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;
- Dated certificate of the gamma radiation source including type, activity, and location of individual source capsules within the source rack;
- Calibration of I/Es and dosimetry systems;
- Qualification of alarm and safety device(s) operation;
- For continuous mode processors, qualification of conveyor operation and establishment of the conveyor speed for each item to be irradiated;
- For batch mode processors, qualification of timer settings for each item to be irradiated;
- Dose mapping studies to confirm Dose Uniformity; and
Establishment of sterilizer load configuration for each API, drug product, medical device, or non-product item.
4. Performance Qualification (PQ) Studies for Gamma Radiation Sterilization should include, and not be limited to, documentation of the following:
- A minimum of three (3) consecutive, successful runs for each irradiation cycle using dosimeters and production cycle parameters for load configuration, conveyor speed, exposure time, timer setting, and minimum absorbed dose to provide evidence of reproducibility;
- Confirmation that the required sterilization dose was delivered; and
- Meeting all validation acceptance criteria.
5. Association for the Advancement of Medical Instrumentation (AAMI) Method 1 should be used when the minimum absorbed dose is based on drug product, API, medical device, and/or non-product item bioburden.
6. An Overkill Sterilization Cycle may be used provided that at least three (3) prospective validation cycles are run using biological indicators (BI) (Bacillus pumilus) to demonstrate acceptable sterilization.
7. Establishment of a Sterilization Dose Using AAMI Method 1 for a Single Production Batch includes the following steps:
- Determine the average indigenous bioburden of the API, drug product, medical device, or non-product item using ten (10) randomly collected samples;
- Determine the verification dose for a Sterility Assurance Level (SAL) of 10-2 from an AAMI table using the average bioburden (see ANSI/AAMI/ISO 11137-2:2006);
- Verify that the verification dose does not exceed the established maximum sterilization dose limit;
- Irradiate one hundred (100) samples of the product batch at the verification dose;
- Perform a sterility test on each of the one hundred (100) samples
- If there are no more than two (2) samples with positive sterility tests, then accept the verification dose; and
- Using the AAMI table, determine the sterilization dose for the required SAL (e.g., 10-6) based on the average bioburden for the batch.
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:
- Determine the average indigenous bioburden of the API, drug product, medical device, or non-product item using ten (10) randomly collected samples;
- Obtain the VDMAX 25 from the AAMI table using the average bioburden and selected sterilization dose (see ANSI/AAMI/ISO 11137-2:2006);
- Obtain ten (10) random samples and irradiate them at the VDMAX obtained from the table;
- Determine the dose applied to the samples;
- Verify that the highest dose to the samples did not exceed the Verification Dose* by more than ten (10) percent;
- 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;
- Perform a sterility test on each of the ten (10) samples;
- 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;
- If there are two (2) positive sterility tests out of the ten (10) sterility tests, a conformity verification dose experiment should be performed; and
- 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:
- Determine the average indigenous bioburden of the API, drug product, medical device, or non-product item using ten (10) randomly collected samples;
- Obtain the VDMAX 15 from the AAMI table using the average bioburden and selected sterilization dose (see ANSI/AAMI/ISO 11137-2:2006);
- Obtain ten (10) random samples and irradiate them at the VDMAX obtained from the table;
- Determine the dose applied to the samples;
- 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;
- 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;
- Perform a sterility test on each of the ten (10) samples;
- If there are no more than one positive sterility test from the ten (10) sterility test, then accept the verification dose and substantiate the 15kGy;
- If there are two (2) positive sterility tests out of the ten (10) sterility tests, a conformity verification dose experiment should be performed; and
- If there are more than two (2) positive sterility tests, the verification dose should not be accepted.
11. Radiation Sterilization Systems should be subject to a maintenance program and include, and not be limited to:
- Calibration of I/Es, including dosimeters, at least annually; and
- Radiation source addition, redistribution, or replacement, based on weekly performance monitoring.
Process Interruptions During Sterilization that delay the completion of sterilization beyond the specified time limit should be investigated and the effect on the API, drug product, medical device, and/or non-product item determined and documented.
13. Dosimeters should be used during routine sterilization to provide a measure of absorbed dose within specified limits. Selection of dosimeters should be based on the following:
- Temperature sensitivity;
- Humidity sensitivity;
- Dose rate dependence; and
- Stability of the absorbance reading after irradiation.
14. Dosimeters should be:
- Used within the calibration date;
- Placed in a location having a known dose relationship to the minimum and maximum doses; and
- Read within a defined time interval after gamma radiation sterilization and documented in the sterilization record.
- Dosimeters placed so, at least, two (2) are exposed to the irradiation source at all times, including in the first and last container;
- Dosimeters placed in at least one irradiation container for each pathway during the irradiation cycle;
- Positive indication of correct position of the source and an interlock between the source position and conveyor movement; and
- Continuous monitoring and recording devices for conveyor speed.
16. Batch Mode Irradiation Processors should have:
- At least two (2) dosimeters exposed in positions related to the minimum and maximum dose; and
- Monitoring and recording of source movement and exposure time.
17. Absorbed Dose Readings Outside Specified Limits should be investigated by the contract facility Quality Authority. A copy of the investigation should be forwarded to the sponsor Site Quality Authority and the processed material designated Quarantine-hold until the investigation is completed and a final disposition assigned.
18. Process Documentation should include, and is not limited to, the following:
- Accountability of API, drug product, medical device, or non-product items before and after sterilization by batch number or lot number;
- Load pattern identification;
- Dosimeter placement and retrieval;
- Sterilization batch number;
- Specified minimum and maximum dose;
- Process parameters, including timer setting and conveyor speed;
- Sterilization date(s);
- Dosimeter readings and analysis;
- Records of processing including conveyor path and source position;
- Process interruptions, deviations, and actions taken; and
- Identification of the person performing the operation.
19. A System (e.g., labelling, use of radiation sensitive colour disks) should be in place to differentiate each irradiated and non-irradiated carrier or box. Irradiated items should be stored in an area that is segregated from non-irradiated items