Method 2 does not entail the measurement of the bioburden. It relies on a protocol for a series of incremental-dose experiments to establish a dose at which approximately one in a hundred samples will be nonsterile. A sterilization dose then is established by extrapolation from this 10^–2 sterility level using a dose-resistance factor calculated from observations of the incremental-dose experiments that characterize the remaining microbial resistance. This resistance is estimated from the lowest incremental dose at which at least one sample is sterile and from the dose at which the surviving population is estimated to be 0.01 microorganisms per sample.

The Verification-Dose (VDmax) Method, a relatively new method, is included in the current AAMI–ISO guidelines specifically to substantiate a 25-kGy dose. This method was officially introduced as an AAMI Technical Information Report (28) and is now part of ISO 11137-2: 2006. Kowalski and Tallentire proposed this method to substantiate a 25-kGy dose (29). The method is similar to dose-setting Method 1 because it requires a determination of bioburden and a verification dose experiment.

By substantiating a 25-kGy dose, this method verifies that the bioburden on the product is less radiation-resistant than a microbial population of maximal resistance, consistent with an SAL of 10^–6 at 25 kGy. Verification is undertaken at an SAL of 10^–1. Ten items are irradiated during the verification-dose experiment. The dose corresponding to this SAL (VDmax) reflects both the magnitude of the bioburden and the associated maximal resistance. If no more than one of ten sterility tests is positive, a 25-kGy sterilization dose is substantiated.

Other regulatory considerations

Although radiation sterilization has appeared in the United States Pharmacopeia since 1965, the US Food and Drug Administration regards a radiation-sterilized drug as a new product. Manufacturers must submit new drug applications and prove the products' safety.

In the United Kingdom, sterilization by ionizing radiation has been a recognized method since 1980, when the Ministry of Health agreed to accept materials exposed to a radiation dose of 25 kGy. Medicines controlled under the UK Medicines Act of 1968 are subjected to individual assessment by the Medicines and Healthcare Products Regulatory Agency's Committee on Safety of Medicines. This committee requires proof of sterility, proof that the drug's potency is unaffected by the process, and proof that degradation products are not harmful.

Although the British Pharmacopoeia recognizes gamma irradiation as a suitable sterilization process, the manufacturer must prove that no product degradation has taken place.

Most European countries allow pharmaceuticals to be radiation sterilized, provided that authorization has been obtained from the appropriate health authorities.

Conclusion

While the author does not believe that irradiation normally should replace traditional methods of sterilization for common, large-volume parenterals, irradiation should be considered seriously to sterilize powders for injection and small-volume parenterals that currently are sterilized by nonterminal sterilization processes.

Geoffrey P. Jacobs, PhD, is managing director of Dr. Geoffrey P. Jacobs Associates, PO Box 16352, Jerusalem 91162, Israel, tel. +972 2 6422227, fax +972 2 6432372, hida@zahav.net.il

Keywords: irradiation, product stability, sterilization, validation.

References

1. G.P. Jacobs, "Gamma Radiation Sterilization," in Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C. Boylan, Eds., (Marcel Dekker, New York, Vol. 6, 1992), pp. 303–332.

2. M.R. Cleland and J.A. Beck, "Electron Beam Sterilization," in Encyclopedia of Pharmaceutical Technology, J. Swarbrick and J.C. Boylan, Eds., (Marcel Dekker, New York, Vol. 5, 1992), pp. 105–136.

3. Nordion, "2003 World List of Suppliers of Contract Gamma Services," (MDS Nordion, Ottawa, Canada), http:// http://www.mds.nordion.com/, last accessed March 29, 2007.