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.
ISO also allows 25-kGy doses to be substantiated using Methods 1 and 2. The new ISO guidelines (ISO 11137-2:2006) allow dose-setting
by other methods that provide assurance equivalent to that of the above ISO methods in achieving the specified sterility requirements.
All ISO methods require periodic audits to confirm the appropriateness of the sterilization dose.
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.
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, firstname.lastname@example.org
Keywords: irradiation, product stability, sterilization, validation.
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.