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Understanding validation for verification dose maximum sterilization: lower sterilization doses are now available with the VDmax method of validation and may be used as a viable alternative to providing assurance of sterility without using the large sample sizes required by other methods.

When manufacturing a medical device that is intended to be labeled sterile, it will typically undergo a terminal sterilization process. Radiation is one of the most common and safest sterilization modalities. The different methods (Method 1, Method 2 and VDmax) that can be used for validating a terminal sterilization dose can be found in ISO 11137-2:2013 Sterilization of healthcare products--Radiation --Part 2: Establishing the sterilization dose. This particular standard provides guidance for a 15 and 25 kGy sterilization dose.

Additional Verification Dose maximum (VDmax) sterilization doses are now available in ISO 13004:2013 Sterilization of health care products--Radiation --Substantiation of a selected sterilization dose: Method VDmax[SD]. Given that the lower sterilization doses are now available with this method, they may be used as viable alternatives to providing the assurance of sterility needed without using the large sample sizes required by the other methods.

For a product to have a sterile label claim, it usually needs to have a Sterility Assurance Level (SAL) of [10.sup.6]. An SAL is the "probability of a single viable microorganism occurring on an item after sterilization" [ISO 11139:2006, 2.46]. The concept of SAL and probability is the basis for how the VDmax tables were derived and provides the foundation for determining the number of samples that are tested and the acceptance criteria for the results. The standards outline the steps needed to perform a validation: bioburden with a recovery efficiency, verification dosing, and test of sterility with a passing method suitability test. These procedures are outlined below along with some considerations for testing that may be useful when trying to meet the bioburden limits of the various VDmax tables.

The standard gives the option to validate at a selected sterilization dose for quarterly release of a product. To validate for quarterly release, the bioburden estimate is taken from the average of three individual lots or batches of production (using 10 data points per lot) followed by the test of sterility. In cases where it is not practical to test three lots (due to infrequent production of a particular device or similar reasons), a single lot of product can be validated.

When considering sterilization by radiation, the determination or substantiation of the sterilization dose is based on product bioburden. Bioburden is defined as the "population of viable microorganisms on or in product and/or sterile barrier system" [ISO 11139:2006, 2.2]. In other words, how dirty the product is prior to sterilization. The sterilization dose that is able to be used depends on how much control is had over the manufacturing process and how much bioburden is ultimately on the product. Thus, the bioburden of a device (both in terms of numbers and types of organisms) is connected to the resulting sterilization dose.

Testing to determine bioburden is typically performed via an extraction of the product (in the case of a solid device) or direct testing (if it is a liquid or a gel). The testing determines the population of aerobic and fungal microorganisms found on a device. Bioburden testing should occur after all steps of production, including packaging but not sterilization, are complete. Product may either be tested as individual test articles, or in the case where very low bioburden levels have been demonstrated or are expected, test articles may be pooled together for extraction. The pooling method would aid in obtaining bioburden numbers that would fall into the lower ranges of the dose tables.

As part of the testing, a recovery efficiency, also referred to as a correction factor, must be determined. The value represents the effectiveness of the method chosen to extract the bioburden from the device. Once the data are obtained, the recovery efficiency is used to calculate a bioburden estimate. The estimate is commonly a representation of the aerobic bacteria and fungal organisms found on a device, and can help guide selection of the sterilization dose for the product.

The data are then used to obtain a verification dose, which is not the same as the sterilization dose. It is a sub-lethal radiation exposure that is at a lower SAL ([10.sup.-1]) than is provided by a full sterilization dose ([10.sup.-6] SAL). It allows for subsequent testing of 10 test articles for the test of sterility, as opposed to 100 that would be required for a Method 1 or 2 validation. This verification dose is determined by the devices' calculated bioburden estimate and is derived from the table in the applicable standard that corresponds to the selected sterilization dose to be substantiated.

Test articles are then exposed to the sub-lethal verification dose and subjected to a test of sterility per the guidance found in ISO 11737-2:2009(R) 2014 Sterilization of medical devices--Microbiological methods--Part 2: Tests of sterility performed in the definition, validation and maintenance of a sterilization process. The test of sterility is validated by the completion of a method suitability test, also commonly referred to as a bacteriostasis/fungistasis test. General information regarding this test can be found in current Pharmacopeias. However, it should be noted that the incubation temperature(s) and medium (media) have to be the same as those used in the test of sterility.

The acceptance criteria for completing a successful validation is no more than one positive test of sterility per 10 articles tested. If two positive tests are observed, an additional 10 samples should be tested with no further positives allowed. Upon completion of a successful validation, the continued appropriateness of the sterilization dose is demonstrated by dose audit testing on a quarterly basis. Dose audit testing consists of the bioburden determination of 10 samples using the validated recovery efficiency to assure that the limits of the selected table are not being exceeded. It will also show that there is continued control through the manufacturing process. A test of sterility with samples that have been exposed to the established verification dose is also performed and should meet the above listed acceptance criteria.

By Sean Shepherd, B.S., RM/SM(NRCM), Senior Study Director; Wendy Wangsgard, Ph.D., RM(NRCM), Senior Scientist; Nelson Laboratories Inc.
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Title Annotation:Testing
Author:Shepherd, Sean; Wangsgard, Wendy
Publication:Medical Design Technology
Article Type:Cover story
Date:Mar 1, 2016
Words:1019
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