Drug makers have sterilized pharmaceuticals by gamma irradiation for more than 40 years. High-energy gamma irradiation is used mainly in the healthcare industries to sterilize disposable medical devices. Over the years, however, the number of radiation-sterilized pharmaceuticals has gradually increased. Pharmaceutical companies now radiation sterilize drugs such as ophthalmic preparations, topical ointments, veterinary products, and parenterals. Regulatory pressure to adopt terminal-sterilization processes has promoted radiation sterilization.
Radiation sterilization may be performed using either gamma rays from a radioisotope source (usually cobalt-60) or electron-beam or X-ray irradiation. Gamma-ray irradiation, however, is by far the more common method.
Like all methods of sterilization, irradiation involves a compromise between inactivation of the contaminating microorganisms and damage to the product being sterilized. The imparted energy, in the form of gamma photons or electrons, does not always differentiate between molecules of the contaminating microorganism and those of the pharmaceutical substrate.The interaction between high-energy gamma radiation and matter forms ion pairs by ejecting electrons, leading to free-radical formation and excitation. The free radicals are extremely reactive because each has an unpaired electron on one of its outer orbitals. Free-radical reactions may involve gas liberation, double-bond formation and scission, exchange reactions, electron migration, and cross-linking. In fact, any chemical bond may be broken and any potential chemical reaction may take place. In crystalline materials, this may result in vacancies, interstitial atoms, collisions, thermal spurs, and ionizing effects. Polymerization is a particularly common result in unsaturated compounds. In microorganisms, radiation-induced damage may express itself in various biological changes that may lead to cell death. Although DNA generally is considered the major subject of cellular damage, membrane damage also may contribute significantly to reproductive-cell death. In solutions, a molecule may receive energy directly from the incident radiation (the "direct effect") or, in aqueous solutions such as parenterals, by the transfer of energy from the radiolysis products of water (e.g., hydrogen and hydroxyl radicals and the hydrated electron) to the solute molecule (the "indirect effect"). In dilute solutions, most of the energy is imparted to the water, as is the case with many parenteral solutions. The indirect radiation effect therefore would account for most of the resulting possible radiation damage.
The process of radiation-induced damage by electrons is similar to that for gamma photons. In electron irradiation, the high-energy electrons produced outside the target molecule ionize the molecular species as they pass through the medium and release their energy. The ionization process leads to the production of secondary electrons with a range of energies capable of breaking bonds in the medium near the ionization event. The high-energy electrons usually are produced either by accelerating them across a large drop in potential in a direct-current machine or by a linear or circular electron accelerator.
X-rays are electromagnetic photons emitted when high-energy electrons strike any material. X-rays therefore can be produced by an electron accelerator. X-ray sterilization is not as fast as electron-beam irradiation. Since electron-beam and X-ray machines are powered electrically, the handling, shipping, and disposal of radioisotopes is not necessary. A disadvantage of electron-beam irradiation is its low penetration power, although more modern machines have overcome this problem. X-ray machines may penetrate even more than gamma-ray machines.
The chapters about gamma-radiation and electron-beam sterilization in the Encyclopedia of Pharmaceutical Technology contain general reviews of radiation sterilization (1, 2).
Contract sterilizers usually perform irradiation (1, 3). Though the contract sterilizer usually assumes many process-validation duties, the drug manufacturer bears final responsibility for the product's sterility. The contract sterilizer essentially is responsible for guaranteeing the delivered radiation dose.
The effect of radiation on pharmaceuticals
Any processing such as sterilization in the manufacture of a pharmaceutical product must cause minimal degradation. This requirement applies to radiation processing. Data on the feasibility of irradiating final pharmaceutical products (parenteral products in particular), active ingredients, or excipients can be obtained from the scientific literature. Reviews on the effects of gamma and electron-beam irradiation are readily available (4–17). Although many of the cited investigations offer only a superficial examination of the irradiated drugs, the reported data give useful insights into the overall radiation stability of these products and indicate whether more extensive testing of the products should be undertaken.