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Gamma Radiation Sterilization

Introduction This document provides guidance for validation of gamma radiation sterilization processes used to sterilize active pharmaceutical ingredients (API), drug products, medical devices, and non-product items, such as, APA gowning articles, containers, and closures with direct or potential contact with sterile raw materials (RM), APIs, drug products, or medical devices. 1. Critical Process Parameters for gamma radiation sterilization include: • Exposure time, • Timer setting (batch mode processing), • Conveyor speed (continuous mode processing), • Package size and bulk density, and • Dose measurement. These parameters should be monitored or controlled and documented on the sterilization record. 2. Compatibility Studies should be performed according to an approved protocol to demonstrate that the API, drug product, medical device, or non-product item is not adversely affected by exposure beyond the sterilization radiation dose limit. The evaluation should include the following: • Functionality; • Effects of gamma radiation on the API, drug product, or medical device (i.e., bio-compatibility); • Appearance; and • Effects of aging determined by stability testing. 3. Gamma Radiation Commissioning and/or Qualification should include, and not be limited to, documentation of the following: • Verification that the gamma irradiator is installed according to design criteria; • Identification of irradiator location within the facility and flow of materials through the facility; • Description of the construction and operation of the irradiator, including the conveyor system and timer; • Description of the irradiation carriers, including materials of construction and dimensions; • Identification of I/Es used to control, monitor, and record critical process parameters;

Title: Gamma Radiation Sterilization Guidance Number: 107 Prepared by: Date: Supersedes:

Checked by: Date: Date Issued:

Approved by: Date: Review Date:

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8. AAMI Method VDMAX should be used to confirm a selected sterilization dose according to the following requirements: • VDMAX 25 applies when the product has an average bioburden of

<1,000; and • VDMAX 15 applies when the product has an average bioburden of <1.5.

9. Substantiation of a Sterilization Dose Using AAMI Method VDMAX 25 for a Single Production Batch includes the following steps: a. Determine the average indigenous bioburden of the API, drug product,

medical device, or non-product item using ten (10) randomly collected samples;

b. Obtain the VDMAX 25 from the AAMI table using the average bioburden and selected sterilization dose (see ANSI/AAMI/ISO 11137-2:2006);

c. Obtain ten (10) random samples and irradiate them at the VDMAX

obtained from the table; d. Determine the dose applied to the samples; e. Verify that the highest dose to the samples did not exceed the

Verification Dose* by more than ten (10) percent; f. Verify that the arithmetic mean of the highest and lowest doses

delivered to the product is not less than ninety (90) percent of the VDMAX 25;

g. Perform a sterility test on each of the ten (10) samples; h. If there are no more than one positive sterility test from the ten (10)

sterility tests, then accept the verification dose and substantiate the 25kGy;

i. If there are two (2) positive sterility tests out of the ten (10) sterility tests, a conformity verification dose experiment should be performed; and

j. If there are more than two (2) positive sterility tests, the verification dose should not be accepted.

10. Substantiation of a Sterilization Dose Using AAMI Method VDMAX 15 for a

Single Production Batch includes the following steps:

a. Determine the average indigenous bioburden of the API, drug product, medical device, or non-product item using ten (10) randomly collected samples;

b. Obtain the VDMAX 15 from the AAMI table using the average bioburden and selected sterilization dose (see ANSI/AAMI/ISO 11137-2:2006);

c. Obtain ten (10) random samples and irradiate them at the VDMAX obtained from the table;

d. Determine the dose applied to the samples; e. Verify that the highest dose to the samples did not exceed the

verification dose by more than 0.1kGy or by more than ten (10) percent, whichever is greater;

f. Verify that the arithmetic mean of the highest and lowest doses delivered to the product is not less than ninety (90) percent of the VDMAX 15;

g. Perform a sterility test on each of the ten (10) samples;