Gamma Irradiation in the Pharmaceutical Manufacturing Environment

Many sterilization methods are available for pharmaceuticals, healthcare devices, and labware, including steam, sterile-filtration, ethylene oxide, vapor-phase hydrogen peroxide, electron-beam irradiation, and gamma irradiation. Each technique needs to be evaluated before use based on various criteria. Most importantly, one must consider how the technique will affect the final product characteristics and performance.

This article reviews the considerations for using gamma irradiation in pharmaceutical manufacturing. Specifically, the author examines what gamma irradiation is, how it works, and what manufacturers need to consider when evaluating the method for terminal sterilization of a product or component. The article, while not exhaustive, is intended to provoke consideration of this effective sterilization method.

Background

Gamma irradiation is a fast, effective method for sterilization. The high-energy gamma rays (i.e., photons) from Cobalt 60 result in ionization events which can cause desirable effects (e.g., sterilization) as well as potential undesirable or unintentional effects (e.g., change in the product's molecules or byproducts). Photons have no charge or mass, allowing them to penetrate deeply into a material. The photons' penetration ability makes them ideally suited for sterilization of even relatively dense products. The photons can cause electron displacement, free radical formation, and, ultimately, bond breakage, when they penetrate a product. This mode of action can change the large biological molecules needed to support life such as DNA and enzymes, effectively rendering any living organisms present nonviable and unable to reproduce (i.e., sterile).

This depth of penetration is one of the greatest advantages of gamma irradiation as a sterilization method. A pharmaceutical or healthcare product in its final package (e.g., in its shipping carton) can, in most cases, be easily penetrated with gamma irradiation. As outlined below, all sterilization methods have positive and negative characteristics that need to be evaluated on a case-by-case basis as to the specific impact on the product and process. The author will review some of the common issues related to pharmaceutical products.

Benefits of gamma irradiation include the following:

• Depth of photon penetration allows for sterilization of materials of various density levels

• Process does not require addition of heat or moisture

• Well documented for its effectiveness as a sterilization process

• Does not produce residuals as are of concern with Ethylene Oxide sterilization

• Simple methods are available for documenting a high sterility assurance level (SAL) such as 10^-6

• Allows for terminal sterilization.

As with any process, one must also consider the potential negative aspects of its use. Because gamma irradiation produces ionization events, it can lead to unintended or undesirable effects. Each product must be tested in its final form with irradiation before a final decision to sterilize is made. A material's tolerance to gamma irradiation must be documented and its effects known. The earlier in the development process that this is done, the more time and options will be available to adapt or modify the product or processes needed to make the product successful. Early testing also means that all applicable data (e.g., safety, efficacy, and potency) is produced for a product that also includes the effects of the sterilization process.

Pharmaceutical products cover a wide range of materials (e.g., containers, closures, excipients, and processes). The following sections examine the effect of gamma irradiation as a sterilization process on these materials individually.

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.

Foil pouches and most plastic polymer pouches withstand irradiation well. These are most commonly used for bulk powdered ingredients to provide them in usable quantities for mixing/dispensing into a final formulation in a cleanroom. Manufacturers of these pouches are frequently a good source of the information needed to make a wise material selection. For example, manufacturers will know the composition of the polymer used to make the pouch. Also, through customer feedback, they may be able to help in the selection between related formulations.

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.

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 E).

• 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.

Conclusion

No single idea will solve all the potential challenges related to sterilization. A combination of tests are required for optimum results. This article, therefore, cannot address all the possible options to consider when selecting a sterilization method, but it does aim to demonstrate that making minor changes early in the development process can enable terminal irradiation. Terminal sterilization can have many benefits as long as one considers the critical factors to the product's success and usability. These factors may include the cost and time to manufacture a finished product, available facilities and equipment to make and sterilize the product with the chosen method, stability, safety, efficacy, potency, costs, regulatory requirements, and even customer expectations. Each factor must be considered to successfully select a sterilization process.

Sources

1. AAMI/ISO 11137:2006 Sterilization of Healthcare Products—Radiation, Part 1 2 and 3.

2. AAMI TIR 33:2005 Sterilization of HealthCare Products—Radiation-Substantiation of a Selected Sterilization Dose-Method VDmax.

3. AAMI TIR 40:2009 Sterilization of Healthcare Products-Radiation-Guidance on Dose Setting Using a Modified Method 2 .

4. AAMI TIR 17:2008 Compatibility of Materials Subject to Sterilization.

5. K.J. Hemmerich, "Polymer Materials Selection for Radiation Sterilized Products," Medical Device and Diagnostic Industry, Feb. 2000.

6. R. Garcia et al., Pharm. and Med. Packag. News (May 2004).

7. J. Masefield and R. Brinston, Medical Device Technology, 18 (2), March/April 2007.

8. V. Reitz, "The Best of All Worlds," Medical Design, pp. 42–45 (Sept. 2006).

9. K. Latta et al., International Jrnl. of Pharma. Compound.,13 (2), March/ April 2009

10. International Atomic Energy Agency, Technical Reports Series No. 149, Manual on Radiation of Medical and Biological Materials, 1973.

Betty Howard is the Radiation TechTeam Manager for STERIS Isomedix Services, Radiation Technology Center at Steris, 7828 Nagle Ave., Morton Grove, IL 60053, tel. 847.966.1160, betty_howard@steris.com.