Radiation Sterilization of Parenterals - Pharmaceutical Technology

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Radiation Sterilization of Parenterals
Irradiation is an established method of sterilization for pharmaceutical products. Radiation sterilization can be achieved with gamma rays, electron beams, and X-rays. Each of these techniques has its advantages and disadvantages. The author describes these methods, the ways to find the correct sterilization doses, and the regulatory and safety concerns about irradation sterilization.

Pharmaceutical Technology

It is necessary to examine each new compound to assess its radiation stability, even though data may be available for closely related compounds. A thorough knowledge of radiation chemistry would be necessary to infer the behavior of one compound from another. Furthermore, with a formulated medication, the stability of an individual component may change when irradiated as part of the product.

Although sterilization doses of radiation usually are on the order of 25 kGy, a higher dose such as 50 kGy is useful for feasibility studies to indicate the type of radiolytic decomposition that may be expected at sterilization-dose levels.

Several analytical tools should be used to detect radiation-induced degradation. Each technique usually reveals a change in a specific moiety of the irradiated molecule, and it is therefore essential to examine all generated data to discover the extent of degradation. Stability-indicating assays should be used wherever possible. As with all stability studies, assays should be carried out during an extended time period to reveal the product's long-term stability. Accelerated aging may be undertaken under conditions recommended by the appropriate regulatory authority such as the US Food and Drug Administration.

Even when radiolysis products are within acceptable compendial limits, one must establish conclusively that the products formed cause no adverse effects at the concentrations found. Radiolysis products, however, generally are not unique to irradiation. It often suffices to show that radiolysis products are the same as those found when the drug is subjected to other sterilization procedures and occur at similar concentrations.

Irradiation of water. When discussing the irradiation of pharmaceuticals, particularly parenterals, the effects of irradiation on water must be considered. The formation of the various radiolysis products of water reflects the complexity of this "simple" pharmaceutical system. While none of the radical species formed are stable, they may react with the product's active ingredient, excipients, or both. The only resulting final products, however, are H2O, H2O2, and H2. Studies of the feasibility of radiosterilizing water in various container materials have been carried out in several laboratories (18–20).

A study of the effect of irradiated water on oxidation-susceptible drugs such as beta-lactam antibiotics showed that the drugs generally are not degraded. Furthermore, levels of H2O2 produced are below toxic levels (21).

Irradiation of powders for injection. The author's investigations of the radiation sterilization of parenterals have focused on powders of the beta-lactam group of antibiotics (essentially penicillins and cephalosporins). The rationale for these studies was beta-lactams' susceptibility to hydrolysis, particularly at elevated temperatures, which precludes the sterilization of parenteral solutions by conventional methods such as autoclaving. The necessity of sterilizing powders for injection by costly and highly demanding aseptic processes makes sterilization by irradiation most desirable.

Other applications. Other specific applications of irradiation to sterilize parenterals include complex drug-delivery systems and multicomponent parenteral units such as those in which the drug powder and solvent are compartmentalized until administration. Irradiation also may be used to decontaminate problematic raw materials such as active ingredients or pharmaceutical adjuncts used to manufacture parenterals.

Minimizing radiolysis. The formation of radiolysis products sometimes can be reduced. For example, irradiation may be undertaken in anoxia, at low temperatures, or by incorporating suitable additives if the degradation pathways are known. Of course, additives must not be toxic or interfere with the efficacy of the drug. They may include energy-transfer systems, -SH containing molecules, scavengers of radiolysis products of water, or reagents that convert radiolysis products to the parent compound. One example of such a radiation-tailored formulation is urea broth, which is used to identify Proteus species and differentiate it from other Gram-negative intestinal bacteria (22).

Radiolysis sometimes may be reduced by using electron-beam irradiation rather than gamma irradiation. The dose rate may be an important factor in electron-beam irratiation. Although no general rule exists, many drugs show less breakdown at a higher dose rate, i.e., with electron-beam irradiation. Reduced breakdown may result from the consumption of all the oxygen (which generally increases radiation damage) and the completion of sterilization before oxygen can be replenished. The process also may last too short a time to produce long-lived free radicals that could increase radiation-induced damage. On the other hand, the high dose rate could cause increased damage in some cases because of the high concentration of gamma photons close to the substrate.


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