Final, filled products
Terminal sterilization covers all handling stages of the product. Irradiation also provides a documented, high SAL (such as
10-6 ) just as it can for medical devices (1–3, 6). Because final, filled products can be in liquid or suspension form, they need
to be evaluated thoroughly (9, 10). Some basic observations from personal experience as well as published sources (4, 7, 9,
10) provide a starting point for evaluating materials:
Liquids are more difficult to irradiate than dry powder. Liquids may undergo pH changes if not buffered. They provide easy
mobility to any reactive species created from the ionization process. Irradiation, as discussed earlier, creates ionization
events or free radical formation. In a liquid state, these charged species can move freely throughout the solution and create
more damage than in the limited-mobility dry or solid state. They also can be quite dense, resulting in wider dose distributions.
- When free radicals are created, they do not remain free for long. The net effect may be scission to smaller polymers or cross-linkage
to longer polymers, additions, and deletions that must be evaluated for safety, efficacy, potency and byproducts.
- In general, proteins are less stable then many other compounds.
- Aromatic rings (alternating double bonded structures) are more stable than aliphatic materials.
- Heparin, steroids, antibiotics, and vitamins in dry form have been gamma irradiated successfully.
Available literature also suggests ways to improve the results of an irradiation-sterilized product (4, 7, 9, 10):
Transform liquids into solids to reduce free radical mobility and to increase the likelihood of a recombination event
rather than a scission or cross-linkage. In many cases, even a product that is stable at room temperature can be frozen for
the irradiation process by being irradiated in the presence of dry ice.
- Consider adding free radical scavengers or antioxidants. The amounts and acceptability of the chosen compound need to be determined
for the specific formulation, but the addition can affect the success of an irradiation process (e.g., ascorbate, Vitamin
- Purge the filled product of oxygen by overlaying it with an inert gas such as argon or nitrogen. This process reduces the
available oxygen and limits the reactions, requiring it to be present.
- Keep the radiation dose as low as possible. Current published dose setting standards (The Association for the Advancement
of Medical Instrumentation's guides 11137:2006, TIR 33, and TIR 40 provide options for relatively low minimum doses that still
provide a high SAL) (1–3).
- Work with a good microbiology laboratory to determine methods for properly quantifying total viable contamination level (bioburden).
This point is especially important because the higher the estimated bioburden, the higher the minimum sterilization dose will
be. Dilution factors and low-extraction efficiencies, for instance, can increase a low or nonexistent bioburden significantly.
Because measured bioburden level can directly impact required minimum doses for sterilization, this value must be accurate
(i.e., not inflated) to avoid the use of a higher dose than needed for sterilization.
- Develop a relatively tight dose range for irradiation. Remember that a dose is always a range. This range includes the minimum
dose required to give the SAL desired (or required) but also a maximum dose allowable for the product to be sterile as well
as safe and effective. Supporting a tight dose range requires working closely with the contract irradiator to determine capabilities
and may include modifications to carton sizes, density, or the number of cartons processed per carrier in an irradiator. Many
factors affect the dose range that can be provided, so one must discuss the capabilities of the facility that will process
the product before finalizing the dose range. Working together and starting early are critical to success.
- Pay attention to timing. If the product contains material capable of supporting microbial growth, the time between manufacture
and sterilization will affect the required dose.