory Testing –
Microbiology
Sterilization of medical devices –
Microbiological methods – Part 1: Estimation of
the population of microorganisms on a product
(ANSI/AAMI/ISO 11737-1:1998)
Sterilization of medical devices –
Microbiological methods – Part 2: Tests of
sterility performed in the validation of a
sterilization process (ANSI/AAMI/ISO 11737-
2:1998)
Sterilization: How is it validated?
Aseptic Processing
IQ, OQ, PQ of manufacturing environment
control equipment – cleanrooms, isolators,
hepa filters.
Media fills – run microbiological growth
medium in place of product through entire
production process
Filtration
 Microbial challenge studies
 Filter integrity testing
Sterilization: How is it validated?
Ethylene Oxide
Equipment IQ, OQ, PQ
 Do chamber studies with thermocouples, humidity
sensors, EO concentration measurement devices.
(Usually performed by contract by sterilizers.)
Fractional cycles with products and biological
indicators (B.I.s are most commonly B. subtilis spore
strips.)
 Exposed products & B.I.s are tested for sterility.

Half & full cycles with biological indicators

Validation support testing
 Product bioburden, B-F test, EO residuals
Sterilization: How is it validated?
Radiation
Dose mapping study
 Dosimeters are placed in products at contract sterilizer.
Determination of product bioburden
 First, do bioburden test method validation
Verification dose resistance experiment
 Dose is determined based on product bioburden.
 Irradiate products at “sublethal” verification dose level.
 Test the verification dosed samples for sterility.
 Before sterility test, do B-F testing to validate test method.
Sterilization: How is it validated?
Steam
IQ, OQ, PQ of steam sterilizer
Temperature profiles of product during
sterilization cycles (using thermocouples)
Fractional and/or half cycles with
product & B.I.s (G. stearothermophilus)
 Then sterility testing of product & B.I.s
Other Considerations for Sterile
Products
Biocompatibility of finished products and
manufacturing materials.
Microbial environmental monitoring of the
manufacturing environment.
Cleaning validations for reusable devices
Product/Packaging validation and expiration
dating.
Bacterial endotoxin testing for blood contact
products.
 Some Useful References
ANSI/AAMI/ISO standards and TIRs
available at www.aami.org
USP 25 – order from www.usp.org
PBL Compliance Guides
 Sterility Assurance Compliance
 Assessing Biocompatibility

 Online at www.pacificbiolabs.com
 Thanks

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