The task of picking a validation method for sterilized devices is largely a matter of following guidance and standards from groups such as the Association for the Advancement of Medical Instrumentation (AAMI). The AAMI has recently been working with the ISO and the American Standards Institute (ANSI) to develop what is called harmonized guidance, or a set of guidelines that combines standards from different countries.

Validating radiation sterilization

The predominant standard for radiation sterilization is ANSI/AAMI/ISO 11137 Sterilization of Healthcare Products: Requirements for Validation and Routine Control - Radiation Sterilization. It has been revised and is now a three-part document.

Part 1 addresses:

• Quality management systems

• Characterizing the sterilizing agent

• Process and equipment

• Defining device characteristics

• Defining a process by establishing a maximum acceptable dose using approved methods defined in Part 2

• Installation qualification, operational qualification, and performance qualification of the irradiator equipment and the performance qualification of load characteristics

• Establishing a routine monitoring program to establish procedures for handling the product before, during, and after irradiation

• Product release which includes calibrations and maintenance of the sterilizer

• Auditing to demonstrate continued effectiveness of the process, which includes establishing a frequency of audits for bioburden and sterilization dose for methods outlined in Part 2

Part 2 addresses:

• How to establish and maintain product families for dose setting, substantiation, and auditing

• Product grouping to set up categories of devices or components and thus reduce the amount of testing needed to validate. It is entirely possible that all devices a manufacturer produces can be considered one product group, as far as sterilization dose requirements are concerned. But this needs documented justification. Standards for developing and monitoring product families have been established for radiation-sterilized products in AAMI/ISO 15843. A similar approach has been developed for devices sterilized by EO in AAMI TIR 28. Product adoption and process equivalency for EO sterilization has been useful for grouping and adopting new products.

• Selecting and establishing the methods used for microbiological testing of the product

• Selecting an appropriate method for dose setting

Part 2 defines three methods to set a dose, or the amount of radiation to be administered to the product. The most common, Method 1, sets the dose using bioburden data collected from the product. Bioburden is a count of microorganisms that contaminate a device. Method 1 establishes a range of sterilization-dose values based on bioburden between 1 and one million organisms per device. The VDmax Method also uses bioburden data to substantiate a minimum sterilization dose of 15 or 25 kGy. This method is limited to a maximum bioburden of 1.5 colony-forming units (CFU) per device for VDmax 15 and 1,000 CFU per device for VDmax 25 kGy. The third method, Method 2, is not as widely used. It establishes a sterilizing dose based on fractional positive data collected from the incremental dosing of the product. Like Method 1, it can establish a wide range of sterilization-dose values based upon fractional data.

After selecting a dose-setting method the key steps in the experimental process include bioburden determination and the verification-dose experiment. Selecting the samples to undergo testing is determined on the use of the device or component in clinical practice.

Auditing Methods

After validation, the effectiveness of the sterilization dose is demonstrated through bioburden and dose audits. Auditing-frequency guidelines are outlined in Part I of standard 11137. Conducting sterilization dose audits can take two approaches. One sets audits at three-month intervals. The other establishes a rational for a frequency of auditing. The rational should:

• Characterize the bioburden and describe its limits

• Include resistance data of the organisms

• Summarize the sterilization method to establish a minimum sterilization dose

• Identify the dose to be used for routine processing and the minimum sterilization dose safety margin

• Iidentify manufacturing process control

• Identify monitoring used to control the manufacturing

A manufacturer who demonstrates a history of four successful audits may provide bioburden and dose-audit data to qualify for a reduced frequency of auditing. Companies that demonstrate a controlled bioburden and sterility may be allowed to audit periods up to 12 months.

Validating ethylene-oxide sterilization

EO validation standards are being revised but many standard methods still apply. One of the most common ways to validate EO sterilization is called the overkill method. However, parametric-release programs are becoming a widely-used approach for validation now that sterilization facilities have developed processes with faster kill times, lower EO residuals, and shorter cycle times. Before applying either method, determine the effect of the EO process on the product and packaging. The required bioburden, or sterility assurance level (SAL) should also be defined by the device's intended use. The SAL may vary between 10^-3 for topical devices and 10^-6 for blood-contact invasive devices.

Standard 1994 ANSI/AAMI/ISO 11135 Medical devices: Validation and routine control of ethylene oxide sterilization provides guidance for the overkill method. It assumes the bioburden is at maximum levels of 1,000 for EO sterilized devices. The natural bioburden is also less resistant to the biological indicator (BI) intended for release and can be reduced to zero following a half-cycle response. The BI should inactivate at the device's worst-case location. After successfully validating the sterilization method, release of sterilized product is typically performed by testing BIs. After a successful validation, annual revalidation would be performed using a documented review process. Routine bioburden monitoring is also recommended to verify control of the manufacturing process. A revalidation study every two years should demonstrate the resistance of the product bioburden has not exceeded the BI challenge. This challenge could be exposure for a half cycle on the finished device and BIs. Results should be similar to those from the original validation.

Parametric release is another commonly-used validation method for EO-sterilized devices. Standards 1994 ANSI/AAMI/ISO 11135 and 2001 AAMI TIR 20 Parametric release for ethylene oxide sterilization provides guidance for a sterilization routine based on measurement and documentation of the process parameters instead of using a biological-indicator sterility test. One of the first steps in the validation program determines the lethality of the sterilization. This is done by conducting a series of partial cycles following one of two methods, called A or B. Method A exposes BIs to graded exposures and counts the BIs. The data is plotted on a survivor curve. Method B uses sets of BIs exposed to graded exposures. The BI is sterility tested to determine survivors. The generated data is used to calculate a D-value — the exposure time required to reduce one log of organism. Data from Method A or B determines the minimum EO-gas-exposure time required for full sterilization.

The parametric release of product following a successful validation is based on conformance of the physical processing parameters established during validation. The release of product is not based on BI testing specifications. The final product must conform to acceptable EO residuals determined by ANSI/AAMI/ISO 10993-7: 1995 and endotoxin levels determined by ANSI/AAMI ST 72: 2002. Annual process monitoring can assure the design and process parameters have not changed. Requalifications use confirmation tests to verify resistance through microbiological studies and assures the process is unchanged.

The language of sterilization validation

Here are a few common terms used in sterilization validation.

Bioburden - the number of microorganisms that contaminate a device

Biological Indicators (BI) - they monitor a sterilization process by directly determining whether the most resistant microorganisms (Geobacillus or Bacillus species) are present.

Colony-forming units (CFU) - the number of viable microbial cells collected for a given unit sample.

Dose - the amount of radiation to be administered to the device, measured in grays. 1 gray (kGy) = 100 rad.

Dosimetric release - a method that ensures that the absorbed dose (measured in kGy) the device receives is greater than or equal to the predetermined minimum sterilization dose.

Parametric release - assures the device is sterilized based on information collected during the manufacturing process and on the compliance with specific GMP requirements.

Want to learn more? Take a class

There's more to validating sterilization than what you can pick up in one article. That's why the TechTeam at Steris holds seminars that let attendees learn more about different sterilization technologies, materials compatibility, validation guidelines, AAMI guidelines, laboratory services, and packaging for sterilization. The seminars give attendees an opportunity to speak directly with specialists and address any questions they have regarding a sterilization process. The next seminar will be October 18 at Disney's Grand Californian Hotel in Anaheim, Calif. Visit www.steris.com/isomedix/TechTeam/seminars.htm for more information.