STERILIZATIONAn overview

Presented by:

Pacific BioLabsHercules, CA

SterilizationWhat 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?

DefinitionsSterile: Free from any living

organismsSterilization: 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 facilitiesSome specialty food product manufacturers

Some Products Requiring SterilityMedical Devices

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 SelectionAdvantages and DisadvantagesGamma 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 SelectionE-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 SelectionEthylene 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 SelectionEthylene 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?

FDACDER – 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 StandardsEthylene 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 StandardsRadiation 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 StandardsRadiation 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 StandardsIndustrial 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

FacilitiesAdditional standards on:Steam, dry heat & EO table top sterilizersSafe handling & biological decontamination

of reusable medical devices (ANSI/AAMI ST35)

Chemical sterilants & disinfectantsFlash sterilization (steam at 132C)Processing of reusable surgical textiles

ANSI/AAMI/ISO Standards Laboratory Testing –

MicrobiologySterilization 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 processFiltration 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 indicatorsValidation 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 devicesProduct/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 GuidesSterility Assurance ComplianceAssessing BiocompatibilityOnline at www.pacificbiolabs.com

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