Containers: vials, tubes, and pouches

Empty containers can often be treated as traditional devices or labware for the purpose of setting and evaluating a sterilization dose (1, 2). Published literature can help companies select materials to be irradiated and understand how they react to the process (4, 5). Although literature references are no substitute for real, direct testing of a product, they can help manufacturers avoid costly mistakes and provide solutions or alternatives should a problem arise. The most common reason for a gamma process to fail is not its inability to provide sterile product, but rather its effects on materials and the resulting functionality of the product.

The most common container for individual units of pharmaceuticals is the glass vial. For bulk active pharmaceutical ingredients (APIs) or bulk fillers, the most common container is probably the sealed pouch. The most critical properties of glass such as integrity, chemistry, and reactivity, will not change when irradiated; glass will continue to look and behave as expected and produce no byproducts. Glass will, however, in most cases, discolor as a result of added processing aids used in its formation. The glass will darken further as the dose is increased. This change is important to consider when clarity of the glass container is critical to the process (e.g., if visual clarity is needed to confirm mixing after reconstitution at site of use). If clear glass is needed, steam may be a preferred method of sterilization. Adding cerium to the glass formulation will reduce the discoloration, but this particular resin is more expensive and more difficult to obtain than standard silicate resin vials.

Lotions, ointments, and gels

Lotions, ointments, and gels are most commonly presented to a sterilization process in small aluminum or plastic tubes or small foil packets. The deep penetration of gamma irradiation allows for effective sterilization of the contents in the unit pack (e.g., 2- or 4-oz tubes, 2 or 4 gram packets). Because a key property of a lotion is its feel, viscosity must be considered. Irradiation can make lotions feel thicker or, in most cases, thinner after the process. If it is evaluated early in development, then the viscosity can be adjusted. For example, one could make the lotion thicker initially so that the final, sterile product has the desired thickness.

Additional considerations when irradiating lotions are color and odor. Color may change during processing, so it is necessary to treat the product with the highest dose expected from the sterilization process (i.e., the worst-case dose) and evaluate whether the end product appears acceptable. Scent and odor also should be evaluated early in the development process with worst-case dose samples. Many scents added to lotions come from materials that are easily changed when irradiated. After irradiation, a nicely scented lotion can end up with no scent or an offensive odor.

Active pharmaceutical ingredients (APIs)

Most commonly, bulk material is presented to the sterilization process in pouches or containers made specifically for the manufacturing process. The material is then mixed into the final formulation in a controlled, clean environment. For these types of materials, the following should be considered.

Test the material with gamma irradiation early. Earlier consideration in the development process ensures that any obtained data (e.g., function, safety) incorporates the effects of the sterilization process. Because an irradiated molecule may be different than an unirradiated molecule, it is important to prove that the final product provides the promised benefits. Irradiation can affect not only the drug but also the excipients, containers, and closures. Even a minor change in charge, conformation, or solubility can have a dramatic effect on the intended use of the product. The drug development process takes considerable time and involves many steps (e.g. discovery, pre-Investigational New Drug [IND], IND, IND, and Phase I–III studies). The sterilization process needs to be evaluated early, even at the pre-IND stage to ensure the same formulation of product is used throughout all testing.

Each API is unique. How and where the API is manufactured or extracted can make similar compounds function differently. A single difference in a process can change the yield of a material and changes in the production process can affect the outcome after a sterilization process. A simple literature search will not provide enough information to make a final decision about what sterilization method to use. There is no substitute for testing the product in the very conditions in which it will be sterilized. This is especially true for pharmaceutical products, because there is little data about individual products—or their extensive development processes—available in the public domain because of patent restrictions and the extended time a product is in development. Literature searches may provide ideas on what to investigate but will not likely provide a quick fix to a problem.