The utilization of X-Ray irradiation as an alternate advanced terminal sterilization technique to electron beam irradiation of sterile compound drug products is a pivotal topic of conversation for delivering the most safe and effective drug therapies for patients. The rationale is the boosted capability of modern X-Ray sterilization to penetrate denser packaging configurations adding greater flexibility to the types/formats of drug products that can benefit from the least potential deleterious effects to compounded sterile preparations during terminal sterilization. X-Rays propagate in the same direction as the electrons generating a stream of X-Rays towards the drug product and multiple layers of drug products can be sterilized simultaneously. Of radiation sterilization techniques, X-ray sterilization can achieve the highest dose uniformity ratio (DUR), the ratio between maximum and minimum dose required for sterilization. DUR measures the range of doses delivered to the drug product and is important for optimization of irradiation sensitive materials in order to minimize degradation both of the drug product in the context of potency and the packaging materials. We discuss the actions required when changing the terminal radiation sterilization method, from electron beam to X-Ray. The International Standards Organization clearly articulates requirements of terminal sterilization with ISO EN 11137-1 (Sterilization of health care products - Radiation: Requirements for development, validation, and routine control of a sterilization process for medical devices), which is the primary and definitive regulatory guideline to the terminal sterilization validation process when selecting and investing in X-Ray technology.This addresses both the technological elements of testing, calibrating, and delivering the proper dose in Kilogray (kGy) and the microbiological elements of ensuring the sterility of the compounded drug product.
When switching to X-Ray sterilization, the key focal points are transferring the two crucial product-based irradiation criteria, particularly the sterilization dosage (mandatory to attain the desired sterility assurance level) as well as the maximal tolerated dosage (that the product is qualified to withstand without a change in potency).
The three points of interest for an advanced terminal sterilization technology change:
1) Understanding requirements pertaining to the radiation resource (sterilizing agent).
2) Establishing or transferring the sterilization dosage.
3) Establishing or transferring the maximum acceptable dosage.
Requirements on the Radiation Source
There is a requirement in EN/ISO 11137-1 in clause 5.1.2 that for electron beam as well as X-Ray sterilization the energy level will be specified and documented as a target dose with limits.
The Transference of an Established Sterilization Dose
EN/ISO 11137-1 clearly states in clause 8.4.2 that transference of a sterilization dose (and corresponding verification dose) to a radiation source different from that on which the dose was originally established shall not be permitted unless data are available to demonstrate the differences in processing and operation conditions of the two radiation sources have no effect on the microbial effectiveness or microorganism kill rate. To show that microbial effectiveness is not modified or affected, a dose verification experiment utilizing the selected radiation source to which it is planned to move is undertaken. Following this validation, a transfer of the established sterilization dose from one radiation source to another is permitted when a dose verification experiment has been run and passes. Dose verification experiments include the irradiation processing at a specified sub-lethal dose applied based on product bioburden, followed by an ISO sterility test of a specified maximum concentration compounded drug sample set (see EN/ISO 11137-2).
Transfer of a Developed Maximum Acceptable Dose
Clause 8.4.1 of EN/ISO 11137-1 states that transferring a maximum tolerated dose to a different radiation source from that on which the dose was originally established requires a documented assessment that the differences in irradiation conditions do not affect the validity of the established maximum acceptable dose. Validity is most closely associated with testing of potency pre-exposure to irradiation vs. post-exposure; moreover, this may also include full drug product stability testing.
MediZap will soon offer X-Ray technology that opens up additional drug delivery configurations including: Bulk Drug Raw Materials, Finished Goods Mini IV Bags, and Finished Goods Large Volume Vials (30ml+) for Human and Vet use.