Guide to validation of terminal sterilization process of drugs (GUI-0074): Process validation, sterilization by ionizing radiation

On this page

• Introduction
• Product/material definition and qualification
• Sterilizing agent specifications
• Sterilization process definition
• Sterilization dose setting/dose substantiation
• Equipment qualification
• Dose distribution studies
• Loading patterns
• Temperature control

Introduction

Radiation sterilization is used mainly to sterilize heat-sensitive materials and products. However, many materials, drugs and packaging materials are also radiation-sensitive. This method is allowed only when the absence of harmful effects on the material/product has been confirmed prior to use.

Radiation processing (in the context of this guide) means exposing a material/product to ionizing radiation in a controlled way. This ensures that a pre-determined radiation dose is delivered to the material/product.

This section of this guide covers radiation processes employing:

• gamma radiation generated by the radionuclide ⁶⁰Co (Cobalt-60) or ¹³⁷Cs (Cesium-137)
• a beam from an electron generator
• a beam from an X-ray generator

Product/material definition and qualification

A product/material qualification program demonstrates the effects of ionizing irradiation on the product/material. The most important outcome of product qualification is to determine the product's maximum acceptable dose D_max,acc.

Your product/material qualification must test the product/material using the D_maxT considered to be worst case for product functionality. The worst-case product/material qualification dose may not always be the highest dose (for example, complex cross-linking effects).

A third factor is the D_minP. The ratio of the D_maxP to the D_minP is known as the D_max/D_min ratio or dose uniformity ratio (DUR). This ratio determines if the required dose range can be successfully delivered to the product as configured.

Sterilizing agent specifications

There are significant differences between the 3 ionizing radiation technologies that affect process validation:

• Gamma radiation delivers a specified dose relatively slowly.
• Both electron beam generators and X-rays deliver the same dose much more quickly.

As a result, you must validate each source of radiation separately for a product/material.

Before you adopt an alternate radiation source, you must evaluate validation requirements based on the potential product/material effects (and any microbiological effects). At a minimum, you must:

• define the type of radiation to be used in sterilization
• specify the energy level of the electron beam for electron bean generators and X-rays
• assess the potential for induced radioactivity in product/material (for electrons with energy greater than 10 MeV or X-rays with energy greater than 5 MeV)

Sterilization process definition

To establish the maximum acceptable (D_maxT) dose, the:

• product/material must represent what will be routinely fabricated
• source of radiation must be able to precisely deliver the required doses

Sterilization dose setting/dose substantiation

There are 3 basic methods used to establish a minimum radiation sterilization dose:

1. Method VD_max dose substantiation:

• verifies that the radiation resistance of the product/material bioburden is less than a microbial population of maximal resistance consistent with attainment of a 10^-6 SAL at a selected sterilization dose of either 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5 or 35 kGy

2. Dose-setting method 1:

• depends upon experimental verification that the radiation resistance of the product/material bioburden is less than or equal to the resistance of a microbial population having the standard distribution of resistances (SDR)
• the SDR specifies microorganism resistance in terms of D10 values and the probability of occurrence in the total population
• using computational methods, for increasing levels of average bioburden having the SDR, the doses required to achieve SAL of 10^-2, 10^-3, 10^-4, 10^-5 and 10^-6 is calculated

3. Dose-setting method 2:

• uses the radiation resistance of the naturally occurring product/material bioburden
• sterility tests are conducted on samples that have been exposed to a series of incremental doses to estimate the dose at which 1 in 100 is expected to be non-sterile (SAL of 10^-2)
• the microorganisms surviving exposure to such a dose should have a more homogeneous D10 value than the initial bioburden
• from the incremental dose experiment, an estimate made of this D10 value is used to extrapolate SAL values less than 10^-2 to determine the sterilization dose

Note: Dose-setting methods use the bioburden on the product and the resistance of that bioburden to tailor a specific radiation treatment for a specific product.

For guidance on bioburden calculations, consult:

• ISO 11137-2: Sterilization of health care products – Radiation – Part 2: Establishing the sterilization dose

For guidance on sterilization using radiation, consult:

• ISO 11137-1: Sterilization of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices
• ISO/TS 11137-4: Sterilization of health care products — Radiation — Part 4: Guidance on process control
• ISO/TS 13004: Sterilization of health care products — Radiation — Substantiation of selected sterilization dose: Method VD_max^SD
• ISO 11137-2: Sterilization of health care products – Radiation – Part 2: Establishing the sterilization dose
• ISO 11137-3: Sterilization of health care products — Radiation — Part 3: Guidance on dosimetric aspects

Equipment qualification

Your irradiator specification should include, at a minimum:

• a description of the irradiator, its characteristics and method of operation
• a description and validation status of software used to control/monitor the process
• location, space and environment where the irradiator is to be installed within the premises
• a description of the conveyor system including its operation, construction and range of speed
• the dimensions, materials and nature of construction of the irradiation container(s)
• for gamma irradiators, the type of radionuclide and the geometry of the gamma source
• for X-ray irradiators, the dimension, materials and nature of construction of the X-ray converter
• for electron beam and X-ray irradiators, the characteristics of the beam (electron energy, scan width and uniformity)

Instruments that need calibration for electron beam, X-ray and gamma radiation processing technologies include:

• timers
• recorders
• dosimeters
• calorimeters
• thickness gauges
• spectrophotometers

Dose distribution studies

Dose distribution studies are performed to determine the D_max and D_min positions in a process load in relation to the radiation source.

You should:

• perform dose studies according to written procedures, using properly placed and calibrated dosimeters
• document the location of each dosimeter
  • dosimeters to be placed to capture minimum and maximum doses
  • if using a reference monitoring position, place the dosimeter at the monitoring position as well
• use dosimeters that can measure the dose over the desired range
• collate the data from all runs into a dose-map profile for each type of irradiation container, product conveyor path and irradiation source
• conduct dose distribution studies for each product/material-loading configuration and size
  • also place products into processing categories/density families, where the dose distribution studies would be performed for the processing category/density family, if applicable
• evaluate each test run performed and certify the completed studies

Note: The studies should prove that the dose uniformity requirements as outlined in your process specification are consistently achieved. To conclude your process is validated, operational consistency of the dose uniformity must be demonstrated.

Loading patterns

The way the product/material is presented to the radiation source is critical to achieving the specified D_max/D_min ratio, doses and desired SAL (sterility assurance level). How the product/material will be presented to the source, including detailed loading diagrams (if applicable), should be outlined in the processing specification.

Validation studies must confirm that the:

• product in the D_min position will receive a dose that meets or exceeds D_minP
• product in the D_max position will receive a dose not exceeding D_maxP during routine processing

If reference monitoring is used, then the dosimeter must be placed in the monitoring position that was determined from the dose distribution studies.

Temperature control

For temperature-sensitive products/materials, the following information should form part of your process validation documentation:

• the allowed temperature range of the product when it arrives at the irradiation facility
• the time available for irradiation before the product temperature rises to the maximum tolerated level